This phase I trial studies the side effects and best doses of cabozantinib s-malate and nivolumab with or without ipilimumab in treating patients with genitourinary (genital and urinary organ) tumors that have spread from where it first started (primary site) to other places in the body (metastatic). Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving cabozantinib s-malate and nivolumab alone or with ipilimumab works better in treating patients with genitourinary tumors.
PRIMARY OBJECTIVES: I. Determine the dose limiting toxicity (DLT) and recommended phase II dose (RP2D) of the combination of cabozantinib s-malate (cabozantinib) and nivolumab (cabo-nivo) and separately the combination of cabozantinib, nivolumab and ipilimumab (cabo-nivo-ipi) in patients with genitourinary tumors. (Phase I) II. Assess safety and tolerability of cabozantinib, nivolumab and ipilimumab (cabo-nivo-ipi) in patients with genitourinary tumors at this novel dose. (Dose Level 8 Cohort) SECONDARY OBJECTIVES: I. Preliminarily evaluate the activity, as determined by objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the modified Immune-Related Response Criteria (irRC), derived from RECIST 1.1, of: Ia. Cabo-nivo and cabo-nivo-ipi in patients with advanced/refractory metastatic urothelial carcinoma (checkpoint inhibition therapy naive) and with renal cell carcinoma in the second-line and beyond setting. Ib. Cabo-nivo in patients with adenocarcinoma and with rare histologies (including squamous or small cell carcinomas of the bladder, renal medullary carcinoma, sarcomatoid bladder and renal cell carcinomas, plasmacytoid carcinoma of the bladder and others) in the first line or beyond setting. Ic. Cabo-nivo in patients with urothelial carcinoma previously treated with checkpoint inhibition therapy in the second line or beyond setting. Id. Cabo-nivo-ipi in patients with squamous cell carcinoma of the penis. II. To evaluate the activity as determined by progression free survival (PFS) and overall survival (OS) of: IIa. Cabo-nivo and cabo-nivo-ipi in patients with advanced/refractory metastatic urothelial carcinoma (checkpoint inhibition therapy naive) or with renal cell carcinoma in the second-line and beyond setting. IIb. Cabo-nivo in patients with adenocarcinoma and with rare histologies (including squamous, small cell carcinomas of the bladder, renal medullary carcinoma, sarcomatoid bladder and renal cell carcinomas, plasmacytoid carcinoma of the bladder and others) in the first line or beyond setting. IIc. Cabo-nivo in patients with urothelial carcinoma previously treated with checkpoint inhibition therapy in the second line or beyond setting. IId. Cabo-nivo-ipi in patients with squamous cell carcinoma of the penis. III. To obtain additional data to evaluate the safety of both combinations in patients with clear cell renal cell carcinoma (ccRCC). IV. To assess the number of malignant soft tissue and bone lesions on fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET)/computed tomography (CT) (scan 1) versus combined fluorine F 18 sodium fluoride (18F-NaF) and 18F-FDG PET/CT (scan 2). V. To assess response assessment by RECIST 1.1 using CT of the chest, abdomen, and pelvis with intravenous (IV) contrast versus assessment by combined 18F-NaF and 18F-FDG PET/CT (scan 2) using number of malignant and change (modified PET RECIST \[PERCIST\]) of soft tissue and bone lesions. VI. To test the feasibility of automated density and volume application (ADaVA) as a means of assessing tumor response. VII. To assess PDL-1 and MET expression data and in exploratory fashion analyze their association to response or clinical benefit. EXPLORATORY OBJECTIVES: I. To assess overall response rates (ORR) on patients who have been challenged or re-challenged with ipilimumab therapy post disease progression. II. To assess effects of treatment in patients with bone-only disease. III. To use circulating tumor deoxyribonucleic acid (ctDNA) analysis to assess the level of ctDNA at multiple time points during therapy and correlate with outcomes (e.g., objective responses, disease burden, PFS, OS, and adverse events). OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 treatment arms. PART I: Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28 and nivolumab intravenously (IV) over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 21 cycles, patients receive nivolumab IV over 30 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. After progression, patients may receive cabozantinib s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 cycles followed by cabozantinib s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-cycle 21 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography or magnetic resonance imaging and collection of blood samples throughout the trial. Patients may also undergo echocardiography at baseline and biopsies throughout the trial. PART II: Patients receive cabozantinib s-malate PO QD on days 1-21, nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 90 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of 4 cycles with ipilimumab, patients continue receiving cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 21 cycles, patients receive nivolumab IV over 30 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. After progression, patients may receive cabozantinib s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 cycles followed by cabozantinib s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-cycle 21 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography or magnetic resonance imaging and collection of blood samples throughout the trial. Patients may also undergo echocardiography at baseline and biopsies throughout the trial. After completion of study treatment, patients are followed up at 16 weeks, and then every 3 months thereafter.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
152
Undergo biopsies
Undergo collection of blood
Given PO
Undergo CT scan
Undergo echocardiography
Given IV
Undergo MRI
Given IV
City of Hope Comprehensive Cancer Center
Duarte, California, United States
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
NCI - Center for Cancer Research
Bethesda, Maryland, United States
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Recommended phase II dose (Phase I)
Will be defined as the highest dose for which no more than 1/6 patients experience a dose limiting toxicity evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The safe dose level of cabozantinib and nivolumab, as well as of cabozantinib, nivolumab, and ipilimumab will be established.
Time frame: Up to 4-6 weeks
Incidence of adverse events (Phase I)
Will be evaluated according National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The safety and tolerability of a novel dose of cabozantinib, nivolumab and ipilimumab in patients with genitourinary cancer will be assessed.
Time frame: Up to 30 days post treatment
Clinical response rate
Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1 and Immune-Related Response Criteria. The response rate may be used to guide the further development of the combinations.
Time frame: Up to 3 years
Fraction of patients who have been identified as being alive and progression free at two months
May be determined as well and reported on both arms. This fraction will be considered as a secondary endpoint for the expansion cohorts as well, and this information may be used to guide the further development of the combinations. A Kaplan-Meier curve for progression free survival will also be presented as a secondary endpoint, in addition to reporting the fraction without progression at two months.
Time frame: At 2 months
PDL-1 and MET expression
PDL-1 and MET expression data will be obtained in patients with urothelial carcinoma checkpoint inhibition naive, clear cell renal cell carcinoma, adenocarcinoma of the bladder, squamous cell carcinoma of the bladder, urothelial carcinoma with prior checkpoint inhibition therapy, and penile cancer. Data will be obtained in pre- and post-treatment biopsies and analyze, in at least an exploratory fashion, their association to response or clinical benefit.
Time frame: Up to day 1 of final cycle
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