Clinical Trials /

Nivolumab, Cabozantinib S-Malate, and Ipilimumab in Treating Patients With Recurrent Stage IV Non-small Cell Lung Cancer

NCT03468985

Description:

This partially randomized phase II trial studies how well nivolumab, cabozantinib s-malate, and ipilimumab work in treating patients with stage IV non-small cell lung cancer that has come back. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab, cabozantinib s-malate, and ipilimumab may work better than cabozantinib s-malate alone in treating patients with stage IV non-small cell lung cancer.

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

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab, Cabozantinib S-Malate, and Ipilimumab in Treating Patients With Recurrent Stage IV Non-small Cell Lung Cancer
  • Official Title: A Randomized Phase II Trial of Nivolumab, Cabozantinib Plus Nivolumab, and Cabozantinib Plus Nivolumab Plus Ipilimumab in Patients With Previously Treated Non-Squamous NSCLC

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01008
  • SECONDARY ID: NCI-2017-01008
  • SECONDARY ID: EA5152
  • SECONDARY ID: EA5152
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT03468985

Conditions

  • c-MET Gene Amplification
  • MET Exon 14 Mutation
  • Metastatic Non-Squamous Non-Small Cell Lung Carcinoma
  • Recurrent Non-Squamous Non-Small Cell Lung Carcinoma
  • RET/PTC Rearrangement
  • ROS1 Gene Rearrangement
  • Stage IV Non-Small Cell Lung Cancer AJCC v7

Interventions

DrugSynonymsArms
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL184Arm B (nivolumab, cabozantinib s-malate)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm C (nivolumab, cabozantinib s-malate, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (nivolumab)

Purpose

This partially randomized phase II trial studies how well nivolumab, cabozantinib s-malate, and ipilimumab work in treating patients with stage IV non-small cell lung cancer that has come back. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab, cabozantinib s-malate, and ipilimumab may work better in treating patient with stage IV non-small cell lung cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To demonstrate whether combination therapy of nivolumab and cabozantinib s-malate
      (cabozantinib), or of nivolumab and cabozantinib, and ipilimumab as compared to nivolumab
      alone, extends progression-free survival (PFS) for this patient population with non-squamous
      non-small cell lung cancer (NSCLC).

      SECONDARY OBJECTIVES:

      I. To estimate the overall survival for each arm of the trial. II. To estimate the best
      overall response rate for each arm of the trial. III. To estimate the progression free
      survival of the targeted therapy arm of the trial.

      IV. To describe the toxicity profile of monotherapy with nivolumab, and the combination of
      nivolumab and cabozantinib, and the combination of nivolumab and cabozantinib and ipilimumab,
      in this patient population with non-squamous NSCLC.

      TERTIARY OBJECTIVES:

      I. To adjust progression free survival for each arm based on PD-L1 tumor status.

      OUTLINE: Patients are randomized to 1 of 3 arms. Patients with ROS1 gene rearrangement, MET
      exon 14 splice mutations, MET high amplification, or RET gene rearrangement are assigned to
      Arm T.

      ARM A: Patients receive nivolumab intravenously (IV) over 60 minutes on day 1. Courses repeat
      every 28 days in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive nivolumab IV over 60 minutes on day 1 and cabozantinib s-malate
      orally (PO) daily on days 1-28. Courses repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      ARM C: Patients receive nivolumab IV over 60 minutes on day 1, cabozantinib s-malate PO daily
      on days 1-28, and ipilimumab IV over 90 minutes every 8 weeks. Courses for nivolumab and
      cabozantinib s-malate repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      ARM T: Patients with ROS1 gene rearrangement, MET exon 14 splice mutations, MET high
      amplification, or RET gene rearrangement receive nivolumab IV over 60 minutes on day 1 and
      cabozantinib s-malate PO daily on days 1-28. Courses repeat every 28 days in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for up to 3
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (nivolumab)ExperimentalPatients receive nivolumab IV over 60 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Arm B (nivolumab, cabozantinib s-malate)ExperimentalPatients receive nivolumab IV over 60 minutes on day 1 and cabozantinib s-malate PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    • Cabozantinib S-malate
    Arm C (nivolumab, cabozantinib s-malate, ipilimumab)ExperimentalPatients receive nivolumab IV over 60 minutes on day 1, cabozantinib s-malate PO daily on days 1-28, and ipilimumab IV over 90 minutes every 8 weeks. Courses for nivolumab and cabozantinib s-malate repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    • Cabozantinib S-malate
    Arm T (nivolumab, cabozantinib s-malate, ipilimumab)ExperimentalPatients with ROS1 gene rearrangement, MET exon 14 splice mutations, MET high amplification, or RET gene rearrangement receive nivolumab IV over 60 minutes on day 1 and cabozantinib s-malate PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    • Cabozantinib S-malate

    Eligibility Criteria

            Inclusion Criteria:
    
              -  ELIGIBILITY CRITERIA FOR STEP 0
    
              -  Patients with tumors with the following molecular alterations must submit testing
                 results via Medidata Rave to determine eligibility to Arm T; the study chair,
                 co-chair, biology co-chair, or a delegate must review the molecular testing and agree
                 that the testing meets eligibility outlined below:
    
                   -  ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or
                      deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib
                      therapy)
    
                   -  MET exon 14 splice mutations on DNA analysis (may have progressed on prior
                      crizotinib therapy)
    
                   -  MET high amplification by FISH or DNA analysis or other MET mutations predicted
                      to be sensitive to MET inhibitor (no prior targeted therapy allowed)
    
                   -  RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy
                      allowed)
    
                        -  Institutions will be notified of the patient's eligibility status for Arm T
                           within two (2) business days of submission of the molecular testing reports
    
                        -  If patients do not have tumors with the above molecular alterations noted
                           proceed directly to step 1
    
              -  ELIGIBILITY CRITERIA FOR STEP 1
    
              -  For patients with known molecular alterations, institution has been notified that
                 patient is deemed eligible for Arm T per review of molecular testing reports
    
              -  Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC)
    
              -  Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th
                 edition of the lung cancer tumor, node, and metastasis (TNM) classification system
    
              -  Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS]
                 are eligible); mixed tumors will be categorized by the predominant cell type; if small
                 cell elements are present the patient is ineligible
    
              -  Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI)
                 sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene
                 rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified
                 clinical testing methods; negative circulating tumor DNA results alone are not
                 acceptable; prior testing for tumor PD-L1 status is not required
    
              -  Patients must have progressed radiographically following first line platinum-based
                 chemotherapy, no additional lines of therapy are permitted
    
                   -  NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one
                      line of therapy if 12 months or greater elapsed between completion of adjuvant
                      therapy and initiation of first-line systemic therapy; if less than 12 months
                      elapsed, adjuvant chemotherapy counts as one line of therapy
    
                   -  Exception for targeted therapy sub-study (Arm T): At least one line of prior
                      chemotherapy or targeted therapy is required, but there is no limit on number of
                      prior treatments
    
              -  Patients must have measurable disease as defined by Response Evaluation Criteria in
                 Solid Tumors (RECIST) version 1.1 criteria; baseline measurements and evaluation of
                 ALL sites of disease must be obtained within 4 weeks prior to registration
    
              -  No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-1/PD-L1 immune
                 checkpoint inhibitor therapy (such as nivolumab, pembrolizumab, atezolizumab) or CTLA4
                 inhibitor therapy (such as ipilimumab); no prior allergic reaction to small molecule
                 tyrosine kinase inhibitors or monoclonal antibodies
    
                   -  Exception for targeted therapy sub-study (Arm T): Prior crizotinib may be allowed
                      depending on the gene alteration
    
              -  Any prior chemotherapy (based on administration schedule) must have been completed in
                 greater than or equal to the following times prior to registration:
    
                   -  Chemotherapy/ targeted oral therapy administered in a daily or weekly schedule
                      must be completed >= 1 week prior to registration;
    
                   -  Any chemotherapy administered in an every 2 week or greater schedule must be
                      completed >= 2 weeks prior to registration
    
                   -  Additionally, patients should be recovered to equal to or less than grade 1
                      Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 from
                      toxicities related to any prior treatment, unless adverse event (AE)(s) are
                      clinically nonsignificant and/or stable on supportive therapy
    
              -  No prior radiation therapy for bone metastasis within 2 weeks, any other radiation
                 therapy within 4 weeks prior to registration
    
              -  Patients with no known brain metastasis must have baseline brain imaging within 12
                 weeks prior to study registration not demonstrating brain metastases OR
    
              -  Patients with known brain metastases must have baseline brain imaging within 4 weeks
                 prior to study registration and meet all of the following criteria:
    
                   -  Have completed treatment to all symptomatic brain metastases (with whole brain
                      radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone
                      complete neurosurgical resection >= 3 months prior to registration
    
                   -  Be clinically stable from brain metastases at time of screening, if no treatment
                      was administered
    
                   -  Known leptomeningeal disease is not allowed
    
              -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1
    
                   -  NOTE: Participants with impaired decision-making capacity (IDMC) should not be
                      allowed to participate in this study due to its complexity
    
              -  Patients must have anticipated life expectancy greater than 3 months
    
              -  Within 2 weeks prior to registration: Absolute neutrophil count >= 1,500/mm^3
    
              -  Within 2 weeks prior to registration: Platelets >= 100,000/mm^3
    
              -  Within 2 weeks prior to registration: Hemoglobin >= 9 g/dL
    
              -  Within 2 weeks prior to registration: Subject has prothrombin time (PT)/international
                 normalized ratio (INR) and partial thromboplastin time (PTT) test =< 1.3 x the
                 laboratory upper limit of normal (ULN)
    
              -  Within 2 weeks prior to registration: Total bilirubin =< 1.5 x ULN
    
              -  Within 2 weeks prior to registration: Aspartate aminotransferase (AST) (serum glutamic
                 oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic
                 pyruvic transaminase [SGPT]) =< 3 x ULN
    
              -  Within 2 weeks prior to registration: Serum albumin >= 2.8 g/dL
    
              -  Within 2 weeks prior to registration: Lipase =< 2.0 x ULN and no radiologic or
                 clinical evidence of pancreatitis
    
              -  Within 2 weeks prior to registration: Serum calcium (absolute or albumin corrected),
                 magnesium and potassium >= lower limit of normal (LLN)
    
              -  Within 2 weeks prior to registration: Creatinine =< 1.5 x ULN or calculated
                 (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 m^2
                 (normalized to body surface area [BSA]) for patients with creatinine levels greater
                 than 1.5 times the institutional normal
    
              -  Within 2 weeks prior to registration: Screening urine dipstick must equal 0 or
                 "trace"; if urine dipstick results are >= 1+, or if dipstick was not performed,
                 calculation of urine protein creatinine (UPC) is required and patients must have a UPC
                 ratio =< 1 to participate in the study
    
              -  No history of the following:
    
                   -  Clinically-significant gastrointestinal bleeding within 6 months prior to
                      registration
    
                   -  Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to
                      registration
    
                   -  Drug induced pneumonitis within 3 months prior to registration
    
                   -  Signs indicative of pulmonary hemorrhage within 3 months before the first dose of
                      study treatment
    
                   -  Radiographic evidence of cavitating pulmonary lesion(s)
    
                   -  Tumor invading any major blood vessels
    
                   -  Evidence of tumor invading the GI tract (esophagus, stomach, small or large
                      bowel, rectum or anus), or any evidence of endotracheal or mainstem endobronchial
                      tumor within 28 days before the first dose of cabozantinib
    
              -  No concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin
                 or warfarin-related agents, heparin, low molecular weight heparin (LMWH), thrombin or
                 factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel); (low dose aspirin
                 [=< 81 mg/day] and prophylactic LMWH are permitted)
    
              -  No concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct
                 thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel); allowed
                 anticoagulants are the following:
    
                   -  Low-dose aspirin for cardioprotection (per local applicable guidelines) is
                      permitted
    
                   -  Low molecular weight heparins (LMWH) or unfractionated heparin is permitted
    
                   -  Anticoagulation with therapeutic doses of LMWH is allowed in subjects without
                      known brain metastases who are on a stable dose of LMWH for at least 6 weeks
                      before first dose of study treatment, and who have had no clinically significant
                      hemorrhagic complications from the anticoagulation regimen or the tumor
    
              -  No concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin,
                 carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)
    
              -  No cardiovascular disorders including:
    
                   -  Congestive heart failure (CHF): New York Heart Association (NYHA) class III
                      (moderate) or class IV (severe) at the time of screening
    
                   -  Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) >
                      150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive
                      treatment within 7 days prior to registration
    
                   -  Any of the following within 6 months prior to registration:
    
                        -  Unstable angina pectoris
    
                        -  Clinically-significant cardiac arrhythmias
    
                        -  Stroke (including transient ischemic attack [TIA], or other ischemic event)
    
                        -  Myocardial infarction
    
              -  No gastrointestinal disorders associated with a high risk of perforation or fistula
                 formation within 3 months prior to registration:
    
                   -  Active peptic ulcer disease
    
                   -  Inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
                      diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
    
                   -  Known malabsorption syndrome
    
                   -  Bowel obstruction or gastric outlet obstruction
    
                   -  Percutaneous endoscopic gastrostomy (PEG) tube placement
    
              -  No gastrointestinal disorders associated with a high risk of perforation or fistula
                 formation within 6 months prior to registration:
    
                   -  Abdominal fistula
    
                   -  Gastrointestinal perforation
    
                   -  Intra-abdominal abscess; Note: Complete resolution of an intra-abdominal abscess
                      must be confirmed prior to initiating treatment with cabozantinib even if the
                      abscess occurred more than 6 months prior to registration
    
              -  None of the following conditions:
    
                   -  Grade 3 or greater infection, or infection requiring intravenous systemic
                      treatment within 28 days prior to registration; patients should be off
                      antibiotics at the time of registration.
    
                   -  Serious non-healing wound/ulcer/bone fracture within 28 days prior to
                      registration
    
                   -  History of organ transplant
    
                   -  Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
                      prior to registration
    
                   -  History of surgery as follows:
    
                        -  Major surgery (as an example, surgery requiring anesthesia and a > 24 hour
                           hospital stay) within 3 months prior to registration, with wound healing at
                           least 28 days prior to registration
    
                        -  Minor surgery within 28 days prior to registration with complete wound
                           healing at least 10 days prior to registration
    
                        -  Minor procedures within 7 days prior to registration such as thoracentesis,
                           paracentesis, or 18 g or smaller needle biopsy of tumor
    
                        -  Patients with clinically relevant ongoing complications from prior surgery
                           are not eligible
    
              -  Patients must have corrected QT interval calculated by the Fridericia formula (QTcF)
                 =< 500 ms within 28 days before registration
    
              -  Patients must be able to swallow tablets
    
              -  No currently active other malignancies which require systemic treatment
    
              -  No patients that have a condition requiring systemic treatment with either
                 corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
                 medications within 14 days of study drug administration; inhaled or topical steroids
                 and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in
                 the absence of active autoimmune disease; patients are permitted to use topical,
                 ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal
                 systemic absorption); physiologic replacement doses of systemic corticosteroids are
                 permitted, even if < 10 mg/day prednisone equivalents; a brief course of
                 corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of
                 non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by
                 contact allergen) is permitted
    
              -  No patients with known active autoimmune disease or known history of autoimmune
                 disease for which recurrence may affect vital organ function or require immune
                 suppressive treatment including systemic corticosteroids; these include but are not
                 limited to patients with a history of immune related neurologic disease, multiple
                 sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
                 gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
                 connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
                 ulcerative colitis, autoimmune hepatitis; patients with a history of toxic epidermal
                 necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
                 excluded because of the risk of recurrence or exacerbation of disease; patients with
                 vitiligo, endocrine deficiencies including type I diabetes mellitus or thyroiditis
                 managed with replacement hormones including physiologic corticosteroids are eligible;
                 patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and
                 psoriasis controlled with topical medication and patients with positive serology, such
                 as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the
                 presence of target organ involvement and potential need for systemic treatment but
                 should otherwise be eligible
    
              -  No ongoing major illness or psychosocial issues that would limit compliance with the
                 protocol
    
              -  Women must not be pregnant or breast-feeding
    
                   -  All females of childbearing potential must have a blood test or urine study
                      within 2 weeks prior to 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:
                      1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 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 of childbearing potential (WOCBP) and males who are sexually active with WOCBP
                 must use an accepted and effective method of contraception or abstain from sexual
                 intercourse for at least one week prior to the start of treatment, and continue for 5
                 months after the last dose of protocol treatment for women of childbearing potential
                 and 7 months after the last dose of protocol treatment for males who are sexually
                 active wit
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Progression-free survival (PFS)
    Time Frame:From randomization to documented disease progression or death from any cause, whichever occurs first, assessed up to 5 years
    Safety Issue:
    Description:Will be estimated using the Kaplan-Meier method and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparison of PFS will use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Other comparisons of groups will be made using the logrank test and Cox modeling.

    Secondary Outcome Measures

    Measure:Overall survival
    Time Frame:From randomization to death from any cause, assessed up to 5 years
    Safety Issue:
    Description:Will be estimated using the Kaplan-Meier method and Cox proportional hazards models will be used to estimate the treatment hazard ratios.
    Measure:Best objective response evaluated according to Response Evaluation Criteria in Solid Tumors 1.1 criteria
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Response rates (complete response and partial response) will be compared using Fischer's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.
    Measure:Incidence of toxicity evaluated according to Common Terminology Criteria for Adverse Events version 4 criteria
    Time Frame:Up to 5 years
    Safety Issue:
    Description:Toxicity will be compared using Fischer's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

    Details

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

    Last Updated

    April 26, 2018