Phase 1 study of PSMA ADC, an antibody-drug conjugate targeting prostate-specific membrane antigen, in chemotherapy-refractory prostate cancer.

Autor: Petrylak DP; Department of Urology, Yale University, New Haven, Connecticut., Kantoff P; Dana-Farber Cancer Institute, Boston, Massachusetts., Vogelzang NJ; Comprehensive Cancer Center of Nevada, Las Vegas, Nevada., Mega A; Miriam Hospital, Providence, Rhode Island., Fleming MT; Virginia Oncology Associates, Hampton, Virginia., Stephenson JJ Jr; Cancer Centers of the Carolinas, Greenville, South Carolina., Frank R; Western CT Health Network, Norwalk, Connecticut., Shore ND; Carolina Urologic Research Center, Myrtle Beach, South Carolina., Dreicer R; University of Virginia Cancer Center, Charlottesville, Virginia., McClay EF; California Cancer Associates for Research & Excellence, Encinitas, California., Berry WR; Cancer Centers of North Carolina, Raleigh, North Carolina., Agarwal M; Associates in Oncology and Hematology, Rockville, Maryland., DiPippo VA; Progenics Pharmaceuticals, Inc., New York, New York., Rotshteyn Y; Progenics Pharmaceuticals, Inc., New York, New York., Stambler N; Progenics Pharmaceuticals, Inc., New York, New York., Olson WC; Progenics Pharmaceuticals, Inc., New York, New York., Morris SA; Progenics Pharmaceuticals, Inc., New York, New York., Israel RJ; Progenics Pharmaceuticals, Inc., New York, New York.
Jazyk: angličtina
Zdroj: The Prostate [Prostate] 2019 May; Vol. 79 (6), pp. 604-613. Date of Electronic Publication: 2019 Jan 20.
DOI: 10.1002/pros.23765
Abstrakt: Background: Prostate-specific membrane antigen (PSMA) is a well-characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibody-drug conjugate (ADC) is a fully human IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA-positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer.
Methods: In this first-in-man dose-escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate-specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging.
Results: Fifty-two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first-cycle and late dose-limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose-proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent.
Conclusions: In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti-tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer.
(© 2019 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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