SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03737994

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

A Biomarker-Driven Protocol for Previously Treated ALK-Positive Non-Squamous NSCLC Patients: The NCI-NRG ALK Protocol

This National Cancer Institute (NCI)-NRG ALK Protocol phase II trial studies how well a combination of different biomarker/ALK inhibitors work in treating patients with stage IV ALK positive non-squamous non-small cell lung cancer. Lorlatinib, ceritinib, alectinib, brigatinib, ensartinib, and crizotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pemetrexed, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether a combination of biomarker/ALK inhibitors or chemotherapy may work better in treating patients with ALK positive non-squamous non-small cell lung cancer.

NCT03737994 ALK Gene Rearrangement ALK Positive Lung Non-Squamous Non-Small Cell Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8
MeSH: Lung Neoplasms
HPO: Neoplasm of the lung

9 Interventions

Name: Alectinib

Description: Given PO

Type: Drug

C1156Y L1196 (including L1196M) F1174 No ALK-resistance mutations

Name: Brigatinib

Description: Given PO

Type: Drug

G1202 (including G1202del and G1202R) C1156Y I1171 L1196 (including L1196M) V1180 F1174 No ALK-resistance mutations

Name: Carboplatin

Description: Given IV

Type: Drug

No ALK-resistance mutations

Name: Ceritinib

Description: Given PO

Type: Drug

I1171 L1196 (including L1196M) V1180 No ALK-resistance mutations

Name: Cisplatin

Description: Given IV

Type: Drug

No ALK-resistance mutations

Name: Crizotinib

Description: Given PO

Type: Drug

L1196 (including L1196M) ALK L1198F mutation (alone or combination with ALK inhibitor) MET amplification

Name: Ensartinib

Description: Given PO

Type: Drug

L1196 (including L1196M) No ALK-resistance mutations

Name: Lorlatinib

Description: Given PO

Type: Drug

G1202 (including G1202del and G1202R) C1156Y I1171 L1196 (including L1196M) V1180 F1174 No ALK-resistance mutations Compound mutation

Name: Pemetrexed

Description: Given IV

Type: Drug

No ALK-resistance mutations


Primary Outcomes

Description: Will be defined as the number of subjects whose best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of evaluable subjects per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. For each ALK inhibitor therapy, the primary analysis is to compare the response rate for the patients who have the relevant mutation (G1202/C1156Y /I1171/L1196/ V1180/F1174/compound mutation) to those patients who receive the same ALK inhibitor therapy who have no mutations using Fisher's exact test. For the no ALK-resistance mutation patients, the primary analysis is to compare the response rate for those patients who are randomized concurrently and receive pemetrexed with cisplatin or carboplatin to those patients who receive ALK inhibitor therapy using Fisher's exact test. The ORR for each mutation/regimen combination and the associated 95% confidence intervals (using Clopper-Pearson method) will also be reported.

Measure: Objective response rate (ORR)

Time: Up to 24 weeks

Secondary Outcomes

Description: Will be assessed according to RECIST 1.1. Will be estimated for each mutation (or no mutation)/regimen combination. The Kaplan-Meier method will be used to estimate the distribution and median with 95% confidence intervals constructed through use of the Brookmeyer and Crowley method. PFS rates at specific time-points will also be estimated using the Kaplan-Meier method, with 95% confidence intervals calculated on the basis of Greenwood's estimate for the variance.

Measure: Progression-free survival (PFS)

Time: From second step registration to the date of the first recorded occurrence of disease progression or death from any cause (whichever occurs first), assessed up to 7 years

Description: Will be assessed according to RECIST 1.1. Will be estimated for each mutation (or no mutation)/regimen combination. The Kaplan-Meier method will be used to estimate the distribution and median with 95% confidence intervals constructed through use of the Brookmeyer and Crowley method.

Measure: Duration of response

Time: From the first occurrence of a documented BOR of CR or PR to the first date of recorded disease progression or death from any cause (whichever occurs first), assessed up to 7 years

Description: Will be estimated for each mutation (or no mutation)/regimen combination. The Kaplan-Meier method will be used to estimate the distribution and median with 95% confidence intervals constructed through use of the Brookmeyer and Crowley method. OS rates at specific time-points will also be estimated using the Kaplan-Meier method, with 95% confidence intervals calculated on the basis of Greenwood's estimate for the variance.

Measure: Overall survival (OS)

Time: From second step registration to the date of death from any cause, assessed up to 7 years

Description: Will be defined as the rate of central nervous response (CNS) response among patients with known CNS metastasis but no prior CNS radiation therapy determined using modified RECIST 1.1. Will be estimated for each mutation (or no mutation)/regimen combination. The associated 95% confidence intervals (using Clapper-Pearson method) will also be reported.

Measure: Intracranial objective response rate

Time: Up to 7 years

Description: Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be summarized regardless of relationship to protocol treatment as assessed by the investigator. All adverse events, adverse events leading to withdrawal, interruption or modification of protocol treatment, grade >= 3 adverse events, and serious adverse events will be summarized. Deaths and cause of death will be summarized. The rate of treatment-related adverse events will be reported with the frequency and severity (e.g., type, grade, and attribution).

Measure: Incidence of adverse events

Time: Up to 30 days post treatment

Other Outcomes

Description: For each resistance mutation, the agreement of the biopsy result (present, absent, unavailable) and the cfDNA result (present, absent, unavailable) will be assessed at the end of the trial. Agreement of cfDNA and biopsy results will be considered separately for MET amplification and for the gene mutations.

Measure: Biopsy mutation and circulating free deoxyribonucleic acid (cfDNA) mutation results

Time: Up to 30 days post treatment

Purpose: Screening

Allocation: Randomized

Parallel Assignment


There are 3 SNPs

SNPs


1 C1156Y

For each ALK inhibitor therapy, the primary analysis is to compare the response rate for the patients who have the relevant mutation (G1202/C1156Y /I1171/L1196/ V1180/F1174/compound mutation) to those patients who receive the same ALK inhibitor therapy who have no mutations using Fisher's exact test. --- C1156Y ---

Patients with a history of prior radiation pneumonitis are not excluded - Active inflammatory gastrointestinal disease (such as Crohns, ulcerative colitis), chronic diarrhea, symptomatic diverticular disease, or any gastrointestinal disease that would affect the absorption of oral medications or increase the risk of toxicity - Clinically significant cardiovascular abnormalities, as determined by the treating/registering physician, such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia, or myocardial infarction within 6 months - Active and clinically significant bacterial, fungal, or viral infection - Patients with active or chronic pancreatitis based on lipase elevation, symptoms, and radiographic findings - Other concomitant serious illness or organ system dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug - Patients must not plan to receive any other investigational agents during the course of therapy - Patients with active malignancy other than ALK-positive non-squamous NSCLC within the last 2 years are excluded (note: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, papillary thyroid cancer treated with curative intent, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for 2 years are eligible) - No chemotherapy and/or immunotherapy allowed after step 1 registration ALK Gene Rearrangement ALK Positive Lung Non-Squamous Non-Small Cell Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Lung Neoplasms PRIMARY OBJECTIVES: I. To assess whether ALK kinase domain mutations (G1202/C1156Y/I1171/L1196/ V1180/ F1174/compound mutation) associated with drug resistance are prognostic for objective response to subsequent ALK inhibitor therapy. --- C1156Y ---

Patients with a C1156Y mutation receive either lorlatinib PO QD, brigatinib PO QD, or alectinib PO twice daily (BID). --- C1156Y ---


2 G1202R

OUTLINE: Patients with a G1202R or G1202del mutation receive either lorlatinib orally (PO) once daily (QD) or brigatinib PO QD. --- G1202R ---


3 L1198F

Patients with an ALK L1198F mutation alone or with another mutation, and patients with high level MET amplification receive crizotinib PO BID. --- L1198F ---



HPO Nodes


HPO:
Neoplasm of the lung
Genes 43
WT1 KRAS SLC22A18 STK11 IRF1 AKT1 C11ORF95 PRKN PPP2R1B ERBB2 TRPV3 TSC1 POU6F2 TSC2 EWSR1 RELA KEAP1 REST DIS3L2 SFTPA2 GPC3 MBTPS2 LMNA PTEN BRAF BRCA2 EGFR RB1 TRIP13 PDGFRB TERT SFTPC PIK3CA TRIM28 DICER1 MAP3K8 HPGD SLCO2A1 H19 TP53 NOTCH3 BAP1 WRN