Clinical Trials /

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

NCT03737994

Description:

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.

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

Active, not recruiting

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT03737994

Trial Eligibility

Document

Title

  • Brief Title: Targeted Treatment for ALK Positive Patients Who Have Previously Been Treated for Non-squamous Non-small Cell Lung Cancer
  • Official Title: A Biomarker-Driven Protocol for Previously Treated ALK-Positive Non-Squamous NSCLC Patients: The NCI-NRG ALK 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

  • 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, AP26113C1156Y
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, 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, XalkoriALK L1198F mutation (alone or combination with ALK inhibitor)
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)-, Lorbrena, PF-06463922C1156Y
PemetrexedMTA, Multitargeted Antifolate, PemfexyNo ALK-resistance mutations

Purpose

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.

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 SCIENCE OBJECTIVE:

      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. Cycles 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). Cycles 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. Cycles 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. Cycles 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. Cycles 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. Cycles repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

      Patients with a compound mutation receive lorlatinib PO QD. Cycles 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. Cycles 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
      cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
      Pemetrexed-based treatment repeats every 21 days for up to 6 cycles 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. Cycles 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. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Alectinib
  • Brigatinib
  • Lorlatinib
Compound mutationExperimentalPatients with a compound mutation receive lorlatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Lorlatinib
F1174ExperimentalPatients with F1174 receive either lorlatinib PO QD, alectinib PO BID, or brigatinib PO QD. Cycles 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. Cycles 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. Cycles 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. Cycles 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. Cycles 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 cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Pemetrexed-based treatment repeats every 21 days for up to 6 cycles 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. Cycles 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 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:

          -  PRIOR TO STEP 2 REGISTRATION: 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

          -  PRIOR TO STEP 2 REGISTRATION: 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 TO STEP 2 REGISTRATION: 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

          -  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

          -  PRIOR TO STEP 2 REGISTRATION: 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

          -  PRIOR TO STEP 2 REGISTRATION: 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

          -  PRIOR TO STEP 2 REGISTRATION: Active and clinically significant bacterial, fungal, or
             viral infection

          -  PRIOR TO STEP 2 REGISTRATION: Patients with active or chronic pancreatitis based on
             lipase elevation, symptoms, and radiographic findings

          -  PRIOR TO STEP 2 REGISTRATION: 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

          -  PRIOR TO STEP 2 REGISTRATION: Patients must not plan to receive any other
             investigational agents during the course of therapy

          -  PRIOR TO STEP 2 REGISTRATION: 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)

          -  PRIOR TO STEP 2 REGISTRATION: 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)
Time Frame:Up to 24 weeks
Safety Issue:
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 patients who are randomized concurrently to the pemetrexed with cisplatin or carboplatin arm and the respective ALK inhibitor therapy arm. The response rates will be compared 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)
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 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:Duration of response
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 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: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
Time Frame:Up to 7 years
Safety Issue:
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:Incidence of adverse events
Time Frame:Up to 30 days post treatment
Safety Issue:
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).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

August 27, 2021