A phase I/II study of MM-111, a novel bispecific antibody that targets the ErB2/ErB3 heterodimer, in combination with trastuzumab in advanced refractory HER2-positive breast cancer.

Abstract

TPS119 Background: The ErbB2/ErbB3 oncogenic heterodimer is the most potent ErbB receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. MM-111 is a novel bispecific antibody fusion protein that specifically targets the ErbB2/ErbB3 heterodimer and abrogates binding of ErbB3’s ligand heregulin. In preclinical models of HER-2+ solid tumors, MM-111 inhibits ligand-induced ErbB3 phosphorylation, cell cycle progression, and tumor growth. ErbB2 (HER2) is a well established target of anticancer agents such as trastuzumab and lapatinib for HER2+ cancers, specifically breast and gastric. ErbB3 signaling has emerged as an important mechanism of resistance to ErbB2 (HER-2) targeted agents in clinical use, and preclinical data demonstrates that MM-111 potentiates the antitumor activity of trastuzumab. This first-in-human phase I/II study evaluates the safety and tolerability of MM-111 in combination with trastuzumab and preliminarily explores efficacy in HER-2+ advanced breast cancer (ABC). Methods: This is a phase I/II, open label, multicenter, dose-escalation study that will evaluate the safety, pharmacokinetics (PK), and efficacy of MM-111 + trastuzumab. There is a dose escalation phase followed by an expansion cohort. The dose escalation phase utilizes a standard “3 + 3” design where doses of MM-111 will be escalated until the phase II dose is identified in combination with trastuzumab given at the approved dose and regimen. Once the MTD or phase II dose is identified, an expansion cohort will be enrolled to further evaluate the safety and efficacy of doublet. Key exploratory analyses will include an evaluation of safety and efficacy and levels of expression and/or amplification of HER2 and heregulin. As of January 1 2011, cohorts 1 thru 2 have been completed without DLT. A total of 7 patients have been treated. Enrollment to cohort 3 is ongoing.