Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
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.
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Tagawa Scott T, Thomas Charlene, Arham Abdul Baseet, Holmes Aaron, Marulanda Corzo Valentina, Okobi Tobechukwu, Vallabhajosula Shankar, Avlonitis Vasilios, Huicochea Castellanos Sandra, Nauseef Jones T, O'Dwyer Elisabeth, Fatima Maham, Gregos Peter, Yuan Sarah, Sternberg Cora N, Molina Ana, Nanus David M, Bander Neil H, Osborne Joseph
Аннотация
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.
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.