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

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: NCT04310007
Recruitment Status : Recruiting
First Posted : March 17, 2020
Last Update Posted : June 6, 2023
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Lung Non-Squamous Non-Small Cell Carcinoma Recurrent Lung Non-Squamous Non-Small Cell Carcinoma Stage IV Lung Cancer AJCC v8 Procedure: Biospecimen Collection Drug: Cabozantinib S-malate Procedure: Computed Tomography Drug: Docetaxel Procedure: Echocardiography Drug: Gemcitabine Hydrochloride Drug: Nab-paclitaxel Biological: Nivolumab Drug: Paclitaxel Biological: Ramucirumab Phase 2

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Study Design
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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 117 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase II Trial of Cabozantinib and Cabozantinib Plus Nivolumab Versus Standard Chemotherapy in Patients With Previously Treated Non-Squamous NSCLC
Actual Study Start Date : May 22, 2020
Estimated Primary Completion Date : June 30, 2024
Estimated Study Completion Date : June 30, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Step 1, Arm A (cabozantinib S-malate)
Patients in Step 1, Arm A receive cabozantinib S-malate PO QD. Cycles repeat every 21 days 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. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
 Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection

Drug: Cabozantinib S-malate
Given PO
Other Names:
  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL-184
  • XL184

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography

Procedure: Echocardiography
Undergo ECHO
Other Name: EC
Experimental: Step 1, Arm B (cabozantinib S-malate, nivolumab)
Patients in Step 1, Arm B receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days 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. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
 Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection

Drug: Cabozantinib S-malate
Given PO
Other Names:
  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL-184
  • XL184

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography

Procedure: Echocardiography
Undergo ECHO
Other Name: EC

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • CMAB819
  • MDX-1106
  • NIVO
  • Nivolumab Biosimilar CMAB819
  • ONO-4538
  • Opdivo
Active Comparator: Step 1, Arm C (standard chemotherapy)
Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour 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 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
 Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography

Drug: Docetaxel
Given IV
Other Names:
  • Docecad
  • RP56976
  • Taxotere
  • Taxotere Injection Concentrate

Procedure: Echocardiography
Undergo ECHO
Other Name: EC

Drug: Gemcitabine Hydrochloride
Given PO
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • FF 10832
  • FF-10832
  • FF10832
  • Gemcitabine HCI
  • Gemzar
  • LY-188011
  • LY188011

Drug: Nab-paclitaxel
Given IV
Other Names:
  • ABI 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 Paclitaxel

Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat

Biological: Ramucirumab
Given IV
Other Names:
  • Anti-VEGFR-2 Fully Human Monoclonal Antibody IMC-1121B
  • Cyramza
  • IMC-1121B
  • LY3009806
  • Monoclonal Antibody HGS-ETR2
Experimental: Step 2, Arm Z (cabozantinib S-malate, nivolumab)
Patients in Step 2, Arm Z receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days 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. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.
 Procedure: Biospecimen Collection
Undergo blood collection
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection

Drug: Cabozantinib S-malate
Given PO
Other Names:
  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL-184
  • XL184

Procedure: Computed Tomography
Undergo CT
Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography

Procedure: Echocardiography
Undergo ECHO
Other Name: EC

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • CMAB819
  • MDX-1106
  • NIVO
  • Nivolumab Biosimilar CMAB819
  • ONO-4538
  • Opdivo


Outcome Measures
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Primary Outcome Measures :
  1. 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) ]
    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 :
  1. 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 ]
    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.

  2. 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 ]
    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.

  3. Toxicity profile of monotherapy with cabozantinib, and the combination of nivolumab and cabozantinib [ Time Frame: Up to 3 years after completion of study treatment ]
    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.


Other Outcome Measures:
  1. The RECIST1.1 response at each time point [ Time Frame: Every 6 weeks for the first year on study, and then every 12 weeks after year one ]
    The measurement of each time point will be performed using the revised CHOI criteria will be only applied to arms A and B, which will include anti-angiogenic therapy. Both the RECIST1.1 and revised CHOI criteria will assess the overall best response as CR, partial PR, stable disease (SD), or progressive disease (PD). Their concordance will be assessed using the weighted Cohen's kappa coefficient (k) with quadratic weights. As a rule of thumb, the level of concordance between the two criteria will be considered poor (k <0), slight (k 0-0.20), fair (k 0.21-0.40), moderate (k 0.41-0.60), substantial (k 0.61-0.80), and almost perfect (k 0.81 - 1).

  2. Agreement between central view and site review in terms of progression-free survival [ Time Frame: After the completion of study treatment ]
    The progression status and the progression time will be assessed in agreement. The progression status is a binary measurement and the agreement will be assessed using the Cohen's kappa coefficient. For progression time, will assess the temporal agreement using the method developed by Zeng et al.

  3. Correlative biomarker research [ Time Frame: After the completion of study treatment ]
    Correlative biomarker research will be performed on tissue and blood specimens collected within this trial.


Eligibility Criteria
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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:

  • RANDOMIZATION (STEP 1): Patient must be >= 18 years of age
  • RANDOMIZATION (STEP 1): Patient must have pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC). Patients with NSCLC not otherwise specified (NOS) are eligible. Mixed tumors will be categorized by predominant cell type. If small cell elements are present, the patient is ineligible
  • RANDOMIZATION (STEP 1): Patient must have metastatic Stage IVA or IVB disease (includes M1a, M1b, and M1c), according to the 8th edition of the lung cancer TNM classification system. Recurrent metastatic NSCLC ineligible for curative therapy (in the treating investigator's opinion) is also allowed
  • RANDOMIZATION (STEP 1): Patient's tumor must be known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (for example at a minimum, negative for EGFR Exon 19 deletions, EGFR exon 20 insertions, and Exon 21 L858R, L861Q mutations ) AND negative for ALK gene rearrangements (by fluorescence in situ hybridization [FISH], next generation sequencing [NGS], or immunohistochemistry [IHC]) by routine Clinical Laboratory Improvement Act (CLIA)- or Food and Drug Administration (FDA)-certified clinical testing methods. CLIA or FDA approved circulating tumor deoxyribonucleic acid (DNA) testing is acceptable as an alternative to tissue testing

  • RANDOMIZATION (STEP 1): Patient must have radiographic and/or clinical progression (per local investigator assessment) following one, but only one, line of platinum-based chemotherapy AND one, but only one, line of prior checkpoint inhibitor (anti-PD-1 or PD-L1) immunotherapy, either concurrently or sequentially in either order. A minimum of two doses of prior immunotherapy is required. Only one prior line of therapy is allowed if patients received chemotherapy and immunotherapy together (patients may not receive subsequent single agent chemotherapy), and greater than two prior lines of therapy are not allowed.

    • NOTE: Lines of therapy are defined by clinical or radiographic progression. For patients with recurrent metastatic NSCLC following treatment for stage 1-3 NSCLC, platinum-based chemotherapy received within 12 months of recurrence and/or immunotherapy received within 6 months of recurrence will meet the requirement for prior chemotherapy and/or immunotherapy but subsequent receipt of more immunotherapy and/or platinum-based chemotherapy is also allowed.
    • NOTE: Prior anti-VEGF antibody therapy (ie bevacizumab) is allowed. Prior ipilimumab, or investigational agents not excluded below, in combination with the required prior therapies above are allowed.
    • NOTE: Prior receipt of one or two lines of targeted therapy for ROS1, RET, MET, BRAF, ERBB2/HER2, or KRAS G12C positive NSCLC is allowed and will not count toward the line of therapy limit. However, progression is still required after chemotherapy and immunotherapy as above. Patients with ROS1, RET, MET positive NSCLC are strongly encouraged to get appropriate targeted therapy (such as crizotinib, entrectinib, lorlatinib, selpercatinib, pralsetinib, capmatinib, tepotinib, or another investigational, off-label, or approved agent directed against ROS1, RET, or MET positive NSCLC) prior to participation and will be stratified.
    • NOTE: No prior predominantly VEGFR directed TKI therapy (such as cabozantinib, lenvatinib, or sitravantinib) is allowed, except for the agents named above.
  • RANDOMIZATION (STEP 1): The investigator must document the intended chemotherapy regimen should their patient be randomized to Arm C (docetaxel and ramucirumab, OR single agent chemotherapy - docetaxel, gemcitabine, paclitaxel, nab-paclitaxel). The patient must not have received the selected chemotherapy agent previously for metastatic disease

  • RANDOMIZATION (STEP 1): Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to randomization:

    • FDA approved targeted oral therapy must be completed >= 1 week prior
    • Chemotherapy and/or immunotherapy must be completed >= 2 weeks prior
    • Prior investigational agents must be completed >= 4 weeks prior.
  • RANDOMIZATION (STEP 1): Prior radiation therapy is allowed with a 2 week washout prior to randomization. Patient must not receive any systemic treatment with radionuclides within 6 weeks prior to randomization. Patient must have no clinically relevant ongoing complication from prior radiation therapy
  • RANDOMIZATION (STEP 1): 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
  • RANDOMIZATION (STEP 1): Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents (such as anthracycline or 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
  • RANDOMIZATION (STEP 1): Patient must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have met the eligibility criteria outlined above
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have measurable disease as defined by RECIST v1.1. Measurements must be obtained within 4 weeks prior to randomization/registration
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have recovered to equal to or less than grade 1 toxicities related to prior treatment, unless toxicities are clinically non significant and/or stable on supportive therapy (as determined by the treating physician)
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Absolute neutrophil count >= 1,500/mcL (obtained within 2 weeks prior to randomization)
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Platelets >= 100,000/mcL (obtained within 2 weeks prior to randomization)
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Hemoglobin >= 9 g/dL (obtained within 2 weeks prior to randomization)
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (for patients with Gilbert's disease total bilirubin must be =< 3 x ULN) (obtained within 2 weeks prior to randomization)
  • RANDOMIZATION (STEP 1 - 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)
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Creatinine =< 1.5 x ULN OR calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73m^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 >= 50ml/min/1.73m^2 (obtained within 2 weeks prior to randomization)
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 msec within 28 days prior to Step 1 randomization
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must be able to swallow tablets

  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with brain metastases are eligible as follows:

    • Previously treated brain metastases must have been treated with radiation > 2 weeks prior to randomization or surgery > 3 months prior to randomization OR
    • Untreated (active) brain metastases are allowed if they are clinically asymptomatic, < 1 cm, non-hemorrhagic, the patient is not on systemic anticoagulation, and the investigator believes that central nervous system (CNS) specific treatment is unlikely to be required during the first 3 months of study treatment.
    • NOTE: Symptomatic leptomeningeal disease is NOT allowed
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with known history of human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with known history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral at time of randomization (suppressive therapy is allowed, if indicated)
  • RANDOMIZATION (STEP 1 - 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 randomization
  • STEP 2 (CROSSOVER ARM Z): Patient must have met all eligibility requirements for Step 1 at time of registration to Step 1 to be eligible for Step 2
  • STEP 2 (CROSSOVER ARM Z): Patient must have radiographic progressive disease per RECIST criteria after >= 2 cycles of therapy on Arm C. The scan showing progression must be completed within 6 weeks prior to Step 2 registration
  • STEP 2 (CROSSOVER ARM Z): Patient must have an ECOG performance status 0-2
  • STEP 2 (CROSSOVER ARM Z): Patient must have recovered to equal to or less than grade 1 toxicities related to prior treatment, unless the adverse event(s) are clinically non significant and/or stable on supportive therapy (as determined by the treating physician)
  • STEP 2 (CROSSOVER ARM Z): Absolute neutrophil count >= 1,500/mcL (obtained within 2 weeks prior to registration to Step 2)
  • STEP 2 (CROSSOVER ARM Z): Platelets >= 100,000/mcL (obtained within 2 weeks prior to registration to Step 2)
  • STEP 2 (CROSSOVER ARM Z): Hemoglobin >= 9 g/dL (obtained within 2 weeks prior to registration to Step 2)
  • STEP 2 (CROSSOVER ARM Z): Total bilirubin =< 1.5 x institutional ULN (for patients with Gilbert's disease total bilirubin must be =< 3 x ULN) (obtained within 2 weeks prior to registration to Step 2)
  • STEP 2 (CROSSOVER ARM Z): AST(SGOT) and ALT(SGPT) =< 2.5 x ULN (obtained within 2 weeks prior to registration to Step 2)
  • STEP 2 (CROSSOVER ARM Z): Creatinine =< 1.5 x ULN OR calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73m^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 >= 50ml/min/1.73m^2 (obtained within 2 weeks prior to registration to Step 2)
  • STEP 2 (CROSSOVER ARM Z): Patient must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days prior to Step 2 registration

Exclusion Criteria:

  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not be pregnant or breast-feeding due to the unknown effects of cabozantinib and nivolumab on human development and for the potential risk for adverse events in nursing infants with the treatment regimens being used.

    • All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization/registration to rule out pregnancy.
    • A patient of childbearing potential is anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 6 months after completion of treatment on the study
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have clinically significant gastrointestinal bleeding within 6 months prior to randomization
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have pulmonary hemorrhage or hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to randomization
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have active drug induced pneumonitis within 3 months prior to randomization. Prior immune mediated pneumonitis of grade 3 or 4 are not eligible regardless of time window
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have current radiographic evidence of tumor invading major blood vessel, evidence of tumor cavitation > 1 cm, evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or evidence of endotracheal or mainstem endobronchial tumor
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have peptic ulcer disease, known malabsorption syndrome, bowel obstruction or gastric outlet obstruction within 3 months prior to randomization
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to randomization
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have grade 3 or greater infection, or infection requiring intravenous systemic treatment within 14 days prior to randomization. Patients must be off antibiotics at the time of randomization
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have serious non-healing wound/ulcer/bone fracture within 28 days prior to randomization
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have history of organ transplant
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have concurrent symptomatic untreated hypothyroidism
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have history of major surgery within 3 months prior to randomization, minor surgery within 28 days prior to randomization, other minor procedures within 7 days prior to randomization, or clinically relevant ongoing complications from prior procedures
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 160 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have unstable angina pectoris, clinically-significant cardiac arrhythmias, stroke (including transient ischemic attack [TIA]), or myocardial infarction within 6 months prior to randomization
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have a diagnosis of deep vein thrombosis/pulmonary embolism (DVT/PE) within 6 months of randomization unless stable, asymptomatic, and treated with low-molecular-weight heparin (LMWH) or a permitted oral anticoagulant for at least 7 days before randomization

  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not be receiving anticoagulants (i.e., warfarin, aspirin, clopidogrel) except:

    • Prophylactic use of low-dose aspirin (100 mg po daily or less) and/or low dose molecular weight heparin (LMWH) is permitted.
    • Therapeutic doses of low dose molecular weight heparin (LMWH) or specified direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban are allowed in patients without untreated brain metastases who are on a stable dose 7 days prior to study randomization, and without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not receive strong CYP3A4 inducers (e.g., dexamethasone (> 1 mg daily dosing), phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort) within 7 days prior to randomization

  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not be on continuous systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days prior to randomization, with the following exceptions:

    • 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, 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
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not have 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 (e.g., immune-related neurologic disease, multiple sclerosis, autoimmune neuropathy, Guillain-Barre syndrome, etc.).
  • RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not have had any prior allergic reaction or hypersensitivity to study drug components or related drugs (multitargeted small molecule tyrosine kinase inhibitors or checkpoint inhibitor monoclonal antibodies)
  • STEP 2 (CROSSOVER ARM Z): Patient must not have intervening anticancer treatment or major surgical procedure(s) between Step 1 and Step 2, except palliative radiation which was completed >= 1 week prior to registration to Step 2
  • STEP 2 (CROSSOVER ARM Z): Patient may not have central nervous system progression, but patients with stable CNS disease are allowed
  • STEP 2 (CROSSOVER ARM Z): Patient must not have any intercurrent illness or disease complication that the investigator believes would limit the ability to safely tolerate the combination of cabozantinib and nivolumab

  • STEP 2 (CROSSOVER ARM Z): Patient must not be pregnant or breast-feeding due to the unknown effects of cabozantinib and nivolumab on human development and for the potential risk for adverse events in nursing infants with the treatment regimens being used.

    • All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to Step 2 to rule out pregnancy.
    • A patient of childbearing potential is anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  • STEP 2 (CROSSOVER ARM Z): Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 6 months after completion of treatment on the study
Contacts and Locations
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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): NCT04310007


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Joel W Neal ECOG-ACRIN Cancer Research Group
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04310007    
Other Study ID Numbers: NCI-2020-01541
NCI-2020-01541 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA5191 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA5191 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
First Posted: March 17, 2020    Key Record Dates
Last Update Posted: June 6, 2023
Last Verified: March 2023
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:
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Carcinoma
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Paclitaxel
Docetaxel
 Albumin-Bound Paclitaxel
Gemcitabine
Nivolumab
Ramucirumab
Antineoplastic Agents, Immunological
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Lexatumumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action