A phase I/II and pharmacologic study of MM-111 in patients with advanced, refractory HER2-positive (HER2+) cancers.

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TPS169 Background: The ErbB2/ErbB3 oncogenic heterodimer is the most potent ErbB receptor pairing with respect to strength of interaction, ligand–induced tyrosine phosphorylation, and downstream signaling through mitogen-activated protein kinase and phosphoinositide-3 kinase pathways. Recently, ErbB3 signaling has emerged as an important hypothesized mechanism of resistance to ErbB2 (HER2) 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 blocks ligand binding to ErbB3. In HER2+ gastric, breast, ovarian, and lung cancer cell lines and xenografts, MM-111 inhibits ligand-induced ErbB3 phosphorylation, tumor cell cycle progression, and tumor growth. This first-in-human phase I-II study evaluates the safety and tolerability of MM-111 and provides preliminary efficacy data in HER-2+ advanced breast cancer (ABC). Methods: Patients (pts) aged ≥ 18 years with histologically confirmed HER2+ advanced solid tumors that have progressed or recurred on standard therapy or for which no standard therapy exists, and adequate performance status, bone marrow reserve, and organ function, are eligible for the phase I portion. Phase II is restricted to pts with HER2+ ABC who have progressed on prior trastuzumab or lapatinib therapy. Pts with stable central nervous system lesions are eligible. Phase I employs a standard 3 + 3 dose escalation design. Once the maximum tolerated (MTD) or feasible dose (MFD) is determined, up to 25 additional pts with HER2+ ABC will be enrolled, for a planned total of 40-49 pts in both phases. Primary endpoints are determination of MTD/MFD (phase I) and 6-month progression-free survival (phase II). Secondary endpoints include determination of dose-limiting toxicity, adverse event, pharmacokinetic, and immunogencity profiles of MM-111, as well as overall response and clinical benefit rates of MM-111 in HER2+ ABC. MM-111 is administered intravenously weekly in 4-week cycles. 8 pts have been enrolled in the phase I portion (7 ABC, 1 advanced gastric cancer), and enrollment in the phase I portion is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merrimack Pharmaceuticals Merrimack Pharmaceuticals Merrimack Pharmaceuticals Chemotherapy Foundation Merrimack Pharmaceuticals Merrimack Pharmaceuticals

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