Targeted Treatment for ALK Positive Patients Who Have Previously Been Treated for Non-squamous Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This National Cancer Institute (NCI)-NRG Anaplastic Lymphoma Kinase (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.

Detailed Description
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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. II. To assess whether subsequent pemetrexed based chemotherapy improves objective response comparing to ALK inhibitor therapy for no ALK mutation patients. III. To evaluate objective responses of patients with specific genetic alterations (ALKL1198F/mesenchymal-to-epithelial transition (MET) double mutation or high-level MET gene amplification) treated with crizotinib. SECONDARY OBJECTIVES: I. Progression-free survival (PFS). II. Duration of response (DOR). III. Overall survival (OS). IV. Intracranial objective response rate (ORR). V. Safety and tolerability. CORRELATIVE SCIENCE OBJECTIVE: I. Establish concordance between tumor and liquid biopsies. STUDY OUTLINE: This study has a two-step registration process. After the first registration, tissue and blood are submitted to determine ALK mutation and MET amplification status. At the second registration, participants are assigned to treatment based on identified ALK mutation and MET amplification status. All participants receive their assigned treatment at the standard dose until disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up for 30 days, every 3 months for 2 years, every 6 months for 3 years, and annually thereafter. NOTE: no mutations in this record means no ALK mutation and no MET amplification.

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

Conditions
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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

Intervention / Treatment
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* Drug: Alectinib
* Drug: Brigatinib
* Drug: Carboplatin
* Drug: Ceritinib
* Drug: Cisplatin
* Drug: Crizotinib
* Drug: Ensartinib
* Drug: Lorlatinib
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRIOR TO STEP 1 REGISTRATION Patients must have histologically or cytologically confirmed stage IV ALK-positive non-squamous non-small cell lung carcinoma (NSCLC) (includes M1a, M1b, M1c stage disease, American Joint Committee on Cancer [AJCC] 8th edition). ALK rearrangement must have been demonstrated by a Food and Drug Administration (FDA) approved assay (Vysis fluorescence in situ hybridization [FISH] or Ventana immunohistochemistry [IHC]) or by next generation sequencing (NGS) Patient must be willing and able to undergo a fresh biopsy or if patient has a biopsy after progression on current tyrosine-kinase inhibitor (TKI) within 3 months of study enrollment (and has continued TKI for clinical benefit per treating physician) this tissue may be used. Must have sufficient tissue Patient must have progressive disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 after one second generation ALK inhibitor, including LDK378 (ceritinib), alectinib, ensartinib, and brigatinib (may not have received more than one second-generation ALK inhibitor). Patient may have received prior crizotinib; however, the second generation ALK inhibitor received must be the last treatment given prior to study enrollment Prior lorlatinib (third-generation ALK inhibitor) is not allowed Prior chemotherapy is not allowed except for one prior cycle received at the time of original diagnosis of metastatic NSCLC with no evidence of disease progression following the cycle. NOTE: prior adjuvant or neoadjuvant chemotherapy is allowed if last dose was received more than 12 months prior to enrollment The patient or a legally authorized representative must provide study-specific informed consent prior to Step 1 Registration PRIOR TO STEP 2 REGISTRATION Absolute neutrophil count (ANC) >= 1500 cells/mm^3 (within 28 days prior to step 2 registration) Platelets >= 100,000 cells/mm^3 (within 28 days prior to step 2 registration) Estimated creatinine clearance >= 60 mL/min by the Cockcroft Gault formula (within 28 days prior to step 2 registration) Total bilirubin =< 1.5 x upper limit of normal (ULN) (except for patients with documented Gilbert's syndrome) (within 28 days prior to step 2 registration) Aspartate aminotransferase (AST) =< 2.5 x ULN; =< 5 x ULN if liver metastases are present (within 28 days prior to step 2 registration) Alanine aminotransferase (ALT) =< 2.5 x ULN; =< 5 x ULN if liver metastases are present (within 28 days prior to step 2 registration) Patients with asymptomatic treated or untreated brain metastases are eligible. Treated brain metastases are eligible as long as patients have measurable disease outside the brain according to RECIST 1.1. Patients must be on a stable or decreasing dose of steroids for at least 7 days prior to step 2 registration. Anticonvulsants are allowed as long as the patient is neurologically stable and not deteriorating Patients enrolled with asymptomatic brain metastases (mets) must have at least one measurable target extracranial lesion according to RECIST 1.1 Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Acute effects of any prior therapy resolved to baseline severity or to Common Terminology Criteria for Adverse Events (CTCAE) grade =< 1 (except for alopecia, hearing loss) Not taking any medications that may interact with selected study medication based on stratification Patients must be able to take oral medications (i.e. swallow whole tablets/capsules) All females of childbearing potential must have a blood test or urine study within 14 days prior to Step 2 Registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Women must not be pregnant or breast-feeding due to potential harm to the fetus or infant from ALK inhibitors and the unknown risk. Women of childbearing potential and sexually active males must agree to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study Exclusion Criteria: Major surgery within 2 weeks of study entry. Minor surgical procedures (e.g., port insertion, pleurex catheter placement) are allowed and all wounds must not show signs of infection or draining Palliative RT (< 10 fractions) must have been completed at least 48 hours prior to study entry. Stereotactic or small field brain irradiation must have completed at least 1 week prior to study entry. Whole brain RT or other palliative RT must have been completed at least 2 weeks prior to study entry Prior dose of next generation ALK inhibitor (LDK378 [ceritinib], alectinib, ensartinib, lorlatinib) within 5 days prior to step 2 registration. Prior dose of brigatinib within 7 days prior to step 2 registration History of interstitial lung disease or interstitial fibrosis, including a history of pneumonitis, obliterative bronchiolitis, pulmonary fibrosis. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lorlatinib<br>Participants with G1202 (including G1202del and G1202R), C1156Y, I1171, L1196 (including L1196M), V1180, or F1174 mutations, compound mutation*, or no mutations, can be assigned to receive lorlatinib. *Compound mutation = two or more resistance mutation excluding those with L1198F or L1189F/MET amplification = L1198F mutation alone or in combination, or no ALK mutation but any MET amplification. | Drug: Lorlatinib<br>* 100 mg orally once a day with or without food. Treatment continues until disease progression or unacceptable toxicity.<br>* Other names: PF-06463922;|
| Experimental: LDK378 (ceritinib)<br>Participants with I1171, L1196 (including L1196M), or V1180 mutations, or no having no ALK-resistance mutations or MET amplifications, can be assigned to receive ceritinib | Drug: Ceritinib<br>* 450 mg orally once a day with food. Treatment continues until disease progression or unacceptable toxicity.<br>* Other names: Zykadia;|
| Experimental: Alectinib<br>Participants with C1156Y, L1196 (including L1196M), or F1174 mutations, or no having no ALK-resistance mutations or MET amplifications, can be assigned to receive Alectinib. | Drug: Alectinib<br>* 600 mg orally twice daily with food. Treatment continues until disease progression or unacceptable toxicity.<br>* Other names: RO5424802;|
| Experimental: Brigatinib<br>Participants with G1202 (including G1202del and G1202R), C1156Y, I1171, L1196 (including L1196M), V1180, or F1174 mutations, or having no ALK-resistance mutations or MET amplifications, can be assigned to receive brigatinib. | Drug: Brigatinib<br>* 90 mg orally once a day (with or without food) for the first 7 days; if tolerated, with no respiratory symptoms, increase the dose to 180 mg once daily. Treatment continues until disease progression or unacceptable toxicity.<br>* Other names: AP26113;|
| Experimental: Ensartinib<br>Participants with L1196 (including L1196M) mutations or having no ALK-resistance mutations or MET amplifications can be assigned to receive ensartinib. | Drug: Ensartinib<br>* 225 mg orally once a day with or without food. Treatment continues until disease progression or unacceptable toxicity.<br>* Other names: X-396;|
| Experimental: Crizotinib<br>Participants with ALK L1198F (alone/ in combination with another ALK mutation) or mesenchymal-to-epithelial transition (MET) amplification can be assigned to receive crizotinib | Drug: Crizotinib<br>* 250 mg orally twice daily with or without food. Treatment continues until disease progression or unacceptable toxicity.<br>* Other names: Xalkori;|
| Active Comparator: Pemetrexed +/- Cisplatin or Carboplatin<br>Participants with no ALK-resistance mutations or MET amplifications can be assigned to receive pemetrexed, which optionally can be combined with cisplatin or carboplatin. | Drug: Carboplatin<br>* Carboplatin is optional. Dosing of area under the curve (AUC) = 5 once every 3 weeks (on Day 1 of a 21 day cycle with pemetrexed) intravenously, prepared and administered per institution policy. Continues for 4-6 cycles.<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Cisplatin is optional. 75 mg/m^2 intravenously once every 3 weeks (on Day 1 of a 21 day cycle with pemetrexed), prepared and administered per institution policy.<br>* Other names: Platosin;Drug: Pemetrexed<br>* Pemetrexed may be given alone or with either cisplatin or carboplatin. Pemetrexed 500 mg/m2 administered intravenously on Day 1 of a 21 day cycle, optionally with cisplatin or carboplatin for 4-6 cycles. Then pemetrexed (as a single agent) continues until progression or significant toxicity.<br>* Other names: Pemfexy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR), Per Investigator Assessment Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria | ORR= number of subjects with best overall response (BOR) of complete or partial response (CR, PR) divided by number of evaluable subjects. BOR= best response recorded from start of treatment to first progression (PD)/new anticancer therapy, otherwise last follow-up. CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes < 10mm. PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions. PD: 20% increase of target lesions and/or new lesion(s). ORR was to be compared using Fisher's exact test within each ALK inhibitor treatment arm (each mutation vs. no mutation) and also within the subset of subjects with no mutation comparing each experimental arm vs. pemetrexed. Due to early accrual closure (few subjects), only the number of subjects with BOR of CR or PR are provided, by mutation, no statistical testing. Analysis was to occur after each patient was potentially followed ≥ 24 weeks. | Baseline to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS), Per Investigator Assessment Using RECIST v1.1 Criteria | Progression-free survival time is defined as the time from second step registration to the date of the first disease progression / progressive disease (PD), death, or last known follow-up (censored). Progressive disease is defined as a 20% increase of target lesions and/or new lesion(s). Percentage of participants progression-free at a given time (PFS) was to be estimated by the Kaplan-Meier method. Median PFS and PFS at specific time points was to be reported, with 95% confidence intervals, for each mutation (or no mutation)/regimen combination. Due to early accrual closure resulting in few participants, only the number of participants who progressed or died, by mutation, with no statistical testing. | Baseline to the date of the first disease progression / progressive disease, death, or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months. | 
| Duration of Overall Response, Per Investigator Assessment Using RECIST v1.1 | Duration of overall response (DOR) is defined as the time from the first occurrence of a documented BOR of CR or PR to the first date of recorded disease progression (PD) or death from any cause (whichever occurs first). BOR is the best response recorded from the start of treatment to first progression (PD)/new anticancer therapy, otherwise last follow-up. CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes < 10mm. PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions. PD: 20% increase of target lesions and/or new lesion(s). Median DOR was to be estimated, with 95% confidence intervals, for each mutation/regimen combination using the Kaplan-Meier method. Due to early accrual closure resulting in few subjects, only the mean and range DOR are provided, by mutation, and no statistical testing was done. | Baseline to the date of the first disease progression / progressive disease, death, or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months. | 
| Overall Survival (OS) | Survival time is defined as the time from second step registration to the date of death, or last known follow-up (censored). Percentage of participants alive at a given time (OS) was to be estimated by the Kaplan-Meier method. Median OS and OS at specific time points was to be reported, with 95% confidence intervals, for each mutation/regimen combination. Due to early accrual closure resulting in few patients, only the number of participants who died are provided, by mutation, and no statistical testing was done. | Baseline to the date of death or last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months. | 
| Intracranial Objective Response Rate, Per Investigator Assessment Using RECIST v1.1 | Intracranial objective response rate (IORR) is defined as the number of participants with central nervous system (CNS) metastasis complete or partial response (CR, PR) divided by the number of evaluable participants with baseline CNS metastasis and no prior CNS radiation therapy. Participants who required additional treatment (for their non-cranial systemic disease) would be considered as non-responders (if they have not previously had an intracranial response). CR: disappearance of target and non-target lesions; no new lesions; pathological lymph nodes < 10mm. PR: 30% decrease in target lesions; non-target lesions not progressed or not evaluated; no new lesions. IORR was to be estimated for each mutation/regimen combination, with the associated 95% confidence intervals (using Clapper-Pearson method). Due to early accrual closure resulting in few subjects, only the number of subjects with CR or PR are provided, by mutation, with no statistical testing. | Baseline to 24 weeks | 
| Number of Participants by Highest Grade Adverse Event Reported | Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. | Baseline to the date of last known follow-up. Maximum follow-up time was 33.6 months, median 8.9 months. |