STARLITE 2: Phase 2 study of nivolumab plus
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lutetium-labeled anti–carbonic anhydrase IX (CAIX) monoclonal antibody girentuximab (
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Lu-girentuximab) in patients with advanced clear cell renal cell carcinoma (ccRCC).
Authors: Feldman Darren R. , Motzer Robert J. , Knezevic Andrea , Voss Martin H , Lyashchenko Serge K. , Park Hijin , Larson Steven M. , Pandit-Taskar Neeta 
Published: February 2025

TPS608

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
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Zr has shown promise as a novel PET tracer and labeling with
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Lu promise as a therapeutic agent in ccRCC. Targeted delivery of radiation to ccRCC cells may prime the immune response by enhancing tumor antigen presentation, providing rationale for combining
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Lu-girentuximab with nivolumab. This phase 2, open-label, single arm study evaluates
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Lu-girentuximab in combination with nivolumab in patients (pts) with previously treated ccRCC.
Methods:
Pts with biopsy-proven RCC of clear cell type or with CAIX expression, progressive disease (PD) after ≥1 immunotherapy (IO) agent, adequate organ/marrow function, and ≥1 evaluable lesion by RECIST 1.1 that is also avid on
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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
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Lu- girentuximab q12-14 weeks for a maximum of 3 doses plus nivolumab 240mg q2 weeks until PD or unacceptable toxicity. Due to expected cumulative myelosuppression, each subsequent
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Lu-girentuximab dose given to the same patient is reduced by 25% (dose 2 = 75% of dose 1; dose 3 = 75% of dose 2). Tumor imaging is performed q12 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
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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). Based on DLTs, the
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Lu-girentuximab dose will either be escalated to 2405 MBq/m
2
(cohort 2; single agent MTD) or de-escalated to 1353 MBq/m
2
(cohort -1) for the next cohort. 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 during safety lead-in), a second stage will open (n = 19) for a total of 29 pts with ≥4 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
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Zr-girentuximab PET is performed at baseline and before each
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Lu-girentuximab dose with results correlated with RECIST response on conventional imaging. In addition, whole body planar and SPECT imaging are performed after each
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Lu-girentuximab dose to evaluate distribution, lesion uptake and dosimetry. The pre-specified number of DLTs was exceeded in cohort 2 such that dosing reverted back to cohort 1, in which accrual is ongoing. Clinical trial information:
NCT05239533
.