Clinical Trials /

Testing the Addition of the Pill Chemotherapy, Cabozantinib, to the Standard Immune Therapy Nivolumab Compared to Standard Chemotherapy for Non-small Cell Lung Cancer

NCT04310007

Description:

This phase II trial compares cabozantinib alone and the combination of cabozantinib and nivolumab to standard chemotherapy in the treatment of patients with non-squamous non-small cell lung cancer (NSCLC). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ramucirumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as docetaxel, gemcitabine hydrochloride, paclitaxel, and nab-paclitaxel, 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. Giving cabozantinib alone or in combination with nivolumab may be more effective than standard chemotherapy in treating patients with non-small cell lung cancer.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of the Pill Chemotherapy, Cabozantinib, to the Standard Immune Therapy Nivolumab Compared to Standard Chemotherapy for Non-small Cell Lung Cancer
  • Official Title: A Randomized Phase II Trial of Cabozantinib and Cabozantinib Plus Nivolumab Versus Standard Chemotherapy in Patients With Previously Treated Non-Squamous NSCLC

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-01541
  • SECONDARY ID: NCI-2020-01541
  • SECONDARY ID: EA5191
  • SECONDARY ID: EA5191
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04310007

Conditions

  • Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  • Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
  • Stage III Lung Cancer AJCC v8
  • Stage IIIA Lung Cancer AJCC v8
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IIIC Lung Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Unresectable Lung Non-Squamous Non-Small Cell Carcinoma

Interventions

DrugSynonymsArms
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Arm A (cabozantinib S-malate)
DocetaxelDocecad, RP56976, Taxotere, Taxotere Injection ConcentrateArm C (standard chemotherapy,cabozantinib S-malate, nivolumab)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)
Nab-paclitaxelABI 007, ABI-007, Abraxane, Albumin-bound Paclitaxel, Albumin-Stabilized Nanoparticle Paclitaxel, Nanoparticle Albumin-bound Paclitaxel, Nanoparticle Paclitaxel, Paclitaxel Albumin, paclitaxel albumin-stabilized nanoparticle formulation, Protein-bound PaclitaxelArm C (standard chemotherapy,cabozantinib S-malate, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm B (cabozantinib S-malate, nivolumab)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm C (standard chemotherapy,cabozantinib S-malate, nivolumab)
RamucirumabAnti-VEGFR-2 Fully Human Monoclonal Antibody IMC-1121B, Cyramza, IMC-1121B, LY3009806, Monoclonal Antibody HGS-ETR2Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)

Purpose

This phase II trial compares cabozantinib alone and the combination of cabozantinib and nivolumab to standard chemotherapy in the treatment of patients with non-squamous non-small cell lung cancer (NSCLC). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ramucirumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as docetaxel, gemcitabine hydrochloride, paclitaxel, and nab-paclitaxel, 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. Giving cabozantinib alone or in combination with nivolumab may be more effective than standard chemotherapy in treating patients with non-small cell lung cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine whether cabozantinib alone, or the combination of nivolumab and cabozantinib,
      as compared to standard chemotherapy alone, extends progression-free survival (PFS) for this
      patient population with non squamous NSCLC.

      SECONDARY OBJECTIVES:

      I. To evaluate the progression free survival (PFS) and best overall radiographic response
      rate of the targeted therapy arm of the trial.

      II. To determine the overall survival for each arm of the trial. III. To evaluate the best
      overall radiographic response rate for each arm of the trial.

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

      EXPLORATORY IMAGING OBJECTIVES:

      I. To describe time point tumor response assessment, overall best response, progression-free
      survival and overall survival using the conventional Response Evaluation Criteria in Solid
      Tumors (RECIST) 1.1 criteria and the exploratory revised CHOI criteria with all measurements
      performed by the central review.

      II. To compare the progression-free survival using the RECIST1.1 imaging response assessment
      measurements by site study personnel to those performed by central review.

      EXPLORATORY CORRELATIVE OBJECTIVE:

      I. To perform correlative biomarker research on tissue and blood biospecimens collected
      within this trial.

      OUTLINE: Patients without known molecular alterations are randomly assigned to 1 of 3 arms.
      Patients with known molecular alterations are assigned to Arm B.

      ARM A: Patients receive cabozantinib S-malate orally (PO) once daily (QD). Cycles repeat
      every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients may
      continue to receive therapy after investigator-assessed RECIST 1.1 defined progression,
      including stable clinical and performance status and have potential for continued clinical
      benefit.

      ARM B: Patients receive cabozantinib S-malate PO QD and nivolumab intravenously (IV) over 30
      minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or
      unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed
      RECIST 1.1 defined progression, including stable clinical and performance status and have
      potential for continued clinical benefit.

      ARM C:

      STEP 1: Patients receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on
      day 1, or docetaxel IV over 1 hour on day 1 or on days 1 and 8, or gemcitabine hydrochloride
      IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30
      minutes on days 1, 8, and 15. Cycles repeat every 3 weeks in the absence of disease
      progression or unacceptable toxicity and at the discretion of the treating physician.
      Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined
      progression, including stable clinical and performance status and have potential for
      continued clinical benefit.

      STEP 2: Patients receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day
      1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable
      toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1
      defined progression, including stable clinical and performance status and have potential for
      continued clinical benefit.

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

Trial Arms

NameTypeDescriptionInterventions
Arm A (cabozantinib S-malate)ExperimentalPatients receive cabozantinib S-malate PO QD. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit.
  • Cabozantinib S-malate
Arm B (cabozantinib S-malate, nivolumab)ExperimentalPatients receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit.
  • Cabozantinib S-malate
  • Nivolumab
Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)Active ComparatorSee Detailed Description
  • Cabozantinib S-malate
  • Docetaxel
  • Gemcitabine Hydrochloride
  • Nab-paclitaxel
  • Nivolumab
  • Paclitaxel
  • Ramucirumab

Eligibility Criteria

        Inclusion Criteria:

          -  ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have pathologically
             confirmed non-squamous non-small cell lung carcinoma (NSCLC)

          -  ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have stage IV disease
             (includes M1a, M1b, or recurrent earlier stage disease), according to the 8th edition
             of the lung cancer Tumor Node Metastasis (TNM) classification system

          -  ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have predominant
             non-squamous histology (patients with NSCLC no 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

          -  ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient's tumor(s) must be tested
             and known negative for EGFR tyrosinase kinase inhibitor (TKI) sensitizing mutations
             (EGFR Exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements (by
             fluorescence in situ hybridization [FISH], next generation sequencing [NGS], or
             immunohistochemistry [IHC]) by routine Clinical Laboratory Improvement Act
             (CLIA)-certified clinical testing methods. Negative circulating tumor deoxyribonucleic
             acid (DNA) results alone are not acceptable. Prior testing for tumor PD-L1 status is
             not required

          -  ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patients WITHOUT tumors with known
             molecular alterations in ROS1, MET, RET, or must have progressed radiographically (per
             local investigator assessment) following one, but only one, line of platinum-based
             chemotherapy AND one, but only one, line of prior immunotherapy. Lines of therapy are
             defined by clinical or radiographic progression. Patients may have received
             chemotherapy and immunotherapy either concurrently or sequentially in either order.
             Patient must have received at least 2 prior doses of checkpoint inhibitor therapy in
             an every 2, 3, or 4 week schedule. No submission of molecular testing is required and
             patients may be registered for Step 0 then proceed directly to Step 1 screening OR
             Patients with tumors with known molecular alterations in ROS1, MET, and RET must have
             progressed radiographically (per local investigator clinical assessment) on at least
             one line of prior chemotherapy or targeted therapy, but there is no limit on number of
             prior number. Reciept of prior immunotherapy is allowed but not required.

               -  Known molecular alterations in ROS1 , MET, and RET are defined as below ROS1 gene
                  rearrangement by FISH or DNA analysis. In addition to above requirements, these
                  patients must have progressed on at least one prior ROS1 TKI therapy

               -  MET exon 14 splice mutations on DNA analysis. In addition to above requirements,
                  prior MET directed TKI therapy is optional

               -  MET mutations predicted to be sensitive to MET inhibitor. In addition to above
                  requirements, prior MET directed TKI therapy is optional

               -  High MET amplification by FISH (characterized by a fluorescence in situ
                  hybridization MET/CEP7 ratio of 5 or greater); OR MET amplification by DNA NGS
                  CLIA certified assay. In addition to above requirements, prior MET directed TKI
                  therapy is optional

               -  RET gene rearrangement by FISH or DNA analysis. In addition to above
                  requirements, prior RET directed TKI therapy is optional

                    -  During Step 0 screening, CLIA reports of the testing results must be
                       submitted via Medidata Rave for central review for instructions. The central
                       review will be performed by the study chair, co-chair, biology co-chair,
                       and/or a delegate to determine that the results indicate a patient's
                       eligibility for targeted therapy. CLIA reports that contain information
                       pertaining to any of the above mutations will be uploaded to Medidata Rave
                       for central review of documentation for determination of patient eligibility
                       for targeted therapy (Arm T). Central testing of tissue will not be
                       performed. 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. Patients with tumors with the above known molecular
                       alterations are eligible for cohort Arm Z following Step 1 eligibility
                       review. Patients without tumors with the above known molecular alterations
                       for randomization to Arm A, B or C following Step 1 eligibility review

          -  ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): NOTE: Patients with a prior or
             concurrent malignancy whose natural history or treatment does not have the potential
             to interfere with the safety or efficacy assessment of the investigational regimen (in
             the opinion of the treating physician) are eligible for this trial

          -  ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patients with known history or
             current symptoms of cardiac disease, or history of treatment with cardiotoxic agents
             (such as anthracycline or human epidermal growth factor receptor (HER2)-directed
             antibody therapy, but not prior checkpoint inhibitor therapy), must have a clinical
             risk assessment of cardiac function using the New York Heart Association functional
             classification. To be eligible for this trial, patients must be class 2B or better

          -  ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have Eastern
             Cooperative Oncology Group (ECOG) performance status 0-1

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Patient must have met the eligibility criteria outlined above

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Patient must have measurable disease as defined by RECIST version (v) 1.1 criteria.
             Measurements must be obtained within 4 weeks prior to randomization/registration

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Patient must have an anticipated life expectancy greater than 3 months

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Any prior chemotherapy (based on administration schedule) must have been completed in
             greater than or equal to the following times prior to randomization/registration:

               -  Chemotherapy/targeted oral therapy administered in a daily or weekly schedule
                  must be completed >= 1 week prior to randomization/registration

               -  Any chemotherapy administered in an every 2 week or greater schedule must be
                  completed >= 2 weeks prior to randomization/registration

               -  Additionally, patient should be recovered to equal to or less than grade 1
                  toxicities related to any prior treatment, unless adverse events (AE[s]) are
                  clinically non significant and/or stable on supportive therapy (as determined by
                  the treating physician)

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Leukocytes >= 3,000/mcL (obtained within 2 weeks prior to randomization/registration)

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Absolute neutrophil count >= 1,500/mcL (obtained within 2 weeks prior to
             randomization/registration)

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Platelets >= 100,000/mcL (obtained within 2 weeks prior to randomization/registration)

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Hemoglobin >= 9 g/dL (obtained within 2 weeks prior to randomization/registration)

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained within 2
             weeks prior to randomization/registration)

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             ULN (obtained within 2 weeks prior to randomization/registration)

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             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 creatinine =<
             1.5 x ULN or creatinine clearance >= 50 ml/min/1.73 m^2 (obtained within 2 weeks prior
             to randomization/registration)

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Patient must have corrected QT interval calculated by the Fridericia formula QTc
             corrected by Fridericia (QTcF) =< 500 ms within 28 days prior to
             randomization/registration

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Patient must be able to swallow tablets

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Patients with treated brain metastases are eligible if follow-up brain imaging after
             central nervous system (CNS)-directed therapy shows no evidence of progression

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Patients with new or progressive brain metastases (active brain metastases) are
             eligible if the treating physician determines that immediate CNS specific treatment is
             not required and is unlikely to be required during the first cycle of study treatment.

               -  Patient must meet one of the following criteria with respect to brain metastases:
                  Patients with no known brain metastasis must have baseline brain imaging within
                  12 weeks prior to study randomization/registration not demonstrating brain
                  metastases OR patients with known brain metastases must have baseline brain
                  imaging and completed treatment to all symptomatic brain metastases (with whole
                  brain radiation or radiosurgery; or complete neurosurgical resection >= 3 months
                  prior to randomization/registration) >= 4 weeks prior to
                  randomization/registration. They must be clinically stable. Known leptomeningeal
                  disease is not allowed

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Known human immunodeficiency virus (HIV)-infected patients on effective
             anti-retroviral therapy with undetectable viral load within 6 months of registration
             are eligible for this trial

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV
             viral load must be undetectable on suppressive therapy at time of
             registration/randomization, if indicated

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Patients with a known history of hepatitis C virus (HCV) infection must have been
             treated and cured. For patients with HCV infection who are currently on treatment,
             they are eligible if they have an undetectable HCV viral load at time of
             registration/randomization

          -  ADDITIONAL ELIGIBILITY CRITERIA FOR STEP 1 (REGISTRATION) TARGETED ARM T: Patient was
             registered to step 0, targeted arm and central review results report the patient is
             eligible for arm T

          -  ADDITIONAL ELIGIBILITY CRITERIA FOR STEP 1 (REGISTRATION) TARGETED ARM T: Patients
             with ROS1 gene rearrangements must have progressed on at least one prior ROS1 targeted
             therapy such as crizotinib

          -  ADDITIONAL ELIGIBILITY CRITERIA FOR STEP 1 (REGISTRATION) TARGETED ARM T: Patient must
             have progressed radiographically (per local investigator clinical assessment) on at
             least one line of prior chemotherapy or targeted therapy, but there is no limit on
             number of prior number. Prior immunotherapy is allowed but not required. Prior
             bevacizumab with chemo is allowed.

               -  NOTE: The requirement for prior chemotherapy will be met if patients have
                  recurrence within 6 months after prior adjuvant platinum based chemotherapy for
                  early stage disease, or recurrence within 6 months after prior radiotherapy plus
                  platinum based chemotherapy for locally advanced disease

               -  NOTE: Patients with unresectable stage III NSCLC who have received chemo and
                  radiation then consolidation durvalumab, followed by progression are eligible if
                  progression happens after > 2 doses of durvalumab. Prior bevacizumab with chemo
                  is also allowed

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have met all eligibility
             requirements for Step 1 at time of registration to Step 1 to be eligible for Step 2

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have radiographic
             progressive disease per RECIST criteria after >= 2 cycles of therapy on arm C

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must be registered to step 2
             within 4 weeks of the last dose of treatment administration from step 1

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have an ECOG performance
             status between 0-2

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have recovered to
             baseline (pre-step 1) or Common Terminology Criteria for Adverse Events (CTCAE) v.5.0
             =< grade 1 from toxicity due to all prior therapies except alopecia and other
             non-clinically significant adverse events (AEs)

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Leukocytes >= 3,000/mcL (obtained
             within 2 weeks prior to randomization/registration)

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Absolute neutrophil count >= 1,500/mcL
             (obtained within 2 weeks prior to randomization/registration)

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Platelets >= 100,000/mcL (obtained
             within 2 weeks prior to randomization/registration)

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Hemoglobin >= 9 g/dL (obtained within 2
             weeks prior to randomization/registration)

          -  Total bilirubin =< 1.5 x institutional ULN (obtained within 2 weeks prior to
             randomization/registration)

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Aspartate aminotransferase (AST) (serum
             glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum
             glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (obtained within 2 weeks prior to
             randomization/registration)

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Creatinine =< 1.5 x ULN OR calculated
             (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 m^2
             (normalized to BSA) for patients with creatinine levels greater than 1.5 times the
             institutional normal creatinine =< 1.5 x ULN or creatinine clearance >= 50 ml/min/1.73
             m^2 (obtained within 2 weeks prior to randomization/registration)

          -  STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have corrected QT
             interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before
             registration

        Exclusion Criteria:

          -  ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
             Patient must not have had any prior radiation therapy for bone metastasis within 2
             weeks, or any other radiation therapy within 4 weeks prior to
             randomization/registration

          -  ELIGIBILITY CRITERIA FOR STEP
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS) for patient population with non-squamous no-small cell lung cancer (NSCLC)
Time Frame:After 58 events (From time of randomization to documented disease progression [site review of imaging] or death from any cause, whichever occurs first)
Safety Issue:
Description:The final analysis of PFS will be performed when the full information of PFS is reached (i.e., 58 events for each of the two primary comparisons). The two primary comparisons of PFS will each use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Estimates of PFS including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Cox proportional hazards models, stratified, on the same factors, will be used to estimate the treatment hazard ratios. At the final analyses, in the event that both primary PFS comparisons of the combination of nivolumab with cabozantinib and cabozantinib alone versus the standard chemotherapy are statistically significant, PFS will be compared between the two experimental arms (combination of nivolumab with cabozantinib versus [vs.] cabozantinib alone), using a stratified log rank test with a one-sided type I error rate of 10%.

Secondary Outcome Measures

Measure:Overall survival (OS) for each arm
Time Frame:From time of randomization to documented disease progression (site review of imaging) or death from any cause, whichever occurs first, assessed up to 3 years
Safety Issue:
Description:The final analysis of OS will be performed when the full information of PFS is reached (i.e., 58 events for each of the two primary comparisons). OS will be tested in a hierarchical fashion if the primary comparison of PFS between treatment arms is statistically significant, using a log rank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Estimates of OS, including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Cox proportional hazards models, stratified, on the same factors, will be used to estimate the treatment hazard ratios. OS will be further tested in a hierarchical fashion if the comparison of PFS between the two experimental arms is statistically significant. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. Subset analyses of PFS and OS by treatment arm will be estimated and compared within subsets.
Measure:Best objective response for each arm
Time Frame:Every 6 weeks for the first year on study, and then every 12 weeks after year one
Safety Issue:
Description:Will be evaluated via Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response rates (complete response [CR] + partial response [PR]) and toxicity will be compared using Fisher'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. Modeling procedures will implement backward selection; variables significant at the 0.10 level in the univariate setting will be chosen for inclusion in an initial full model, and at each step the least significant variable will be removed from the model. Only those covariates with p < 0.05 will remain in any final models, unless there are factors identified by the study team as crucial to model interpretation. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals.
Measure:Toxicity profile of monotherapy with cabozantinib, and the combination of nivolumab and cabozantinib
Time Frame:Up to 3 years after completion of study treatment
Safety Issue:
Description:Will be determined using the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Response rates (complete response [CR] + pathologic response [PR]) and toxicity will be compared using Fisher'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. Modeling procedures will implement backward selection; variables significant at the 0.10 level in the univariate setting will be chosen for inclusion in an initial full model, and at each step the least significant variable will be removed from the model. Only those covariates with p < 0.05 will remain in any final models, unless there are factors identified by the study team as crucial to model interpretation. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals.

Details

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

Last Updated

January 11, 2021