There are 77 clinical trials
This study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of U3-1402 in the study population and to determine the recommended dose for expansion of U3-1402 in the study population - For Dose Expansion, to investigate the antitumor activity of U3-1402 The number of treatment cycles is not fixed in this study. Participants will continue study treatment (for approximately 36 months) until they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity) or other stopping reasons have been met.
Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1, with no deterioration over the previous 2 weeks Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R --- --- L861Q ---
3. Has documentation of EGFR-activating mutation(s) detected from tumor tissue: G719X, exon deletion 19, L858R, or L861Q. --- L858R --- --- L861Q ---
Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR activating mutations: G719X, exon 19 deletion, L858R, or L861Q Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1, with no deterioration over the previous 2 weeks Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R --- --- L861Q ---
Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR activating mutations: G719X, exon 19 deletion, L858R, or L861Q Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1, with no deterioration over the previous 2 weeks Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R --- --- L861Q --- --- L858R --- --- L861Q ---
Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR activating mutations: G719X, exon 19 deletion, L858R, or L861Q Non-Small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q ---
Description: Evaluated using RECIST 1.1
Measure: Overall response rate (ORR) assessed by Independent Central Review Committee (Central Review) in the dose expansion period Time: Approximately within 36 monthsDescription: Evaluated using RECIST 1.1
Measure: Overall response rate (ORR) in the dose escalation period Time: Approximately within 36 monthsDescription: Evaluated using RECIST 1.1
Measure: Overall response rate (ORR) in the dose expansion period Time: Approximately within 36 monthsThe purpose of this study is to evaluate the safety and tolerability of itacitinib in combination with osimertinib in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC).
- Documented evidence of somatic activating mutation in EGFR (eg, G719X, exon 19 deletion, L858R, L861Q) in a tumor tissue sample. --- L858R --- --- L861Q ---
Description: ORR defined as the percentage of subjects who have a confirmed best overall response of complete response (CR) or partial response (PR).
Measure: Phase 2: Objective response rate (ORR) based on RECIST v1.1 Time: Screening and 8-week intervals throughout the study, approximately 2 years.Description: Defined as the percentage of maximal tumor shrinkage observed at the lowest point (nadir) compared with baseline.
Measure: Phase 2: Depth of response (DpR) based on RECIST v1.1 Time: Screening and 8-week intervals throughout the study, approximately 2 years.This phase Ib trial studies the side effects and best dose of osimertinib and navitoclax when given together and to see how well they work in treating patients with previously treated epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer that has spread to other places in the body or has not responded to previous treatment with initial EGFR kinase inhibitor. Osimertinib and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.. Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- L858R --- --- L861Q ---
AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients must have the ability to swallow oral dosage forms - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Hemoglobin >= 8.0 g/dL - Platelets >= 100,000/mcL - Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Creatinine =< 2.0 mg/dL - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration) - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion - Intrauterine device (IUD) - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) - Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment - Patients who are receiving any other investigational agents - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol - Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk of thrombocytopenia with navitoclax; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding - Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug - Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Congenital long QT syndrome or family history of long QT syndrome - Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because AZD9291 and navitoclax have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9291 and navitoclax, breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Patients with human immunodeficiency virus (HIV) on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- T790M --- --- L858R --- --- L861Q ---
Description: Incidence of toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.
Measure: Incidence of toxicity (dose escalation) Time: Up to 2 yearsDescription: Will be measured as at least 50% of patients achieving the expected dose duration and intensity. The proportion of patients completing 3 courses of therapy with > 75% of total dose of each drug will be quantified. The combination dosing will be considered potentially feasible if at least 50% of patients achieve the expected dose duration and intensity (95% confidence interval 30%-70%).
Measure: Feasibility of the combination therapy in T790M+ lung cancer (dose expansion) Time: Up to 12 weeks (3 cycles of treatment)Description: Pharmacokinetic calculations will incorporate consideration of the dosing change in navitoclax between the two measurement days.
Measure: Pharmacokinetics parameters (maximum observed plasma drug concentration, area-under-the concentration-time-curve, trough drug concentration at steady state, and half-life) of osimertinib in combination with navitoclax Time: Pre-dose, 1, 2, 4, 6, and 8 hours after navitoclax administration (day 3 of cycle 1 and day 1 of cycle 2)Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Calculated in the 20 patient expansion cohort and compared to the expected response rate of 61% in T790M+ lung cancer.
Measure: Objective response rate Time: Baseline up to 30 days after completion of study drugDescription: Change in plasma concentration of EGFR T790M and other EGFR mutations will be studied in an exploratory fashion and compared to tumor response on imaging.
Measure: Change in plasma concentration of EGFR T790M and other EGFR mutations Time: Baseline to up to 2 yearsDescription: Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.
Measure: Biomarkers of apoptosis such as BCL2-like 1 (BCL-XL) and BCL2-like 11 (apoptosis facilitator) (BIM) levels in tumor tissue Time: BaselineA Phase I, Open-Label, Two Parts Study to Assess the Safety, Tolerability,Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Chinese Patients with Advanced Non-Small Cell Lung Cancer who have Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent Study Objective: 1, Primary Objective To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550) after single then multiple doses of AZD9291 administered orally once daily in Chinese patients with locally advanced or metastatic non small cell lung Cancer (NSCLC) who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) agent. 2, Secondary objective(s) To investigate the safety and tolerability of AZD9291 when given orally to Chinese patients with locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR TKI agent. To obtain a preliminary assessment of the anti-tumour activity of AZD9291 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
In addition other lines of therapy may have been given - Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 6. World Health Organisation (WHO) performance status 0-1 7. --- L858R --- --- L861Q ---
Description: Pharmacokinetics of AZD9291 after single dosing by assessment of maximum plasma AZD9291 concentration
Measure: Cmax of AZD9291 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of maximum plasma concentration
Measure: Cmax of AZ5104 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of maximum plasma concentration
Measure: Cmax of AZ7550 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 after single dosing by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of AZD9291 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of AZ5104 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of AZ7550 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Rate and extent of absorption of single dose AZD9291 by assessment of apparent clearance following oral administration
Measure: CL/F of AZD9291 After Single Dosing Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of maximum plasma concentration at steady state
Measure: C(ss, Max) of AZD9291 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of maximum plasma concentration at steady state
Measure: C(ss, Max) of AZ5104 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of maximum plasma concentration at steady state
Measure: C(ss, Max) of AZ7550 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval
Measure: AUC(ss) of AZD9291 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval
Measure: AUC(ss) of AZ5104 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval
Measure: AUC(ss) of AZ7550 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of apparent plasma clearance at steady state
Measure: CL(ss)/F of AZD9291 After Multiple Dosing Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
Measure: Objective Response Rate (ORR) Time: Treatment discontinuation plus 28 days or 12 months after last subject first dose (LSFD). Results are based on data cut off of 2 Nov 2016.This phase I/II trial studies the side effects and best dose of onalespib lactate when given together with erlotinib hydrochloride and to see how well they work in treating patients with EGFR-mutant non-small cell lung cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Erlotinib hydrochloride and onalespib lactate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.. Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q ---
Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.. Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q --- --- L858R --- --- L861Q ---
m^2 for patients with creatinine levels above institutional normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 upper limit of normal (ULN) - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib and/or onalespib administration - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients who are receiving any other investigational agents - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib and/or onalespib - History of pneumonitis attributed to an EGFR inhibitor; history of radiation pneumonitis is allowed provided steroid administration for pneumonitis was not required - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or multigated acquisition scan (MUGA) - Drugs that are known to increase torsades de pointes should be avoided; patients must discontinue these medications prior to enrollment on study; selection of alternate concomitant medications with no or minimal torsades de pointes potential is recommended - Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with erlotinib and onalespib - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Prior treatment with a Hsp90 inhibitor - Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist; although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary - Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q ---
m^2 for patients with creatinine levels above institutional normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 upper limit of normal (ULN) - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib and/or onalespib administration - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients who are receiving any other investigational agents - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib and/or onalespib - History of pneumonitis attributed to an EGFR inhibitor; history of radiation pneumonitis is allowed provided steroid administration for pneumonitis was not required - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or multigated acquisition scan (MUGA) - Drugs that are known to increase torsades de pointes should be avoided; patients must discontinue these medications prior to enrollment on study; selection of alternate concomitant medications with no or minimal torsades de pointes potential is recommended - Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with erlotinib and onalespib - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Prior treatment with a Hsp90 inhibitor - Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist; although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary - Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q --- --- L858R --- --- L861Q ---
Description: Will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0
Measure: Incidence of dose-limiting toxicities from onalespib lactate in combination with erlotinib hydrochloride (Phase I) Time: Up to 28 daysDescription: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.
Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase II) Time: Up to at least 1 yearDescription: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.
Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase I) Time: Up to at least 1 yearDescription: Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.
Measure: Progression-free survival Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to at least 1 yearThe primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. Safety and efficacy will also be measured.
- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment confirmed centrally. --- L858R --- --- L861Q ---
- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment that have not been confirmed centrally. --- L858R --- --- L861Q ---
Description: Defined as the rate of complete responses [CR] or partial responses [PR] to treatment in accordance to the guidelines of RECIST version 1.1 criteria
Measure: Objective response rate Time: Baseline up to 78 weeks after patient entryDescription: Patient safety and adverse events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the U.S. National Cancer Institute (NCI), version 4
Measure: Grade 3 or 4 adverse events and SAEs Time: Baseline up to 78 weeks after patient entryDescription: Time from treatment start to the time of death due to any cause
Measure: Overall survival Time: Baseline up to 78 weeks after patient entryDescription: Time from treatment start to the time at which the patient discontinues treatment due to any cause
Measure: Time to treatment failure Time: Baseline up to 78 weeks after patient entryDescription: Time from the first documented response to documented disease progression or death
Measure: Duration of response Time: Baseline up to 78 weeks after patient entryDescription: Percentage of patients with complete response, partial response or stable disease for a minimum of 24 weeks, assessed in accordance with the modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, during all study period from baseline up to 78 weeks after patient entry
Measure: Disease control rate Time: Baseline up to 78 weeks after patient entryDescription: Correlation ratio of mutational status and documented clinical response
Measure: Correlation ratio between mutational status and clinical response Time: Baseline up to 78 weeks after patient entryDescription: Measured by Percentage of patients with a positive EGFR mutation in plasma
Measure: Overall plasma EGFR mutation status Time: Baseline up to 78 weeks after patient entryDescription: Percentage of patients who develop anti-drug mutations in tumour tissue
Measure: Acquired resistance to osimertinib (AZD9291) by histology Time: Baseline up to 78 weeks after patient entryDescription: Percentage of patients who develop anti-drug mutations in plasma
Measure: Overall plasma acquired resistance to osimertinib (AZD9291) Time: Baseline up to 78 weeks after patient entryHsp90 inhibitor AUY922 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of Hsp90 inhibitor AUY922 when given together with erlotinib hydrochloride and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer.
Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.. Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- T790M --- --- L858R --- --- L861Q ---
Gilbert's syndrome) Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- L858R --- --- L861Q ---
Description: To determine the maximally tolerated dose (MTD), and recommended phase II dose of AUY922 when given in combination with erlotinib for patients with acquired resistance to erlotinib. (Phase I) Escalation of dose will be in a 3+3 design. If no dose limiting toxicities (DLTs) are seen in 3 patients enrolled at that dose level, then dose will be escalated to the next dose level and the next 3 patients will be enrolled at that dose. Alternatively, if 1 DLT is seen in 3 patients at that dose level, 3 more patients will be added at that same dose level. If 1 DLT is seen in 6 patients at that dose level, MTD will be determined to be at that dose. If more than 1 DLT is seen at that dose level, then the prior lower dose level will be the considered the MTD. DLT is defined as any of the following related to the investigational agent: Death and grade 3 and 4 specific hematological and non-hematological toxicities defined in the protocol.
Measure: Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I) Time: During the first 4 weeks of treatment for each patient.Description: Overall response rate (ORR) will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan or MRI: Complete response (CR) defined as disappearance of all target lesions. Partial Response (PR), defined as >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions
Measure: Overall Response Rate (ORR), Defined as Complete Response(CR) + Partial Response (PR) Using the Modified RECIST 1.1 Criteria for All Patients Treated at Dose of 70mg/m2 AUG922 Time: At 8 weeks from treatment initiationDescription: To characterize the toxicity profile for the combination of erlotinib and AUY922. Toxicity data will be collected every week for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
Measure: Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II) Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment for up to 2 years and half yearsDescription: Adverse events will be collected weekly for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE
Measure: Incidence of Reported Adverse Events in Phase I Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment, for up to 2 years and half yearsDescription: Median Progression Free Survival (PFS) will be calculated from time of treatment initiation until the first documentation of progressive disease. Patients will be considered to have progressive disease when CT scan or MRI show at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Measure: Progression-free Survival (Phase II) Time: From the time of first treatment with AUY922 to disease progression for up to 2 years post treatmentDescription: Overall survival (OS) is defined as the time from treatment initiation until death due to any cause.
Measure: Overall Survival (Phase II) Time: From the time of first treatment with AUY922 to death, followed up to 2 years post treatmentDescription: Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.
Measure: Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II) Time: From the time of first treatment with AUY922 to death, followed for up to 2 yearsThis study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with osimertinib in the study population - For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles. The number of treatment cycles is not fixed in this study. Participants will continue study treatment for 36 months unless they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).
3. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011): 1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression (Response Evaluation Criteria in Solid Tumors [RECIST version 1.1] or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI. 4. Is currently receiving, and is able to discontinue erlotinib, gefinitib, or afatinib; or is currently receiving osimertinib at the prescribed 80 mg dose and is able to interrupt osimertinib. --- L858R --- --- L861Q ---
Description: Categories: during dose escalation, during dose expansion
Measure: Number of participants with clinically significant safety measures when taking DS-1205c in combination with osimertinib Time: within 36 monthsDescription: DS-1205a is the free form of DS-1205c when DS-1205c is administered alone
Measure: Area under the plasma concentration time curve (AUC) for DS-1205a Time: during Cycle 0 of the dose escalation period (within 28 days)Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)
Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss) Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)
Measure: Plasma concentration of DS-1205a versus time Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)
Measure: Tmax Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)
Measure: Ctrough Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, osimertinib, and osimertinib active metabolites
Measure: AUCtau Time: during the dose expansion period, within 36 monthsDescription: Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.
Measure: Objective response rate (ORR), graded according to RECIST version 1.1 Time: within 36 monthsDescription: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression
Measure: Duration of response (DOR) Time: within 36 monthsDescription: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate
Measure: Disease control rate (DCR) Time: first dose to 36 monthsDescription: PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD, or death due to any cause
Measure: Progression-free survival (PFS) Time: baseline to objective disease progression or death from any cause (within 36 months)This study will test if local therapies in addition to erlotinib can improve responses and delay the time until new treatment is required. This study will also collect blood samples for research blood tests.
At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.. Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R --- --- G719A --- --- L861Q ---
- Any medical co-morbidities that would preclude surgery or radiation therapy Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R --- --- G719A --- --- L861Q ---
Description: At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.
Measure: Feasibility as Measured by at Least Five Patients Will Need to Complete Local Therapy. Time: 2 yearsThis phase I trial studies the side effects and best dose of sapanisertib when given together with osimertinib in treating patients with stage IV EGFR mutation positive non-small cell lung cancer that has progressed after treatment with an EGFR tyrosine kinase inhibitor. Sapanisertib and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Descriptive statistics and plotting of data will also be used to better understand potential relationships.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically or cytologically confirmed non-squamous NSCLC - NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q) - Progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including osimertinib [AZD9291] allowed for dose escalation only) - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent to a fresh tumor biopsy (mandatory for dose expansion cohort only; optional for dose escalation) - For the dose expansion portion ONLY, patient must: 1) have progression of disease with erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) tumors must be EGFR T790M negative confirmed by central testing prior to treatment (If EGFR-T790M status is unknown, patient may consent for trial for biopsy and testing for EGFR T790M will be performed as part of the initial biopsy for the trial: patients who test positive for EGFR T790M by central testing will be ineligible for the dose expansion), 3) be treatment naive for 3rd generation EGFR-TKI (CO-1686 and osimertinib [AZD9291]) and mTOR inhibitors - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 28 days prior to start of protocol therapy; the CT from a combined positron emission tomography (PET)/CT may be used if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 90 g/L (or >= 9 g/dL) - Platelets >= 100 x 10^9/L - Calculated creatinine clearance of > 50 mL/min using Cockcroft Gault equation equation or 24-hour urine sampling - Total bilirubin =< 1.5 institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Fasting plasma glucose =< 130 mg/dL (or 7.2 mmol/L) - Glycosylated hemoglobin (Hb A1c) =< 7% - Fasting triglycerides =< 300 mg/dL (3.42 mmol/L) - Cholesterol =< 300 mg/dL (7.75 mmol/L) - Fridericia's correction formula (QTcF) =< 470 msec - Patients must have had sufficient time between a prior therapy and resolution of toxicities from the prior therapies prior to registration as follows: - Prior EGFR inhibitor: A minimum of 7 days must have elapsed from the last dose of the prior EGFR inhibitor and resolution of any drug-related toxicity to =< grade 1 except for alopecia - Chemotherapy: A minimum of 21 days must have elapsed from the last dose and resolution of toxicity to =< grade 1 excluding =< grade 2 peripheral neuropathy or alopecia - Surgery: A minimum of 21 days must have elapsed following major surgery and resolution of toxicity to < grade 1 and complete wound healing must have occurred - Radiation: A minimum of 14 days must have elapsed following radiation therapy and resolution of all radiation induced toxicity excluding alopecia - Treatment with an investigational drug: A minimum of 3 months or five half-lives of the compound, whichever is greater, must have elapsed from last treatment date - Ability to understand and the willingness to sign a written informed consent document - Available for follow-up of their disease after treatment until progressive disease is documented and resolution of related adverse events until < grade 2 Exclusion Criteria: - Any serious intercurrent or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol including but not limited to: - Uncontrolled diabetes mellitus (fasting plasma glucose > 130 mg/dL or 7.2 mmol/L) - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease - Active infections - Gastrointestinal disease limiting the ability to swallow oral medications or absorb oral medications including refractory nausea and vomiting, chronic gastrointestinal diseases, inflammatory bowel disease; malabsorption syndromes - Patients with enteric stomata or significant bowel resection - Prior history of corneal ulceration - Patients with any evidence of severe or uncontrolled systemic liver disease including those with known hepatitis B and hepatitis C (excluding treated hepatitis C that has been cured) - Active bleeding diatheses - Significant active cardiovascular or pulmonary disease including: - Uncontrolled hypertension (i.e., systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg); use of anti-hypertensive agents to control hypertension before cycle 1 day 1 is allowed - Pulmonary hypertension - Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas analysis or pulse oximetry on room air - Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement - History of arrhythmia requiring an implantable cardiac defibrillator - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) e.g. --- L858R --- --- L861Q ---
medically significant (symptomatic) bradycardia, complete left bundle branch block, third degree heart block and second-degree heart block or history of arrhythmia requiring an implantable cardiac defibrillator; or within the last 6 months before administration of the first dose of drug: - Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) - Placement of a pacemaker for control of rhythm - Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures - Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures - New York Heart Association (NYHA) class III or IV heart failure - Pulmonary embolism - Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTcF >= 470 msec (mean value) obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value, or history of congenital long QT syndrome, or torsades de pointes); any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Left ventricular ejection fraction (LVEF) by either multigated acquisition (MUGA) or echocardiography (ECHO) less than lower limit of normal - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Concurrent anti-cancer therapy - History of hypersensitivity attributed to compounds of similar chemical or biologic composition to MLN0128 (TAK-228) or osimertinib (AZD9291) - Pregnant women or women who are breast feeding are not eligible for the study; the effects of MLN0128 (TAK-228) and osimertinib (AZD9291) on the developing human fetus are unknown - Women of non-child bearing potential must be: - Women more than 50 years must be post-menopausal for at least 12 months following the end of all exogenous hormonal treatments OR - Women under 50 years must be postmenopausal for at least 12 months following the end of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution OR - Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation - Women of child bearing potential must have a negative serum or urine pregnancy test within 7 days of registration and must agree to: - Practice 1 highly effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 120 days (or longer, as mandated by local labeling [e.g., United Surgical Partners International (USPI), Summary of Product Characteristics (SmPC), etc.;]) after the last dose of study drug, OR - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient; NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together - Male patients, even if surgically sterilized (i.e., status postvasectomy) must agree to: - Practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR - Practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient; NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together - Not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug - Inability to discontinue drugs that are strong cytochrome P450 3A4 (CYP3A4) or P450 3A5 (CYP3A5), cytochrome P450 2C19 (CYP2C19), and cytochrome P450 2C9 (CYP 2C9) inhibitors and/or inducers; and substrates of CYP 3A4/5 or CYP1A2 that are sensitive or have a narrow therapeutic window at least three weeks prior to study registration - Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug - Consumption of grapefruit or grapefruit juice is not permitted during the study; patients should not consume food or beverages containing the fruit or juice of grapefruits or Seville oranges within 7 days before the first dose of study drug and throughout the study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - No concomitant use of proton pump inhibitors (PPI) is allowed; any prior PPI must be discontinued at least one week before receiving MLN0128 (TAK-228) Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically or cytologically confirmed non-squamous NSCLC - NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q) - Progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including osimertinib [AZD9291] allowed for dose escalation only) - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent to a fresh tumor biopsy (mandatory for dose expansion cohort only; optional for dose escalation) - For the dose expansion portion ONLY, patient must: 1) have progression of disease with erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) tumors must be EGFR T790M negative confirmed by central testing prior to treatment (If EGFR-T790M status is unknown, patient may consent for trial for biopsy and testing for EGFR T790M will be performed as part of the initial biopsy for the trial: patients who test positive for EGFR T790M by central testing will be ineligible for the dose expansion), 3) be treatment naive for 3rd generation EGFR-TKI (CO-1686 and osimertinib [AZD9291]) and mTOR inhibitors - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 28 days prior to start of protocol therapy; the CT from a combined positron emission tomography (PET)/CT may be used if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 90 g/L (or >= 9 g/dL) - Platelets >= 100 x 10^9/L - Calculated creatinine clearance of > 50 mL/min using Cockcroft Gault equation equation or 24-hour urine sampling - Total bilirubin =< 1.5 institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Fasting plasma glucose =< 130 mg/dL (or 7.2 mmol/L) - Glycosylated hemoglobin (Hb A1c) =< 7% - Fasting triglycerides =< 300 mg/dL (3.42 mmol/L) - Cholesterol =< 300 mg/dL (7.75 mmol/L) - Fridericia's correction formula (QTcF) =< 470 msec - Patients must have had sufficient time between a prior therapy and resolution of toxicities from the prior therapies prior to registration as follows: - Prior EGFR inhibitor: A minimum of 7 days must have elapsed from the last dose of the prior EGFR inhibitor and resolution of any drug-related toxicity to =< grade 1 except for alopecia - Chemotherapy: A minimum of 21 days must have elapsed from the last dose and resolution of toxicity to =< grade 1 excluding =< grade 2 peripheral neuropathy or alopecia - Surgery: A minimum of 21 days must have elapsed following major surgery and resolution of toxicity to < grade 1 and complete wound healing must have occurred - Radiation: A minimum of 14 days must have elapsed following radiation therapy and resolution of all radiation induced toxicity excluding alopecia - Treatment with an investigational drug: A minimum of 3 months or five half-lives of the compound, whichever is greater, must have elapsed from last treatment date - Ability to understand and the willingness to sign a written informed consent document - Available for follow-up of their disease after treatment until progressive disease is documented and resolution of related adverse events until < grade 2 Exclusion Criteria: - Any serious intercurrent or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol including but not limited to: - Uncontrolled diabetes mellitus (fasting plasma glucose > 130 mg/dL or 7.2 mmol/L) - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease - Active infections - Gastrointestinal disease limiting the ability to swallow oral medications or absorb oral medications including refractory nausea and vomiting, chronic gastrointestinal diseases, inflammatory bowel disease; malabsorption syndromes - Patients with enteric stomata or significant bowel resection - Prior history of corneal ulceration - Patients with any evidence of severe or uncontrolled systemic liver disease including those with known hepatitis B and hepatitis C (excluding treated hepatitis C that has been cured) - Active bleeding diatheses - Significant active cardiovascular or pulmonary disease including: - Uncontrolled hypertension (i.e., systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg); use of anti-hypertensive agents to control hypertension before cycle 1 day 1 is allowed - Pulmonary hypertension - Uncontrolled asthma or oxygen (O2) saturation < 90% by arterial blood gas analysis or pulse oximetry on room air - Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement - History of arrhythmia requiring an implantable cardiac defibrillator - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) e.g. --- L858R --- --- L861Q ---
Description: Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4). CTCAE version 5.0 will be utilized beginning April 1, 2018.
Measure: Maximum tolerated dose of sapanisertib in combination with osimertinib in patients with EGFRmutant (m) non-small cell lung cancer (NSCLC) Time: 28 daysDescription: Toxicities will be graded according to the NCI CTCAE v4. CTCAE version 5.0 will be utilized beginning April 1, 2018.
Measure: Dose-limiting toxicity (DLT) of sapanisertib in combination with osimertinib in patients with EGFRm NSCLC Time: 28 daysDescription: Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.
Measure: Non-DLTs associated with the administration of sapanisertib and osimertinib Time: Up to 30 days after completion of study treatmentDescription: PK analyses will be descriptive and will permit the evaluation of the PK profile of Tsapanisertib when combined with osimertinib.
Measure: Pharmacokinetic (PK) profiles of sapanisertib in combination with osimertinib Time: Baseline, and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib administration, before administration and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib on day 26 of course 1; and day 1 of course 2Description: Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure: Response rate Time: Up to 2 yearsDescription: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure: Disease control rate Time: Up to 2 yearsDescription: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure: Progression free survival Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 yearsDescription: Will be assessed using RECIST 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure: Response rate of patients with T790M- NSCLC in an expansion cohort Time: Up to 2 yearsDescription: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure: Disease control rate of patients with T790M- NSCLC in an expansion cohort Time: Up to 2 yearsDescription: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.
Measure: Progression free survival of patients with T790M- NSCLC in an expansion cohort Time: At 6 monthsDescription: Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and or generalized estimating equations as appropriate. Potential predictors include clinical predictors and molecular correlates analyzed in tumor and blood. Descriptive statistics and plotting of data will also be used to better understand potential relationships.
Measure: Biomarkers of response and resistance to the combination, explored by studying baseline biopsies, resistance biopsies, and serial plasma deoxyribonucleic acid specimens Time: Up to 2 yearsThe purpose of this study is to determine the safety, the antitumor activity and the pharmacokinetics of ASP8273 in EGFR tyrosine kinase inhibitor (EGFR-TKI)-naïve patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations.
- Patients confirmed to have the deletion of exon 19 (del ex19), L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study site who are documented to have any of the above-stated EGFR activating mutations can be enrolled in the study). --- L858R --- --- L861Q ---
Description: ECG: Electrocardiogram
Measure: Safety assessed by 12-lead ECG Time: Up to 18 monthsDescription: The overall response rate is defined as the proportion of subjects whose best overall response is rated as Complete response (CR) or Partial Response (PR)among all analyzed subjects
Measure: Overall response rate Time: Up to 18 monthsDescription: The disease control rate is defined as the proportion of subjects whose best overall response is rated as Complete response (CR), Partial Response (PR), or Stable disease (SD) among all analyzed subjects
Measure: Disease control rate Time: Up to 18 monthsA Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene
- Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R --- --- L861Q ---
Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a phase II, open label, single arm study assessing the safety and efficacy of AZD9291 (80 mg, orally, once daily) in Asia Pacific patients with a confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) sensitising mutation positive (ie, G719X, exon 19 deletion, L858R, L861Q) and T790M mutation positive (hereafter referred to as EGFRm+ and T790M+) un-resectable, locally advanced or metastatic NSCLC (Stage IIIB-IV), who have progressed on an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor(EGFR-TKI), either as first line treatment or following one line of EGFR-TKI and one line of platinum containing doublet chemotherapy. --- L858R --- --- L861Q ---
Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
Measure: Objective Response Rate (ORR) According to RECIST 1.1 Time: RECIST tumour assessments every 6 weeks from time of first dose until objective disease progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.
Measure: Disease Control Rate (DCR) According to RECIST 1.1 Time: RECIST tumour assessments every 6 weeks from time first dose until date of progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).Investigators hypothesize that addition of pembrolizumab will enhance the efficacy of carboplatin and pemetrexed in EGFR (epidermal growth factor receptor) mutation and ALK (anaplastic lymphoma kinase) positive NSCLC patients who have disease progression following prior TKIs (tyrosine kinase inhibitors).
If the patient is lost to follow-up, survival will be censored on the last date the patient was known to be alive.. Inclusion Criteria: - Exon 19 deletion or Exon 21 L858R or L861Q or exon 18 G719X or S7681 EGFR mutation positive NSCLC patients, or ALK rearranged NSCLC patients previously treated with a tyrosine kinase inhibitor with progressive and measurable disease. --- L858R --- --- L861Q ---
Inclusion Criteria: - Exon 19 deletion or Exon 21 L858R or L861Q or exon 18 G719X or S7681 EGFR mutation positive NSCLC patients, or ALK rearranged NSCLC patients previously treated with a tyrosine kinase inhibitor with progressive and measurable disease. --- L858R --- --- L861Q ---
Description: The primary endpoint is Response Rate (RR) defined as the rate of complete and partial response. Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (<10mm short axis). Partial Response (PR): Persistence of one or more non-target lesion(s) but does not qualify for PD. Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression).
Measure: The number of patients that respond to treatment Time: 12 monthsDescription: PFS is defined as the duration of time from registration to time of progression. Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression).
Measure: Progression free survival (PFS) time Time: 12 monthsDescription: Overall survival is defined as the time from registration to time of death. If the patient is lost to follow-up, survival will be censored on the last date the patient was known to be alive.
Measure: Overall survival (OS) time Time: 12 monthsAlflutinib Mesylate Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.
4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) 5. Documented evidence of definitely EGFR T790M+ state in the tumor tissue after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). --- L858R --- --- L861Q ---
Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03
Measure: Incidence and Severity of Treatment-Emergent Adverse Events Time: Adverse events will be collected from baseline until 28 days after the last doseDescription: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out Cmax.
Measure: Maximum Plasma Concentration [Cmax] of single dose Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out tmax.
Measure: Peak Plasma Time [tmax] of single dose Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day1 to figure out AUC.
Measure: Area under the plasma concentration versus time curve (AUC) of single dose Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out terminal rate constant.
Measure: Terminal rate constant of single dose Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out clearance.
Measure: Clearance of single dose Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out half life.
Measure: Half life of single dose Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out volume of distribution.
Measure: Volume of distribution of single dose Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out mean resistance time.
Measure: Mean resistance time of single dose Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Cmax of Alflutinib and 2 metabolites at steady state following multiple doses.
Measure: Steady state Cmax of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: tmax of Alflutinib and 2 metabolites at steady state following multiple doses.
Measure: Steady state tmax of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Cmin of Alflutinib and 2 metabolites at steady state following multiple doses.
Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: AUC of Alflutinib and 2 metabolites at steady state following multiple doses.
Measure: Steady state AUC of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Clearance of Alflutinib and 2 metabolites at steady state following multiple doses.
Measure: Steady state clearance of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Accumulation ratio of Alflutinib and 2 metabolites following multiple doses.
Measure: Accumulation ratio of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Time dependency of Alflutinib and 2 metabolites following multiple doses.
Measure: Time dependency of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Evaluation of objective response rate assessed by RECIST 1.1
Measure: Objective response rate of Alflutinib Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 monthsDescription: Duration of response assessed by RECIST 1.1
Measure: Duration of response of Alflutinib Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 monthsDescription: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival
Measure: Progression free survival of Alflutinib Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 monthsDescription: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate disease progression rate
Measure: Disease progression rate of Alflutinib Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 monthsDescription: Clinical benefit rate was calculated by adding up complete remission, partial remission and stabilization of disease assessed by RECIST 1.1
Measure: Clinical benefit rate of Alflutinib Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 monthsThe purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure.
- Investigator confirmed progression according RECIST 1.1 during EGFR-TKI treatment within 28 days of the enrollment - Activating mutation (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) in the EGFR gene or have had at least partial response with EGFR TKI lasting ≥ 6 months - Patient must be able to comply with the protocol Exclusion Criteria: - Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined disease progression for more than 28 days while on previous EGFR-TKI treatment. --- G719A --- --- L858R --- --- L861Q ---
Description: The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).
Measure: Number of Patients With T790M Mutation Detected by Amplification Refractory Mutation System (ARMS) Assay Time: up to 2 yearsDescription: The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.
Measure: Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient Time: up to 2 yearsDescription: The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.
Measure: Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure Time: up to 2 yearsDescription: The investigators will employ Analysis of Variance (ANOVA) method to analyze the differences of T790M mutation by ddPCR in patients among the different Clinical modes of TKI failure.
Measure: Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure Time: up to 2 yearsThe purpose of this study is to try to improve the odds that your cancer may be cured. Pemetrexed and cisplatin are traditional chemotherapy drugs that have been shown to help some patients with non-small cell lung cancer. Many different types of cancer cells, including your type of lung cancer, have a protein on their surface called the epidermal growth factor receptor (EGFR). Stimulation of these receptors can result in growth of cancer cells and progression of cancer. In addition, your cancer has an EGFR mutation (a specific abnormality in the genetic code for EGFR). Erlotinib (TarcevaTM) is a newer drug which has shown benefit for patients with lung cancers that contain an EGFR mutation. Erlotinib works by blocking this receptor and depriving the cancer cells of this message to grow and multiply. In this research study, we plan to combine erlotinib with traditional chemotherapy drugs to see if the combination works better than chemotherapy alone. The main purpose of this research is to find out the good and bad effects that the combination of these 3 drugs (pemetrexed, cisplatin and erlotinib) has when given to patients with early stage non-small cell lung cancer before surgery. A secondary purpose is to find out the good and bad effects that occur when erlotinib is given to patients after surgery for 2 years.
Inclusion Criteria: - Pathologic confirmation of NSCLC - Patients must have previously untreated stage IB-IIIA NSCLC (T1-3N0-2M0) - Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q) - Patients must be candidates for resection with curative intent - Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Age greater or equal to 18 years - Karnofsky performance status greater or equal to 70% - Normal marrow function: leukocytes greater than or equal to 3,000/μl, absolute neutrophil count greater than or equal to 1,500/μl, platelets greater than or equal to 100,000/μl, hemoglobin greater than or equal to 9 gm/dl - Adequate renal function, with creatinine less than or equal to 1.3 mg/dl or calculated creatinine clearance greater to or equal to 60ml/min by Cockroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl) - Adequate hepatic function: Total bilirubin within normal limits, AST < 1.5 X UNL, alkaline phosphatase < 1.5 X UNL - Women of childbearing age must have a negative urine or blood pregnancy test - Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter - Patients must have ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior chemotherapy or radiation therapy, with the exception of chemotherapy for nononcologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis) - Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients must not be receiving any other investigational agents - Any evidence of interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) - Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher) - Peripheral neuropathy > grade 1 - Known HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study drugs. --- L858R --- --- L861Q ---
- Other serious illness or medical condition including unstable cardiac disease requiring treatment, history of significant neurologic or psychiatric disorders (including psychotic disorders, dementia, or seizures), or active uncontrolled infection - Women who are pregnant or breast-feeding - Psychiatric illness or social situation that would limit compliance with study requirements Inclusion Criteria: - Pathologic confirmation of NSCLC - Patients must have previously untreated stage IB-IIIA NSCLC (T1-3N0-2M0) - Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q) - Patients must be candidates for resection with curative intent - Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Age greater or equal to 18 years - Karnofsky performance status greater or equal to 70% - Normal marrow function: leukocytes greater than or equal to 3,000/μl, absolute neutrophil count greater than or equal to 1,500/μl, platelets greater than or equal to 100,000/μl, hemoglobin greater than or equal to 9 gm/dl - Adequate renal function, with creatinine less than or equal to 1.3 mg/dl or calculated creatinine clearance greater to or equal to 60ml/min by Cockroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl) - Adequate hepatic function: Total bilirubin within normal limits, AST < 1.5 X UNL, alkaline phosphatase < 1.5 X UNL - Women of childbearing age must have a negative urine or blood pregnancy test - Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter - Patients must have ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior chemotherapy or radiation therapy, with the exception of chemotherapy for nononcologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis) - Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients must not be receiving any other investigational agents - Any evidence of interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) - Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher) - Peripheral neuropathy > grade 1 - Known HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study drugs. --- L858R --- --- L861Q ---
Description: Complete Response (CR): Disappearance of all clinical evidence of tumor. Partial Response (PR): A 50% or greater decrease in the sum of the products of measured lesions. No simultaneous increase in the size of any lesion or the appearance of new lesions may occur. Non-measurable lesions must remain stable or regress for this category. Minor Response (MR): A > 25% and < 50% decrease in the sum of the products of measured lesions. No simultaneous increase in the size of any lesion or the appearance of new lesions may occur. Non-measurable lesions must remain stable or regress for this category. Stable Disease (SD): A less than 25% decrease. This includes a decrease of less than 25% in the sum of the products of the measured lesions, and any increase of less than 25% in the sum of the products of the measured lesions. There may be no appearance of new disease sites for this category. Progressive Disease (PD): A ≥25% increase in one or more lesions, or appearance of new lesions.
Measure: Number of Patients With Pathologic Complete Response Rate Time: Patients will undergo a CT scan of chest every 3 months for year 1 and every 4 months for year 2. In years 3 and 4, a chest CT or chest x-ray every 6 months.Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy.
bevacizumab, ipilumimab) 4. Patients with a known activating mutation in epidermal growth factor receptor (EGFR) (Exon 19 deletion, G719A, S768I, V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to treatment with a first-line EGFR tyrosine kinase inhibitor (TKI) (erlotinib, afatinib, or gefitinib). --- G719A --- --- S768I --- --- V769L --- --- T790M --- --- L833F --- --- L858R --- --- L861Q ---
Description: The ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence from the start of treatment.
Measure: Objective Response Rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria. Time: From start of treatment up to 4 years, or until disease progression, whichever comes firstDescription: The DR for Complete Response (CR) and Partial Response (PR) will be measured from the date that the best response is first recorded until the date that PD is documented. For patients who continue treatment post progression, the date of Disease Progression (PD) documentation will be used for analysis.
Measure: Duration of Response (DR) according to RECIST Version 1.1 criteria. Time: From start of treatment up to 4 years, or until disease progression, whichever comes firstDescription: DCR will be defined as the percentage of patients who have achieved CR, PR, or Stable Disease (SD) for at least 12 weeks.
Measure: Disease Control Rate (DCR) according to RECIST Version 1.1 criteria. Time: From start of treatment up to 4 years, or until disease progression, whichever comes firstDescription: PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 1 year. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis.
Measure: Progression Free Survival (PFS) according to RECIST Version 1.1 criteria. Time: From start of treatment up to 4 years, or until disease progression, whichever comes firstDescription: OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 1 year.
Measure: Overall Survival (OS) according to RECIST Version 1.1 criteria. Time: From start of treatment up to 4 years, or until disease progression, whichever comes firstThe primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib or gefitinib. Overall safety, pharmacokinetics and anti-tumor activity for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib, gefitinib or BIBW 2992 will be evaluated as secondary objectives. Initially a standard, 3+3 dose escalation will be performed to determine the MTD of BIBW 2992 when administered together with cetuximab in patients with advanced non small cell lung cancer and acquired resistance to erlotinib or gefitinib. Subsequently, the preliminary efficacy and safety of the identified MTD of cetuximab administered with BIBW 2992 will be explored in a combo arm via a further expansion of MTD cohort up to a total of 140 EGFR mutation positive NSCLC with acquired resistance to erlotinib/gefitinib. Furthermore, the safety and preliminary anti-tumor activity of the combination therapy in EGFR mutant NSCLC patients who developed acquired resistance (AR) to BIBW 2992, will be assessed in a sequential arm. The sequential arm will use a two-stage design with an early stopping rule after 12 patients with acquired resistance to BIBW 2992 have received up to 5 courses of BIBW 2992 plus cetuximab. If no responses are seen in 12 patients during 5 courses of combination therapy, accrual in the sequential arm will stop. If 1 or more responses are observed, the sequential arm will expand up to about 40 patients.
Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.. Inclusion criteria: 1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. --- L858R --- --- L861Q ---
Women of childbearing potential (WOCBP), or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial; pregnancy or breast-feeding Inclusion criteria: 1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. --- L858R --- --- L861Q ---
Description: A DLT was defined as an AE or laboratory abnormality that a) related to the study regimen; b) or met any of the following criteria: CTCAE Grade 2 or higher decrease in cardiac left ventricular function CTCAE Grade 2 diarrhea lasting for 7 or more days, despite appropriate use of standard anti-diarrheal therapy CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for at least 2 days CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days CTCAE Grade ≥3 rash despite standard medical management CTCAE Grade ≥3 fatigue lasting for more than 7 days CTCAE Grade 4 hypomagnesaemia or Grade 3 hypomagnesaemia with clinical significant sequelae All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an interruption of afatinib and/or cetuximab for more than 14 days until recovery to baseline or Grade 1, whichever was higher.
Measure: The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT). Time: from day 1 treatment until progression or undue toxicity, up to 28 daysDescription: Safety of afatinib when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to the U.S. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version (v) 3.0
Measure: Highest CTCAE Grade Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 daysDescription: Frequency (%) of patients with adverse events leading to treatment discontinuation
Measure: Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 daysDescription: Frequency (%) of patients with drug-related serious adverse events
Measure: Frequency (%) of Patients With Related Serious Adverse Events Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 daysDescription: Area Under the Concentration-time Curve (AUC) of Afatinib in plasma at steady state over a uniform dosing interval tau (15 days) (AUCtau,ss) after oral administration of Afatinib and cetuximab combination therapy
Measure: Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55Description: Minimum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmin,ss). Maximum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmax,ss).
Measure: Concentration of Afatinib in Plasma for the Combination Arm Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55Description: Peak-trough fluctuation (PTF) of plasma afatinib for the combination arm. PTF = 100*(Cmax-Cmin)/Caverage where Caverage = AUC/time, where time equals 24 hours.
Measure: Peak-trough Fluctuation (PTF) Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55Description: Terminal half-life of Afatinib in plasma at steady state (t1/2,ss)
Measure: t1/2,ss Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55Description: mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days
Measure: MRTpo,ss Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55Description: Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/F,ss)
Measure: CL/F,ss,15 Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55Description: Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days
Measure: Vz/F,ss Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55Description: Predose plasma concentrations (Cpre,ss) of Afatinib at Course 1, Visit 2, 3, 4 and 5, at Course 2, Visit 1 and 2 and at Course 3, Visit 1.
Measure: Predose Plasma Concentrations of Afatinib for the Combination Arm Time: Up to 57 daysDescription: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Disease control = CR + PR + SD.
Measure: Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1) Time: up to 116 weeksDescription: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective tumor response = CR + PR.
Measure: Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1) Time: up to 116 weeksDescription: Duration of objective response was measured from the time measurements criteria were met for CR/PR (whichever was first recorded) until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since treatment started).
Measure: Duration of Objective Response (According to RECIST v1.1) Time: up to 116 weeksDescription: Duration of disease control was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence SD, PR or CR.
Measure: Duration of Disease Control (According to RECIST v1.1) Time: up to 116 weeksDescription: Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.
Measure: Progression-Free Survival (PFS) Time Time: up to 116 weeksA multi-centre observational, non-interventional study is to dynamically monitor the changes of circulating tumor DNA (ctDNA) in late stage NSCLC patients under Gefitinib treatment.
- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) - Able to comply with the required protocol and followed-up procedures, and able to receive oral medications Exclusion Criteria: - Histologically confirmed small cell lung cancer or other metastatic tumors - Patient had received prior chemotherapy or EGFR-TKIs treatment - Patients who harbor Exon20 T790M mutation Inclusion Criteria: - Provision of informed consent - Histologically confirmed stage IIIB/IV NSCLC. --- G719A --- --- L858R --- --- L861Q ---
- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) - Able to comply with the required protocol and followed-up procedures, and able to receive oral medications Exclusion Criteria: - Histologically confirmed small cell lung cancer or other metastatic tumors - Patient had received prior chemotherapy or EGFR-TKIs treatment - Patients who harbor Exon20 T790M mutation Carcinoma, Non-Small-Cell Lung Bronchial Neoplasms Carcinoma, Bronchogenic Lung Diseases Lung Neoplasms Carcinoma Neoplasms Lung Diseases Carcinoma, Non-Small-Cell Lung Lung Neoplasms Bronchial Neoplasms Carcinoma, Bronchogenic null --- G719A --- --- L858R --- --- L861Q ---
This is a study for patients with advanced non-small cell lung cancer with changes to their cancer cells called EGFR mutations. Mutated EGFR is important in the growth of cancer cells. Medical studies have shown that patients with EGFR mutation-positive lung cancer gain more benefit from targeted therapy drugs such as EGFR inhibitors than with standard chemotherapy. However, a significant proportion of patients carrying these sensitizing mutations do not respond well to the first-generation EGFR-TKIs (erlotinib and gefitinib), indicating the existence of intrinsic resistance mechanisms. Moreover, despite initial response to EGFR-TKIs, acquired resistance is inevitable in all patients. The investigators have recently shown that Cripto-1 overexpression in EGFR mutant NSCLC contributes to the intrinsic resistance to EGFR-TKIs through activation of the SRC oncogene. They have also shown that a combination of an EGFR-TKI (both erlotinib and osimertinib) and a Src inhibitor are synergistic in Cripto-1 overexpressing tumors in the laboratory. This study will be testing a combination of two drugs, dasatinib and osimertinib, to overcome resistance to EGFR-TKIs. Osimertinib (AZD9291) is a third-generation EGFR-TKI, which selectively blocks the activity of EGFR mutants, but spares that of wild type. The advantage of using osimertinib is that it inhibits not only the sensitizing EGFR mutations, but also the T790M mutant, which is the most common mechanism of acquired resistance. Dasatinib is a potent, orally available ABL1/SRC TKI, approved for the treatment of chronic myeloid leukemia (CML) in first-line and in patients with imatinib-resistant disease or intolerant, and is being actively studied in patients with advanced solid tumors. The first part of the study will involve finding the highest dose of dasatinib that can be given with osimertinib without causing severe side effects, finding out the side effects seen by giving dasatinib at different dose levels with osimertinib, and measuring the levels of dasatinib and osimertinib in blood at different dose levels. The second part will determine the effects of the combination of dasatinib and osimertinib and determine if the amount of Cripto-1 protein in your tumor or blood makes you more likely to have a good response to the combination of dasatinib and osimertinib.
- Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q). --- L858R --- --- L861Q ---
Description: Number of patients with drug related adverse events and number of patients who can tolerate dosing of dasatinib when given in combination with osimertinib
Measure: Phase I : Number of patients with drug-related adverse events as assessed by CTCAEv4.0 Time: 9 monthsDescription: The rate of patients non-responding (progressive disease or stable disease lasting 4 months or less) to the combination of osimertinib and dasatinib
Measure: Phase II : Number of patients that do not progress according to RECIST v1.1 Time: 9 monthsDescription: Number of patients with treatment-related adverse events in the phase II study, who are treated at the same dose that has been selected based on the phase I part
Measure: Number of patients with treatment-related adverse events in the phase II study Time: 18 monthsDescription: To describe the concentration of osimertinib when administered with dasatinib. Blood is obtained from patients before each cycle and 4 hours after start of the first 2 cycles.
Measure: Concentration of orimertinib in blood Time: 18 monthsDescription: Determination of the time between the start of the experimental treatment and progression of the tumor
Measure: Progression-free survival Time: 3 yearsDescription: Determination of the time between start of the experimental treatment and death
Measure: Overall survival Time: 3 yearsDescription: Determination of the duration of the response to the treatment, calculated from start of treatment in case of partial response and from the declaration of complete response in case of complete response. The end of the response will be when the tumor progresses
Measure: Duration of response Time: 3 yearsThe purpose of this study is to evaluate the efficacy of Olmutinib(Olita®) in patients with T790M-positive non-small cell lung cancer (NSCLC) confirmed using DNA extracted from extracellular vesicles of bronchoalveolar lavage fluid.
4. Confirmation that the tumor harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group performance status of 0 to 2 6. --- L858R --- --- L861Q ---
Description: defined as the proportion of patients who achieved complete remission(CR) or partial remission(PR) based on RECIST version 1.1
Measure: Objective response rate (ORR) Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 monthsDescription: defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1
Measure: Disease control rate (DCR) Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 monthsDescription: defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first
Measure: Progression-free survival (PFS) Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 monthsTo evaluate the safety, efficacy and immunogenicity of SCT510 combined with paclitaxel and carboplatin compared with bevacizumab combined with paclitaxel and carboplatin in the first-line treatment of locally advanced metastatic or recurrent squamous cell non-small cell lung cancer.
21 (L858R, L861Q)) and ALK fusion.Subjects who have not previously undergone EGFR and ALK gene testing will need to undergo genetic testing during the screening period.Among them, subjects whose EGFR or ALK gene status cannot be determined for various reasons can be enrolled;Subjects who are known to have EGFR sensitive mutations and/or ALK fusion may also be enrolled if they are currently unable to obtain the corresponding targeted drugs (including the rejection of the subjects) and chemotherapy is standard treatment at the research center; 5. --- L858R --- --- L861Q ---
Description: the proportion of subjects whose CR（complete response） and PR（partial response）combined , according to RECIST 1.1 criteria
Measure: Objective response rate Time: 12 weeksDescription: the proportion of subjects whose CR（complete response） and PR（partial response）combined , according to RECIST 1.1 criteria
Measure: Objective response rate Time: 18 weekDescription: the proportion of subjects with CR（complete response）, PR（partial response） and SD（Stable disease） combined，according to RECIST 1.1 criteria
Measure: Disease control rate Time: 12 weeks and 18 weeksDescription: The time from the first assessment of CR（complete response） or PR（partial response） to the first assessment of PD（progressive disease） or any cause of death，according to RECIST 1.1 criteria
Measure: Duration of Response Time: 3 yearsDescription: The time from randomization to PD（progressive disease） or any cause of death，according to RECIST 1.1 criteria
Measure: Progression free survival Time: 3 yearsDescription: The proportion of subjects who survived longer than 1 year after randomization
Measure: 1-year overall survival rate Time: 1 yearDescription: Defined as the time from randomization of subjects to death from any cause
Measure: Overall survival Time: 3 yearsIn recent years, with the progress in the treatment field, Non-Small Cell Lung Cancer(NSCLC) has become the most successful cancer species in precision medicine. Patients with positive driving genes such as EGFR, ALK, ROS1, BRAF and so on have clearly targeted drugs, which bring survival benefits to patients.However, about 50% of patients still lack a clear driving gene target, which has become the focus of current research.In the field of wild-type NSCLC with negative driver genes, the classic first-line treatment regimen is the two-drug regimen containing platinum.The study by Kimura T in the first-line treatment of 54 wild-type advanced NSCLC patients with carboplatin and pemetrexed showed that the ORR, mPFS and mOS of patients with wild-type non-squamous NSCLC treated with carboplatin permetrexine were 35.8%, 5.4 months and 12.7 months respectively. Anlotinib is a multi-target receptor tyrosine kinase inhibitor in domestic research and development.In the phase â…¢ study, patients who failed at least two kinds of systemic chemotherapy (third line or beyond) or drug intolerance were treated with anlotinib or placebo, the anlotinib group PFS and OS were 5.37 months and 9.46 months, the placebo group PFS and OS were 1.4 months and 6.37 months. The efficacy and safety of Anlotinib combined with Pemetrexed and Carboplatin followed by maintenance therapy with Anlotinib plus Pemetrexed as the first-line treatment in patients with advanced nonsquamous NSCLC deserve further exploration.
Exclusion Criteria: - Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer),Lung sarcomatoid carcinoma; - Had histologically confirmed lung squamous cell carcinoma, or adenosquamous carcinoma; - Patients with pathological fracture in bone metastasis of non-small-cell lung cancer; - Tumor histology or cytology confirmed EGFR mutagenesis [EGFR sensitive mutations include 18 exon point mutations (G719X), 19 exon deletions, 20 exon S768I mutations and 21 exon point mutations (L858R and L861Q)] and ALK gene rearrangement positivity, include EGFR/ALK status cannot be determined for various reasons; - Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor; - Medical history and combined history： 1. Active brain metastases, cancerous meningitis, spinal cord compression, or imaging CT or MRI screening for brain or pia mater disease (a patient with brain metastases who have completed treatment and stable symptoms in 28 days before enrollment may be enrolled, but should be confirmed by brain MRI, CT or venography evaluation as no cerebral hemorrhage symptoms and metastases in midbrain, pons, cerebellum, medulla oblongata, or spinal cord, brain metastases and local radiotherapy after two weeks to allow group); 2. The patient is participating in other clinical studies or completing the previous clinical study in less than 4 weeks; 3. Had malignant tumors except NSCLC within 5 years before enrollment(except for patients with cervical carcinoma in situ , basal cell or squamous cell skin cancer who have undergone a curative treatment, local prostate cancer after radical resection, ductal carcinoma in situ or papillary thyroid cancer after radical resection); 4. Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy;Note: Under the premise of prothrombin time international normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for preventive purposes; 5. Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g; 6. --- S768I --- --- L858R --- --- L861Q ---
Description: PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.
Measure: Progression-free survival，PFS Time: each 42 days up to PD or death(up to 24 months)Description: ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.prior to progression or any further therapy.
Measure: Objective Response Rate,ORR Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)Description: Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.
Measure: Disease Control Rate,DCR Time: each 42 days up to intolerance the toxicity or PD (up to 24 months).Description: Defined as the time until death due to any cause.
Measure: Overall Survival,OS Time: each 42 days up to intolerance the toxicity or PD (up to 24 months) .Description: Number of Participants with Adverse Events.
Measure: Safety(Number of Participants with Adverse Events ) Time: each 42 days up to intolerance the toxicity or PD (up to 24 months).Anlotinib which has shown an affirmatory efficacy in ALTER0303 controlled trial as a 3rd-line treatment on advanced NSCLC is a tyrosine kinase inhibitor with a favorable safety profile in phase I trial which mainly targets VEGFR1/2/3, FGFR, PDGFR and c-kit. The purpose of this trail is to establish whether advanced non-squamous NSCLC patients could benefit from the combination treatment of docetaxel, carboplatin and anlotinib as the first-line and maintenance treatment.
Exclusion Criteria: - Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer), Lung sarcomatoid carcinoma; - Had histologically confirmed lung squamous cell carcinoma, or adenosquamous carcinoma; - Patients with pathological fracture in bone metastasis induced by non-small-cell lung cancer; - Tumor histology or cytology confirmed EGFR mutagenesis [EGFR sensitive mutations include 18 exon point mutations (G719X), 19 exon deletions, 20 exon S768I mutations and 21 exon point mutations (L858R and L861Q)] and ALK gene rearrangement positivity, include EGFR/ALK status cannot be determined for various reasons; - Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor; Medical history and combined history： - Active brain metastases, cancerous meningitis, spinal cord compression, or imaging CT or MRI screening for brain or pia mater disease (a patient with brain metastases who have completed treatment and stable symptoms in 28 days before enrollment may be enrolled, but should be confirmed by brain MRI, CT or venography evaluation as no cerebral hemorrhage symptoms and metastases in midbrain, pons, cerebellum, medulla oblongata, or spinal cord, brain metastases and local radiotherapy after two weeks to allow group); - The patient is participating in other clinical studies or completing the previous clinical study in less than 4 weeks; - Had malignant tumors except NSCLC within 5 years before enrollment(except for patients with carcinoma in situ of the cervix , basal cell or squamous cell skin cancer who have undergone a curative treatment, local prostate cancer after radical resection, ductal carcinoma in situ or papillary thyroid cancer after radical resection); - Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy; Note: Under the condition of prothrombin time international normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for preventive purposes; - Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g; - The effects of surgery or trauma have been eliminated for less than 14 days before enrollment in subjects who have undergone major surgery or have severe trauma; - Severe acute or chronic infections requiring systemic treatment; Suffering from severe cardiovascular disease: myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmias (including men with QTc interval ≥ 450 ms, women ≥ 470 ms); according to NYHA criteria, grades III to IV Insufficient function, or cardiac color Doppler ultrasound examination indicates left ventricular ejection fraction (LVEF) <50%; - There is currently a peripheral neuropathy of ≥CTCAE 2 degrees, except for trauma; - Respiratory syndrome (≥CTC AE grade 2 dyspnea), serous effusion (including pleural effusion, ascites, pericardial effusion) requiring surgical treatment; Long-term unhealed wounds or fractures; - Decompensated diabetes or other ailments treated with high doses of glucocorticoids; - Factors that have a significant impact on oral drug absorption, such as inability to swallow, chronic diarrhea, and intestinal obstruction; - Clinically significant hemoptysis (daily hemoptysis greater than 50ml) within 3 months prior to enrollment; or significant clinically significant bleeding symptoms or defined bleeding tendency, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood ++ and above, or suffering from vasculitis; - Events of venous/venous thrombosis occurring within the first 12 months prior to enrollment, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism; - Physical examination and laboratory findings: 1. --- S768I --- --- L858R --- --- L861Q ---
Description: Clinical response of treatment according to RESIST v1.1 criteria (PFS, progression-free survival)
Measure: progression-free survival Time: Estimated about 24 months.Description: Clinical response of treatment according to RESIST v1.1 criteria (OS, overall survival)
Measure: Overall Survival Time: Estimated about 24 months.Description: Clinical response of treatment according to RESIST v1.1 criteria (DCR, disease control rate)
Measure: Disease Control Rate Time: Estimated about 24 months.Description: Clinical response of treatment according to RESIST v1.1 criteria (ORR, Overall Response Rate)
Measure: Overall Response Rate Time: Estimated about 24 months.This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of rifampicin on the pharmacokinetic (PK) parameters of AZD9291 and metabolites AZ5104 and AZ7550 following multiple oral dosing of both rifampicin and AZD9291 in a fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients who complete Part A will be able to enter part B, and continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.
4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R --- --- L861Q ---
Description: Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).
Measure: Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max) Time: Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).
Measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau) Time: Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).
Measure: Assessment of Css,Max for AZD9291 Before and After Rifampicin Time: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).
Measure: Assessment of Css,Max for AZ5104 (Metabolite) Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).
Measure: Assessment of Css,Max for AZ7550 (Metabolite) Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).
Measure: Assessment of Css,Max for Rifampicin Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).
Measure: Assessment of AUCtau for AZD9291 Before and After Rifampicin Time: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).
Measure: Assessment of AUCtau for AZ5104 (Metabolite) Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).
Measure: Assessment of AUCtau for AZ7550 (Metabolite) Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).
Measure: Assessment of AUCtau for Rifampicin Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).
Measure: Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).
Measure: Assessment of Tss,Max for Rifampicin Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).
Measure: Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).
Measure: Assessment of Css,Min for Rifampicin Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).
Measure: Assessment of CLss/F for AZD9291 Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).
Measure: Assessment of CLss/F for Rifampicin Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).
Measure: Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max) Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.Description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).
Measure: Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau) Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of simvastatin and simvastatin acid, following multiple oral dosing of AZD9291 in a fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.
4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R --- --- L861Q ---
Description: Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration
Measure: Cmax of Simvastatin Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part ADescription: Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of Simvastatin Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part ADescription: Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax
Measure: Tmax of Simvastatin and Simvastatin Acid Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part ADescription: Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration
Measure: CL/F of Simvastatin Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part ADescription: Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration
Measure: Cmax of Simvastatin Acid Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part ADescription: Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of Simvastatin Acid Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part ADescription: Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose
Measure: AUC(0-t) of Simvastatin and Simvastatin Acid Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part APurpose of the study is to determine the following in patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. - the safety and tolerability of ASP8273. - the pharmacokinetics (PK) of ASP8273. - the antitumor activity of ASP8273.
- Patients confirmed to have the del ex19, L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study site who are documented to have any of the above-stated EGFR activating mutations can be enrolled in the study). --- L858R --- --- L861Q ---
Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using the Japan Clinical Oncology Group (JCOG) Japanese translation of the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE ver 4.0 - JCOG)
Measure: Phase I: Safety and tolerability of ASP8273 as assessed by Dose Limiting Toxicities (DLTs) Time: Up to Day 23Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated
Measure: Phase II: Overall response rate (CR+PR) at Week 24 Time: Week 24Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product
Measure: Phase I: Safety and tolerability of ASP8273 as assessed by adverse events (AEs) Time: Up to 18 monthsDescription: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation
Measure: Phase I: Safety and tolerability of ASP8273 as assessed by laboratory tests Time: Up to 18 monthsDescription: Vital signs to be measured includes blood pressure, pulse rate and temperature
Measure: Phase I: Safety and tolerability of ASP8273 as assessed by vital signs Time: Up to 18 monthsDescription: including the assessment of QT intervals
Measure: Phase I: Safety and tolerability of ASP8273 as assessed by 12-lead ECG Time: Up to 18 monthsDescription: The overall response rate is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated
Measure: Phase I: Overall response rate (CR+PR) Time: Up to 18 monthsDescription: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.
Measure: Phase I: Disease control rate (CR+PR+SD) Time: Up to 18 monthsDescription: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product
Measure: Phase II: Safety and tolerability of ASP8273 as assessed by adverse events (AEs) Time: Up to 18 monthsDescription: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation
Measure: Phase II: Safety and tolerability of ASP8273 as assessed by laboratory tests Time: Up to 18 monthsDescription: Vital signs to be measured includes blood pressure, pulse rate and temperature
Measure: Phase II: Safety and tolerability of ASP8273 as assessed by vital signs Time: Up to 18 monthsDescription: including the assessment of QT intervals
Measure: Phase II: Safety and tolerability of ASP8273 as assessed by 12-lead ECG Time: Up to 18 monthsDescription: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.
Measure: Phase II: Disease control rate Time: Up to 18 monthsDescription: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated
Measure: Phase II: Overall response rate (CR+PR) Time: Up to 18 monthsThis is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of rosuvastatin, following multiple oral dosing of AZD9291 in the fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily as a single agent until: disease progression; they are no longer deriving clinical benefit; or any other reason.
4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R --- --- L861Q ---
Description: Rate and extent of absorption of rosuvastatin by assessment of Cmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1 [Period 1] and Day 32 [Period 3], respectively).
Measure: Assessment of Maximum Plasma Concentration (Cmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.Description: Rate and extent of absorption of rosuvastatin by assessment of AUC from time zero extrapolated to infinity. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).
Measure: Assessment of AUC From Time Zero Extrapolated to Infinity for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.Description: Rate and extent of absorption of rosuvastatin by assessment of tmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).
Measure: Assessment of Time to Maximum Plasma Concentration (Tmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.Description: Rate and extent of absorption of rosuvastatin by assessment of AUC0-t. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).
Measure: Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration at Time "t" (AUC0-t) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.Description: Rate and extent of absorption of rosuvastatin by assessment of CL/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).
Measure: Assessment of Apparent Plasma Clearance (CL/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.Description: Rate and extent of absorption of rosuvastatin by assessment of Vz/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).
Measure: Assessment of Apparent Volume of Distribution (Vz/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.Description: Rate and extent of absorption of rosuvastatin by assessment of t1/2(lambda_z). Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).
Measure: Assessment of Terminal Elimination Half-life (t1/2[lambda_z]) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291 Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of AUCtau. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).
Measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUCtau) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).
Measure: Assessment of Maximum Plasma Concentration at Steady State (Css,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of tss,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).
Measure: Assessment of Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,min over the dosing interval. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).
Measure: Assessment of Minimum Plasma Concentration at Steady State (Css,Min) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.Description: Rate and extent of absorption for AZD9291 by assessment of CLss/F after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).
Measure: Assessment of Apparent Plasma Clearance at Steady State (CLss/F) for AZD9291 Following Administration of AZD9291 and Rosuvastatin Together Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.Description: Assessment of MRCss,max for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).
Measure: Assessment of the Metabolite to Parent Ratios of Css,Max (MRCss,Max) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.Description: Assessment of MRAUCtau for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).
Measure: Assessment of the Metabolite to Parent Ratios of AUCtau (MRAUCtau) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.This phase I trial studies the side effects and best dose of c-Met inhibitor INCB028060 and erlotinib hydrochloride when given together in treating patients with previously treated non-small cell lung cancer. C-Met inhibitor INCB028060 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
G719X, exon 19 deletion, L858R, L861Q) - Systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or World Health Organization [WHO]) while on continuous treatment with gefitinib or erlotinib - Patients must have measurable disease; disease in previously irradiated sites is considered measurable if there is clear disease progression following radiation therapy - Failed 1-2 prior chemotherapies for advanced disease; prior erlotinib is allowed in the dose finding phase and expansion cohort A (Patients in expansion cohort B must be erlotinib naïve and have v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KRAS] wild type tumor) - Patients must be willing to be off therapy for a minimum of two weeks (In expansion cohort A patients on erlotinib do not have to discontinue treatment) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Life expectancy greater than 3 months - Hemoglobin > 9 g/dL (International System [SI] units: 90 g/L) without transfusion support or growth factors within 10 days of starting INC280 - Platelet count >= 75 x 10^9/L - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L without growth factor support - Total bilirubin =< 2 x upper limit of normal (ULN) - Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.5 x upper limit of normal (ULN) - Serum creatinine =< 2 x ULN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting serum triglyceride level =< 500 mg/dL Exclusion Criteria: - Patients who have had major surgery within 4 weeks of initiation of study medication, excluding the placement of vascular access - Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data - Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia - Severely impaired lung function - Active (acute or chronic) or uncontrolled infection - Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy - Liver disease (i.e. --- L858R --- --- L861Q ---
Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.
Measure: Maximum tolerated dose (MTD) of c-Met inhibitor INCB028060 and erlotinib, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4 Time: Up to 28 days after a full course of therapyDescription: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.
Measure: Toxicities as measured by NCI CTCAE V4 Time: Up to 30 daysDescription: Response rate among patients with measurable disease will be summarized by exact binomial confidence intervals.
Measure: Overall response rate among patients with measurable disease, measured by RECIST 1.1 Time: Up to 30 daysDescription: Summarized with Kaplan-Meier plots. Median time to progression will be estimated using standard life table methods.
Measure: Progression-free survival Time: Duration of time from start of treatment to time of progression or death, assessed up to 30 daysDescription: Summarized with Kaplan-Meier plots. Median time to progression will be estimated using standard life table methods.
Measure: Overall survival Time: Duration of time from the start of treatment to death from any cause, assessed up to 30 daysASK120067 Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.
Inclusion Criteria: - Patients of either gender, aged from 18 years older to 70. - Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. --- L858R --- --- L861Q ---
Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN. - History of hypersensitivity to active or inactive excipients of ASK120067 or drugs with a similar chemical structure or class to ASK120067 - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements Inclusion Criteria: - Patients of either gender, aged from 18 years older to 70. - Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. --- L858R --- --- L861Q ---
Description: Evaluation of objective response rate assessed by RECIST 1.1
Measure: Objective response rate Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations and NCI CTCAE v4.03
Measure: Incidence and Severity of Treatment-Emergent Adverse Events Time: Adverse events will be collected from baseline until 28 days after the last doseDescription: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival
Measure: Progression free survival Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.Description: Duration of response assessed by RECIST 1.1
Measure: Duration of response Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.Description: Evaluation of Disease control rate assessed by RECIST 1.1
Measure: Disease control rate Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.Description: difined as the time from date of first dose until date of death due to any cause
Measure: Overall survival Time: Time from treatment start to the time of death due to any cause or withdrawal from study,whichever came first, assessed up to approximately 2 years.Description: Collect plasma concentrations of ASK120067 and 1 metabolites following single dose at designated time points of Day 1 to figure out Cmax
Measure: Maximum Plasma Concentration [Cmax] of single dose ASK120067 Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out tmax
Measure: Peak Plasma Time [tmax] of single dose ASK120067 Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day1 to figure out AUC
Measure: Area under the plasma concentration versus time curve (AUC) of single dose ASK120067 Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out terminal rate constant
Measure: Terminal rate constant of single dose single dose ASK120067 Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out clearance
Measure: Clearance of single dose ASK120067 Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out half life
Measure: Half life of single dose ASK120067 Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)Description: Collect plasma concentrations of f ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out volume of distribution
Measure: Volume of distribution of single dose ASK120067 Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out mean resistance time
Measure: Mean resistance time of single dose ASK120067 Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)Description: Cmax of ASK120067 and 1 metabolite at steady state following multiple doses
Measure: Steady state Cmax of multiple doses ASK120067 Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)Description: Tmax of ASK120067 and 1 metabolite at steady state following multiple doses
Measure: Steady state tmax of multiple doses ASK120067 Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)Description: Cmin of ASK120067 and 1 metabolite at steady state following multiple doses
Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses ASK120067 Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)Description: AUC of ASK120067 and 1 metabolite at steady state following multiple doses
Measure: Steady state AUC of multiple doses ASK120067 Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)Description: Clearance of ASK120067 and 1 metabolite at steady state following multiple doses
Measure: Steady state clearance of multiple doses ASK120067 Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)Description: Accumulation ratio of ASK120067 and 1 metabolite following multiple doses
Measure: Accumulation ratio of multiple doses ASK120067 Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)Description: Time dependency of ASK120067 and 1 metabolite following multiple doses
Measure: Time dependency of multiple doses ASK120067 Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)This is one randomized, double-blind, placebo-controlled, multi-center, phase III clinical study to evaluate the efficacy and safety of Toripalimab injection (JS001) or placebo combined with standard 1st-line chemotherapy in treatment-naïve advanced non-small cell lung cancer (NSCLC); and evaluate the population with the best predictive biomarkers, i.e., positive diagnosis population. About 450 subjects with advanced non-small cell lung cancer without activated EGFR mutation (exon 19 deletion, or exon 21 L858R, exon 21 L861Q, exon 18 G719X or exon 20 S768I mutations) and ALK fusion will be 2:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. The stratification will be based on the following factors: PD-L1 expression (TC≥1% vs TC＜1%); Smoking state (often smoking vs no smoking or infrequent smoking); Pathological type (squamous cell carcinoma vs non-squamous cell carcinoma).
About 450 subjects with advanced non-small cell lung cancer without activated EGFR mutation (exon 19 deletion, or exon 21 L858R, exon 21 L861Q, exon 18 G719X or exon 20 S768I mutations) and ALK fusion will be 2:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. --- L858R --- --- L861Q ---
Description: Progression free survival (PFS) evaluated by investigators according to the response evaluation criteria in solid tumors (RECIST 1.1)
Measure: PFS Time: Up to 2 approximately yearsDescription: Overall survival (OS)
Measure: OS Time: Up to 2 approximately yearsDescription: PFS evaluated by the Blinded Individual Review Committee (BIRC) based on RECIST1.1 criteria
Measure: PFS Time: Up to 2 approximately yearsDescription: Objective response rate (ORR) evaluated by investigators and BIRC based on RECIST1.1
Measure: ORR Time: Up to 2 approximately yearsDescription: Duration of response (DOR) evaluated by investigators and BIRC based on RECIST1.1
Measure: DOR Time: Up to 2 approximately yearsDescription: Disease control rate (DCR) evaluated by investigators and BIRC based on RECIST1.1
Measure: DCR Time: Up to 2 approximately yearsDescription: Time to response (TTR) evaluated by investigators and BIRC based on RECIST1.1
Measure: TTR Time: Up to 2 approximately yearsDescription: Overall incidence of adverse events (AEs); incidence of grade 3 and above AEs; incidence of serious adverse events (SAEs); incidence of AEs leading to termination of the investigational drug; incidence of AEs interruption of the investigational drug
Measure: Incidence of AEs/SAEs Time: From date of consent informed until 60 days after the last investigational product administration. Up to 2 approximately yearsThis partially randomized phase II trial studies how well nivolumab, cabozantinib s-malate, and ipilimumab work in treating patients with stage IV non-small cell lung cancer that has come back. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab, cabozantinib s-malate, and ipilimumab may work better than cabozantinib s-malate alone in treating patients with stage IV non-small cell lung cancer.
Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.. Inclusion Criteria: - ELIGIBILITY CRITERIA FOR STEP 0 - Patients with tumors with the following molecular alterations must submit testing results via Medidata Rave to determine eligibility to Arm T; the study chair, co-chair, biology co-chair, or a delegate must review the molecular testing and agree that the testing meets one of the molecular eligibility criteria below: - ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib therapy) - MET exon 14 splice mutations on DNA analysis (may have progressed on prior crizotinib therapy) - MET high amplification by FISH or DNA analysis or other MET mutations predicted to be sensitive to MET inhibitor (no prior targeted therapy allowed) - RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy allowed) - Institutions will be notified of the patient's eligibility status for Arm T within two (2) business days of submission of the molecular testing reports - If patients do not have tumors with the above molecular alterations noted proceed directly to step 1 - ELIGIBILITY CRITERIA FOR STEP 1 - For patients with known molecular alterations, institution has been notified that patient is deemed eligible for Arm T per review of molecular testing reports - Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC) - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer tumor, node, and metastasis (TNM) classification system - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required - Patients must have progressed radiographically following first line platinum-based chemotherapy, no additional lines of therapy are permitted - NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Exception for targeted therapy sub-study (Arm T): At least one line of prior chemotherapy or targeted therapy is required, but there is no limit on number of prior treatments - Patients must have measurable disease as defined by RECIST v. 1.1 criteria; baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to registration - No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-1/PD-L1 immune checkpoint inhibitor therapy (such as nivolumab, pembrolizumab, atezolizumab) or CTLA4 inhibitor therapy (such as ipilimumab); no prior allergic reaction to small molecule tyrosine kinase inhibitors or monoclonal antibodies - Exception for targeted therapy sub-study (Arm T): Prior crizotinib may be allowed depending on the gene alteration - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to registration: - Chemotherapy/ targeted oral therapy administered in a daily or weekly schedule must be completed >= 1 week prior to registration; - Any chemotherapy administered in an every 2 week or greater schedule must be completed >= 2 weeks prior to registration - Additionally, patients should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy - No prior radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks prior to registration - Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases OR - Patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria: - Have completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone complete neurosurgical resection >= 3 months prior to registration - Be clinically stable from brain metastases at time of screening, if no treatment was administered - Known leptomeningeal disease is not allowed - Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - NOTE: Participants with impaired decision-making capacity (IDMC) should not be allowed to participate in this study due to its complexity - Patients must have anticipated life expectancy greater than 3 months - Absolute neutrophil count >= 1,500/mm^3 (within 2 weeks prior to registration) - Platelets >= 100,000/mm^3 (within 2 weeks prior to registration) - Hemoglobin >= 9 g/dL (within 2 weeks prior to registration) - Subject has prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) test =< 1.3 x the laboratory upper limit of normal (ULN) (within 2 weeks prior to registration) - Total bilirubin =< 1.5 x ULN (within 2 weeks prior to registration) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN (within 2 weeks prior to registration) - Serum albumin >= 2.8 g/dL (within 2 weeks prior to registration) - Serum calcium (absolute or albumin corrected), magnesium and potassium >= lower limit of normal (LLN) (within 2 weeks prior to registration) - NOTE: serum calcium, magnesium and potassium can be replaced if values are below LLN - Creatinine =< 1.5 x ULN or calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 --- L858R --- --- L861Q ---
- Serious non-healing wound/ulcer/bone fracture within 28 days prior to registration - History of organ transplant - Concurrent symptomatic untreated hypothyroidism within 7 days prior to registration - History of surgery as follows: - Major surgery (as an example, surgery requiring anesthesia and a > 24 hour hospital stay) within 3 months prior to registration, with wound healing at least 28 days prior to registration - Minor surgery within 28 days prior to registration with complete wound healing at least 10 days prior to registration - Minor procedures within 7 days prior to registration such as thoracentesis, paracentesis, or 18 g or smaller needle biopsy of tumor - Patients with clinically relevant ongoing complications from prior surgery are not eligible - Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before registration - Patients must be able to swallow tablets - No currently active other malignancies which require systemic treatment - No patients that have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - No patients with known active autoimmune disease or known history of autoimmune disease for which recurrence may affect vital organ function or require immune suppressive treatment including systemic corticosteroids; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, autoimmune hepatitis; patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including type I diabetes mellitus or thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - No ongoing major illness or psychosocial issues that would limit compliance with the protocol - Women must not be pregnant or breast-feeding due to contraindications with the study agents - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy - A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use an accepted and effective method of contraception or abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment for women of childbearing potential and 7 months after the last dose of protocol treatment for males who are sexually active with WOCBP - Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral therapy are excluded because there are no safety data with the combination of antiretroviral therapy and cabozantinib or ipilimumab or nivolumab with ipilimumab - Patients with known chronic active hepatitis B (defined as a positive hepatitis B surface antigen and/or hepatitis B viral load in the last Inclusion Criteria: - ELIGIBILITY CRITERIA FOR STEP 0 - Patients with tumors with the following molecular alterations must submit testing results via Medidata Rave to determine eligibility to Arm T; the study chair, co-chair, biology co-chair, or a delegate must review the molecular testing and agree that the testing meets one of the molecular eligibility criteria below: - ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib therapy) - MET exon 14 splice mutations on DNA analysis (may have progressed on prior crizotinib therapy) - MET high amplification by FISH or DNA analysis or other MET mutations predicted to be sensitive to MET inhibitor (no prior targeted therapy allowed) - RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy allowed) - Institutions will be notified of the patient's eligibility status for Arm T within two (2) business days of submission of the molecular testing reports - If patients do not have tumors with the above molecular alterations noted proceed directly to step 1 - ELIGIBILITY CRITERIA FOR STEP 1 - For patients with known molecular alterations, institution has been notified that patient is deemed eligible for Arm T per review of molecular testing reports - Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC) - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer tumor, node, and metastasis (TNM) classification system - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required - Patients must have progressed radiographically following first line platinum-based chemotherapy, no additional lines of therapy are permitted - NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Exception for targeted therapy sub-study (Arm T): At least one line of prior chemotherapy or targeted therapy is required, but there is no limit on number of prior treatments - Patients must have measurable disease as defined by RECIST v. 1.1 criteria; baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to registration - No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-1/PD-L1 immune checkpoint inhibitor therapy (such as nivolumab, pembrolizumab, atezolizumab) or CTLA4 inhibitor therapy (such as ipilimumab); no prior allergic reaction to small molecule tyrosine kinase inhibitors or monoclonal antibodies - Exception for targeted therapy sub-study (Arm T): Prior crizotinib may be allowed depending on the gene alteration - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to registration: - Chemotherapy/ targeted oral therapy administered in a daily or weekly schedule must be completed >= 1 week prior to registration; - Any chemotherapy administered in an every 2 week or greater schedule must be completed >= 2 weeks prior to registration - Additionally, patients should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy - No prior radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks prior to registration - Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases OR - Patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria: - Have completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone complete neurosurgical resection >= 3 months prior to registration - Be clinically stable from brain metastases at time of screening, if no treatment was administered - Known leptomeningeal disease is not allowed - Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - NOTE: Participants with impaired decision-making capacity (IDMC) should not be allowed to participate in this study due to its complexity - Patients must have anticipated life expectancy greater than 3 months - Absolute neutrophil count >= 1,500/mm^3 (within 2 weeks prior to registration) - Platelets >= 100,000/mm^3 (within 2 weeks prior to registration) - Hemoglobin >= 9 g/dL (within 2 weeks prior to registration) - Subject has prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) test =< 1.3 x the laboratory upper limit of normal (ULN) (within 2 weeks prior to registration) - Total bilirubin =< 1.5 x ULN (within 2 weeks prior to registration) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN (within 2 weeks prior to registration) - Serum albumin >= 2.8 g/dL (within 2 weeks prior to registration) - Serum calcium (absolute or albumin corrected), magnesium and potassium >= lower limit of normal (LLN) (within 2 weeks prior to registration) - NOTE: serum calcium, magnesium and potassium can be replaced if values are below LLN - Creatinine =< 1.5 x ULN or calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 --- L858R --- --- L861Q ---
Description: Will be estimated using the Kaplan-Meier method and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparison of PFS will use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Other comparisons of groups will be made using the logrank test and Cox modeling.
Measure: Progression-free survival (PFS) Time: From randomization to documented disease progression or death from any cause, whichever occurs first, assessed up to 5 yearsDescription: Will be estimated using the Kaplan-Meier method and Cox proportional hazards models will be used to estimate the treatment hazard ratios.
Measure: Overall survival Time: From randomization to death from any cause, assessed up to 5 yearsDescription: According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response rates (complete response and partial response) will be compared using Fischer's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.
Measure: Best objective response evaluated Time: Up to 5 yearsDescription: Evaluated according to Common Terminology Criteria for Adverse Events version 5 criteria. Toxicity will be compared using Fischer's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.
Measure: Incidence of toxicity Time: Up to 5 yearsDescription: As measured by RECIST 1.1 criteria.
Measure: Time to tumor response Time: Up to 5 yearsDescription: A combined analysis of the data from the selected Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN) trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.
Measure: Effects of tobacco on provider-reported cancer-treatment toxicity (adverse events (both clinical and hematologic) and dose modifications Time: Up to 5 yearsDescription: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.
Measure: Effects of tobacco on patient-reported physical symptoms and psychological symptoms Time: Up to 5 yearsDescription: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.
Measure: Assessment of quitting behaviors, behavioral counseling/support and cessation medication utilization Time: Up to 5 yearsDescription: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.
Measure: Effects of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit Time: Up to 5 yearsThis is an open-label, single centre, Phase I study to determine the brain exposure of [11C]osimertinib in patients with EGFRm NSCLC with brain metastases.
For TKI-naïve patients, confirmation of EGFR mutation known to be associated with EGFR-TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) as assessed by local and/or central laboratory via tissue/cytology is required. --- L858R --- --- L861Q ---
Description: Measurement of the brain standard uptake value (SUV) seen on PET scan at baseline.
Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest Time: PET Scan on Day 1Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken at baseline.
Measure: Pharmacokinetics of [11C]osimertinib Time: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken at baseline.
Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) Time: Measurement collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken at baseline.
Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) Time: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.Description: Measurement of the brain standard uptake value (SUV) seen on PET scan after a single dose of oral osimertinib.
Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest Time: PET Scan on Day 2Description: Measurement of the brain standard uptake value (SUV) seen on PET scan after at least 21days of continuous oral osimertinib dosing.
Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest Time: PET Scan on Day 29Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
Measure: Pharmacokinetics of [11C]osimertinib Time: Blood samples collected on Day 292, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
Measure: Pharmacokinetics of [11C]osimertinib Time: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) Time: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) Time: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.
Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) Time: Measurement collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.
Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) Time: Measurement collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.Description: Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.
Measure: Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio Time: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose.Description: Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
Measure: Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax) Time: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose.Description: Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.
Measure: Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve Time: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose.Description: Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
Measure: Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax) Time: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose.Description: Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.
Measure: Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio Time: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose.Description: Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
Measure: Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax) Time: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose.Description: Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.
Measure: Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve Time: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose.Description: Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
Measure: Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax) Time: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose.Description: Collection and assessment of adverse events graded using CTCAE (version 4.03).
Measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with IV [11C]osimertinib administration Time: From study Day 1 and until 30 days after the study drug is discontinued.Description: Collection and assessment of adverse events using CTCAE (version 4.03)
Measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with continuous oral osimertinib Time: From study Day 1 and until 30 days after the study drug is discontinued.The study is designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of EGF816 in combination with INC280 and to estimate the preliminary anti-tumor activity of EGF816 in combination with INC280 in patients with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.
L861Q, G719X, S768I) - Presence of at least one measurable lesion according to RECIST v.1.1 - ECOG performance status ≤1 - Patients must be screened for HBV. --- L861Q ---
Description: ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Measure: Phase II Groups 1, 2 and 3: Overall Response Rate per RECIST 1.1 Time: At least 24 weeksDescription: Frequency of treatment-emergent adverse events
Measure: Phase II Group 4 Incidence and severity of AEs/SAEs, dose interruptions, reductions and dose intensity Time: At least 24 weeksDescription: Assessment of the safety of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment
Measure: Safety of INC280 and EGF816: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs (Phase I/II) Time: At least 24 weeksDescription: Assessment of the tolerability of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment
Measure: Frequency of dose interruption, frequency of reduction and dose intensity (Phase I/II) Time: At least 24 weeksDescription: ORR is defined as proportion of patients with best overall response of (PR+CR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Measure: Overall Response Rate (Phase Ib and Phase II Group 4) Time: At least 24 weeksDescription: DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Measure: Disease Control Rate (Phase I/II) Time: At least 24 weeksDescription: Progression-free survival (PFS). PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
Measure: Progression Free Survival (Phase I/II) Time: At least 24 weeksDescription: DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
Measure: Duration of Response (Phase I/II) Time: At least 24 weeksDescription: OS is defined as the time from first dose of the study treatment to the date of death due to any cause.
Measure: Overall Survival (Phase I/II) Time: At least 24 weeksDescription: TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Measure: Time to Response (Phase I/II) Time: At least 24 weeksThis is a research study to find out if a drug called, osimertinib, is safe and effective in treating advanced Non-Small Cell Lung Cancer (NSCLC) by targeting the treatment of epidermal growth factor receptor (EGFR) mutation exon 18 G719X, exon 20 S7681, or exon 21 L861Q. Patients on the study will not have had previous tyrosine kinase inhibitor (TKI) treatment.
A Study Osimertinib in Patients With Stage 4 Non-small Cell Lung Cancer With Uncommon EGFR Mutations This is a research study to find out if a drug called, osimertinib, is safe and effective in treating advanced Non-Small Cell Lung Cancer (NSCLC) by targeting the treatment of epidermal growth factor receptor (EGFR) mutation exon 18 G719X, exon 20 S7681, or exon 21 L861Q. --- L861Q ---
Overall survival as noted by follow-up via composite of telephone or medical record review.. Overall survival as defined as time from starting study therapy until death from any causes.. Inclusion Criteria: - EGFR mutations as performed on a CLIA certified laboratory demonstrating EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q. --- S768I --- --- L861Q ---
- Grade ≥ 2 blurred vision, conjunctivitis, corneal ulcer, dry eye, or keratitis Inclusion Criteria: - EGFR mutations as performed on a CLIA certified laboratory demonstrating EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q. --- S768I --- --- L861Q ---
- Grade ≥ 2 blurred vision, conjunctivitis, corneal ulcer, dry eye, or keratitis Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a research study to find out if a drug called, osimertinib, is safe and effective in treating advanced Non-Small Cell Lung Cancer (NSCLC) by targeting the treatment of epidermal growth factor receptor (EGFR) mutation exon 18 G719X, exon 20 S7681, or exon 21 L861Q. --- L861Q ---
Patients who have one of the following EGRF mutations: exon 18 G719X, exon 20 S7681, or exon 21 L861Q) may be eligible to participate in this study. --- L861Q ---
Description: RECIST 1.1 will be used to measure confirmed partial or complete responses to the study drug.
Measure: Objective response rate as assessed by the investigator using Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name) Time: Up to 3 yearsDescription: Progression will be defined as time from starting study therapy to disease progression or death (whichever occurs first)
Measure: Progression free survival as measured by Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name) as assessed by the investigator. Time: Up to 5 yearsDescription: Evaluation of safety using the National Cancer Institute (NCI) CTCAE version 4.03
Measure: AEs as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Time: Up to 3 yearsDescription: Overall survival as defined as time from starting study therapy until death from any causes.
Measure: Overall survival as noted by follow-up via composite of telephone or medical record review. Time: Up to 5 yearsThis is a Phase 1b, open-label, multicentre study of AZD6094 in combination with gefitinib in patients with epidermal growth factor receptor (EGFR) mutation positive (m+) and progressed on EGFR Tyrosine kinase inhibitor (TKI) treatment.
3. Histologically or cytologically confirmed locally advanced or metastatic NSCLC patients who are harbouring an EGFR mutation known to be associated with EGFR-TKI sensitivity (including exon 19 deletion, L858R, L861Q, G719X). --- L858R --- --- L861Q ---
The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin).
- Confirmation prior to enrolment into the study that the tumour harbours the following EGFR mutations known to be associated with EGFR-targeted TKI sensitivity: Ex19Del, L858R, L861Q, and G719X. --- L858R --- --- L861Q ---
There are Epidermal Growth Factor Receptor (EGFR) mutations known to be associated with EGFR-targeted TKI sensitivity ( Ex19Del, L858R, L861Q, and G719X). --- L858R --- --- L861Q ---
Description: This will be assessed as the time from the start date of 2nd line chemotherapy until death due to any cause or censoring (at end of 24 months).To assess efficacy of permetrexed + cisplatinum/carboplatin as the 2nd line of treatment of NSCLC.
Measure: Overall Survival Time: 24 months from last subject inDescription: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death (by any cause in the absence of progression). To assess efficacy of 2nd line treatment and beyond.
Measure: Response to Therapy as assessed by the physician Time: 24 months from last subject inDescription: This will be assessed as the time from start date of line of therapy to end date of line of therapy or death date. To describe treatment patterns for 2nd line and beyond.
Measure: Time on treatment by line of therapy and between therapies Time: 24 months from last subject inDescription: This will be assessed as the number and Time from the dates of admission and exit of attendance. To describe Healthcare resource utilization for 2nd line treatment and beyond.
Measure: Admission of planned/unplanned hospitalizations, emergency department visits and outpatient/physician visits Time: 24 months from last subject inDescription: For each of the symptoms in EORTC QLQ-LC13 and EORTC QLQ-C30, Time from inclusion until the date of first clinically meaningful symptom deterioration or death by any cause in the absence of a clinically meaningful symptom deterioration. To assess the impact of 2nd and subsequent lines of therapy on patients' disease-related symptoms and health related quality of life.
Measure: Time to symptom deterioration Time: 24 months from last subject inDescription: This will be assessed as the number of patients with two consecutive assessments, which showed a clinically meaningful improvement in that symptom from baseline. To assess the impact of 2nd and subsequent lines of therapies on patients' disease-related symptoms and health related quality of life.
Measure: Symptom Improvement Rate Time: 24 months from last subject inDescription: This will be assessed as the time from the date of complete or partial response until the first date of recurrence or progression. To assess the efficacy of 2nd line treatment and beyond.
Measure: Duration of Response as defined by the physician Time: 24 months from last subject inDescription: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death by any cause. This will be done to assess efficacy of pemetrexed + cisplatin/carboplatin as the 2nd line treatment of NSCLC.
Measure: Progression Free Survival Time: 24 months from last subject inThis phase I/Ib trial studies the side effects and best dose of pembrolizumab when given together with afatinib dimaleate in treating patients with non-small cell lung cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, or has come back and does not respond to erlotinib hydrochloride. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and afatinib dimaleate together may be an effective treatment for non-small cell lung cancer.
Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.. Inclusion Criteria: - Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator - Be willing and able to provide written informed consent for the trial - Have a life expectancy of at least 3 months - Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale - Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy - There is no limit to the number of prior treatments for this phase I trial - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L - Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Creatinine clearance should be calculated per institutional standard - Serum total bilirubin =< 1.5 x ULN - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants - Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year - Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria: - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not < 1 week prior to study day 1 and not administered on day of MK-3475 infusion - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent - Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study - Has evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary - Has an active infection requiring intravenous systemic therapy - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment - Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment - Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) - Known hypersensitivity to afatinib or the excipients of any of the trial drugs - Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) - Has received a live vaccine within 30 days prior to the first dose of trial treatment - The presence of poorly controlled gastrointestinal disorders that could affect the absorption of the afatinib (e.g. --- L858R --- --- L861Q ---
Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption) - Subjects that require treatment with a strong inhibitor of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) will be excluded; they may be included if there is an alternate treatment available (not a strong CYP3A4 inhibitor) and they are willing to switch prior to enrollment; if a subject opts to change from a strong CYP 3A4 inhibitor to a weaker CYP 3A4 inhibitor, the subject must stop the strong CYP 3A4 inhibitor 7 days before study drug administration - Receiving drugs known to be strong inducers or inhibitors of permeability (P)-glycoprotein that are known to interact with afatinib including, but not limited to: ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; the subject must stop the strong inducer or inhibitor of P-glycoprotein 7 days before or 5 half lives before study drug administration (whichever timepoint is longer) - Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study - Hormonal treatment within 2 weeks prior to start of study treatment - Radiotherapy within 4 weeks prior to enrollment, except as follows: - Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to enrollment, and - Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor-investigator prior to enrolling - Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of study Inclusion Criteria: - Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator - Be willing and able to provide written informed consent for the trial - Have a life expectancy of at least 3 months - Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale - Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy - There is no limit to the number of prior treatments for this phase I trial - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L - Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Creatinine clearance should be calculated per institutional standard - Serum total bilirubin =< 1.5 x ULN - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants - Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year - Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria: - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not < 1 week prior to study day 1 and not administered on day of MK-3475 infusion - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent - Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study - Has evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary - Has an active infection requiring intravenous systemic therapy - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment - Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment - Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) - Known hypersensitivity to afatinib or the excipients of any of the trial drugs - Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) - Has received a live vaccine within 30 days prior to the first dose of trial treatment - The presence of poorly controlled gastrointestinal disorders that could affect the absorption of the afatinib (e.g. --- L858R --- --- L861Q ---
Description: Descriptive summaries will be provided for number and proportion with specific type and grade of toxicities.
Measure: Maximum tolerated dose (MTD) recommended dose of pembrolizumab in combination with lead in pembrolizumab and afatinib dimaleate Time: Day 21Description: Will be determined by the overall assessment of the MTD and toxicities observed in the dose de-escalation portion of this study.
Measure: Recommended phase II dose Time: Day 21Description: Descriptive summaries will be provided for numbers and proportion of patients responding.
Measure: Overall response rate per RECIST 1.1 Time: Up to 3 yearsDescription: Kaplan-Meier plot and life-table summary will be used.
Measure: Progression free survival Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 3 yearsDescription: Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.
Measure: Changes in plasma EGFR-mutant DNA levels Time: Baseline to up to 3 yearsDescription: Descriptive associations with response rate and PFS will be performed. Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.
Measure: Changes in PDL1 expression by immunohistochemistry Time: Baseline to up to 3 yearsA phase IIb, open-label, single-arm study to assess the safety and efficacy of BPI-7711 capsule in patients with metastatic or recurrent non-small cell lung cancer with EGFR mutation and T790M mutation positive.
- Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R --- --- L861Q ---
Description: Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
Measure: ORR according to RECIST 1.1 by an Independent Central Review (ICR) Time: up to 52 weeksDescription: Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
Measure: ORR according to RECIST 1.1 by investigators Time: up to 52 weeksDescription: DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.
Measure: Disease control rate (DCR) according to RECIST 1.1 Time: up to 104 weeksDescription: PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from BPI-7711 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
Measure: Progression free survival(PFS) according to RECIST 1.1 Time: up to 104 weeksThis study is a multi-center, open-label, dose-finding phase Ib clinical study with extension phase, which is aimed at evaluating the efficacy and safety of GB226 combined with fruquintinib in treatment of relapsed or metastatic NSCLC patients with EGFR-sensitive mutations who have failed to respond to EGFR-TKI treatment,evaluating the pharmacokinetic characteristics of GB226 and fruquintinib, and the immunogenicity of GB226, and preliminarily evaluating the antitumor activity of GB226 and fruquintinib.
Inclusion Criteria: 1. Aged 18-75 years, male or female; 2. Understanding the procedures and contents of the study, and voluntarily signing the written informed consent form; 3. Histologically or cytology confirmed relapsed or metastatic NSCLC; 4. EGFR gene sensitive mutation is confirmed positive, any of following is met: exon 19 deletion (19DEL), exon 21 point mutation (L858R / L861Q), 18 exon point mutation (G719X), 20 exon point mutation (S768I). --- L858R --- --- L861Q ---
Description: Assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Measure: Incidence of Adverse Event Time: all adverse events will be recorded from the time the consent form is signed through 90 days following cessation of treatment.Description: Assessment of serious adverse events (SAEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Measure: Incidence of Serious Adverse Event Time: all adverse events will be recorded from the time the consent form is signed through 90 days following cessation of treatment.Description: Incidence of Dose Limited Toxicity
Measure: Dose Limited Toxicity Time: Day 1 to Day 28 after first doseDescription: Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 4.03
Measure: Maximum Tolerated Dose Time: Day 1 to Day 28 after first doseDescription: Objective response rate in accordance with RECIST 1.1. ORR will be calculated as the percent of patients in each of the expansion cohorts whose best confirmed response is complete response (CR) or partial response (PR).
Measure: ORR Time: up to 52 weeksDescription: Progression-free survival. From start of treatment to time of progression or death, whichever occurs first
Measure: PFS Time: up to 52 weeksDescription: Duration of Response. Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause.
Measure: DOR Time: up to 52 weeksDescription: Disease control rate.DCR will be the proportion of patients in each of the expansion cohorts whose best confirmed response is CR, PR, or stable disease (SD).
Measure: DCR Time: up to 52 weeksDescription: Overall Survival. From start of treatment to time of death.
Measure: OS Time: up to 52 weeksDescription: incidence of anti-GB226 antibody(ADA)
Measure: ADA Time: up to 52 weeksDescription: Pharmacokinetics of GB226 and Fruquinitinib by assessment of Cmax
Measure: Cmax Time: up to 16 weeksDescription: Pharmacokinetics of GB226 and Fruquinitinib by assessment of AUC
Measure: AUC Time: up to 16 weeksA Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive
- Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R --- --- L861Q ---
Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
Measure: Objective Response Rate (ORR) Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).
Measure: Duration of Response (DoR) Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.
Measure: Disease Control Rate (DCR) Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
Measure: Progression-Free Survival (PFS) Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)This is a Phase 1/1b open-label study evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of ABBV-399 in subjects with advanced solid tumors. Enrollment is closed for Arms A and D.
- Subject must have metastatic NSCLC with documented Epidermal Growth Factor Receptor (EGFR) mutation(s) known to be sensitive to osimertinib, including del19, L858R, G719X or L861Q. --- L858R --- --- L861Q ---
Description: AUC (0-t) = Area under the serum concentration versus time curve from time zero (pre-dose) to the time of the last measurable concentration.
Measure: Area under the curve (AUC) from time zero to the last measurable concentration AUC (0-t) Time: Up to 24 monthsDescription: Maximum observed plasma concentration (Cmax)
Measure: Maximum observed plasma concentration (Cmax) Time: Up to 24 monthsDescription: Time to Cmax (Tmax)
Measure: Time to Cmax (Tmax) Time: Up to 24 monthsDescription: ORR is defined as the proportion of the subjects who have a complete response (CR) or partial response (PR).
Measure: Objective response rate (ORR) Time: Up to 24 monthsDescription: PFS is defined as the time from the first dose date of ABBV-399 to either disease progression or death, whichever occurs first.
Measure: Progression free survival (PFS) Time: Up to 24 monthsDescription: DOR is defined as the time from the subject's initial CR or PR to the time of disease progression.
Measure: Duration of overall response (DOR) Time: Up to 24 monthsThis study will treat patients with advanced NSCLC who have already received at least one course of specific anti-cancer treatment but the tumour has started to re-grow following that treatment. This is the first time this drug has ever been tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment, it will measure the levels of drug in the body, it will also measure the anti-cancer activity. By using these pieces of information together the best dose of this drug to use in further clinical trials will be selected.
- Patients (with the exception of 1st line expansion cohort) must fulfil one of the following: - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR - Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI. - Previous treatment with a single-agent EGFR TKI (e.g. --- L858R --- --- L861Q ---
Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by investigator assessment) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
Measure: Objective Response Rate (ORR) for Dose Expansion Population Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.
Measure: Best Objective Response (BOR) for Dose Escalation Population Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 25 months (at time of analysis)Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by independent central review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
Measure: Objective Response Rate (ORR) for Extension Population Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).
Measure: Duration of Response (DoR) for Dose Expansion Population Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent central review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
Measure: Progression-Free Survival (PFS) for Dose Expansion Population Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.
Measure: Best Objective Response (BOR) for 80mg AZD9291 Extension Population Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of SH-1028 with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene.
- Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR-TKI sensitivity (including exon 19 deletion, L858R, L861Q, G719X or dual mutation) for treatment-naive NSCLC patients (without systemic therapy or with relapse after previous surgery; patients with locally treatment for non-target lesions are accepted ).(This criteria applies to treatment-naïve NSCLC patients in Part B). - Patients must have confirmation of T790M+ mutation status, which have experienced disease progression while on a previous continuous treatment with an EGFR-TKI or clinical benefit from EGFR-TKI according to the Jackman criteria while on continuous treatment with an EGFR-TKI (PR/CR, or SD continued ≥6 months); Patients can receive more than one line of systemic therapy. --- L858R --- --- L861Q ---
Description: optional，use NGS to analyse the gene associated with NSCLC and to determine the reason of SH-1028-resistance.
Measure: Biomakers (eg. AF value of KRAS，MET mutation or other gene mutations ) of drug-resistance measured by next-generation sequencing (NGS). Time: at end of treatment，an average of 1 years.This is an open-label phase 1, safety, PK, and preliminary efficacy study of oral Gefitinib and IV Tremelimumab in previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as Erlotinib or Gefitinib. The primary objective of this phase I, is to determine the safety and tolerability of oral Gefitinib in combination with escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Secondary objectives include evaluation of, pharmacokinetics, immunogenicity, antitumor activity of Gefitinib and Tremelimumab combination. The exploratory objectives are to evaluate biomarkers that may correlate with activity or prospectively identify patients likely to respond to Tremelimumab and Gefitinib. The biological rationale for such a study is that even though the disease is progressing it is likely that EGFR sensitive clones, although diminished under the pressure from the EGFR TKI, are still present. Therefore, withdrawing the inhibitory pressure of the EGFR TKI can potentially allow regrowth of the EGFR sensitive cells. On the other hand, the proliferation of EGFR resistant clones needs to be suppressed by another therapeutic approach. Until today no association of chemotherapy and TKI EGFR has demonstrated clinical benefit. Moreover, patients may have received chemotherapy and the likelihood of chemosensitivity is very low. So, the association of Gefitinib with immune checkpoint blockade is very attractive and may result in clinical benefit in NSCLC with EGFRmut.
Inclusion Criteria: 1. Provision of written informed consent ; 2. Female or male patients aged 18 years or over at the time of consent ; 3. World Health Organisation (WHO) Performance Status 0 to 1 (Appendix C) ; 4. Cytologically or histologically confirmed NSCLC with an activating EGFR TK mutations known to be associated with EGFR TKI sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) as determined locally using a well-validated and robust methodology ; 5. Prior objective clinical benefit defined by either partial, complete or SD (>/= 4months) after initiation of EGFR TKI treatment ; 6. Patients could have received first line chemotherapy or chemotherapy between the EGFR TKI and inclusion in the study but must present a systemic objective progression ; 7. A washout period is not required for patients who are being treated with Gefitinib at the time of study entry. --- L858R --- --- L861Q ---
- Previous allogenic bone marrow transplant Inclusion Criteria: 1. Provision of written informed consent ; 2. Female or male patients aged 18 years or over at the time of consent ; 3. World Health Organisation (WHO) Performance Status 0 to 1 (Appendix C) ; 4. Cytologically or histologically confirmed NSCLC with an activating EGFR TK mutations known to be associated with EGFR TKI sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) as determined locally using a well-validated and robust methodology ; 5. Prior objective clinical benefit defined by either partial, complete or SD (>/= 4months) after initiation of EGFR TKI treatment ; 6. Patients could have received first line chemotherapy or chemotherapy between the EGFR TKI and inclusion in the study but must present a systemic objective progression ; 7. A washout period is not required for patients who are being treated with Gefitinib at the time of study entry. --- L858R --- --- L861Q ---
Description: The primary objective of this phase 1 study is to determine the safety and tolerability of oral Gefitinib in combination with three escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Overall safety profile will be characterized by type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCICTCAE] Version 4.03), timing of adverse events and laboratory abnormalities in the first and in the following cycles
Measure: safety and tolerability of the association between Gefitinib (fixed dose) and Tremelimumab (dose escalation) Time: Up to 42 daysDescription: To obtain a preliminary assessment of the anti-tumour activity of Gefitinib + Tremelimumab by evaluation of tumour response using modified Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and evaluation of Disease control rate and PFS
Measure: Anti-tumour activity of Gefitinib + Tremelimumab Time: From day 1 cycle 1 every 8 weeks for 24 weeks and then every 6 weeks until progression or death whichever comes first assessed up to 30 monthsDescription: Immunogenicity results will be analyzed descriptively by summarizing the number and percentage of subjects who develop detectable anti-Tremelimumab antibodies. The immunogenicity titer will be reported for samples confirmed positive for the presence of anti-Tremelimumab antibodies.
Measure: Immunogenicity of Tremelimumab in combination with Gefitinib Time: At day 1 cycle 1 and then every 8 weeks from day 1 cycle 2 until progression or death whichever comes first assessed up to 30 monthsDescription: Gefitinib pharmacokinetic parameters comprise the area under the curve from time t0 to t (AUC0-t), AUC from time t0 to the infini (AUC0-∞) and maximal concentration (Cmax)
Measure: Pharmacokinetics of Gefitinib Time: At first Tremelimumab administration and then every 4 weeks until progression or death whichever comes first assessed up to 30 monthsDescription: Tremelimumab pharmacokinetic parameters comprise the area under the curve from time t0 to t (AUC0-t), AUC from time t0 to the infini (AUC0-∞) and maximal concentration (Cmax)
Measure: Pharmacokinetics of Tremelimumab Time: Before and after injection of Tremelimumab at day 1 cycle 1 and at day 8 and day 15 of cycle 1 and then before and after injection at day 1 for every cycle (4 weeks) until progression or death whichever comes first assessed up to 30 monthsThe purpose of this study is to assess the safety and tolerability of ASP8273 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). This study will also determine the pharmacokinetics (PK) of ASP8273, evaluate the potential inhibition of CYP3A4 by ASP8273 and the antitumor activity of ASP8273 as well as determine the effect of food on the bioavailability of ASP8273.
Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.. Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q ---
Exclusion Criteria: - Any ongoing toxicity ≥ Grade 2 attributable to prior Non-Small-Cell Lung Cancer (NSCLC) treatment - Prior EGFR inhibitor within 6 days; received prior treatment with any other agent with antitumor activity chemotherapy, radiotherapy, or immunotherapy within 14 days; any investigational therapy within 28 days or 5 half-lives, whichever is shorter; blood transfusion or hemopoietic factor within 14 days; major surgery within 14 days; any strong CYP3A4 inhibitors within 7 days - Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) or Human Immunodeficiency Virus (HIV) - Symptomatic Central Nervous System (CNS) metastasis - Active infection requiring systemic therapy within 14 days - Severe or uncontrolled systemic diseases including uncontrolled hypertension - History of or active interstitial lung disease - Screening QTcF >450 msec or current medication known to prolong QT - ≥ Grade 2 cardiac arrhythmia or uncontrolled atrial fib of any grade; Class 3 or 4 New York Heart Association congestive heart failure; history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months - History of gastrointestinal ulcer or bleeding within 3 months; any digestive tract dysfunction - Concurrent corneal disorder or ophthalmologic condition making subject unsuitable - RP2D cohort subjects: contraindications to midazolam, any other midazolam within 7 days, or any medications or supplements known to be strong CYP3A inhibitors within 7 days or inducers within 12 days - Any other malignancy requiring treatment Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q ---
Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using NCI CTCAE v4.03.
Measure: Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs) Time: up to 18 monthsDescription: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Measure: Safety and tolerability as assessed by adverse events (AEs) Time: up to 18 monthsDescription: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation.
Measure: Safety and tolerability as assessed by laboratory tests Time: up to 18 monthsDescription: Vital signs to be measured includes blood pressure, pulse rate and temperature.
Measure: Safety and tolerability as assessed by vital signs Time: up to 18 monthsDescription: Maximum concentration (Cmax), the time after dosing when Cmax occurs (tmax), area under the concentration - time curve from time 0 up to the last quantifiable concentration (AUClast), area under the concentration - time curve from time 0 extrapolated to infinity (AUCinf), apparent terminal elimination half-life (t1/2), apparent oral systemic clearance (CL/F), Apparent volume of distribution (Vz/F)
Measure: Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F Time: Cycle 0: Dose Escalation Days 1-2, FE Days 1-6; Cycle 1: Dose Escalation/Response Expansion/RP2D/FE Days 1,8,15, RP2D Day 21, Exon 20 Days 8,15; Cycle 2 & 3: Dose Escalation/Response Expansion/RP2D Days 1,2, FE Day 1; Exon 20 days 1, 2 & Cycle 3Description: Defined as proportion of subjects whose best overall response is Complete Response (CR) or Partial Response (PR) among all analyzed subjects.
Measure: Best overall response rate Time: Up to 18 monthsDescription: Defined as the proportion of subjects whose best overall response is rated as CR, PR or Stable Disease (SD) among all analyzed subjects.
Measure: Disease control rate Time: Up to 18 monthsDescription: Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.
Measure: Progression free survival Time: Up to 18 monthsThis study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with gefitinib in the study population - For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population. In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles. The number of treatment cycles is not fixed in this study. Participants will continue study treatment for 36 months unless they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).
Inclusion Criteria: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 3. Has acquired resistance to EGFR tyrosine kinase inhibitor (TKI) according to the Jackman criteria (PMID: 19949011): 1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression [Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 4. Is currently receiving and able to interrupt gefitinib or discontinue erlotinib, afatinib, or osimertinib 5. Has been receiving gefitinib, erlotinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period; participants who have been receiving gefitinib must be taking gefitinib at a dose of 250 mg/day 6. Has radiological documentation of disease progression while receiving continuous treatment with gefitinib, erlotinib, afatinib, or osimertinib 7. Has at least one measurable lesion per RECIST version 1.1 8. --- L858R --- --- L861Q ---
Has history of pancreatitis within the past 6 months Inclusion Criteria: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 3. Has acquired resistance to EGFR tyrosine kinase inhibitor (TKI) according to the Jackman criteria (PMID: 19949011): 1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression [Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 4. Is currently receiving and able to interrupt gefitinib or discontinue erlotinib, afatinib, or osimertinib 5. Has been receiving gefitinib, erlotinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period; participants who have been receiving gefitinib must be taking gefitinib at a dose of 250 mg/day 6. Has radiological documentation of disease progression while receiving continuous treatment with gefitinib, erlotinib, afatinib, or osimertinib 7. Has at least one measurable lesion per RECIST version 1.1 8. --- L858R --- --- L861Q ---
Description: An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product
Measure: Number of participants with adverse events (AEs) Time: within 36 monthsDescription: Categories: DS-1205a, gefitinib
Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss) Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, gefitinib
Measure: Plasma concentration of DS-1205a versus time Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, gefitinib
Measure: Tmax Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, gefitinib
Measure: Ctrough Time: during the dose expansion period, within 36 monthsDescription: Categories: DS-1205a, gefitinib
Measure: AUCtau Time: during the dose expansion period, within 36 monthsDescription: Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.
Measure: Objective response rate (ORR), graded according to RECIST version 1.1 Time: within 36 monthsDescription: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression
Measure: Duration of response (DOR) Time: within 36 monthsDescription: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate
Measure: Disease control rate (DCR) Time: within 36 monthsDescription: PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD, or death due to any cause
Measure: Progression-free survival (PFS) Time: within 36 monthsThe purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a 2nd line monotherapy agent in lung adenocarcinoma patients with acquired resistance to prior EGFR tyrosine kinase inhibitors (TKIs).
Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarinoma 3. Patients who have 1 or more than 1 measurable or evaluable but unmeasurable lesions according to RECIST ver1.1 4. Patients who received prior 1st generation EGFR TKIs (gefitinib or erlotinib) monotherapy and meet the following criteria: 1. Patients with EGFR mutation (e.g., G719X, exon 19 deletion, L858R, L861Q, etc) known to be associated with sensitivity to TKIs 2. Patients who showed objective clinical benefit from treatment with an EGFR TKI as defined by either: - Patients who showed complete (CR) or partial response (PR), or - Patients who maintained stable disease (SD) status ≥ 6 months 3. Patients who showed progressive disease (PD, RECIST ver1.1) while on continuous treatment with gefitinib or erlotinib within the last 30 days (However, patients whose progressive disease is limited in the brain cannot participate in this trial.) --- L858R --- --- L861Q ---
Patients who cannot participate in this trial by investigator's judgment Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarinoma 3. Patients who have 1 or more than 1 measurable or evaluable but unmeasurable lesions according to RECIST ver1.1 4. Patients who received prior 1st generation EGFR TKIs (gefitinib or erlotinib) monotherapy and meet the following criteria: 1. Patients with EGFR mutation (e.g., G719X, exon 19 deletion, L858R, L861Q, etc) known to be associated with sensitivity to TKIs 2. Patients who showed objective clinical benefit from treatment with an EGFR TKI as defined by either: - Patients who showed complete (CR) or partial response (PR), or - Patients who maintained stable disease (SD) status ≥ 6 months 3. Patients who showed progressive disease (PD, RECIST ver1.1) while on continuous treatment with gefitinib or erlotinib within the last 30 days (However, patients whose progressive disease is limited in the brain cannot participate in this trial.) --- L858R --- --- L861Q ---
Description: The length of time during and after medication or treatment during which the disease being treated (usually cancer) does not get worse.
Measure: Progression free survival (PFS) Time: By 1 year after enrollment of the last subjectDescription: The proportion of Patients maintaining progress-free status at 16 weeks
Measure: PFS rate at 16 weeks Time: 16 weeksDescription: The proportion of patients with partial response or complete response at their best tumor treatment evaluation
Measure: Objective response rate (ORR) Time: By 1 year after enrollment of the last subjectDescription: The proportion of patients with CR, PR and/or stable disease (SD)
Measure: Disease control rate (DCR) Time: By 1 year after enrollment of the last subjectDescription: The study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a study drug. Certain patient demographic, pathophysiological, and therapeutical features, such as body weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter dose-concentration relationships.
Measure: Population pharmacokinetics (PK) of NOV120101 (Poziotinib) Time: By 3 months after enrollment of the last subjectDescription: Subgroup analysis, in the context of design and analysis of study drug, refers to looking for pattern in a subset of the subjects according to genotype
Measure: Subgroup analyses with the genetic information Time: by 1 year after enrollment of the last patientThe purpose of this study is to determine whether continuing erlotinib beyond disease progression in combination with chemotherapy is beneficial for NSCLC patients who have EGFR mutant disease or who have responded to EGFR TKI.
- Investigator confirmed progression according RECIST 1.1 during EGFR TKI treatment within 28 days of the randomization - Activating mutation (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) in the EGFR gene or have had at least partial response with EGFR TKI lasting ≥ 6 months - Performance status: WHO 0-2 - Measurable disease according to RECIST 1.1 - Patients must be able to comply with study treatments - Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study - Neutrophils ≥ 1'000/μl, Platelets ≥ 100'000/μl, Alanine amino transferase ≤ 2.5 × Upper limit of normal (ULN) (< 5 × ULN if liver metastases), Alkaline phosphatase ≤ 2.5 × ULN (< 5 × ULN if liver metastases), Serum bilirubin ≤ 1.5 × ULN, Serum Creatinine ≤ 1.5 × ULN. - Patient must be able to comply with the protocol Exclusion Criteria: - RECIST 1.1 defined disease progression for more than 28 days while on previous EGFR TKI treatment. --- G719A --- --- L858R --- --- L861Q ---
Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Measure: Safety and toxicity Time: An expected average of 52 weeks after last subject enrolled into our studyThis is a multicentre, open-label, uncontrolled, Phase Ib clinical study. Patients who give informed consent will be screened for the study, including genotyping of the tumour and baseline characteristics. Eligible patients will receive a single pre-treatment of low dose of intravenous cyclophosphamide 200 mg/m2 (Day -3). Patients will commence daily oral therapy with the EGFR TKI afatinib as soon as possible, preferably on the same day as low dose cyclophosphamide. Afatinib will be prescribed according to the Summary of Product Characteristics (SmPC) of the product, and will continue in nominal 21-day cycles for as long as clinically indicated. The first day of dosing with EGF-PTI will be designated Day 1. Immunisation with EGF-PTI will commence 3 days after low dose cyclophosphamide and commencement of EGFR TKI, and will be repeated on Day 14, Day 28, Day 43, and Day 92. After the 5 th vaccination, patients will be followed up every 6 weeks for basic safety data and every 3 months for complete efficacy data, safety data, and maintenance (reduced) doses of EGF-PTI. Patients will continue in the study until disease progression, death, safety concerns (in the opinion of the investigator), non-compliance with the protocol, the patient withdraws from the study, 1 year after randomisation of the last patient, or the study is stopped the sponsor, whichever occurs sooner
4. Centrally confirmed EGFR exon 19 deletion, exon 21 (L858R, L861Q) or exon 18 (G719X) mutation before treatment (concomitant T790M pre-treatment mutation is permitted). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. --- L858R --- --- L861Q ---
Description: Evaluate the safety and tolerability of epidermal growth factor receptor tyrosine kinase inhibitor plus EGF-PTI in newly diagnosed patients with advanced or metastatic non-squamous NSCLC with EGFR mutations who are not candidates for local curative treatment throughout the patient's participation in the study.
Measure: Frequency and severity of Adverse Events Time: 36 monthsDescription: Evaluate the anti-tumor activity of epidermal growth factor receptor tyrosine kinase inhibitor plus EGF-PTI in terms of clinical response. Every 3 months after the first dose of EGF-PTI and throughout the patient's participation in the study.
Measure: Clinical response efficacy assessments Time: 36 monthsPreclinical data in lung cancer cell lines showed that EGFR mutation can potentially be a positive predictor for sensitivity to BKM120. Furthermore, when the erlotinib-resistant model H1975 (LR858 and T790M mutation) was treated with BKM120, significant tumor control was observed (Novartis internal data). Therefore, combining BKM120 with erlotinib could potentially down-modulate PI3K-Akt activity resulting in a synergistic effect on cell growth inhibition and enhancing the response to erlotinib.
These include, but are not limited to mutations in L858R (Exon 21); Exon 19 deletion; G719S, G719A, G719C mutations (Exon 19);or L861Q (laboratory report required at enrollment). --- L858R --- --- G719S --- --- G719A --- --- G719C --- --- L861Q ---
Description: Percentage of patients who are alive and progression-free at 3 months (APF3) from first treatment.
Measure: Progression Free Survival at 3 Months Time: 3 monthsDescription: Defined as the time from first treatment until death from any cause.
Measure: Overall Survival Time: every 3 months after study treatment, projected 24 monthsDescription: Defined as the time from complete or partial response (CR or PR) until objective tumor progression. Tumor measurements will be obtained using CT scans of chest, abdomen and pelvis and assessed per RECIST v 1.1. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.
Measure: Duration of Response Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 monthsDescription: Defined as the percentage of complete and partial responses (CR + PR) among all patients. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.
Measure: Objective Response Rate Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 monthsDescription: Adverse events will be graded using CTCAE v4.3. and will be collected until 30 days after the discontinuation of study treatment for each participant. A non-serious adverse event is any untoward medical occurrence. A serious adverse event (SAE) is an event that meets one or more of the following: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; requires intervention to prevent permanent impairment or damage. Specific AE and SAE terms are provided in the Adverse event module.
Measure: Number of Participants With Serious and Non-serious Adverse Events as a Measure of Safety. Time: Every 2 weeks for 8 weeks, then every 8 weeks thereafter, estimated 24 monthsThis is an open-label, non-randomized, multicenter phase Ib/II study, which is composed of a phase Ib dose escalation part and a phase II dose expansion part. Patients will receive selumetinib in combination with gefitinib 250mg daily. This study will enroll EGFR-mutated NSCLC patients who have developed acquired resistance to EGFR TKI treatment.
A tumor harboring an EGFR mutation known to be associated with drug sensitivity (ie, exon 19 deletion , L858R, L861Q, G719X etc.). --- L858R --- --- L861Q ---
Description: Frequency and characteristics of DLTs to the selumetinib and gefitinib combination using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0. (an expected average of 18 weeks) If one patient experiences a DLT in a group of 3 or more evaluable patients, then the cohort will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete cohort of 6 evaluable patients, then dose escalation may occur.
Measure: To determine the MTD and/or RP2D Time: an expected average of 18 weeksDescription: to estimate overall clinical activity of selumetinib combined with gefitinib in EGFR-mutated NSCLC patients who have acquired resistance to EGFR TKIs
Measure: Overall Response Rate (ORR) Time: Patients will be followed up for 2 years(post disease progression)This is a 2-part study in patients with epidermal growth factor receptor mutation positive (EGFRm+) non-small cell lung cancer (NSCLC) whose disease has progressed on treatment with an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI): Part A will determine the effect of food on the pharmacokinetics (PK) of AZD9291; Part B will allow patients further access to AZD9291 and will provide for additional safety data collection. Part A is a randomised, open-label, 2 treatment period crossover study in which patients will each receive a single oral dose of AZD9291 (1 x 80 mg tablet) at breakfast time (approximately 0800) in each of 2 treatment periods (once immediately following a high fat meal [fed], and once in the fasted state [fasted]), with a washout period of 9 days between doses. Approximately 38 patients are planned to be enrolled and dosed; at least 30 evaluable patients will be required to complete Part A (ie, the last PK sample in Treatment Period 2 [TP 2] has been collected). Additional patients may be enrolled to allow for at least 30 evaluable patients.
5. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R --- --- L861Q ---
Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 72 hours.
Measure: AUC(0-72) of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration.
Measure: Cmax of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Area under the plasma concentration curve from zero extrapolated to infinity.
Measure: AUC of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Area under the plasma concentration curve from time zero to last quantifiable dose.
Measure: AUC(0-t) of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours.
Measure: AUC(0-120) of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZD9291 by assessment of time to Cmax.
Measure: Tmax of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZD9291 by assessment of the terminal half-life.
Measure: t1/2 of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration.
Measure: CL/F of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution.
Measure: Vz/F of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 72 hours.
Measure: AUC(0-72) of AZ5104 and AZ7550 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of maximum plasma concentration.
Measure: Cmax of AZ5104 and AZ7550 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Area under the plasma concentration curve from time zero to last quantifiable dose for AZ5104 and AZ7550 (metabolites to AZD9291).
Measure: AUC(0-t) of AZ5104 and AZ7550 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 120 hours.
Measure: AUC(0-120) of AZ5104 and AZ7550 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of time to Cmax.
Measure: Tmax of AZ5104 and AZ7550 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of the terminal half-life.
Measure: t1/2 of AZ5104 and AZ7550 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.The current first line treatment of patients with EGFR activating mutation lung cancer is EGFR TKI. Compared to platinum-based chemotherapy, EGFR-TKIs are superior in terms of response rate and progression-free survival. However, an acquired resistance occurs almost constantly. The second-line treatment includes platinum-based chemotherapy in the absence of contraindication. This chemotherapy is then administered after discontinuing EGFR TKIs. However, a rebound phenomenon of the disease was described in patients who discontinued EGFR TKIs. Some clinical teams therefore recommend, as a precaution, in order to avoid any withdrawal phenomenon, to never discontinue EGFR TKIs in patients developing an EGFR TKI acquired resistance. It seems therefore useful to conduct a study to better define the therapeutic strategy to adopt in patients developing an acquired resistance after having received EGFR TKIs as first line treatment.
- Presence of one of the EGFR activating mutations in the tumor (exon 19 deletion or L858R, G719X or L861Q) - One additional line of previous chemotherapy is allowed if administered in adjuvant or neoadjuvant setting and received more than six months before. --- L858R --- --- L861Q ---
Description: Efficacy will be assessed by the PFS, define as time between randomization of the patient in the study and disease progression (local, regional, distant and second cancer) or death (all causes). Alive patients free of progression will be censored at the last follow-up.
Measure: Efficacy by PFS Time: From date of randomization until the date of first documented progression evaluated every 6-9 weeksDescription: difference between the scores of QoL at baseline and at 4 months after inclusion for the three targeted dimensions of EORTC QLQ-C30 (global quality of life, fatigue and physical functioning). A difference or 10 points or more at 4 months after inclusion for one score between the 2 arms will be considered as clinically relevant.
Measure: scores of QoL Time: at 4 months after inclusionDescription: Overall survival defined as time interval between randomization and death (all causes). Alive patients will be censored at the last date of news or data cut off
Measure: Overall survival Time: From date of randomization until the date of death from any cause, whichever came first, assessed up to 100 monthsDescription: Tumoral response (complete response, partial response, stable disease, progression) according to RECIST 1.1
Measure: Tumoral response Time: every 6-9 weeksDescription: Toxicities according to NCI-CTC-AE v.4
Measure: Toxicities Time: From date of randomization until study participation, assessed up to 100 monthsDescription: Rebound phenomenon (flare) defined by a hospitalization or a death within 3 weeks for disease progression after the end of TKI EGFR treatment (in the arm without EGFR TKI) and date of onset
Measure: Rebound phenomenon (flare) Time: within 3 weeks after disease progression before inclusionTo compare clinical response (complete response and partial response) by RECIST) rates by RECIST between erlotinib monotherapy and docetaxel plus cisplatin chemotherapy
- Life expectancy > 12 weeks - Tumor specimen with EGFR gene mutation of exon 19 deletion and L858R, G719X, L861Q mutation - Adequate hematological function: ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, Hb ≥ 9 g/dL - Data of INR and PTT should be available in patients taking anticoagulants concomitantly, with INR ≤ 1.5 and PTT ≤ 1.5 times the upper limit of normal (x ULN ) within 7 days prior to starting study treatment - Adequate liver function: serum bilirubin ≤ 1.5 x ULN; transaminases ≤ 2.5 x ULN - Adequate renal function: 24-hour urine creatinine clearance or creatinine clearance measured and calculated according to the formula of Cockroft and Gault ≥ 60ml/min - Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women - Written informed consent. --- L858R --- --- L861Q ---
Those with exon 19 deletion and L858R, G719X, L861Q mutation were randomized as erlotinib monotherapy or docetaxel plus cisplatin chemotherapy. --- L858R --- --- L861Q ---
The primary objective is to assess the safety and tolerability of multiple doses of Simotinib Hydrochloride in NSCLC patients. The secondary objective is to determine the pharmacokinetic (PK) profile and explore the preliminary anti-tumor activity.
Inclusion Criteria: - Patients with histologically or cytologically confirmed diagnosis of advanced NSCLC, who were previously treated with at least one platinum-based chemotherapy regimen, but had disease relapse; - Patients have ended their chemotherapy or radiotherapy at least 4 weeks prior to study entry and have recovered from any previous toxicity; - EGFR mutation positive (such as E19del, L858R, L861Q, G719X, etc.); - Patients with at least one measurable lesion meeting RECIST; - ECOG performance status 0-2; - Life expectancy ≥12 weeks; - Adequate bone marrow function: ANC ≥1.5 × 109/L, PLT≥80 ×109/L, HB ≥90 g/L; - Adequate hepatic function: serum bilirubin ≤ 2 × ULN, AST and ALT ≤ 2.5 × ULN, and ≤ 5 × ULN are acceptable if the liver has tumor involvement; - Adequate renal function: endogenous creatinine clearance rate (CrCl) ≥ 60 mL/min or serum creatinine ≤ 1.5 × ULN; - Females with childbearing potential must have a negative pregnancy test within 7 days prior to treatment and use an approved contraceptive method during the study; - Males must be surgically sterile or use an approved contraceptive method during the study. --- L858R --- --- L861Q ---
This is a 2 part study in patients with EGFRm+ non small cell lung cancer (NSCLC), whose disease has progressed on an EGFRm TKI, who are refractory or resistant to standard therapy. Part A will assess the effect of multiple oral doses of itraconazole on the single dose pharmacokinetic (PK) parameters of AZD9291. On completion of Part A, patients may continue to take AZD9291 tablets (Part B) following the collection of the 216 hour sample on Day 19 if they and the Investigator deem it appropriate, until such time as their disease progresses, the Investigator believes they are no longer deriving clinical benefit, or they stop taking AZD9291 for any other reason.
4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. ECOG performance status 0-1 with no deterioration over the previous 2 weeks. --- L858R --- --- L861Q ---
Description: Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration
Measure: Cmax of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours
Measure: AUC(0-120) of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration curve from time zero to last quantifiable dose
Measure: AUC(0-t) of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZD9291 by assessment of time to Cmax
Measure: Tmax of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZD9291 by assessment of the terminal half-life
Measure: t1/2 of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration
Measure: CL/F of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution
Measure: Vz/F of AZD9291 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of maximum plasma AZ5104 concentration
Measure: Cmax of AZ5104 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of AZ5104 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of maximum plasma AZ7550 concentration
Measure: Cmax of AZ7550 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.Description: Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity
Measure: AUC of AZ7550 Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.The primary purpose of this study is to compare the efficacy of the study drug LY2875358, given together with erlotinib, against erlotinib, alone. Participants will have Non-Small Cell Lung Cancer (NSCLC) that has advanced to Stage IV. Participants should not have been treated with drugs for Stage IV NSCLC, previously. All participants will get erlotinib alone, for approximately 8 weeks. Participants with radiographic disease control at the end of the erlotinib lead-in study period will be randomly assigned to receive LY2875358 plus erlotinib or erlotinib alone. Participants, who were chosen to receive erlotinib, alone, may cross over to the combination treatment at the time of progression.
Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q ---
Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q --- --- L858R --- --- L861Q ---
This is a Phase 1, open-label study of SH-1028 with dose escalation and dose expansion cohorts in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients who have progressed following prior therapy with an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor (TKI) agent.
5. Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria while on continuous treatment with an EGFR TKI(PR/CR, or SD continued ≥6 months). --- L858R --- --- L861Q ---
This is a Phase 1/2, open-label, multicenter study of HS-10296 with dose escalation, dose expansion and extension cohorts in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients who have progressed following prior therapy with an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor (TKI) agent. The study is designed to evaluate safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of once-daily and orally (PO) administered HS-10296. The overall study design is shown in the flow chart below, which consists of 3 phases: dose escalation, dose expansion and extension cohort.
5. Patients must fulfill one of the following: - Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (followed by systemic objective progression (RECIST or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI. 6. --- L858R --- --- L861Q ---
third generation of EGFR-TKIs is the newest target therapy for NSCLC. However, we did not known the specific mechanisms for those non-responders and patients grow resistance.Next generation sequencing is current the most sensitive and specific method to exam gene mutation, diversion etc. By consistently detect the cf-DNA, we could possibly find out the mechanisms of response and resistance.
- harboured with positive EGFR mutation (19 exon deletion, L858R, G719X, L861Q mutation) - reliable patients history data. --- L858R --- --- L861Q ---
Description: Using next generation sequencing (NGS) method to detect circulating free DNA (cf-DNA) in patients receive third generation EGFR-TKI, periphereal blood sample were collected at baseline and every 2 months to disease progression.
Measure: cf-DNA change from baseline Time: baseline and every 2 months up to 36 months or first documented progression disease.This study is conducted to assess the safety, tolerability and preliminary efficacy of AST2818 in patients with advanced Non Small Cell Lung Cancer (NSCLC).
- Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Documented evidence of definitely EGFR T790M+ state in the tumor tissue after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). --- L858R --- --- L861Q ---
Description: Evaluation of objective response rate assessed by RECIST 1.1
Measure: Objective response rate of Alflutinib Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.Description: Duration of response assessed by RECIST 1.1
Measure: Duration of response of Alflutinib Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival
Measure: Progression free survival of Alflutinib Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.Description: Clinical benefit rate was calculated by adding up complete remission, partial remission and stabilization of disease assessed by RECIST 1.1
Measure: Clinical benefit rate of Alflutinib Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate disease control rate
Measure: Disease control rate of Alflutinib Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03
Measure: Incidence and Severity of Treatment-Emergent Adverse Events Time: Adverse events will be collected from baseline until 28 days after the last doseDescription: Cmax of Alflutinib and 2 metabolites at steady state following multiple doses
Measure: Steady state Maximum Plasma Concentration [Cmax] of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: tmax of Alflutinib and 2 metabolites at steady state following multiple doses.
Measure: Steady state peak plasma time [tmax] of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Cmin of Alflutinib and 2 metabolites at steady state following multiple doses.
Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: AUC of Alflutinib and 2 metabolites at steady state following multiple doses.
Measure: Steady state area under the plasma concentration versus time curve [AUC] of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Clearance of Alflutinib and 2 metabolites at steady state following multiple doses.
Measure: Steady state clearance of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)Description: Accumulation ratio of Alflutinib and 2 metabolites following multiple doses.
Measure: Accumulation ratio of multiple doses Alflutinib and 2 metabolites Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)In this trial, treatment efficacy and safety of retreatment with 1st generation epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI)s(Gefitinib/Erlotinib), will be assessed in patients with sensitizing EGFR mutation positive Non-Squamous Cell Carcinoma patients who previously treated with EGFR TKI and cytotoxic chemotherapy
Inclusion Criteria: 1. Males or females ≥ 19 years of age 2. Non Small Cell Lung Cancer(Non-Squamous Cell Carcinoma) patients who had shown clinical benefits (Complete response(CR) or Partial response(PR) or Stable disease(SD) ≥6 months) from EGFR-TKIs as first line treatment and developed progressive disease, and then received cytotoxic chemotherapy more than 4 cycles and developed progressive disease, and then confirmed T790 negative and sensitizing EGFR mutation(E19Del, L858R, L861Q, G719X, E19insertion) positive in Histologic, cytologic specimen or blood. --- L858R --- --- L861Q ---
Patients who are difficult to include in this study in accordance with the investigator's judgment due to severe adverse effects during previous EGFR TKI treatment Inclusion Criteria: 1. Males or females ≥ 19 years of age 2. Non Small Cell Lung Cancer(Non-Squamous Cell Carcinoma) patients who had shown clinical benefits (Complete response(CR) or Partial response(PR) or Stable disease(SD) ≥6 months) from EGFR-TKIs as first line treatment and developed progressive disease, and then received cytotoxic chemotherapy more than 4 cycles and developed progressive disease, and then confirmed T790 negative and sensitizing EGFR mutation(E19Del, L858R, L861Q, G719X, E19insertion) positive in Histologic, cytologic specimen or blood. --- L858R --- --- L861Q ---
Description: Assessed on based of RECIST 1.1.
Measure: Objective Response Rate(ORR) including rage of CR&PR Time: Through study completion (4 years)Description: Progression-free survival (PFS) the time from first dose of the study drug until the date of disease progression or death by any cause
Measure: Progression Free Survival, PFS Time: Through study completion (4 years)Description: Overall Survival (OR) the time from first dose of the study drug until the date of death by any cause
Measure: Overall Survival Time: Through study completion (4 years)Description: Assessment on the base of NCI-CTCAE (version 4.03)
Measure: The incidence of Adverse Events(including Serious Adverse Events and Adverse Drug Reactions) Time: Through study completion (4 years)Lung cancer has the highest incidence rate in China and is also a very common cancer in the world. BPI-7711 is a new drug developed for patients with non-small cell lung cancer. The purpose of this study is to evaluate the safety, efficacy and PK profile of BPI-7711. The first part of the study will recruit 3~6 patients for different dose levels to evaluate safety. The dose will increase from the lowest level. The second part of the study is the dose expansion. Once efficacy is observed in the dose increasing process, additional 20~30 patients will be enrolled to further evaluate the anti-tumor efficacy. A recommended dose will be selected for Phase II study.
- Prior to enrollment, a central laboratory testing report confirmed the tumor has EGFR positive gene mutation sensitive to EGFR-TKI treatment (including G719X, exon 19 loss, L858R, L861Q etc.). --- L858R --- --- L861Q ---
Description: DLT to be evaluated according to NCI CTCAE V4.03
Measure: Number of patients with dose limiting toxicity ( DLT). Time: From first dosing ( Day -7) to the last dosing of Cycle 1 ( Day 28).Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.
Measure: Maximum plasma concentration (Cmax) of BPI-7711 and its main metabolites. Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.
Measure: Peak Plasma Time (tmax) of BPI-7711 and its main metabolites after single dose. Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.
Measure: Area under the plasma concentration versus time curve (AUC) of BPI-7711 and its main metabolites after single dose. Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.
Measure: Clearance of BPI-7711 and its main metabolites after single dose. Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.
Measure: Half life of BPI-7711 and its main metabolites after single dose. Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Cycle 1 Day1, Cycle Day 8, Cycle 1 Day 15 and Cycle 2 Day1 at designated time. points.
Measure: Blood concentration of BPI-7711 and its main metabolites after single dose under steady state. Time: Pre-dose of Cycle1 Day1, 8, 15. Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h post dose on Cycle 2 Day1Description: Objective response rate evaluated by CT, MRI examination results according to RECIST 1.1.
Measure: Objective response rate (ORR) of BPI-7711 capsule. Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.Description: Best objective response evaluated by CT, MRI examination results according to RECIST 1.1.
Measure: Best objective response (BOR) of BPI-7711 capsule. Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.Description: Disease control rate evaluated by CT, MRI examination results according to RECIST 1.1.
Measure: Disease control rate ( DCR) of BPI-7711 capsule. Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.Description: Duration of response evaluated by CT, MRI examination results according to RECIST 1.1.
Measure: Duration of response ( DoR) of BPI-7711 capsule. Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.Description: Progression free survival evaluated by CT, MRI examination results according to RECIST 1.1.
Measure: Progression free survival (PFS) of BPI-7711 capsule. Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.Description: To test EGFR mutation in plasma circulating tumor DNA (ctDNA).
Measure: EGFR mutation testing. Time: At screening and every two cycles( 21 days as a cycle) from Cycle 1 Day1 until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.Description: To test T790M mutation in plasma circulating tumor DNA (ctDNA).
Measure: T790M mutation testing. Time: At screening and every two cycles( 21 days as a cycle) from Cycle 1 Day1 until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.Until recently, the first line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) was a platine-based chemotherapy. It has been changed by the discovery of EGFR (Epidermal Growth Factor Receptor) mutations and associated treatment with Tyrosine Kinase Inhibitor (TKI) of EGFR. The superiority of EGFR TKI over chemotherapy for EGFR mutated patients has been proved in several phase III trials with gefitinib, erlotinib or afatinib. Nevertheless, all patients will progress after 9 to 12 months of treatment due to the appearance of a treatment resistance. Afatinib is an irreversible EGFR TKI. It binds to its receptor permanently.Contrary to erlotinib and gefitinb which inhibits only EGFR, afatinib inhibits the kinase activity of all HER family (Human Epidermal growth factor Receptor). Nevertheless, there is no proof that afatinib delay the appearance of resistance. Cetuximab is a monoclonal antibody which binds specifically with EGFR. The double inhibition of EGFR by afatinib and cetuximab has demonstrated its efficacy in pre-clinical models. The hypothesis of this study is that the combination between cetuximab and afatinib will permit to delay or decrease the appearance of resistances.
Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q ---
Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q --- --- S768I --- --- T790M --- --- L858R --- --- L861Q ---
The purpose of this phase 1/2 study is to evaluate the safety, recommended phase 2 dose (RP2D), dose limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics of oral TAK-788, anti-tumor activity of TAK-788 in participants with NSCLC with epidermal growth factor receptor (EGFR) or human epidermal growth factor 2 (HER2), and anti-tumor activity of TAK-788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations, and to explore relationship between tumor and/or plasma biomarkers, and TAK-788 efficacy, safety, and/or cytochrome P450 3A (CYP3A) induction. The study will also determine the efficacy of TAK-788 in participants with locally advanced metastatic NSCLC harboring EGFR in-frame exon 20 insertion mutations who have received at least 1 prior line of therapy for locally advanced or metastatic NSCLC.
Part 2: Expansion Cohort 4 Specific Inclusion Criteria: 1. Have one of the following documented by a local test: an activating mutation in EGFR including exon 19 deletions or exon 21 L858R substitution (with or without T790M), or an uncommon activating mutation other than exon 20 insertion including, but not limited to, G719X (where X is any other amino acid), S768I, L861Q, or L861R. --- L858R --- --- T790M --- --- S768I --- --- L861Q ---
A Phase III, Open-Label, Randomized Multicenter Study to Compare AC0010 and Pemetrexed/Cisplatin in Patients With Advanced NSCLC Who Have Progressed Following Prior EGFR TKI.
6. Confirmation of tumor EGFR sensitive mutation positive in previous tumor samples, including G719X, exon 19 deletion, L858R, L861Q. --- L858R --- --- L861Q ---
Description: To assess the Progression-Free Survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure: Progression-Free Survival (PFS) Time: From the date of randomization until the date of first documented progression or the date of death from any cause, whichever came first, assessed up to 24 months.Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure: Objective Response Rate (ORR) Time: Baseline up to 28 days after completion of study drug, assessed up to 24 months.Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure: Duration of Response (DoR) Time: From occurring of CR or PR until progression or the date of death from any cause, whichever came first, assessed up to 24 months.Description: To assess the Disease Control Rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure: Disease Control Rate (DCR) Time: From the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.Description: To assess the Overall Survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure: Overall Survival (OS) Time: From the date of randomization to death or end of study, which is assessed up to 36 months.Description: To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).
Measure: Patient Reported Outcomes by EORTC QLQ-C30 Questionnaire Time: Baseline up to 28 days after completion of study drug, assessed up to 24 months.Description: Clinical chemistry, hematology, urinalysis, vital signs, physical examination, weight, ECG and ECOG Performance status and adverse event will be used to assess safety endpoints.
Measure: Incidence of toxicity, grading with CTCAE 4.03 Time: From the date of randomization until end of treatment,which is assessed up to 24 monthsIn this trial, anti-tumor efficacy of TAGRISSO in NSCLC patients in whom T790 mutations are detected by liquid biopsy.
AE/SAE assessement on the base of NCI-CTCAE (version 4.03).. Inclusion Criteria: 1. Age ≥ 20, and patients who understand information about the trial and voluntarily agree to participate in the trial 2. Histological or cytological confirmation diagnosis of NSCLC and inoperable stage IIIB or IV at the time of study enrolment 3. Patients with EGFR sensitizing mutation (E19Del, L858R, L861Q, G719X) positive, who had shown clinical benefits (responders (CR or PR) and SD ≥6 months) from EGFR-TKIs and had developed progressive disease following those therapy - Patients who have histories of previous exposure to EGFR-TKIs or other systemic chemotherapies are permitted (regardless of the order of treatment) - Treated with at least one of KGFR-TKIs (regardless of treatment with or without systemic chemotherapies) - In case the patient previously received any of the treatments including systemic chemotherapy, radiation therapy, surgery, and hormonal therapy, there should be at least 2 weeks of time interval between the last day of the previous treatment and the start of TAGRISSO™, and the remaining toxicity should be ≤ CTCAE grade 1 at the time of starting study treatment (except alopecia and grade 2, prior platinum-therapy related neuropathy) 4. ECOG performance status 0-2 5. Patients in whom T790 mutations are detected in at least one of the samples including tumor tissues, BALF (cell-free DNA), plasma (cell-free DNA), and pleural effusion (cell-free DNA) 6. --- L858R --- --- L861Q ---
Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to study entry Inclusion Criteria: 1. Age ≥ 20, and patients who understand information about the trial and voluntarily agree to participate in the trial 2. Histological or cytological confirmation diagnosis of NSCLC and inoperable stage IIIB or IV at the time of study enrolment 3. Patients with EGFR sensitizing mutation (E19Del, L858R, L861Q, G719X) positive, who had shown clinical benefits (responders (CR or PR) and SD ≥6 months) from EGFR-TKIs and had developed progressive disease following those therapy - Patients who have histories of previous exposure to EGFR-TKIs or other systemic chemotherapies are permitted (regardless of the order of treatment) - Treated with at least one of KGFR-TKIs (regardless of treatment with or without systemic chemotherapies) - In case the patient previously received any of the treatments including systemic chemotherapy, radiation therapy, surgery, and hormonal therapy, there should be at least 2 weeks of time interval between the last day of the previous treatment and the start of TAGRISSO™, and the remaining toxicity should be ≤ CTCAE grade 1 at the time of starting study treatment (except alopecia and grade 2, prior platinum-therapy related neuropathy) 4. ECOG performance status 0-2 5. Patients in whom T790 mutations are detected in at least one of the samples including tumor tissues, BALF (cell-free DNA), plasma (cell-free DNA), and pleural effusion (cell-free DNA) 6. --- L858R --- --- L861Q ---
Description: Objective response rate (ORR) including rate of CR and PR on based of RECIST 1.1
Measure: ORR Time: through study completion (43 months)Description: Disease control rate (DCR) including rate of CR, PR and SD on based of RECIST 1.1
Measure: DCR Time: through study completion (43 months)Description: Progression-free survival (PFS) the time from first dose of the study drug until the date of disease progression or death by any cause.
Measure: PFS Time: through study completion (43 months)Description: AE/SAE assessement on the base of NCI-CTCAE (version 4.03).
Measure: The frequency of occurrence of grade 3 or higher AE/SAEs Time: through study completion (43 months)This phase I trial studies the side effects and best dose of necitumumab when given together with osimertinib in treating patients with EGFR-mutant non-small cell lung cancer that is stage IV or has come back (recurrent) and who have progressed on a previous EGFR tyrosine kinase inhibitor. Immunotherapy with monoclonal antibodies, such as necitumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving necitumumab with osimertinib may be a better treatment for EGFR-mutant non-small cell lung cancer.
Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 EGFR Exon 19 Deletion Mutation EGFR Exon 20 Insertion Mutation EGFR NP_005219.2:p.G719X EGFR NP_005219.2:p.L858R EGFR NP_005219.2:p.L861Q EGFR NP_005219.2:p.T790M EGFR T790M Mutation Negative Metastatic Lung Non-Small Cell Carcinoma Progressive Disease Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung Disease Progression PRIMARY OBJECTIVES: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q ---
Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 EGFR Exon 19 Deletion Mutation EGFR Exon 20 Insertion Mutation EGFR NP_005219.2:p.G719X EGFR NP_005219.2:p.L858R EGFR NP_005219.2:p.L861Q EGFR NP_005219.2:p.T790M EGFR T790M Mutation Negative Metastatic Lung Non-Small Cell Carcinoma Progressive Disease Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung Disease Progression PRIMARY OBJECTIVES: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q ---
Description: Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 5.0. The recommended phase II dose (RP2D) will be the MTD, pending review of other safety/tolerability considerations. The RP2D will be determined based upon the MTD in the dose escalation portion as well as other considerations such as toxicities at additional courses. After completing the 4 expansion cohorts, the dose level will be re-reviewed to confirm that the RP2D is in fact well tolerated.
Measure: Maximum tolerated dose (MTD) of necitumumab combined with osimertinib Time: 21 daysDescription: Will be graded according to NCI CTCAE version 5.0. Grade and attribution will be summarized by dose level, cycle, organ system and type.
Measure: Incidence of toxicity Time: Up to 1 yearDescription: Will be graded according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR will be calculated as the percent of patients in each of the expansion cohorts whose best confirmed response is complete response (CR) or partial response (PR). Point estimates and associated 90% confidence intervals will be calculated.
Measure: Objective response rate (ORR) in patients treated at the recommended phase II dose Time: Up to 1 yearDescription: Kaplan-Meier plots will be used to summarize the progression-free survival. Medians and associated 95% confidence intervals will be calculated.
Measure: Progression-free survival (PFS) Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 yearDescription: DCR will be the proportion of patients in each of the expansion cohorts whose best confirmed response is CR, PR, or stable disease. Point estimates and associated 90% confidence intervals will be calculated.
Measure: Disease control rate (DCR) with combination osimertinib and necitumumab Time: Up to 1 yearDescription: The PK analyses will be descriptive and will permit comparison of the plasma levels of osimertinib and its metabolites in the presence of necitumumab (in this trial) with levels in other studies where osimertinib is given alone or combined with other drugs. We will estimate mean PK parameters as well as the between-patient variability. Results will be listed and plotted, by dose as well as by objective response, qualitative patterns will be described, and means and standard deviations will be calculated for use in planning follow-up studies.
Measure: Pharmacokinetic (PK) parameters of osimertinib in combination with necitumumab Time: Prior to dosing on day 1 of course 2, 1, 2, 4, 6, 8, and 24 hours after dosing in course 2 (dose escalation and cohort A); prior to treatment on day 1 of course 2 for up to 4 courses (cohorts B, C, and D)Description: Will study biopsied tumor tissue as well as serial plasma deoxyribonucleic acid specimens. For each cohort alone, Fisher's exact test, and in a stratified analysis including all cohorts, an exact logistic regression model, will be used to examine the association with objective response and a Cox proportional hazards model will be used to examine the association with PFS. Odds ratio's and hazard ratio's will be estimated and associated 90% two-sided confidence intervals will be constructed. Testing will be one-sided, at the 0.05-level.
Measure: Presence of biomarkers of response and resistance to previous EGFR-tyrosine kinase inhibitors Time: Up to 1 yearThe purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of HM61713 in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).
The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q ---
The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- L858R --- --- L861Q ---
Description: To assess the anti-tumor efficacy of HM61713 as measured by objective response rate (ORR).
Measure: Objective response rate (ORR) Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 monthsDescription: To assess clinical efficacy of HM61713 regarding disease control rate (DCR).
Measure: Disease control rate (DCR), defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1 Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 monthsDescription: To assess clinical efficacy of HM61713 regarding Duration of overall tumor response (DR).
Measure: Duration of overall tumor response (DR), defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 monthsDescription: To assess clinical efficacy of HM61713 regarding Progression-free survival (PFS).
Measure: Progression-free survival (PFS), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 monthsDescription: To assess clinical efficacy of HM61713 regarding Overall survival (OS).
Measure: Overall survival (OS), defined as the time from first administration of study drug until death from any cause Time: From first dose to end of study or date of death from any cause whichever came first, assessed up to 48 monthsDescription: To assess clinical efficacy of HM61713 regarding Time to progression (TTP).
Measure: Time to progression (TTP), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 monthsDescription: To assess clinical efficacy of HM61713 regarding tumor shrinkage.
Measure: Tumor shrinkage calculated as absolute change and percentage change from baseline in sum of tumor size at each assessment using RECIST tumor response Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 monthsDescription: To determine the pharmacokinetic (PK) profile of HM61713.
Measure: Peak concentration (Cmax) of HM61713 Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)Description: To determine the pharmacokinetic (PK) profile of HM61713.
Measure: Trough plasma concentration (Ctrough) of HM61713 Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)Description: To determine the pharmacokinetic (PK) profile of HM61713.
Measure: Area under the plasma concentration time curve over the 24-hour dosing interval (AUC) of HM61713 Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)Description: To assess patient reported outcomes (PROs) of health-related quality of life (HRQoL), disease/treatment-related symptoms of lung cancer, and general health status.
Measure: Patient reported outcomes (PROs) Time: At baseline and every 6 weeks from time of discontinuation, assessed up to 24 monthsDescription: To evaluate the effect of HM61713 on the QT interval.
Measure: ECG/QTc (absolute values and change from baseline) Time: Adverse events will be collected from baseline until 28 days after the last doseDescription: To assess the safety and tolerability of HM61713.
Measure: Incidence of reported AEs and abnormal laboratory tests (AEs will be assessed using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4). Time: Adverse events will be collected from baseline until 28 days after the last doseDescription: To assess the safety and tolerability of HM61713.
Measure: QTc interval as assessed by digital ECG with central reading. The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS. Time: Adverse events will be collected from baseline until 28 days after the last doseThis phase 1 clinical trial is intended to understand the safety and tolerability of a new anticancer drug in subjects with advanced solid tumors. The patients who qualify for the study will receive a once daily dose of the drug taken by mouth and will undergo several tests to measure the drug in the blood and to understand the safety, tolerability and any effect of the drug on the tumor. The antitumor effect of the drug is not known in human.
- Either of the following: A tumor that harbors an EGFR mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) -OR- Prior objective clinical benefit from EGFR-TKI, as evidenced by complete response (CR), partial response (PR), or stable disease (SD) ≥6 months as defined by RECIST or World Health Organization criteria. --- L858R --- --- L861Q ---
Description: Objective response rate = the sum of complete response [CR] and partial response [PR] rates
Measure: Objective response rate Time: Baseline to not more than 6 monthsDescription: Tumor response will be evaluated every 2 cycles using Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, if measurable tumors are available. Computed tomography (CT) and/or magnetic resonance imaging (MRI) should be used for tumor assessment unless another modality of disease assessment is necessary for the lesions.
Measure: Progression-free survival Time: Baseline to not more than 6 monthsDescription: The various pharmacokinetic parameters will be calculated from plasma concentrations of DS-2248 using non-compartmental analyses.
Measure: Study Part 1 - Determine the plasma pharmacokinetics of DS-2248 Time: Cycle 1 (Days 1, 2, 8, 15); Cycles 2, 3, (Days 1, 8, 15)Description: The various pharmacokinetic parameters will be calculated from plasma concentrations of DS-2248 using non-compartmental analyses.
Measure: Study Part 2 - Determine the plasma pharmacokinetics of DS-2248 Time: Day 1 for Cycle 3 and subsequent cyclesDescription: Disease control rate (DCR) = the sum of complete response rate, partial response rate, and stable disease (SD) rate for a minimum of 12 weeks
Measure: Disease control rate Time: Baseline to not more than 6 monthsThis study is: - A multicenter, prospective, randomized, phase 3 trial. - To prove non-inferiority of Taxotere/Cisplatin compared to Pemetrexed/Cisplatin as a front line treatment of patients with non-squamous cell lung cancer. - 276 patients will be recruited.
Platelet >=100,000/uL, neutrophil >=1,500 /uL Creatinine <=1.5 x upper normal limit or creatinine clearance >=60 mL/min Bilirubin <=1.5 x upper normal limit, Transaminases <=2 x upper normal limit Alkaline phosphatase <=2 x upper normal limit - Written informed consent Exclusion Criteria: - Pregnancy, Lactating woman - Woman in child bearing age who refuses to do pregnancy test - Moderate or greater than grade 1 motor or sensory neurotoxicity - Hypersensitivity to taxane - Comorbidity or poor medical conditions - Other malignancy (except cured basal cell carcinoma or uterine cervical carcinoma in situ) - Concurrent treatment with other investigational drugs within 30 days before randomization - Active treatment with other anticancer chemotherapy - EGFR mutation (exon 19 deletion, L858R, L861Q, G719A/C/S) Inclusion Criteria: - Age >= 18 years old - ECOG performance status 0-2 - Non-squamous cell type non-small cell lung cancer (NSCLC) - Stage IV, Stage IIIB cannot be treated with curative intent or Relapsed after surgery or radiation therapy - No prior chemotherapy except adjuvant chemotherapy and concurrent chemoradiation treatment. --- L858R --- --- L861Q ---
Platelet >=100,000/uL, neutrophil >=1,500 /uL Creatinine <=1.5 x upper normal limit or creatinine clearance >=60 mL/min Bilirubin <=1.5 x upper normal limit, Transaminases <=2 x upper normal limit Alkaline phosphatase <=2 x upper normal limit - Written informed consent Exclusion Criteria: - Pregnancy, Lactating woman - Woman in child bearing age who refuses to do pregnancy test - Moderate or greater than grade 1 motor or sensory neurotoxicity - Hypersensitivity to taxane - Comorbidity or poor medical conditions - Other malignancy (except cured basal cell carcinoma or uterine cervical carcinoma in situ) - Concurrent treatment with other investigational drugs within 30 days before randomization - Active treatment with other anticancer chemotherapy - EGFR mutation (exon 19 deletion, L858R, L861Q, G719A/C/S) Carcinoma, Non Small Cell Lung Carcinoma, Non-Small-Cell Lung Docetaxel is being used in 60mg/m2 3 weekly dosage in Japan and several east Asian institutions. --- L858R --- --- L861Q ---
Description: months after beginning of first cycle chemotherapy
Measure: Progression Free Survival Time: one yearDescription: months from the beginning of first cycle chemotherapy
Measure: Overall Survival (months from the beginning of first cycle chemotherapy) Time: three yearsDescription: Toxicity using CTCAE version 4.0
Measure: Safety Profile Time: four monthsDescription: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Measure: Response rate Time: 6-7th weekTo tested if the adding of consolidative SBRT to TKI in EGFR mutated patients with less than or equal to 5 metastatic sites (primary + 5) will improve progression free survival (PFS) compared to TKI alone.
To evaluate overall survival after SBRT followed by maintenance chemotherapy in comparison to maintenance chemotherapy alone.. Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R --- --- G719A --- --- L861Q ---
- Any medical co-morbidities that would preclude surgery or radiation therapy Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R --- --- G719A --- --- L861Q ---
Description: Evaluate the effect of TKI with or without SBRT on progression free survival
Measure: Progression free survival Time: 4 yearsDescription: To describe local control and out-of-field disease progression
Measure: local control Time: 4 yearsDescription: To evaluate overall survival after SBRT followed by maintenance chemotherapy in comparison to maintenance chemotherapy alone.
Measure: Overall survival Time: 4 yearsTreatment efficacy of osimertinib will be assessed in patients with lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations (cohort 1) and those harboring T790M (cohort 2) which were detected from circulating tumor DNA
5. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from circulating tumor DNA either by PANA mutyper® or Cobas® EGFR mutation test. --- L858R --- --- L861Q ---
6. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from tumor tissue or cytology specimen. --- L858R --- --- L861Q ---
5. Patients must fulfil one of the following: 5.1) Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) from tumor tissue or cytology or circulating tumor DNA 5.2) Must have experienced clinical benefit from prior EGFR-TKI, according to the Jackman criteria (Jackman 2010) followed by systemic objective progression (RECIST) while on continuous treatment with EGFR-TKI 6. T790M mutation detected from circulating tumor DNA either by PANA mutyper® or Cobas® EGFR mutation test. --- L858R --- --- L861Q ---
Description: RECIST v1.1
Measure: Response rate Time: 2 monthsDescription: Percentage of positive cases among cases tested with Mutyper or Cobas
Measure: Sensitivity of testing methods Time: 2 weeksTreatment efficacy of afatinib will be assessed in patients with lung cancer harboring EGFR mutations which were detected from circulating tumor DNA.
Inclusion Criteria: 1. Stage IIIB or IV lung cancer diagnosed radiologically with or without pathologic diagnosis 2. Age> 18 year-old 3. ECOG performance status 0~2. 4. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from circulating DNA 5. --- L858R --- --- L861Q ---
Description: Efficacy evaluation RECIST v1.1
Measure: Efficacy evaluation RECIST v1.1 Time: 2 monthsThis clinical research study is being carried out in two parts, Phase 1 and Phase 2. The primary purpose of the Phase 1 portion of the study is to observe the safety of the combination of rociletinib and MPDL3280A in EGFR-mutant NSCLC patients. The primary purpose of the Phase 2 portion of the study is to evaluate the safety and anti-tumor effects of the combination of rociletinib and MPDL3280A, at the best doses for the combination determined in Phase 1, in patients with EGFR-mutant NSCLC.
Given the limited sample size, no formal statistical analysis is planned.. Inclusion Criteria: - ECOG performance status of 0 or 1 - Adequate hematological and biological function, confirmed by defined laboratory values - Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion - Measurable disease as defined by RECIST v1.1 - Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment - For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). --- L858R --- --- L861Q ---
- For Phase 2 Group A, EGFR TKI treatment-naïve and chemotherapy-naïve Exclusion Criteria: - Unresolved toxicities from prior therapy - Symptomatic, untreated or unstable central nervous system or leptomeningeal metastases - Previous treatment with rociletinib or MPDL3280A, or other 3rd generation EGFR TKI (eg, AZD-9291, HM61713), or PD 1 axis targeted therapy (eg, anti PD 1 or anti-PD L1) - Prior treatment with CD137 agonists or other immune checkpoint blockade therapies, including anti-CTLA-4 therapeutic antibodies - Uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent drainage procedures - Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab (bisphosphonate use for prevention of skeletal events allowed) - Known hypersensitivity to any component of the MPDL3280A or rociletinib formulations or history or hypersensitivity to chimeric humanized antibodies or fusion proteins - History of autoimmune disease - History of prior allogeneic hematopoietic stem cell transplantation or prior solid organ transplantation - Treatment with systemic immunosuppressive medications within 2 weeks prior to first day of study treatment (inhaled corticosteroids and mineralocorticoids allowed) - Live attenuated vaccine within 4 weeks prior to first day of study treatment - Active tuberculosis, active hepatitis, or positive HIV status - Class II to IV heart failure as defined by the New York Heart Association functional classification system - Untreated or uncontrolled cardiovascular disease or other symptomatic cardiac dysfunction - QTCF > 450 ms, inability to measure QT interval on ECG, personal or family history of long QT syndrome, requirement for medications that have the potential to prolong the QT interval - History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan (history of radiation pneumonitis in radiation field may be allowed) - Other malignancies within 5 years prior to enrollment, with the exception of carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ Inclusion Criteria: - ECOG performance status of 0 or 1 - Adequate hematological and biological function, confirmed by defined laboratory values - Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion - Measurable disease as defined by RECIST v1.1 - Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment - For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). --- L858R --- --- L861Q ---
Description: The safety analyses will be performed using the safety population. Safety data analysis will be conducted on all patients receiving at least one dose of rociletinib or MPDL3280A.
Measure: Number of Treatment-emergent Adverse Events, as Assessed by NCI CTCAE v4.03 Time: Continuously, up to approximately 18.5 monthsDescription: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Measure: Maximum Concentration (Cmax) of Rociletinib and Its Metabolites Time: Treatment Day 1 and Day 15Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Tmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Measure: Time to Maximum Concentration (Tmax) for Rociletinib and Rociletinib Metabolites Time: Treatment Day 1 and Day 15Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Measure: Minimum Concentration (Cmin) of Rociletinib and Metabolites Time: Approximately every 6 weeks up to 24 monthsDescription: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. AUC0 24 will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Measure: Area Under the Curve (AUC) of Rociletinib and Rociletinib Metabolites Time: Treatment Day 1 and Day 8Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax, for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Measure: Maximum Concentration (Cmax) of MPDL3280A Time: Cycle 1 Day 1Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Measure: Minimum Concentration (Cmin) of MPDL3280A Time: Approximately every 6 weeks up to 24 monthsDescription: To determine the efficacy of the combination of rociletinib and MPDL3280A based on overall response rate per RECIST v1.1 in the following groups of patients: Group A: Patients with EGFRm advanced or metastatic NSCLC who have not previously received an EGFR TKI or chemotherapy. Group B: Patients with EGFRm advanced or metastatic NSCLC who have progressed on a prior EGFR TKI.
Measure: Objective Response Rate Per RECIST v1.1 in Phase 2 Time: Approximately every 6-9 weeksDescription: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).
Measure: Objective Response Rate Per Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 Time: Approximately every 6-9 weeks, up to 24 monthsDescription: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).
Measure: Duration of Response Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 Time: Approximately every 6-9 weeks, up to 24 monthsDescription: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).
Measure: Progression-free Survival Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 Time: Approximately every 6-9 weeks, up to 24 monthsDescription: Patients who received the combination of rociletinib and MPDL3280A alive at the termination of this study.
Measure: Number of Patients Alive at Study Termination Time: Up to approximately 18.5 monthsDescription: Tumor tissue, plasma, and blood specimens will be used for pharmacodynamic assessment of rociletinib and/or MPDL3280A activity, to evaluate the concordance of mutant EGFR detection between tissue and plasma, and to explore biomarkers that may be predictive of response or resistance to rociletinib and/or MPDL3280A. Biomarkers and changes in biomarker status will be investigated for associations with rociletinib and/or MPDL3280A exposure, safety, and clinical activity. Given the limited sample size, no formal statistical analysis is planned.
Measure: Longitudinal Changes in Blood Based Biomarkers (eg, Mutations in EGFR) in ctDNA Time: Blood samples will be collected from each patient approximately every 3 weeks, up to 24 monthsThe purpose of this study is to test whether the combination of bevacizumab and erlotinib can prolong progression free survival as compared with erlotinib alone as first-line treatment in patients with non small cell lung cancer (NSCLC) with activating mutation of EGFR.
Inclusion Criteria: 1. Age ≥18 years 2. Histological documentation of primary non squamous lung carcinoma 3. Stage IV or IIIB disease with supraclavicular metastatic nodes (according to TNM 7th edition) 4. Activating epidermal growth factor receptor mutation (exon19 deletion or exon 21 L858R mutation or other activating/sensitizing mutations, such as exon 21 L861Q, exon 18 G719S, G719A and G719C, exon 20 S768I and V769L). --- L858R --- --- L861Q ---
Description: as determined by investigator
Measure: progression free survival Time: up to 2 yearsDescription: as determined by an independent central review board blinded to study treatment
Measure: progression free survival Time: up to 2 yearsDescription: samples taken at baseline, 6 weeks, 6 months, and at progression
Measure: number and type of EGFR mutations in plasma samples Time: up to 2 years