Trial of an Alternative Cabozantinib Dosing Schedule in Metastatic Renal Cell Carcinoma and Neuroendocrine Tumors

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 (NETs). The study is comprised of three cohorts; Cohorts A and C will employ the alternative dosing schema with cabozantinib monotherapy in any-line clear cell or non-clear cell mRCC patients and patients with pancreatic or extra-pancreatic NETs, and Cohort B will employ the alternative dosing schema with cabozantinib in combination with standard-dosed nivolumab in front-line clear cell or non-clear cell mRCC patients. Study will accrue a total of 111 patients (Cohort A n=49, Cohort B n=37, Cohort C n=25). Patients in cohorts A and C will be treated with the same cabozantinib alternative dosing schema and schedule, with the exception of Cohort B patients also receiving monthly fix-dosed nivolumab infusions. Patients will start at 40 mg of cabozantinib daily and dose escalate or de-escalate based on pre-specified criteria and at set dosing schedules to allow for smaller median dose changes between adjustments. The de-escalation would be fine-tuned and adjustments would be made in 10 mg average daily dosing increments by utilizing alternate day dosing schedules (e.g. 60 mg/40 mg every other day) rather than decreasing by 20 mg (table 1). The maximum dose of cabozantinib is 60 mg daily, while the lowest dosing level on trial will be 20 mg every other day. Cycles would be 28 days, with weekly follow-up for cycle 1 and bi-weekly follow-up for cycle 2 to allow for prompt dose adjustments, and then monthly. At each check-in, patients in Cohorts A and B that have met the established protocol criteria (outlined in Section 6.3) and were not yet at the maximum dose of 60 mg daily would be eligible for dose-escalation. At each check in, patients in cohort C that have met the established protocol criteria and were not yet at the maximum dose of 60 mg daily will be mandated to start next higher dose level. Patients would also be dose de-escalated as determined by the investigator. Patients who de-escalate may be allowed to re-escalate in the future.