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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03737994
Recruitment Status : Recruiting
First Posted : November 12, 2018
Last Update Posted : July 19, 2019
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Alectinib Drug: Brigatinib Drug: Carboplatin Drug: Ceritinib Drug: Cisplatin Drug: Crizotinib Drug: Ensartinib Drug: Lorlatinib Drug: Pemetrexed Phase 2

  Show Detailed Description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 660 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Biomarker-Driven Protocol for Previously Treated ALK-Positive Non-Squamous NSCLC Patients: The NCI-NRG ALK Protocol
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : December 13, 2025
Estimated Study Completion Date : December 13, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ALK L1198F mutation (alone or combination with ALK inhibitor)
Patients 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.
Drug: Crizotinib
Given PO
Other Names:
  • MET Tyrosine Kinase Inhibitor PF-02341066
  • PF-02341066
  • PF-2341066
  • Xalkori

Experimental: C1156Y
Patients 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.
Drug: Alectinib
Given PO
Other Names:
  • AF-802
  • AF802
  • Alecensa
  • CH5424802
  • RG7853
  • RO5424802

Drug: Brigatinib
Given PO
Other Names:
  • Alunbrig
  • AP 26113
  • AP-26113
  • AP26113

Drug: Lorlatinib
Given PO
Other Names:
  • 2H-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-06463922

Experimental: Compound mutation
Patients with a compound mutation receive lorlatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Lorlatinib
Given PO
Other Names:
  • 2H-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-06463922

Experimental: F1174
Patients 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.
Drug: Alectinib
Given PO
Other Names:
  • AF-802
  • AF802
  • Alecensa
  • CH5424802
  • RG7853
  • RO5424802

Drug: Brigatinib
Given PO
Other Names:
  • Alunbrig
  • AP 26113
  • AP-26113
  • AP26113

Drug: Lorlatinib
Given PO
Other Names:
  • 2H-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-06463922

Experimental: G1202 (including G1202del and G1202R)
Patients 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.
Drug: Brigatinib
Given PO
Other Names:
  • Alunbrig
  • AP 26113
  • AP-26113
  • AP26113

Drug: Lorlatinib
Given PO
Other Names:
  • 2H-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-06463922

Experimental: I1171
Patients 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.
Drug: Brigatinib
Given PO
Other Names:
  • Alunbrig
  • AP 26113
  • AP-26113
  • AP26113

Drug: Ceritinib
Given PO
Other Names:
  • LDK 378
  • LDK378
  • Zykadia

Drug: Lorlatinib
Given PO
Other Names:
  • 2H-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-06463922

Experimental: L1196 (including L1196M)
Patients 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.
Drug: Alectinib
Given PO
Other Names:
  • AF-802
  • AF802
  • Alecensa
  • CH5424802
  • RG7853
  • RO5424802

Drug: Brigatinib
Given PO
Other Names:
  • Alunbrig
  • AP 26113
  • AP-26113
  • AP26113

Drug: Ceritinib
Given PO
Other Names:
  • LDK 378
  • LDK378
  • Zykadia

Drug: Crizotinib
Given PO
Other Names:
  • MET Tyrosine Kinase Inhibitor PF-02341066
  • PF-02341066
  • PF-2341066
  • Xalkori

Drug: Ensartinib
Given PO
Other Name: X-396

Drug: Lorlatinib
Given PO
Other Names:
  • 2H-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-06463922

Experimental: MET amplification
Patients with MET amplification receive crizotinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Crizotinib
Given PO
Other Names:
  • MET Tyrosine Kinase Inhibitor PF-02341066
  • PF-02341066
  • PF-2341066
  • Xalkori

Experimental: No ALK-resistance mutations
Patients 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.
Drug: Alectinib
Given PO
Other Names:
  • AF-802
  • AF802
  • Alecensa
  • CH5424802
  • RG7853
  • RO5424802

Drug: Brigatinib
Given PO
Other Names:
  • Alunbrig
  • AP 26113
  • AP-26113
  • AP26113

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Ceritinib
Given PO
Other Names:
  • LDK 378
  • LDK378
  • Zykadia

Drug: Cisplatin
Given IV
Other Names:
  • Abiplatin
  • 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
  • Platosin

Drug: Ensartinib
Given PO
Other Name: X-396

Drug: Lorlatinib
Given PO
Other Names:
  • 2H-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-06463922

Drug: Pemetrexed
Given IV
Other Names:
  • MTA
  • Multitargeted Antifolate

Experimental: V1180
Patients 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.
Drug: Brigatinib
Given PO
Other Names:
  • Alunbrig
  • AP 26113
  • AP-26113
  • AP26113

Drug: Ceritinib
Given PO
Other Names:
  • LDK 378
  • LDK378
  • Zykadia

Drug: Lorlatinib
Given PO
Other Names:
  • 2H-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-06463922




Primary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: Up to 24 weeks ]
    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.


Secondary Outcome Measures :
  1. 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 ]
    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.

  2. 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 ]
    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.

  3. Overall survival (OS) [ Time Frame: From second step registration to the date of death from any cause, assessed up to 7 years ]
    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.

  4. Intracranial objective response rate [ Time Frame: Up to 7 years ]
    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.

  5. Incidence of adverse events [ Time Frame: Up to 30 days post treatment ]
    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).


Other Outcome Measures:
  1. Biopsy mutation and circulating free deoxyribonucleic acid (cfDNA) mutation results [ Time Frame: Up to 30 days post treatment ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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) (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 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) >= 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03737994


  Show 351 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
NRG Oncology
Investigators
Layout table for investigator information
Principal Investigator: Alice T Shaw NRG Oncology

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03737994     History of Changes
Other Study ID Numbers: NCI-2018-02486
NCI-2018-02486 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-LU003 ( Other Identifier: NRG Oncology )
NRG-LU003 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: November 12, 2018    Key Record Dates
Last Update Posted: July 19, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Cisplatin
Carboplatin
Pemetrexed
Crizotinib
Ceritinib
Ensartinib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Protein Kinase Inhibitors