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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

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ClinicalTrials.gov Identifier: NCT04310007
Recruitment Status : Recruiting
First Posted : March 17, 2020
Last Update Posted : October 21, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE March 16, 2020
First Posted Date  ICMJE March 17, 2020
Last Update Posted Date October 21, 2021
Actual Study Start Date  ICMJE May 22, 2020
Estimated Primary Completion Date May 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 16, 2020)
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%.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 16, 2020)
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: March 16, 2020)
  • 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, B, and T, 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).
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE A Randomized Phase II Trial of Cabozantinib and Cabozantinib Plus Nivolumab Versus Standard Chemotherapy in Patients With Previously Treated Non-Squamous NSCLC
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Cabozantinib S-malate
    Given PO
    Other Names:
    • BMS-907351
    • Cabometyx
    • Cometriq
    • XL-184
    • XL184
  • Drug: Docetaxel
    Given IV
    Other Names:
    • Docecad
    • RP56976
    • Taxotere
    • Taxotere Injection Concentrate
  • 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
  • Biological: Nivolumab
    Given IV
    Other Names:
    • BMS-936558
    • CMAB819
    • MDX-1106
    • NIVO
    • Nivolumab Biosimilar CMAB819
    • ONO-4538
    • Opdivo
  • 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
Study Arms  ICMJE
  • Experimental: Arm A (cabozantinib S-malate)
    Patients 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.
    Intervention: Drug: Cabozantinib S-malate
  • Experimental: Arm B (cabozantinib S-malate, nivolumab)
    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.
    Interventions:
    • Drug: Cabozantinib S-malate
    • Biological: Nivolumab
  • Active Comparator: Arm C (standard chemotherapy,cabozantinib S-malate, nivolumab)
    See Detailed Description
    Interventions:
    • Drug: Cabozantinib S-malate
    • Drug: Docetaxel
    • Drug: Gemcitabine Hydrochloride
    • Drug: Nab-paclitaxel
    • Biological: Nivolumab
    • Drug: Paclitaxel
    • Biological: Ramucirumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 16, 2020)
142
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 1, 2022
Estimated Primary Completion Date May 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04310007
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Joel W Neal ECOG-ACRIN Cancer Research Group
PRS Account National Cancer Institute (NCI)
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP