Phase 1/2 study of fractionated dose lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 ( Lu-J591) for metastatic castration-resistant prostate cancer.

TitlePhase 1/2 study of fractionated dose lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 ( Lu-J591) for metastatic castration-resistant prostate cancer.
Publication TypeJournal Article
Year of Publication2019
AuthorsTagawa ST, Vallabhajosula S, Christos PJ, Jhanwar YS, Batra JS, Lam L, Osborne J, Beltran H, Molina AM, Goldsmith SJ, Bander NH, Nanus DM
JournalCancer
Volume125
Issue15
Pagination2561-2569
Date Published2019 Aug 01
ISSN1097-0142
Abstract

BACKGROUND: Prostate cancer is radiosensitive. Prostate-specific membrane antigen (PSMA) is selectively overexpressed on advanced, castration-resistant tumors. Lutetium-177-labeled anti-PSMA monoclonal antibody J591 ( Lu-J591) targets prostate cancer with efficacy and dose-response/toxicity data when delivered as a single dose. Dose fractionation may allow higher doses to be administered safely.

METHOD: Men with metastatic castration-resistant prostate cancer refractory to or refusing standard treatment options with normal neutrophil and platelet counts were enrolled in initial phase 1b dose-escalation cohorts followed by phase 2a cohorts treated at recommended phase 2 doses (RP2Ds) comprising 2 fractionated doses of Lu-J591 2 weeks apart. Lu-J591 imaging was performed after treatment, but no selection for PSMA expression was performed before enrollment. Phase 2 patients had circulating tumor cell (CTC) counts assessed before and after treatment.

RESULTS: Forty-nine men received fractionated doses of Lu-J591 ranging from 20 to 45 mCi/m ×2 two weeks apart. The dose-limiting toxicity in phase 1 was neutropenia. The RP2Ds were 40 mCi/m and 45 mCi/m ×2. At the highest RP2D (45 mCi/m ×2), 35.3% of patients had reversible grade 4 neutropenia, and 58.8% of patients had thrombocytopenia. This dose showed a greater decrease in prostate-specific antigen (PSA) levels and longer survival (87.5% with any PSA decrease, 58.8% with >30% decrease, 29.4% with >50% decrease; median survival, 42.3 months [95% confidence interval, 19.9-64.7]). Fourteen of 17 (82%) patients with detectable CTCs experienced a decrease in CTC count. Overall, 79.6% of patients had positive PSMA imaging; those with less intense PSMA imaging tended to have poorer responses.

CONCLUSION: Fractionated administration of Lu-J591 allowed higher cumulative radiation dosing. The frequency and depth of PSA decrease, overall survival, and toxicity (dose-limiting myelosuppression) increased with higher doses.

DOI10.1002/cncr.32072
Alternate JournalCancer
PubMed ID31012963
Grant List / / David H. Koch Foundation /
/ / Robert Dow Foundation /
W81XWH-04-1-0267 / / Department of Defense /
/ / Prostate Cancer Foundation Young Investigator Award /
/ / Lawrence and Carol Zicklin Charitable Trust /
ULI RR024996 / / National Institutes of Health /
1-KL2-RR024997-01 / / National Institutes of Health /
PTBF5405 / / National Institutes of Health /
PCF Young Investigator Award / / Prostate Cancer Foundation /
Division: 
Biostatistics and Epidemiology
Category: 
Faculty Publication