CONVERGE-01: Dosimetry, randomized dose optimization, dose escalation, and efficacy of ac-225 rosopatamab tetraxetan in participants with PSMA-positive castration-resistant prostate cancer.

TPS289 Background: Prostate specific membrane antigen (PSMA) is a validated target in metastatic castration resistant prostate cancer (CRPC). Use of an alpha emitter as a radionuclide and a high affinity monoclonal antibody for protein targeting in PSMA-targeted radiopharmaceutical therapy (TRT) offer the promise of improved precision and potency as compared to alternative approaches. Ac-225 rosopatamab tetraxetan (CONV01-ɑ, formerly Ac-225-J591) has been evaluated for safety and efficacy in sequential investigator-initiated trials (Tagawa et al. JCO 2024, Nauseef et al . AACR 2023) with encouraging results in patients with and without prior exposure to PSMA-directed Lu-177-small molecule-based TRT. The phase II CONVERGE-01 trial is the first industry-sponsored study of CONV01-ɑ and will further advance the understanding of safety and efficacy in patients with progressive PSMA PET-positive CRPC. Methods: The study is being conducted in three parts. Part 1 (P1) is a lead-in to evaluate the biodistribution of CONV01-ɑ using In-111 rosopatamab tetraxetan. Each of these patients will then proceed to Part 2 or Part 3. Part 2 (P2) randomizes 1:1 between 45 and 60 kBq/kg in patients with CRPC without prior exposure to Lu-177-PSMA (-617 or -I&T). Part 3 (P3) is a Bayesian Optimal Interval (BOIN) design dose-escalation protocol (45, 55, and 60 kBq/kg, with optional dose expansion) for patients with metastatic CRPC and prior exposure to Lu-177-PSMA. Key study-wide inclusion criteria include PSMA PET-positive (via VISION criteria) progressive CRPC. Metastatic disease on conventional imaging (CT, MRI) is not mandated in P2 (stratification factor: conventional imaging M0 v M1). All patients will have prior exposure to at least 1 androgen receptor signaling inhibitor and have adequate performance status (ECOG 0-1) and organ function (platelets ≥150 k/uL, ANC ≥1.5 k/uL, CrCl ≥60 mL/min). Key study-wide exclusion criteria include: superscans on Tc-99 bone scintigraphy, prior platinum-based chemotherapy or PARP inhibitor use, and prior PSMA-targeted non-TRT use. Additional P2-specific exclusions are: prior chemotherapy for CPRC and radiopharmaceuticals. Treatment: CONV01-α (P2/P3) will be given in a single cycle of two fractions on days 1 and 15. Primary endpoints: biodistribution of radiolabeled CONV01-α (P1), safety and tolerability (P2, P3), determination of RP2D (P3 only), efficacy via PSA50 response (P2, P3 at RP2D). Secondary endpoints: biodistribution and pharmacokinetic profile (P2, P3), characterization of Ac-225 radiation dosimetry (P2), biochemical PFS (P2), PSA50 (P3, all patients treated). Exploratory endpoints include: rPFS, ORR, and DOR via RECIST v1.1 (PCWG3-modified where appropriate), genomic and imaging biomarker nomination. Enrollment began in August 2024. Clinical trial information: NCT06549465 .