A phase I dose-escalation/expansion study of fractionated-dose and multiple cycle anti-PSMA-targeted alpha emitter 225Ac-J591 in patients with prostate cancer

Purpose: To test safety of two regimens at differing levels of radioactivity of PSMA-targeted alpha radionuclide 225Ac-J591. Patients and Methods: Patients with progressive, metastatic androgen pathway modulator resistant prostate cancer were enrolled in two parallel dose-escalation cohorts: (1) fractionated-dose regimen (single cycle of 45 – 65 KBq/kg of 225Ac-J591 on day 1 and day 15; main cohort agnostic to prior receipt of 177Lu-PSMA, additional cohort post 177Lu-PSMA) and (2) multiple cycles of 225Ac-J591 (45 – 65 KBq/kg administered every 6 weeks for up to 4 cycles). PSMA PET not utilized for eligibility. Primary end point was determination of dose-limiting toxicity (DLT) and recommended phase 2 dose (RP2D); the fractionated cohort was expanded. Results: 42 patients were enrolled in fractionated (23 dose-escalation, 11 expansion, 8 post 177Lu-PSMA), 18 multiple dose. All received > 1 prior AR pathway inhibitor, 72% chemotherapy, 18% 177Lu-PSMA. Three patients had DLT in fractionated regimen with RP2D of 60 KBq/kg x2. Seven had DLT in multiple cycle regimen; this regimen is not recommended for further development. Amongst adverse events of special interest, temporary hematologic toxicity was most common [93% thrombocytopenia (32% grade >3), 65% neutropenia (13% grade >3), 63% anemia (20% grade >3)]; dry mouth occurred in 62% (2% grade 2). Across fractionated cohorts with or without prior 177Lu-PSMA, 60% with >50% PSA decline as best response; 28% with >50% PSA decline in multiple cycle. Conclusions: Fractionated dosing of 225Ac-J591 appears promising. Further investigation is underway.