Phase I Trial of Asg-5me in Metastatic Castration Resistant Prostate Cancer (CRPC)

ABSTRACT Background SLC44A4 is a 710 amino acid protein 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 against 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 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, 2.7 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 26 pts have been treated (3, 3, 3, 3, 6, 6, and 2 pts per respective cohort). Mean age was 69.5 (range 56-87), median Gleason score 8 (6-10), mean baseline PSA 82.25 (4.4-1987). Pts received a mean of 3.8 doses (1-12). A DLT occurred at 2.7 mg/kg: Grade (Gr) 4 neutropenia, Gr 3 constipation and diarrhea. 2 DLTs occurred at 3 mg/kg: one with Gr 3 troponin elevation and the second with Gr 3 maculopapular rash, hypoxia, constipation, and Gr 4 neutropenia. Common Gr 1 and 2 adverse events included fatigue, anorexia, peripheral neuropathy, dyspnea and nausea. Gr 3 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 the ADC was 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 3 cohorts and one >50% decrease in retroperitoneal nodes. Conclusions The maximum tolerated dose (MTD) was exceeded at 3 mg/kg. The drug appears to have anti-cancer activity above 2.4 mg/kg. Disclosure L. Reyno: The author is the CMO and Sr Vice President of Agensys, Inc, B. Anand: The author is a director of Agensys, Inc A. Hartford: The author is a director of Agensys, Inc, K. Jelaca-Maxwell: The author is a paid safety consultant of Agensys, Inc, J. Lackey: The author is a director of Agensys, Inc. All other authors have declared no conflicts of interest.