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

• Status: Recruiting
• Trial end date: 2022-05-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Albumin-Bound Paclitaxel; Antibodies; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Docetaxel; Gemcitabine; Immunoglobulins; Nivolumab; Paclitaxel; Ramucirumab

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