Abstract P6-15-15: MM-111 - A Novel Bispecific Antibody Targeting HER-2/HER-3 Z Heterodimer: Safety and Tolerability in a First-In Human Phase I/II Study in Patients with Refractory HER2-Positive (HER-2+) Cancers

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Abstract 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. ErbB3 signaling has emerged as an important mechanism of resistance to ErbB2 (HER-2) targeted agents in clinical use (Sergina et al Nature 2007, Garrett et al SABCS 2009 abstract 63). MM-111 is a novel bispecific antibody fusion protein that specifically targets the ErbB2/ErbB3 heterodimer and abrogates ligand binding. In preclinical models of HER-2+ gastric, breast, ovarian and lung cancers, MM-111 inhibits ligand-induced ErbB3 phosphorylation, cell cycle progression, and tumor growth. This first-inhuman phase 1-2 study evaluates the safety and tolerability of MM-111 and preliminarily explores efficacy in HER-2+ advanced breast cancer (ABC). The safety data obtained during the Phase 1 dose escalation portion of this study provide the basis of this report. Methods: Patients (pts) with histologically confirmed HER-2+ advanced solid tumors progressing or recurring on standard therapy; aged ≥18 years; ECOG PS ≥2 and adequate organ function were eligible for phase I. Pts with stable CNS lesions were also eligible. A Modified Fibonacci schema was used for dose escalation in Phase I. Primary endpoints for Phase 1 were determination of maximum tolerated dose/maximum feasible dose while secondary endpoints included determination of dose-limiting toxicity, adverse events, and pharmacokinetic (PK) and immunogenicity profiles of MM-111. MM-111 was administered intravenously weekly in 4-week cycles. Results: 12 pts (11 ABC and 1 gastric cancer) were treated: median age 59 (range 36-82), median PS 1 (range 0-1), 11♂:1♀, median numberof prior therapies 7 (3-12). A total 19 courses (median 2; range 1-2) of therapy was administered at 4 dose-levels (3 mg/kg, 6mg/kg, 12mg/kg and 20 mg/kg respectively). Common adverse events reported included pain (n=7) fatigue (n=4), dyspepsia (n = 3) and pyrexia (n = 3). There were no treatment interruptions due to adverse events. No dose limiting toxicities were observed and there has been no evidence of cardiotoxicity or immunogenicity to date. PK data indicate dose proportionality at the dose-levels explored and supports weekly dosing. Conclusions: MM-111 is well tolerated at the doses levels studied and the PK profile suggests that weekly dosing is feasible. Enrollment to phase II is anticipated to commence shortly. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-15.

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