PMID- 37922438 OWN - NLM STAT- MEDLINE DCOM- 20240229 LR - 20240425 IS - 1527-7755 (Electronic) IS - 0732-183X (Print) IS - 0732-183X (Linking) VI - 42 IP - 7 DP - 2024 Mar 1 TI - Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of (225)Ac-J591. PG - 842-851 LID - 10.1200/JCO.23.00573 [doi] AB - PURPOSE: 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 (225)Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225. METHODS: 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 (225)Ac-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. RESULTS: Radiochemistry and animal studies were favorable. Thirty-two patients received (225)Ac-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%). CONCLUSION: To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of (225)Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway. FAU - Tagawa, Scott T AU - Tagawa ST AUID- ORCID: 0000-0003-2777-8587 AD - Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY. AD - Department of Urology, Weill Cornell Medicine, New York, NY. AD - Meyer Cancer Center, Weill Cornell Medicine-NewYork Presbyterian Hospital, New York, NY. FAU - Thomas, Charlene AU - Thomas C AUID- ORCID: 0000-0002-7685-0090 AD - Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medicine, New York, NY. FAU - Sartor, A Oliver AU - Sartor AO AUID- ORCID: 0000-0002-8777-7343 AD - Departments of Medicine and Urology, Tulane University School of Medicine, New Orleans, LA. FAU - Sun, Michael AU - Sun M AD - Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY. FAU - Stangl-Kremser, Judith AU - Stangl-Kremser J AUID- ORCID: 0000-0002-8644-2445 AD - Department of Urology, Weill Cornell Medicine, New York, NY. FAU - Bissassar, Mahelia AU - Bissassar M AD - Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY. FAU - Vallabhajosula, Shankar AU - Vallabhajosula S AD - Department of Urology, Weill Cornell Medicine, New York, NY. FAU - Huicochea Castellanos, Sandra AU - Huicochea Castellanos S AUID- ORCID: 0000-0003-2907-8744 AD - Meyer Cancer Center, Weill Cornell Medicine-NewYork Presbyterian Hospital, New York, NY. AD - Division of Molecular Imaging and Therapeutics, Department of Radiology, Weill Cornell Medicine, New York, NY. FAU - Nauseef, Jones T AU - Nauseef JT AUID- ORCID: 0000-0003-2302-4171 AD - Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY. AD - Meyer Cancer Center, Weill Cornell Medicine-NewYork Presbyterian Hospital, New York, NY. FAU - Sternberg, Cora N AU - Sternberg CN AUID- ORCID: 0000-0003-3938-2627 AD - Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY. AD - Department of Urology, Weill Cornell Medicine, New York, NY. AD - Meyer Cancer Center, Weill Cornell Medicine-NewYork Presbyterian Hospital, New York, NY. FAU - Molina, Ana AU - Molina A AD - Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY. AD - Meyer Cancer Center, Weill Cornell Medicine-NewYork Presbyterian Hospital, New York, NY. FAU - Ballman, Karla AU - Ballman K AUID- ORCID: 0000-0002-4492-0357 AD - Meyer Cancer Center, Weill Cornell Medicine-NewYork Presbyterian Hospital, New York, NY. AD - Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medicine, New York, NY. FAU - Nanus, David M AU - Nanus DM AD - Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY. AD - Department of Urology, Weill Cornell Medicine, New York, NY. AD - Meyer Cancer Center, Weill Cornell Medicine-NewYork Presbyterian Hospital, New York, NY. FAU - Osborne, Joseph R AU - Osborne JR AUID- ORCID: 0000-0003-0232-5960 AD - Meyer Cancer Center, Weill Cornell Medicine-NewYork Presbyterian Hospital, New York, NY. AD - Division of Molecular Imaging and Therapeutics, Department of Radiology, Weill Cornell Medicine, New York, NY. FAU - Bander, Neil H AU - Bander NH AD - Department of Urology, Weill Cornell Medicine, New York, NY. AD - Meyer Cancer Center, Weill Cornell Medicine-NewYork Presbyterian Hospital, New York, NY. LA - eng SI - ClinicalTrials.gov/NCT03276572 GR - P50 CA211024/CA/NCI NIH HHS/United States GR - UL1 RR024996/RR/NCRR NIH HHS/United States GR - UL1 TR002384/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article DEP - 20231103 PL - United States TA - J Clin Oncol JT - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JID - 8309333 RN - 0 (Androgen Receptor Antagonists) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, Surface) RN - EC 3.4.21.77 (Prostate-Specific Antigen) RN - 0 (J591 monoclonal antibody) SB - IM CIN - doi: 10.1200/JCO.23.02310 MH - Animals MH - Humans MH - Male MH - Androgen Receptor Antagonists/therapeutic use MH - Antibodies, Monoclonal/administration & dosage/therapeutic use MH - Antigens, Surface MH - Prostate/pathology MH - Prostate-Specific Antigen MH - *Prostatic Neoplasms, Castration-Resistant/drug therapy/radiotherapy MH - Treatment Outcome PMC - PMC10906595 COIS- The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). EDAT- 2023/11/03 18:43 MHDA- 2024/02/29 06:44 PMCR- 2025/03/01 CRDT- 2023/11/03 16:03 PHST- 2025/03/01 00:00 [pmc-release] PHST- 2024/02/29 06:44 [medline] PHST- 2023/11/03 18:43 [pubmed] PHST- 2023/11/03 16:03 [entrez] AID - JCO.23.00573 [pii] AID - 10.1200/JCO.23.00573 [doi] PST - ppublish SO - J Clin Oncol. 2024 Mar 1;42(7):842-851. doi: 10.1200/JCO.23.00573. Epub 2023 Nov 3.