Phase I trial of ASG-5ME in metastatic castration-resistant prostate cancer (CRPC).

Abstract

4568 Background: SLC44A4 is a 710 amino acid protein that is expressed on prostate, pancreas and other cancers. SLC44A4 is found in 95% of primary prostate tumors (75% express moderate to high levels). ASG-5ME is an antibody drug conjugate (ADC) comprised of a fully human antibody targeting SLC44A4, conjugated to the microtubule-disrupting agent monomethyl auristatin E. ASG-5ME has dose-dependent cytotoxic effects in vitro and significant anti-tumor activity in xenograft models. We report results of a phase I study to establish the maximum tolerated dose (MTD) of ASG-5ME for CRPC, conducted by the Prostate Cancer Clinical Trials Consortium. Methods: Patients (pts) had progressive metastatic CRPC. Prior chemotherapy was allowed. Treatment cohorts were 0.3, 0.6, 1.2, 1.8, 2.4, and 3.0 mg/kg. ASG-5ME was given IV q3 weeks. Safety, pharmacokinetic properties, anti-tumor effects, circulating tumor cell (CTC) enumeration, and CTC molecular profiles were assessed. Pts were treated until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) was defined by cycle 1 toxicity. Results: 20 pts have been treated (3, 3, 3, 3, 6, and 2 pts per respective cohort). Mean age was 69 (range 56-87), median Gleason score 8 (6-10), mean baseline PSA 225 (5-1987). Pts received an average of 4 doses (1-12). 2 DLTs occurred in Cycle 1 in the 3 mg/kg cohort: DLT 1: Grade (Gr) 3 troponin elevation and DLT 2: Gr3 maculopapular rash, hypoxia, constipation, and Gr4 neutropenia. Common Gr 1 and 2 adverse events included fatigue, anorexia, peripheral neuropathy, dyspnea and nausea. Gr3 events included: fatigue (2 pts),peripheral neuropathy (1), dyspnea (1) and nausea (1). Serum concentrations of ASG-5ME decreased multi-exponentially and the exposure was dose-proportional. The half-life of intact drug was calculated as 7.01 days (range-3.93-15.9, n=17) after the first dose and 11.2 days ( range-7.75-19.1 days, n=10) after the last dose. PSA declines of >50% were seen in 3/8 pts treated in the last two cohorts and one unconfirmed >50% decrease in retroperitoneal nodes. Conclusions: DLT events observed at 3 mg/kg exceeded the MTD; the MTD is 2.4 mg/kg of doses tested in pts with metastatic CRPC. The drug appears to have anti-cancer activity at 2.4 and 3 mg/kg.