PRadR: PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer, a multicentric phase I/II.

TPS4608 Background: Prostate Specific Membrane Antigen (PSMA) is highly expressed in neovessels of various solid tumors including Renal Cell Carcinoma, especially clear cell (ccRCC), which is the most frequent sub type. In ccRCC, PSMA expression in tumor vessels is correlated with higher grade and stage as well as in match between primary tumor and metastasis. PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA Ligands Radiolabeled with Lutetium-177 (PRLT), which is already used in daily practice for prostate cancer. 177 Lu-PSMA in prostate cancer with renal impairment appeared to be feasible and tolerable in previous studies. The aim of this Phase I/II study NCT06059014 is to assess the safety and clinical activity of this new Radiolabelled Therapy for mccRCC. Methods: PRadR is a multicentric, single-arm, open-label Phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with mccRCC. Patients must have received at least 2 prior regimens, including immunotherapy and antiangiogenic agents as per international guidelines, ECOG 0 to 1, with adequate hematologic, hepatic and renal function with a creatinine clearance according to CKD-EPI ≥ 40 mL/min/1.73m 2 . Only patients with tumor tracer uptake greater than background will be treated with 4 cycles of 7.4 GBq of 177 Lu-PSMA-1 every 6 weeks. The primary endpoints are the incidence of severe toxicity (Safety run in) and the disease control rate at 24 weeks (DCR-24W) as per RECIST V1.1 (Phase II) in patients with a PSMA-positive mccRCC selected through 68 Ga-PSMA PET. Secondary endpoints include overall response rate, duration of response, progression free survival, overall survival and safety according to NCI-CTCAE V5.0. During the safety run in, if more than one patient experiences severe toxicity during the first cycle over the first 6 treated patients, then a lower activity of 177 Lu-PSMA-1 will be evaluated in an additional cohort of 6 patients (5.9 GBq). Using a Fleming-A’Hern single stage design with a target DCR 24w of 30% and an inefficacy bound of 10% (α=5% one sided and 90% power) a total of 33 evaluable patients are required. If at least 7 successes (CR, PR or SD) at 24 weeks of treatment are observed, 177 Lu-PSMA-1 will deserve further investigation in this setting. Translational studies will consist in comparing efficacy and toxicity to dosimetry of 177Lu-PSMA-1 in normal tissues and tumor lesions, and biomarkers obtained from blood samples or tumor tissues. First patient was enrolled in November 2023. Clinical trial information: NCT06059014 .