70: Phase 2 Study of Nivolumab plus 177Lutetium-labeled Anti–Carbonic Anhydrase IX Monoclonal Antibody Girentuximab in Patients with Advanced Clear Cell Renal Cell Carcinoma

Background: Radiolabeled 89Zr-girentuximab shows promise as a novel PET tracer. and labeling with 177Lu shows promise as a therapeutic agent in ccRCC (Muselaers, 2016). Targeted delivery of radiation to ccRCC cells may prime the immune response by enhancing tumor antigen presentation, providing rationale for combining 177Lu-girentuximab with nivolumab. This phase 2, open-label, single arm study aims to evaluate 177Lu-girentuximab in combination with nivolumab in pts with previously-treated ccRCC.

Methods: Pts with biopsy-proven ccRCC, progressive disease after prior systemic therapy including ≥1 immunotherapy, adequate organ/marrow function, and ≥1 evaluable lesion by RECIST 1.1 avid on 89Zr-girentuximab PET will be enrolled. Treatment consists of 177Lu- girentuximab every 12-14 weeks (max 3 doses plus nivolumab 240mg every 2 weeks until progressive disease or unacceptable toxicity). Due to expected cumulative myelosuppression, each subsequent 177Lu-girentuximab dose to the same patient is reduced by 25%. Tumor imaging will be performed every 12 weeks. A safety lead-in is followed by expansion phase. In the safety lead-in phase, the MTD will be determined with a 3+3 design using a starting dose of 1804 MBq/m2 (75% of single-agent MTD). For cohort 2, dose escalation to 2405 MBq/m2 (single-agent MTD) or de-escalation to 1353 MBq/m2 will be DLT-based.

In expansion phase, a Simon 2-stage optimal design will evaluate response rate by RECIST 1.1 within 24 weeks. With ≥1 response in the first Simon stage (n=10; includes pts treated at MTD in safety lead-in), a second stage will open (n=19) for a total n=29 with ≥3 responses indicating the regimen worthy of further study. Secondary endpoints include PFS, OS, and toxicity including a continuous safety monitoring rule during expansion. Exploratory imaging with 89Zr-girentuximab PET will be performed at baseline and before each 177Lu-girentuximab dose with results correlated with RECIST response on CI. The trial is currently enrolling.