High dose Interleukin-2 (HD IL2) immunotherapy is standard therapy in suitable patients (pts) with metastatic clear cell RCC who have good performance status. HD IL-2 is unique among RCC therapies in eliciting durable complete responses (DCR) with a median duration of such responses of 12 years. However, the complete response (CR) proportion for HD IL-2 monotherapy is only 7-9%. There is an urgent need to evaluate HD IL2 combination therapies that could increase the response proportion. IL-2 promotes early steps in the lymphocyte activation cascade, increases trafficking of cytotoxic T lymphocytes to the tumor and induces Th1 differentiation of CD4 T helper cells. Nivolumab, an immune checkpoint inhibitor, blocks the interaction between PD-1 on activated T cells and its ligands that are expressed on immune cells and tumor cells. We hypothesize that the combination of HD IL2 and a PD-1 inhibitor would elicit a potent synergistic anti-cancer immune response reflected in improved response proportion and survival with acceptable toxicity in pts with metastatic clear cell RCC.
This multi-site Ib/II trial will determine safety and efficacy of HD IL-2 in combination with nivolumab for RCC. Pts with metastatic clear cell RCC, 0-2 prior systemic therapies and candidates for HD IL2 and for nivolumab are eligible. Pts will be treated with HD IL-2 (600,000 IU/kg/dose every 8 hours for up to 14 doses) on Days 1-5 and again on Days 15-19, with nivolumab (240 mg IV every 14 days) starting on Day 8 +/- 3 wks. Pts will continue on nivolumab every 2 wks for up to 48 wks barring intolerable toxicities or consent withdrawal or progressive disease. Nivolumab may potentially be continued beyond first progression. The primary objective/endpoint of the phase 1b portion of the trial is safety of the combination/immune mediated grade 3/4 events of interest. The primary endpoint of the phase II portion of the trial is the overall response proportion (ORR) as assessed by RECIST 1.1. Secondary endpoints are safety/toxicity, overall survival and PFS at 2 years. Planned accrual is 23 evaluable subjects over 2 years. Whole blood and serum will be analyzed for circulating immune cell repertoire and baseline tumor tissue will be sequenced.
Clinical trial identification
Legal entity responsible for the study
Prometheus, University of Michigan
A. Alva: Advisory role for Eisai, AstraZeneca and Roche. Received research funding: Genentech, Novartis, Bristol-Myers Squib, BIND Bioscience, Acerta Pharma, Merck, Prometheus Laboratories, Covance, Mirati Therapeutics, United Biosources Corporation, ARIAD, Pfizer & Bayer. All other authors have declared no conflicts of interest.