Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225.
Following investigational new drug-enabling preclinical studies, we enrolled patients with progressive mCRPC that was refractory to or who refused standard treatment options (including androgen receptor pathway inhibitor and had received or been deemed ineligible for taxane chemotherapy). No selection for PSMA was performed. Patients received a single dose of 225Ac-J591 at one of seven dose-escalation levels followed by expansion at the highest dose. Primary end point of dose-escalation cohort was determination of dose-limiting toxicity (DLT) and RP2D.
Radiochemistry and animal studies were favorable. Thirty-two patients received 225Ac-J591 in an accelerated dose-escalation design (22 in dose escalation, 10 in expansion). One patient (1 of 22; 4.5%) experienced DLT in cohort 6 (80 KBq/kg) but none in cohort 7; MTD was not reached, and RP2D was the highest dose level (93.3 KBq/kg). The majority of high-grade adverse events (AEs) were hematologic with an apparent relationship with administered radioactivity. Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: 46.9% had at least 50% PSA decline at any time (34.4% confirmed PSA response), and protocol-defined CTC count response occurred in 13 of 22 (59.1%).
To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of 225Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023 Nov 03 [Epub ahead of print]
Scott T Tagawa, Charlene Thomas, A Oliver Sartor, Michael Sun, Judith Stangl-Kremser, Mahelia Bissassar, Shankar Vallabhajosula, Sandra Huicochea Castellanos, Jones T Nauseef, Cora N Sternberg, Ana Molina, Karla Ballman, David M Nanus, Joseph Osborne, Neil H Bander
Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY., Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medicine, New York, NY., Departments of Medicine and Urology, Tulane University School of Medicine, New Orleans, LA., Department of Urology, Weill Cornell Medicine, New York, NY., Meyer Cancer Center, Weill Cornell Medicine-NewYork Presbyterian Hospital, New York, NY.