STARLITE 2: Phase 2 study of nivolumab plus 177Lutetium-labeled anti-carbonic anhydrase IX (CAIX) monoclonal antibody girentuximab (177Lu-girentuximab) in patients (pts) with advanced clear cell renal cell carcinoma (ccRCC).

TPS4603 Background: CAIX is a cell surface glycoprotein expressed in > 90% of ccRCC but rarely in normal tissues, providing a target for imaging and therapeutic application. Radiolabeling the anti-CAIX monoclonal antibody girentuximab with 89 Zr has shown promise as a novel PET tracer and labeling with 177 Lu promise as a therapeutic agent in ccRCC (Muselaers, Eur Urol, 2016). Targeted delivery of radiation to ccRCC cells may prime the immune response by enhancing tumor antigen presentation, providing rationale for combining 177 Lu-girentuximab with the anti-PD-1 antibody, nivolumab. This phase 2, open-label, single arm study (NCT05239533) is being conducted to evaluate 177 Lu-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 (IO) agent, adequate organ/marrow function, and ≥1 evaluable lesion by RECIST 1.1 that is also avid on 89 Zr-girentuximab PET will be enrolled. There is no limit on number of prior lines of systemic therapy, but pts who stopped IO for immune toxicity are excluded. Treatment consists of 177 Lu-girentuximab every 12-14 weeks for a maximum of 3 doses plus nivolumab 240mg every 2 weeks until progressive disease (PD) or unacceptable toxicity. Due to expected cumulative myelosuppression, each subsequent 177 Lu-girentuximab dose to the same patient is reduced by 25% (dose 2 = 75% of dose 1; dose 3 = 75% of dose 2). Tumor imaging is performed every 12 weeks. Pts will be evaluated in a safety lead-in phase followed by an expansion phase. In the safety lead-in phase, the MTD of 177 Lu-girentuximab in combination with nivolumab will be determined with a 3+3 design using a starting dose of 1804 MBq/m 2 (75% of single agent MTD). For cohort 2, dose escalation to 2405 MBq/m 2 (single agent MTD) or de-escalation to 1353 MBq/m 2 will be based on dose-limiting toxicities. In the expansion phase, a Simon 2-stage optimal design is used to evaluate the primary endpoint of 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 of 29 pts 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 89 Zr-girentuximab PET is performed at baseline and before each 177 Lu-girentuximab dose with results correlated with RECIST response on conventional imaging. In addition, whole body planar and SPECT imaging are performed after each 177 Lu-girentuximab dose to evaluate distribution, lesion uptake and dosimetry of 177 Lu-girentuximab. The trial is currently accruing to the safety lead-in phase. Clinical trial information: NCT05239533.