A phase I study of ASG-5ME, a novel antibody-drug conjugate, in pancreatic ductal adenocarcinoma.

176 Background: ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, an ion transporter expressed on >90% of pancreatic ductal adenocarcinoma (PDA). ASG-5ME comprises a fully human antibody covalently linked, with a protease-cleavable linker, to the microtubule-disrupting agent monomethylauristatin E (MMAE). Upon binding to SLC44A4 and internalization, MMAE is released by proteolytic cleavage, binds to tubulin, and subsequently induces cell cycle arrest and apoptosis. Selective targeting of tumor cells by an ADC represents a novel therapeutic approach for patients (pts) with PDA. Methods: This phase I, dose-escalation, multicenter study investigated the safety, PK, and antitumor activity of ASG-5ME in pts with metastatic PDA. Patients received ASG‑5ME IV in cohort-specific doses on Days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Results: Thirty-five pts (median age 63 yrs, range 32-73) were treated at doses of 0.3 to 1.5 mg/kg. All pts had metastatic PDA and ECOG status 0-1. Thirty-three pts (94%) had previously received chemotherapy for metastatic disease or in the perioperative setting; the median number of prior therapies for metastatic PDA was 3 (range 1-6; n=27). The maximum tolerated dose (MTD) was exceeded at the 1.5 mg/kg dose level, with 1 DLT of Grade 4 GI hemorrhage and 4 pts experiencing non-DLT Grade 3 or 4 neutropenia. Thus, 1.2 mg/kg was identified as the MTD and expanded (N=18). The most common AEs observed at the MTD were fatigue (50%), vomiting (44%), decreased appetite (39%), nausea (33%), and abdominal pain (33%); Grade 3 or 4 toxicities at the MTD included fatigue (28%), abdominal pain (22%), vomiting (17%), and neutropenia (17%). Antitumor activity was observed: 1 pt achieved an unconfirmed PR and 12 pts achieved SD. Five patients (14%) had reductions in CA19-9. Serum ASG-5ME exposures were approximately dose proportional. Of 23 pts with archived biopsies available for IHC analysis, 100% expressed SLC44A4 and 15 pts (65%) had high expression. Conclusions: ASG-5ME treatment was generally well tolerated in metastatic PDA pts, with preliminary evidence of antitumor activity. Further study of ASG-5ME in SLC44A4-expressing malignancies is warranted. Clinical trial information: NCT01166490.