This is a multi-site, three-cohort phase II trial of cabozantinib for IMDC all-risk frontline metastatic renal cell carcinoma (mRCC) patients OR any line mRCC patients who have not previously been treated with cabozantinib, and patients with pancreatic or extra-pancreatic neuroendocrine tumors.
Cohorts A and B: Histologically or cytologically confirmed advanced RCC with any clear cell or non-clear cell component. 100% sarcomatoid is permissible.
Cohorts A and B: Patient may have had any number of prior therapies for Cohort A, but for Cohort B patients must not have received any systemic therapy in the metastatic setting
Patients who have received prior (neo)adjuvant immunotherapy with pembrolizumab or similar are eligible for Cohort B IF they completed the adjuvant therapy > 12 months from start of trial therapy
Treatment naïve patients may be treated in Cohort A if deemed not candidates for nivolumab or if felt single agent cabozantinib most appropriate by the treating clinician
Patients who have had systemic anti-cancer therapy or radiotherapy within 14 days or five half-lives, whichever is shorter, prior to entering the study.
Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks, or systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Ongoing clinically relevant complications from prior radiation therapy would preclude eligibility.
Patients with prior therapy with cabozantinib.
Prior systemic therapy directed at advanced RCC is not allowed for patients enrolled to Cohort B (treatment-naïve group).
Parallel
Cabozantinib
DrugCabozantinib initiated at 40 mg daily. Dose-escalate or de-escalate based on pre-specified criteria and at set dosing schedules
Nivolumab
DrugNivolumab injection is to be administered as an IV infusion at a dose of 480 mg on day 1 of each cycle
Cohort A: Average daily dose of cabozantinib > 42.8 mg in at least 70% of patients
To show that alternative cabozantinib dosing can improve average daily dose compared to historical controls
Cohort B: 75% of patients alive and progression free at 12 months
Cohort B: To show that alternative cabozantinib dosing + nivolumab (standard dose) can improve 12-month rate of progression-free survival over standard dose cabozantinib + nivolumab
Cohort C: Decreased rate of grade ≥ 3 adverse events compared to 75% reported in CABINET trial
Cohort C: To show that alternative cabozantinib dosing can improve rates of grade \> 3 adverse events compared to the grade 3-5 adverse events reported in the CABINET trial
Cohort A: Decreased grade ≥ 3 adverse events compared to historical controls (METEOR trial)
Demonstrate that alternative dosing can change overall toxicity compared to historical controls by monitoring grade ≥ 3 adverse events compared to historical controls
Cohort A: Improved median duration of time on drug compared to historical controls
Show that alternative scheduling can change median duration of time on drug compared to historical controls
Cohort A: Objective response rate per RECIST 1.1 criteria of all patients treated
Response rates will be summarized via frequencies and 95% confidence intervals, and compared to historical results using two-sided one-sample exact binomial tests of proportions
Cohort B: Decreased grade ≥ 3 adverse events compared to historical comparison from the CheckMate 9ER trial
Demonstrate that alternative dosing can change overall toxicity compared to historical controls by monitoring grade ≥ 3 adverse events compared to historical controls
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Fox Chase Cancer Center
Lead sponsor
Exelixis
Collaborator
