In a phase I study reported in the Journal of Clinical Oncology, Scott T. Tagawa, MD, MS, FASCO, FACP, and colleagues determined the recommended phase II dose and described preliminary activity of actinium-225–J591—an anti–prostate-specific membrane antigen (PSMA) monoclonal antibody (J591) radiolabeled with the alpha emitter actinium-225—in patients with metastatic castration-resistant prostate cancer.
Scott T. Tagawa, MD, MS, FASCO, FACP
Study Details
Thirty-two patients who were refractory to or refused treatment with standard treatment options and were unselected for PSMA were enrolled into the dual-center trial between October 2017 and January 2021. In the dose-escalation phase, 22 patients received a single dose of Ac-225–J591 at one of seven predetermined dose levels ranging from 13.3 to 93.3 KBq/kg. In the expansion phase, 10 patients received the recommended phase II dose.
Key Findings
In the dose-escalation phase, one patient experienced dose-limiting toxicity at a dose of 80 KBq/kg (grade 4 anemia and thrombocytopenia). No dose-limiting toxicity was observed among six patients receiving the highest dose (93.3 KBq/kg); this dose was the recommended phase II dose and was given to the 10 patients in the expansion cohort.
Among all patients, the majority of high-grade adverse events were hematologic, with an apparent relationship with dose of radioactivity. In addition to the dose-limiting toxicity, three patients had grade 3 anemia, two had grade 3 thrombocytopenia, two had grade 4 thrombocytopenia, two had grade 3 neutropenia, and one had grade 4 neutropenia. Nonhematologic adverse events were primarily grade 1 or 2; no grade 3 events occurred in more than one patient.
Among all 32 patients, 9 (28.1%) had prostate-specific antigen (PSA) rise as best response. A total of 23 had PSA decline, including 15 (46.9%) with a > 50% PSA decline at any time during follow-up and 11 (34.4%) with confirmed ≥ 50% PSA response.
Among 22 patients with paired pre-/post-therapy circulating tumor cell (CTC) counts, CTC response (decrease from ≥ 5 CTCs/7.5 mL to ≤ 4 CTCs/7.5 mL or count remaining at ≤ 4 CTCs at 12 weeks) was observed in 13 patients (59.1%).
The investigators concluded, “To our knowledge, this is the first report of a first-in-human prospective trial of a PSMA-targeted alpha emitter. Treatment with a single dose was tolerated by men with pretreated progressive metastatic castration-resistant prostate cancer, with a majority of patients experiencing declines in both PSA levels and CTC counts…. Further investigation is underway.”
Dr. Tagawa, of Weill Cornell Medicine, New York, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by a Prostate Cancer Foundation Challenge Award, the National Institutes of Health, Department of Defense, and others. For full disclosures of the study authors, visit ascopubs.org.
