There are 10 clinical trials
This randomized, multicenter, Phase III, open-label study will evaluate the efficacy and safety of alectinib versus crizotinib and to evaluate the pharmacokinetics of alectinib in asian participants with treatment-naive ALK-positive advanced NSCLC. Participants will be randomized 2:1 into one of the two treatment groups to receive either alectinib (600 milligrams [mg] twice daily [BID]) or crizotinib (250 mg BID) orally, respectively.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception Exclusion Criteria: - A malignancy within the previous 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact in progression-free survival (PFS) or overall survival (OS) for the current NSCLC) - Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection - Liver disease characterized by: - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than (>) 3× the upper limit of normal (ULN; >=5×ULN for participants with concurrent liver metastases) confirmed on two consecutive measurements; or - Impaired excretory function (e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices; or - Acute viral or active autoimmune, alcoholic, or other types of hepatitis - National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 Grade 3 or higher toxicities because of any previous therapy (e.g., radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Baseline QTc >470 ms or symptomatic bradycardia - Administration of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the receiving the first dose of study treatment and during treatment with alectinib or crizotinib - Administration of agents with potential QT interval prolonging effects within 14 days prior to receiving the first dose of study drug - History of hypersensitivity to any of the additives in the alectinib or crizotinib drug formulation - Pregnant or lactating - Known human immunodeficiency virus (HIV-positivity or acquired immunodeficiency syndrome (AIDS)-related illness - Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol requirements or follow-up procedures; those conditions should be discussed with the participant before study entry Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test. --- P4503A ---
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception Exclusion Criteria: - A malignancy within the previous 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact in progression-free survival (PFS) or overall survival (OS) for the current NSCLC) - Any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or status post-major bowel resection - Liver disease characterized by: - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than (>) 3× the upper limit of normal (ULN; >=5×ULN for participants with concurrent liver metastases) confirmed on two consecutive measurements; or - Impaired excretory function (e.g., hyperbilirubinemia), synthetic function, or other conditions of decompensated liver disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices; or - Acute viral or active autoimmune, alcoholic, or other types of hepatitis - National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 Grade 3 or higher toxicities because of any previous therapy (e.g., radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Baseline QTc >470 ms or symptomatic bradycardia - Administration of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the receiving the first dose of study treatment and during treatment with alectinib or crizotinib - Administration of agents with potential QT interval prolonging effects within 14 days prior to receiving the first dose of study drug - History of hypersensitivity to any of the additives in the alectinib or crizotinib drug formulation - Pregnant or lactating - Known human immunodeficiency virus (HIV-positivity or acquired immunodeficiency syndrome (AIDS)-related illness - Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol requirements or follow-up procedures; those conditions should be discussed with the participant before study entry Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer Lymphoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- P4503A ---
Description: PFS was defined as the time (in months) from randomization to the first documentation of disease progression, as determined by the investigators, or to death from any cause, whichever occurred first.
Measure: Progression-Free Survival (PFS) as Determined by Investigator Using Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 Time: From the date of randomization to the date of the first documented disease progression or death, whichever occurred first (up to overall period of approximately 40 months)Description: PFS was defined as the time (in months) from randomization to the first documentation of disease progression, as determined by an independent review committee, or to death from any cause, whichever occurred first.
Measure: PFS as Determined by Independent Review Committee (IRC) Using RECIST v1.1 Time: Baseline, Week 8, thereafter every 8 weeks until disease progression, death or withdrawal from the study and 4 weeks after permanent discontinuation (up to overall period of approximately 40 months)Description: An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Measure: Percentage of Participants With Non-serious Adverse Events and Serious Adverse Events Time: Up to overall period of approximately 40 monthsDescription: AUC was collected for both alectinib and its major metabolite, M4, and was based on their concentrations in plasma over time.
Measure: Area Under the Plasma Concentration-time Curve (AUC) of Alectinib and Its Metabolite Time: Baseline and Week 4 predose (within 2 hours before administration of study drug)Description: Cmax was collected for both alectinib and its major metabolite, M4, and was based on their concentrations in plasma over time.
Measure: Maximum Plasma Concentration Observed (Cmax) of Alectinib and Its Metabolite Time: Baseline and Week 4 predose (within 2 hours before administration of study drug)Description: Tmax was collected for both alectinib and its major metabolite, M4, and was based on their concentrations in plasma over time.
Measure: Time to Cmax (Tmax) of Alectinib and Its Metabolite Time: Baseline and Week 4 predose (within 2 hours before administration of study drug)The purpose of this study is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of TAK-659 and venetoclax when administered in combination in participants with non-Hodgkin lymphoma (NHL) relapsed and/or refractory after at least 1 prior line of therapy and to evaluate safety and tolerability of TAK-659 and venetoclax when administered in combination.
Use or consumption of: - Medications or supplements that are known to be strong or moderate Cytochrome P4503A (CYP3A) inhibitors or strong or moderate CYP3A inducers and/or P-glycoprotein (P-gp) inhibitors or inducers within 7 days or within 5 times the inhibitor or inducer half-life (whichever is longer) before the first dose of study drugs. --- P4503A ---
Description: Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE), Version 5.0 DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications and that occur within the first cycle.
Measure: Number of Participants with a Dose Limiting Toxicity (DLT) Time: Baseline up to 5 weeksDescription: AE Grades will be evaluated as per NCI CTCAE, version 5.0.
Measure: Percentage of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs), Grade 3 or Higher Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Discontinuation Time: Baseline up to 13 monthsDescription: ORR is calculated as percentage of participants with complete response (CR) + percentage of participants with partial response (PR) as assessed by International Working Group (IWG) criteria for malignant lymphoma.
Measure: Overall Response Rate (ORR) Time: Up to 12 monthsDescription: CR rate is calculated as percentage of participants with CR as assessed by IWG criteria for malignant lymphoma.
Measure: CR Rate Time: Up to 12 monthsDescription: TTP will be measured as the time in months from the first dose of study treatment to the date of the first documented disease progression as assessed using IWG criteria.
Measure: Time to Progression (TTP) Time: Up to 13 monthsDescription: PFS is defined as the time from date of first study drug administration to the day of first documented disease progression or death due to any cause, whichever occurs first.
Measure: Progression-free Survival (PFS) Time: Up to 18 monthsThe goal of this clinical research study is to learn if a combination of ibrutinib, rituximab, and lenalidomide can help control newly diagnosed mantle cell lymphoma (MCL) in patients over 65. The safety of this drug combination will also be studied.
Requires treatment with strong Cytochrome P4503A (CYP3A) inhibitors. --- P4503A ---
Description: Response assessed according to the International Workshop Standardization Response Criteria for Non-Hodgkin's Lymphoma (Cheson, 2014)
Measure: Overall Response Rate (ORR) at 4 Months of Ibrutinib Plus Rituximab and Lenalidomide in Elderly Patients With Newly Diagnosed Mantle Cell Lymphoma (MCL) Time: 4 monthsDescription: Adverse events assessed according to the Common Toxicity Criteria for Adverse Events version 4.03. (CTCAE v4.03)
Measure: Summary of Adverse Events of Ibrutinib Plus Rituximab and Lenalidomide in Elderly Patients With Newly Diagnosed Mantle Cell Lymphoma (MCL) Time: After 1 cycle, 28 daysThis phase II trial studies how well ibrutinib, rituximab, and consolidation chemotherapy consisting of cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine work in treating young patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving ibrutinib together with rituximab and consolidation chemotherapy may be a better treatment for mantle cell lymphoma.
Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.. Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 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) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 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) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Blastoid Variant Mantle Cell Lymphoma CD20 Positive Mantle Cell Lymphoma Pleomorphic Variant Mantle Cell Lymphoma Lymphoma Lymphoma, Mantle-Cell PRIMARY OBJECTIVES: I. To evaluate the response rate of ibrutinib plus rituximab in young newly diagnosed mantle cell lymphoma (MCL) including young high-risk patients. --- P4503A ---
Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.. Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 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) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Inclusion Criteria: - Patient has a confirmed diagnosis of mantle cell lymphoma with CD20 positivity in tissue biopsy - Patients with MCL must be symptomatic and need immediate therapy; symptoms and nature of MCL include any of the following: - Blastoid variant - Pleomorphic variant - B symptoms - Mantle Cell International Prognostic Score (MIPI) > 3 - Ki-67 >= 30% - Bulky tumors > 7 cm or in case of >= 2 tumors, each >= 5 cm in diameter - Disease threatening organ function - Elevated lactate dehydrogenase (LDH) - Peripheral blood white blood cell (PB WBC) > 50,000 - Pancytopenia due to bone marrow MCL - Patient's choice due to anxiety - Pain due to lymphoma - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patients with mantle cell lymphoma with any of the following will be considered "high-risk" for the purpose of this protocol: - Blastoid or pleomorphic histology - Ki-67 index larger than 30% - Bulky tumor of larger than 7 cm or in case of multiple tumors, larger than or equal to 5 cm each in diameter - Somatic mutations in the TP53, c-MYC or NOTCH genes - Size of spleen >= 20 cm - Patient has newly diagnosed disease with no prior therapy - Understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form - Patients should have bi-dimensional measurable disease using the Cheson criteria (measurable disease by computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in single dimension) - Gastrointestinal or bone marrow or spleen only patients are allowable - Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - An absolute neutrophil count (ANC) > 1,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their ANC is >= 500/mm^3 [growth factor allowed]; these patients should be discussed with either the principal investigator [PI] or Co-PI of the study for final approval) - Platelet count > 100,000/mm^3 (patients who have bone marrow infiltration by MCL are eligible if their platelet level is equal to or > than 20,000/mm^3; these patients should be discussed with either the PI or Co-PI of the study for final approval) - Serum bilirubin < 1.5 mg/dl - Creatinine (Cr) clearance >= 30 mL/min - Aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT)/serum glutamic-pyruvate transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present; Gilbert's disease is allowed - Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) - Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated - Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control; men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy - A female of childbearing potential is a sexually mature woman who: 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) Exclusion Criteria: - Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form - Pregnant or breast feeding females - Known human immunodeficiency virus (HIV) infection - Patients with active hepatitis B or C infection (not including patients with prior hepatitis B vaccination); these patients should be cleared by gastrointestinal (GI) consultation for hepatitis B and infectious disease consult for hepatitis C - All patients with central nervous system lymphoma - Significant neuropathy (grades 3 - 4, or grade 2 with pain) within 14 days prior to enrollment - Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma - Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib - Major surgery within 4 weeks of initiation of therapy; clearance letter from primary physician required - Requires anticoagulation with warfarin or equivalent vitamin K antagonist - Requires treatment with strong cytochrome P4503A (CYP3A) inhibitors - Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist - Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study Blastoid Variant Mantle Cell Lymphoma CD20 Positive Mantle Cell Lymphoma Pleomorphic Variant Mantle Cell Lymphoma Lymphoma Lymphoma, Mantle-Cell PRIMARY OBJECTIVES: I. To evaluate the response rate of ibrutinib plus rituximab in young newly diagnosed mantle cell lymphoma (MCL) including young high-risk patients. --- P4503A --- --- P4503A ---
Description: Will be monitored using the Bayesian stopping boundaries calculated based on beta-binomial distribution. Logistic regression will be utilized to assess the effect of patient prognostic factors on the response rate.
Measure: Overall response rate (complete response + partial response) Time: At 8 weeksDescription: Will be monitored using the Bayesian stopping boundaries calculated based on beta-binomial distribution. Logistic regression will be utilized to assess the effect of patient prognostic factors on the toxicity rate. Toxicity data by type and severity will be summarized by frequency tables.
Measure: Incidence of adverse events Time: At 4 weeksDescription: Will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.
Measure: Overall survival Time: Up to 6 yearsDescription: Will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.
Measure: Progression free survival Time: Up to 6 yearsThe primary purpose of this study is to determine the safety profile and the maximum tolerated doses (MTDs)/ potential recommended phase 2 doses (RP2Ds) of the combination treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 + cetuximab, and MLN2480 + irinotecan in participants with advanced nonhematologic malignancies.
Additional exclusion criteria for arm 5 only (MLN2480 + irinotecan): 1. Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the first dose of irinotecan. --- P4503A ---
Description: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. Serious adverse event (SAE) means any untoward medical occurrence that at any dose results in death, is life-threatening, requires inparticipant hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug will be determined by the Investigator.
Measure: Number of Participants With Adverse Events (AEs) Time: From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)Description: Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Measure: Cmax: Maximum Observed Plasma Concentration for MLN2480, MLN0128, Alisertib, Cetuximab, and Irinotecan Time: Cycle 1, Day 10 pre-dose and up to 48 hours post-doseDescription: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480, MLN0128, Alisertib, Cetuximab, and Irinotecan Time: Cycle 1, Day 10 pre-dose and up to 48 hours post-doseDescription: AUC(0-tau) is a measure of the area under the plasma concentration-time curve from time 0 to time tau over a dosing interval, where tau is the length of the dosing interval.
Measure: AUC(0-tau): Area under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for MLN2480, MLN0128, Alisertib, Cetuximab, and Irinotecan Time: Cycle 1, Day 10 pre-dose and up to 48 hours post-doseDescription: Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Measure: Cmax: Maximum Observed Plasma Concentration for Paclitaxel Time: Cycle 1, Day 15 pre-dose and up to 48 hours post-doseDescription: AUC(0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Measure: AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel Time: Cycle 1, Day 15 pre-dose and up to 48 hours post-doseDescription: Terminal Phase Elimination Half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Measure: Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for Paclitaxel Time: Cycle 1, Day 15 pre-dose and up to 48 hours post-doseDescription: ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Measure: Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Time: From 27 days, every other cycle, starting with Cycle 2 until disease progression, death or study closure (up to 13 months)Description: Time to response is defined as the time from the participant's date of enrollment to the date of the first documentation of a confirmed response.
Measure: Time to Response Time: From date of enrollment to the date of the first documentation of a confirmed response (up to 13 months)Description: Duration of response is defined as the time from the date of first documentation of a confirmed response to the date of first documented progression of disease.
Measure: Duration of Response Time: From first documented response until disease progression (up to 13 months)Description: PFS is defined as the time from the date of first study drug administration to the date of first documentation of disease progression or death.
Measure: Progression Free Survival (PFS) Time: Day 27 of every other 28-day cycle starting with Cycle 2 and 30 days after the last dose of study medication (up to 13 months)Description: AUC(0-tlast) is a measure of total plasma exposure to the drug from time 0 to time of the last quantifiable concentration.
Measure: AUC(0-tlast): Area under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel Time: Cycle 1, Day 15 pre-dose and up to 48 hours post-doseThe purpose of this study is to evaluate the safety and pharmacokinetics of enfortumab vedotin as well as assess the immunogenicity and antitumor activity in subjects with metastatic urothelial cancer and other malignant solid tumors that express Nectin-4.
- Any P-glycoprotein (P-gp) inducers/inhibitors or strong cytochrome P4503A (CYP3A) inhibitors within 14 days prior to the first dose of study drug - Thromboembolic events and/or bleeding disorders ≤ 14 days (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE)) prior to the first dose of study drug - Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of enfortumab vedotin. --- P4503A ---
Description: Incidence of tumor response defined as either a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) that is confirmed ≥ 28 days later
Measure: Tumor response Time: up to 24 monthsDescription: Defined as the percentage of subjects who experience a best response of either CR or PR in that cohort. CR and PR must be confirmed ≥ 28 days later.
Measure: Objective response rate Time: up to 24 monthsDescription: Defined as the percentage of subjects who experience a best response of CR, PR or stable disease (SD)
Measure: Disease control rate Time: up to 24 monthsDescription: Time from the date of first infusion to the earliest date of documented disease progression per radiological evidence or death from any cause
Measure: Progression Free Survival (PFS) Time: 36 monthsDescription: Time from the date of first infusion until the date of death from any cause.
Measure: Overall Survival Time: 36 monthsDescription: Time from the date of the first response complete response (CRC) or partial response (PR) to the earliest date of disease progression or death from any cause. DOR is only defined for subjects who have best overall response of CR or PR
Measure: Duration of Response Time: 36 monthsThis randomized, active controlled, multicenter phase III open-label study is designed to evaluate the efficacy and safety of alectinib compared with crizotinib treatment in participants with treatment-naive anaplastic lymphoma kinase-positive (ALK-positive) advanced non-small cell lung cancer (NSCLC). Participants will be randomized in a 1:1 ratio to receive either alectinib, 600 milligrams (mg) orally twice daily (BID), or crizotinib, 250 mg orally BID. Participants will receive treatment until disease progression, unacceptable toxicity, consent withdrawal or death. The study is expected to last approximately 42 months.
A higher score on the global health and functioning subscales is indicative of better functioning.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- P4503A ---
A higher score on the global health and functioning subscales is indicative of better functioning.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test - Life expectancy of at least 12 weeks - Eastern cooperative oncology group performance status (ECOG PS) of 0-2 - Participants with no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC - Adequate renal, and hematologic function - Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment - Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment - Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline) - Negative pregnancy test for all females of child bearing potential - Use of highly effective contraception as defined by the study protocol Exclusion Criteria: - Participants with a previous malignancy within the past 3 years - Any gastrointestinal (GI) disorder or liver disease - National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia) - History of organ transplant - Co-administration of anti-cancer therapies other than those administered in this study - Participants with baseline QTc greater than (>) 470 milliseconds or symptomatic bradycardia - Recipient of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment - Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only - History of hypersensitivity to any of the additives in the alectinib and crizotinib drug formulation - Pregnancy or lactation - Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the principal investigator, pose an unacceptable risk to the participant in this study - Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the participant before trial entry Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- P4503A --- --- P4503A ---
Description: PFS was assessed as time to disease progression or death whichever occurred first by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeter (mm) and the appearance of new lesions.
Measure: Progression-Free Survival (PFS) by Investigator Assessment Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)Description: PFS was assessed percentage of participants with disease progression or death whichever occurred first by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeter (mm) and the appearance of new lesions.
Measure: Percentage of Participants With PFS Event by Investigator Assessment Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)Description: PFS was assessed as time to disease progression or death whichever occurred first by IRC assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions.
Measure: PFS Independent Review Committee (IRC)-Assessed Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)Description: PFS was assessed as percentage of participants with disease progression or death whichever occurred first by IRC assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) Criteria. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions.
Measure: Percentage of Participants With PFS Event by IRC Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)Description: CNS progression was assessed as percentage of participants with an event defined as time from randomization until first radiographic evidence of CNS progression by IRC. The risk for a CNS progression without a prior non-CNS progression with alectinib compared with crizotinib.
Measure: Percentage of Participants With Central Nervous System (CNS) Progression as Determined by IRC Using RECIST V1.1 Criteria Time: Randomization to CNS PD as first occurrence of disease progression (assessed every 8 weeks up to 33 months)Description: CNS progression was assessed as percentage of participants with event defined as time from randomization until first radiographic evidence of CNS progression by IRC. The risk for a CNS progression without a prior non-CNS progression with alectinib compared with crizotinib.
Measure: Percentage of Participants With Central Nervous System (CNS) Progression as Determined by IRC Using Revised Assessment in Neuro Oncology (RANO) Criteria Time: Randomization to the first occurrence of disease progression in the CNS (assessed every 8 weeks up to 33 months)Description: ORR was defined as the percentage of participants who attained CR or PR. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Measure: Percentage of Participants With Objective Response Rate (ORR) of Complete Response (CR) or Partial Response (PR) as Determined by The Investigators According to RECIST V1.1 Criteria Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)Description: DOR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death, whichever occurred first. DOR was evaluated for participants who had a best overall response (BOR) of CR or PR.
Measure: Duration of Response (DOR) According to RECIST V1.1 Criteria as Assessed by the Investigators Time: First occurrence of objective response to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)Description: Overall survival (OS) was defined as the time from randomization to death from any cause.
Measure: Overall Survival (OS) Time: From randomization until death (up to 43 months)Description: Overall survival (OS) was defined as the time from randomization to death from any cause.
Measure: Percentage of Participants With OS Event Time: From randomization until death (up to 43 months)Description: CNS ORR was defined as the percentage of participants who attained CR or PR and had measurable/non-measurable CNS lesions at baseline. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Measure: Percentage of Participants With CNS ORR of CR or PR IRC-assessed According to RECIST v1.1 Criteria Time: Randomization to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)Description: CNS DOR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death, whichever occurred first. DOR was evaluated for participants who had a best overall response (BOR) of CR or PR.
Measure: CNS DOR IRC-assessed According to RECIST v1.1 Criteria Time: First occurrence of CNS objective response to first documented disease progression or death, whichever occurs first (assessed every 8 weeks up to 33 months)Description: An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Measure: Percentage of Participants With Adverse Events Time: Baseline up to 28 months in the crizotinib arm and up to 30 months in the alectinib armDescription: The EORTC QLQ-30 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in global health status or function is defined as a >or=10-point decrease from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point decrease from baseline followed by death within 5 weeks from the last assessment.
Measure: Time to Deterioration by European Organization for The Research And Treatment of Cancer (EORTC) Quality Of Life Questionnaire Core 30 (C30) Time: Baseline, every 4 weeks until disease progression (up to 33 months)Description: The EORTC QLQ-30 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in global health status or function is defined as a >or=10-point decrease from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point decrease from baseline followed by death within 5 weeks from the last assessment.
Measure: Percentage of Participants With Deterioration by EORTC Quality Of Life Questionnaire Core 30 (C30) Time: Baseline, every 4 weeks until disease progression (up to 33 months)Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in lung cancer symptoms is defined as a >or=10-point increase from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point increase above baseline followed by death within 5 weeks from the last assessment.
Measure: Time to Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13) Time: Baseline, every 4 weeks until disease progression (up to 33 months)Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning. Confirmed clinically meaningful deterioration in lung cancer symptoms is defined as a >or=10-point increase from baseline in a symptom score that must be held for at least two consecutive assessments or an initial >or=10-point increase above baseline followed by death within 5 weeks from the last assessment.
Measure: Percentage of Participants With Deterioration by EORTC Quality of Life Questionnaire Lung Cancer Module 13 (LC13) Time: Baseline, every 4 weeks until disease progression (up to 33 months)Description: The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
Measure: Health-Related Quality of Life (HRQoL) by EORTC Quality of Life Questionnaire C30 Score Time: Baseline, every 4 weeks until disease progression (up to 33 months)Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Coughing Time: Baseline, every 4 weeks until disease progression (up to 33 months)Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Dyspnoea Time: Baseline, every 4 weeks until disease progression (up to 33 months)Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Chest Time: Baseline, every 4 weeks until disease progression (up to 33 months)Description: The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
Measure: HRQoL by EORTC Quality of Life Questionnaire LC13 Score Pain in Arm and Shoulder Time: Baseline, every 4 weeks until disease progression (up to 33 months)This is a multi-center, open label, randomized phase II trial for patients with previously untreated metastatic or locally advanced esophagogastric cancer, using a pick the winner design to identify the best combination therapy in terms of progression free survival and neurotoxicity.
- Current use or any use in last two weeks of strong cytochrome P4503A (CYP3A-enzyme), CYP2C8, and/or strong UDP glucuronosyltransferase (UGT1A) inhibitors/inhibitors - Breast feeding, known pregnancy, positive serum pregnancy test or unwillingness to use a reliable method of birth control, during therapy and for 3 months following the last dose of study treatment. --- P4503A ---
Description: To compare the progression free survival
Measure: Progression free survival Time: 42 monthsDescription: Number of participants with treatment-related Neurotoxicity according to CTCAE v4.0
Measure: Number of participants with treatment-related Neurotoxicity Time: 42 monthsDescription: To determine the overall survival of F-Nal-IRI, capecitabine/Carboplatin (CapCar) and capecitabine/oxaliplatin (CapOx)
Measure: Overall survival Time: 54 monthsDescription: To determine the response rate of F-Nal-IRI, CapCar and CapOx
Measure: response rate Time: 42 monthsDescription: To determine the adverse events of F-Nal-IRI, CapCar and CapOx according to NCI common toxicity criteria (CTC) version 4
Measure: adverse events Time: 42 monthsDescription: Overall Quality of life ranging from 0-100 with 100 being best Quality of Life
Measure: Quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ C30)) Time: 42 monthsDescription: The percentage of patients proceeding to subsequent lines of treatment after progression and describe the types of treatment.
Measure: percentage subsequent treatment lines Time: 42 monthsDescription: Reasons for forgoing subsequent treatment after progression on first-line treatment
Measure: the reasons for forgoing subsequent treatment Time: 42 monthsDescription: Percentage of stroma and tumor immune infiltrate in metastatic tumor tissue as predictor of response to treatment and survival.
Measure: Tumor micro environment Time: 54 monthsDescription: Concentration of ADAM12 in blood
Measure: Stromal markers in blood Time: 54 monthsDescription: Growth velocity of tumor organoids after treatment measured in days
Measure: Growth velocity of patient derived tumor organoids Time: 54 monthsDescription: Concentration circulating tumour DNA (ctDNA) as a marker of response to treatment
Measure: ctDNA Time: 54 monthsDescription: Composition of the fecal microbiome as a potential biomarker for response to treatment and toxicity
Measure: Fecal microbiome Time: 54 monthsDescription: The cost effectiveness in terms of QUALYs associated with treatment of F-Nal-IRI, CapCar and CapOx
Measure: Costs associated with treatment of F-Nal-IRI, CapCar and CapOx Time: 54 monthsDescription: Expression of ADAM12 in metastatic tumor tissue
Measure: Stromal Markers in tumor Time: 54 monthsThis is a pilot trial to test perampanel (Fycompa; Eisai, Inc.) in ALS patients. The investigators will focus on safety and preliminary signs of efficacy. Perampanel is approved by the FDA for treatment of seizures in patients with epilepsy. In this study, perampanel will be used off-label for adults with ALS at an oral medication dose on the low end of the recommended dose range for epilepsy. This study will consist of two treatments arms: perampanel and matching placebo randomized at a 1:1 ratio. Subjects will receive medication for 9 months.
Inclusion Criteria: 1. diagnosis of ALS 2. first clinical weakness within past 3 years 3. slow vital capacity >= 60% of predicted within 1 month of treatment 4. may be on stable dose of riluzole for at least 30 days, or otherwise agree to not initiate riluzole for duration of the trial 5. may be on stable dose of edaravone for at least 30 days, otherwise agree to not initiate edaravone for duration of the trial 6. can travel to Stony Brook to receive medical care 7. must have a monitor who can be contacted at regular intervals to report on subject's clinical/psychiatric status Exclusion Criteria: 1. use of tracheostomy or mechanical ventilation within last 3 months 2. hepatic insufficiency or abnormal liver function 3. renal insufficiency 4. clinically significant psychiatric disorder 5. active malignancy 6. history of HIV, clinically significant chronic hepatitis, or other active infection 7. history of stomach or intestinal surgery or condition that could interfere with absorption, distribution, metabolism or secretion of study drug 8. history of alcohol or substance abuse within 3 months prior to entry (subjects will be instructed to refrain from alcohol during the study) 9. use of strong cytochrome P4503A inhibitors or inducers, anticonvulsants or other drugs known to interact strongly with perampanel. --- P4503A ---
10. pregnancy or lactation 11. clinically significant medical condition (other than ALS) that would pose a risk to the subject if they were to participate 12. know hypersensitivity to perampanel 13. currently participating, or has participated in a study with an investigation or marketed compound within 3 months of entry Inclusion Criteria: 1. diagnosis of ALS 2. first clinical weakness within past 3 years 3. slow vital capacity >= 60% of predicted within 1 month of treatment 4. may be on stable dose of riluzole for at least 30 days, or otherwise agree to not initiate riluzole for duration of the trial 5. may be on stable dose of edaravone for at least 30 days, otherwise agree to not initiate edaravone for duration of the trial 6. can travel to Stony Brook to receive medical care 7. must have a monitor who can be contacted at regular intervals to report on subject's clinical/psychiatric status Exclusion Criteria: 1. use of tracheostomy or mechanical ventilation within last 3 months 2. hepatic insufficiency or abnormal liver function 3. renal insufficiency 4. clinically significant psychiatric disorder 5. active malignancy 6. history of HIV, clinically significant chronic hepatitis, or other active infection 7. history of stomach or intestinal surgery or condition that could interfere with absorption, distribution, metabolism or secretion of study drug 8. history of alcohol or substance abuse within 3 months prior to entry (subjects will be instructed to refrain from alcohol during the study) 9. use of strong cytochrome P4503A inhibitors or inducers, anticonvulsants or other drugs known to interact strongly with perampanel. --- P4503A ---
The purpose of this study is to evaluate the effectiveness of ADL5859 in relieving the pain associated with diabetic peripheral neuropathy (DPN) compared with placebo and duloxetine (a marketed drug approved for the treatment of painful DPN). The pain symptoms of DPN are thought to be due to damage to nerves caused by the diabetes.
Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.. Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Peripheral Neuropathy Neuropathic Pain Peripheral Nervous System Diseases Neuralgia Diabetic Neuropathies Participants were permitted to take acetaminophen 650 to 975 mg every 4 to 6 hours (up to a total of 4 grams in 24 hours) as needed for pain relief. --- P4503A ---
Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.. Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Inclusion Criteria: - Male and female participants between 18 and 75 years of age, inclusive - Body weight of at least 45 kilograms (kg) - Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication - No change in diabetic medications is planned for the duration of the study - Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) - Presence of daily pain due to DPN for at least 3 months - Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) - Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs - For male participants, be surgically sterile or agree to use an appropriate method of contraception - For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) - Be willing and able to comply with the protocol requirements - Be able to understand and willing to provide written informed consent in English Exclusion Criteria: - Presence of pain conditions that cannot be distinguished from DPN - Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease - Have a history of a seizure disorder - Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition - History of evidence of symptomatic orthostatic hypotension - History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year - History or evidence of mania, bipolar disorder, or psychosis - History of allergy to acetaminophen or duloxetine - Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II - Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors - Pregnant, lactating, or plans to become pregnant during the study - Presence of foot or toe amputation - Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study Peripheral Neuropathy Neuropathic Pain Peripheral Nervous System Diseases Neuralgia Diabetic Neuropathies Participants were permitted to take acetaminophen 650 to 975 mg every 4 to 6 hours (up to a total of 4 grams in 24 hours) as needed for pain relief. --- P4503A --- --- P4503A ---
Description: The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained up to 3 times per day over a 7-day period. Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with treatment group as a main factor and baseline NPRS score as a covariate. Change from Baseline = NPRS at baseline - NPRS at Week 4; a positive number in the LS mean indicates a reduction in pain intensity from baseline.
Measure: Change From Baseline in Mean Numeric Pain Rating Scale (NPRS) Score Time: Baseline, Week 4Description: A responder was defined as a participant who showed a reduction in average pain (as measured by NPRS) of at least 30% from baseline to Week 4. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The percentage of participants who qualified as responders is presented per treatment arm.
Measure: Percentage of Responders Time: Baseline, Week 4Description: PGIC is a participant-rated instrument that measures the change in the participant's overall status for the previous 2 weeks based on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). The number of participants in each category is presented.
Measure: Patient Global Impression of Change (PGIC) Time: Week 4Description: Sleep Interference was assessed on an 11-point Numeric Rating Scale where a score of 0 indicated "pain did not interfere with sleep" and a score of 10 indicated "pain completely interfered with sleep". Here, "n" signifies "Number of participants" for Baseline and Month 3 telephone interview whereas "n" signifies "number of observations" for Month 1, 2, and 3 because a participant could have had multiple visits during Month 1, 2, and 3 as this was a non-interventional study with no scheduled study visits, except Baseline visit and the Month 3 telephone interview. LS means were calculated using ANCOVA with treatment group as a main factor and baseline SIS score as a covariate. Change from baseline = SIS score at baseline - SIS score at Week 4.
Measure: Change in Sleep Interference Scale (SIS) From Baseline Time: Baseline, Week 4Description: At each of the evening pain assessments, participants assessed their overall pain intensity over the preceding 24 hours using NPRS. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained at Baseline and Week 4. Change from baseline = NPRS at baseline - NPRS at Week 4.
Measure: Change From Baseline in the Evening Assessment of the 24-hour Overall Mean Pain Intensity Score Time: Baseline, Week 4Description: The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken while the participant was at rest. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.
Measure: Change From Baseline in NPRS at Rest in the Clinic Time: Baseline, Week 1, Week 2, Week 3, Week 4Description: The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken after the participant walked 50 feet in the clinic. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4.
Measure: Change From Baseline in NPRS After Walking 50 Feet in the Clinic Time: Baseline, Week 1, Week 2, Week 3, Week 4