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Phase 1 study of PSMA ADC, an antibody‐drug conjugate targeting prostate‐specific membrane antigen, in chemotherapy‐refractory prostate cancer
Author(s) -
Petrylak Daniel P.,
Kantoff Philip,
Vogelzang Nicholas J.,
Mega Anthony,
Fleming Mark T.,
Stephenson Joe J.,
Frank Richard,
Shore Neal D.,
Dreicer Robert,
McClay Edward F.,
Berry William R.,
Agarwal Manish,
DiPippo Vincent A.,
Rotshteyn Yakov,
Stambler Nancy,
Olson William C.,
Morris Stephen A.,
Israel Robert J.
Publication year - 2019
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23765
Subject(s) - medicine , prostate cancer , pharmacokinetics , enzalutamide , docetaxel , glutamate carboxypeptidase ii , chemotherapy , antibody drug conjugate , oncology , cancer , pharmacology , antibody , monoclonal antibody , immunology , androgen receptor
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.