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Biomarker/ALK Inhibitor Combinations in Treating Patients With Stage IV ALK Positive Non-Small Cell Lung Cancer (The NCI-NRG ALK Master Protocol)

NCT03737994

Description:

This National Cancer Institute (NCI) NRG ALK Master Protocol phase II trial studies how well a combination of different biomarker/ALK inhibitors work in treating patients with stage IV ALK positive 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-small cell lung cancer.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Biomarker/ALK Inhibitor Combinations in Treating Patients With Stage IV ALK Positive Non-Small Cell Lung Cancer (The NCI-NRG ALK Master Protocol)
  • Official Title: A Biomarker-Driven Protocol for Previously Treated ALK-Positive NSCLC Patients: The NCI-NRG ALK Master Protocol

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-02486
  • SECONDARY ID: NCI-2018-02486
  • SECONDARY ID: NRG-LU003
  • SECONDARY ID: NRG-LU003
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03737994

Conditions

  • 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

Interventions

DrugSynonymsArms
AlectinibAF-802, AF802, Alecensa, CH5424802, RG7853, RO5424802C1156Y
BrigatinibAlunbrig, AP 26113, AP-26113, AP26113G1202 (including G1202del and G1202R)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboNo ALK-resistance mutations
CeritinibLDK 378, LDK378, ZykadiaI1171
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinNo ALK-resistance mutations
CrizotinibMET Tyrosine Kinase Inhibitor PF-02341066, PF-02341066, PF-2341066, XalkoriL1196 (including L1196M)
EnsartinibX-396L1196 (including L1196M)
Lorlatinib2H-4,8-Methenopyrazolo(4,3-H)(2,5,11)benzoxadiazacyclotetradecine-3-carbonitrile, 7-amino-12-fluoro-10,15,16,17-tetrahydro-2,10,16-trimethyl-15-oxo-, (10R)-, PF-06463922G1202 (including G1202del and G1202R)
PemetrexedMTA, Multitargeted AntifolateNo ALK-resistance mutations

Purpose

This National Cancer Institute (NCI) NRG ALK Master Protocol phase II trial studies how well a combination of different biomarker/ALK inhibitors work in treating patients with stage IV ALK positive 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-small cell lung cancer.

Detailed Description

      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/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 OBJECTIVES:

      I. Establish concordance between tumor and liquid biopsies.

      OUTLINE:

      Patients with a G1202R or G1202del mutation receive either lorlatinib orally (PO) once daily
      (QD) or brigatinib PO QD. Courses repeat every 21 days in the absence of disease progression
      or unacceptable toxicity.

      Patients with a C1156Y mutation receive either lorlatinib PO QD, brigatinib PO QD, or
      alectinib PO twice daily (BID). Courses repeat every 21 days in the absence of disease
      progression or unacceptable toxicity.

      Patients with a I1171 mutation receive either lorlatinib PO QD, ceritinib PO QD, or
      brigatinib PO QD. Courses repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

      Patients with a L1196 mutation receive either lorlatinib PO QD, brigatinib PO QD, ensartinib
      PO QD, alectinib PO BID, or ceritinib PO QD. Courses repeat every 21 days in the absence of
      disease progression or unacceptable toxicity.

      Patients with a V1180 mutation receive either lorlatinib PO QD, brigatinib PO QD, or
      ceritinib PO QD. Courses repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

      Patients with a F1174 mutation receive either alectinib PO BID, lorlatinib PO QD, or
      brigatinib PO QD. Courses repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

      Patients with a compound mutation receive lorlatinib PO QD. Courses repeat every 21 days in
      the absence of disease progression or unacceptable toxicity.

      Patients with an ALK L1198F mutation alone or with another mutation, and patients with high
      level MET amplification receive crizotinib PO BID. Courses repeat every 21 days in the
      absence of disease progression or unacceptable toxicity.

      Patients with no ALK-resistant mutations receive either lorlatinib PO QD, ceritinib PO QD,
      alectinib PO BID, brigatinib PO QD, or ensartinib PO QD, or pemetrexed intravenously (IV)
      over 10 minutes on day 1 and either cisplatin IV or carboplatin IV on day 1. ALK inhibitor
      courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
      Pemetrexed-based treatment repeats every 21 days for up to 6 courses in the absence of
      disease progression or unacceptable toxicity. Maintenance treatment of pemetrexed may
      continue until disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days, every 3 months for
      2 years, every 6 months for 3 years, and annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
ALK L1198F mutation (alone or combination with ALK inhibitor)ExperimentalPatients with ALK L1198F mutation (alone or in combination with another ALK mutation) receive crizotinib PO QD. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Crizotinib
C1156YExperimentalPatients with Cy1156Y mutation receive either lorlatinib PO QD, alectinib PO BID, or brigatinib PO QD. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Alectinib
  • Brigatinib
  • Lorlatinib
F1174ExperimentalPatients with F1174 receive either lorlatinib PO QD, alectinib PO BID, or brigatinib PO QD. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Alectinib
  • Brigatinib
  • Lorlatinib
G1202 (including G1202del and G1202R)ExperimentalPatients with G1202 (including G1202del and G1202R) receive either lorlatinib PO QD or brigatinib PO QD. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Brigatinib
  • Lorlatinib
I1171ExperimentalPatients with I1171 mutation receive either lorlatinib PO QD, ceritinib PO QD, or brigatinib PO QD. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Brigatinib
  • Ceritinib
  • Lorlatinib
L1196 (including L1196M)ExperimentalPatients with L1196 (including L1196M) mutation receive either lorlatinib PO QD, ceritinib PO QD, alectinib PO BID, brigatinib PO QD, or ensartinib PO QD. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Alectinib
  • Brigatinib
  • Ceritinib
  • Crizotinib
  • Ensartinib
  • Lorlatinib
MET amplificationExperimentalPatients with MET amplification receive crizotinib PO QD. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Crizotinib
No ALK-resistance mutationsExperimentalPatients with no ALK-resistant mutations receive either lorlatinib PO QD, ceritinib PO QD, alectinib PO BID, brigatinib PO QD, ensartinib PO QD, or pemetrexed IV over 10 minutes on day 1 with or without either cisplatin IV or carboplatin IV on day 1. ALK inhibitor courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Pemetrexed-based treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Maintenance treatment of pemetrexed may continue until disease progression or unacceptable toxicity.
  • Alectinib
  • Brigatinib
  • Carboplatin
  • Ceritinib
  • Cisplatin
  • Ensartinib
  • Lorlatinib
  • Pemetrexed
V1180ExperimentalPatients with V1180 mutation receive either lorlatinib PO QD, ceritinib PO QD, or brigatinib PO QD. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Brigatinib
  • Ceritinib
  • Lorlatinib

Eligibility Criteria

        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 an 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 have sufficient tissue
             within the last 3 months while on the same tyrosine kinase inhibitor (TKI) for central
             pathology

          -  Patient must have progressive disease as defined by Response Evaluation Criteria in
             Solid Tumors (RECIST) 1.1 after a second generation ALK inhibitor, including LDK378
             (ceritinib), alectinib, ensartinib, and brigatinib or third generation ALK inhibitor
             referring to lorlatinib. The next generation ALK inhibitor must be the last ALK
             inhibitor given (prior crizotinib is allowed)

          -  Patients who have received a cycle of chemotherapy at the time of original diagnosis
             of metastatic NSCLC are eligible as long as they have received a next generation ALK
             inhibitor

          -  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) >= 1500cells/mm^3 (within 28 days prior to step 2
             registration)

          -  Platelets >= 100,000 cells/mm^3 (within 28 days prior to step 2 registration)

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) (within 28 days prior to step 2
             registration)

          -  Total bilirubin =< 1.5 mg/dL (within 28 days prior to step 2 registration)

          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<
             2.5 x ULN, or =< 5 x ULN in patients with liver metastasis (within 28 days prior to
             step 2 registration)

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
             ULN, or =< 5 x ULN in patients with liver metastasis (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 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 (eg, port
             insertion, pleurex catheter placement) are allowed and all wounds must not show signs
             of infection or draining

          -  Radiation therapy (except palliative radiation therapy [RT] to relieve bone pain)
             within 2 weeks of study entry. 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 must have
             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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) 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
Time Frame:Up to 24 weeks
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Progression-free survival (PFS) according to RECIST 1.1
Time Frame: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
Safety Issue:
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. 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:Duration of response (DOR) defined by RECIST 1.1
Time Frame: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
Safety Issue:
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.
Measure:Overall survival (OS)
Time Frame:From second step registration to the date of death from any cause, assessed up to 7 years
Safety Issue:
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:Intracranial objective response rate 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
Time Frame:Up to 7 years
Safety Issue:
Description: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:Incidence of adverse events assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0
Time Frame:Up to 30 days post treatment
Safety Issue:
Description: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).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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