Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in taxane-refractory prostate cancer.

Abstract

158 Background: The unique expression of PSMA type II transmembrane glycoprotein on prostate cancer cells provides a potentially attractive target for antibody therapy. PSMA ADC, a fully humanized antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage and release of free MMAE occur, causing cell cycle arrest and apoptosis. We report results from an ongoing phase I dose escalation study of PSMA ADC in patients (pts) with taxane refractory metastatic prostate cancer (metCRPC). Methods: Eligibility requirements included pts ≥18 years with metCRPC after failure of a taxane- containing regimen and ECOG status of 0 or 1. PSMA ADC is administered by IV infusion Q3W for up to 4 cycles. Adverse events, PK, PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC continue to be assessed. Serum concentrations of PSMA ADC and total antibody are measured by an enzyme-linked immunosorbent assay (ELISA) method, and free MMAE is measured by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method. Dosing cohorts ranged from 0.4 mg/kg to 1.8 mg/kg. Results: The demographics of 15 subjects enrolled in the four dosing cohorts (0.4, 0.7, 1.1 and 1.8 mg/kg) were similar. Treatment has to date been generally well tolerated and the most common laboratory abnormalities were reversible changes in liver and hematological parameters. Exposure to PSMA ADC and serum half life (t1/2) increased in a dose-proportional manner. Similar PK metrics were observed after the first and third doses. Exposure to free MMAE was also dose proportional and approximately <0.1% of PSMA ADC. Conclusions: In this first-in-human evaluation, PSMA ADC appears to exhibit dose-proportional PK and limited release of free MMAE. Ongoing enrollment allows for assessment of potential clinical utility of this unique potential treatment of metCRPC. [Table: see text]

Prostate-Specific Membrane Antigen-Based Therapeutics

“…Preclinical activity has been demonstrated in another mAb conjugated to monomethylauristatin E (MMAE) that recognizes the external domain of PSMA [ 78 ]. This work has led to a phase I dose-escalation study that has shown to be tolerated at the initial dose levels [ 79 ]. Additional early-stage clinical work has involved utilizing enzymatic activation to release cytotoxic substances in PSMA positive cells [ 80 ].…”