Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer

Abstract

Purpose: To assess the efficacy of a single infusion of radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (lutetium-177; (177)Lu) by prostate-specific antigen (PSA) decline, measurable disease response, and survival.

Experimental design: In this dual-center phase II study, two cohorts with progressive metastatic castration-resistant prostate cancer received one dose of (177)Lu-J591 (15 patients at 65 mCi/m(2), 17 at 70 mCi/m(2)) with radionuclide imaging. Expansion cohort (n = 15) received 70 mCi/m(2) to verify response rate and examine biomarkers.

Results: Forty-seven patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received (177)Lu-J591. A total of 10.6% experienced ≥50% decline in PSA, 36.2% experienced ≥30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity, with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. A total of 25.5% experienced grade 4 neutropenia, with one episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m(2)) resulted in more 30% PSA declines (46.9% vs. 13.3%, P = 0.048) and longer survival (21.8 vs. 11.9 months, P = 0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious nonhematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond.

Conclusion: A single dose of (177)Lu-J591 was well tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose response. Imaging biomarkers seem promising.

Conflict of interest statement

Conflict of interest: NHB is an inventor on patents that are assigned to Cornell Research Foundation (“CRF”) for the J591 antibody described in this article. Dr. Bander is a paid consultant to and owns stock in BZL Biologics, the company to which the patents were licensed by CRF for further research and development.

©2013 AACR.

Figures

Figure 1

PSA waterfall plot Each individual subject’s best PSA response on study. Those subjects treated with 65 mCi/m2 of 177Lu-J591 (Cohort 1) are indicated in light gray while those that received 70 mCi/m2 of 177Lu-J591 (the phase I trial maximum tolerated dose) are indicated in blue (Cohort 2) or red (Cohort 3).

Figure 2

Overall survival Probability of survival by dose received. [OS:overall survival; mo: months]

Figure 3

Imaging Left: 99mTc-MDP bone scan: Anterior (A) and posterior (B) images of pretreatment bony metastases. Right:177Lu-J591 scan: Anterior (C) and posterior (D) total body images obtained via dual head gamma camera of sites of uptake 7 days after 177Lu-J591 administration. (Note: Radiolabeled antibody is partially cleared via the liver resulting in non-specific 177Lu localization).