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 ⁸⁹Zr has shown promise as a novel PET tracer and labeling with ¹⁷⁷Lu 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 ¹⁷⁷Lu-girentuximab with the anti-PD-1 antibody, nivolumab. This phase 2, open-label, single arm study (NCT05239533) is being conducted 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 (IO) agent, adequate organ/marrow function, and ≥1 evaluable lesion by RECIST 1.1 that is also avid on ⁸⁹Zr-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 ¹⁷⁷Lu-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 ¹⁷⁷Lu-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 ¹⁷⁷Lu-girentuximab in combination with nivolumab 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 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 the safety lead-in phase), 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 ⁸⁹Zr-girentuximab PET is performed at baseline and before each ¹⁷⁷Lu-girentuximab dose with results correlated with RECIST response on conventional imaging. In addition, whole body planar and SPECT imaging are performed after each ¹⁷⁷Lu-girentuximab dose to evaluate distribution, lesion uptake and dosimetry of ¹⁷⁷Lu-girentuximab. The trial is currently accruing to the safety lead-in phase. Clinical trial information: NCT05239533.