Format

Send to

Choose Destination
Prostate. 2019 May;79(6):604-613. doi: 10.1002/pros.23765. Epub 2019 Jan 20.

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

Author information

1
Department of Urology, Yale University, New Haven, Connecticut.
2
Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Comprehensive Cancer Center of Nevada, Las Vegas, Nevada.
4
Miriam Hospital, Providence, Rhode Island.
5
Virginia Oncology Associates, Hampton, Virginia.
6
Cancer Centers of the Carolinas, Greenville, South Carolina.
7
Western CT Health Network, Norwalk, Connecticut.
8
Carolina Urologic Research Center, Myrtle Beach, South Carolina.
9
University of Virginia Cancer Center, Charlottesville, Virginia.
10
California Cancer Associates for Research & Excellence, Encinitas, California.
11
Cancer Centers of North Carolina, Raleigh, North Carolina.
12
Associates in Oncology and Hematology, Rockville, Maryland.
13
Progenics Pharmaceuticals, Inc., New York, New York.

Abstract

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.

KEYWORDS:

Prostate cancer; antibody-drug conjugate; prostate-specific membrane antigen

PMID:
30663074
DOI:
10.1002/pros.23765

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center