496P - A Phase 1 Study of MM-111; A Bispecific HER2/HER3 Antibody Fusion Protein, Combined with Multiple Treatment Regimens in Patients with Advanced HER2 Positive Solid Tumors

Abstract

ABSTRACT Background Ligand-activated HER3 forms a potent signaling heterodimer with HER2 and is emerging as key tumorigenic node and mediator of drug resistance. MM-111 (111) is a novel molecule that inhibits ligand activated HER3 signaling in HER2+ tumors. Preclinically, MM-111 potentiates the anti-tumor activity of and mitigates resistance to trastuzumab, lapatinib and chemotherapies. This study evaluates the safety of MM-111 combined with standard of care (SOC) HER2-targeting regimens (Rx), namely; capecitabine (X), cisplatin (C), and trastuzumab (T) (Arm 1); lapatinib (L) + /- trastuzumab (Arm 2); and paclitaxel (P) with trastuzumab (Arm 3). Methods This was a multi-arm Phase 1, dose escalation study of MM-111 in combination with SOC regimens to evaluate safety, pharmacokinetics (PK), and anti-tumor activity. Patients were required to have documented advanced HER2+ cancer, with adequate organ function. Each arm was designed to run as a separate Phase 1 study to address safety and tolerability and each arm utilized a 3 + 3 design with standard dosing of the SOC regimen. MM-111 was dosed weekly at 10mg/kg and escalated up to 20mg/kg where possible. Results As of 30 March 2012, thirty patients had been enrolled across three arms. Dose-limiting toxicities (DLTs) included myelosuppression, infection, vomiting, diarrhea, mucositis, hypokalemia, hyponatremia, hypophosphatemia, hyperuricemia and one report of congestive heart failure (CHF). Serious Adverse Events (SAEs) included pneumothorax, confusion, hemiparesis, seizure, sepsis, diarrhea, disease progression and CHF (also DLT). The table below summarizes patient outcomes. Cohort 1 Arm 1 Arm 2 Arm 3 Rx (Dose) X (1000) C (80) T (4/2) L (1000 mg) T (4/2) P (80) T (4/2) 111 (10) 111 (10) 111 (10) Units 111 & T (mg/kg) X C & P (mg/m2) N 6 3 8 DLT 4 0 1 SAE 4 1 2 Cohort 2 XCT LT PT 111 (5) 111 (20) 111 (20) N 3 7 3 DLT 2 1 0 SAE 0 4 0 CR; PR; SD /N 1 CR;2 PR;2 SD /9 2 PR/10 4 PR;5 SD /11 MM-111 dosing required further reduction to 5mg/kg in arm 1 but was safely escalated to 20mg/kg in arms 2 and 3. Conclusion Overall, MM-111 could be safely combined with SOC HER2 regimens. Additional safety, PK and efficacy data will be provided. Disclosure C. McDonagh: Employed by Merrimack. Stock Ownership. S. Frye: employed by Merrimack. Stock Ownership. V. Moyo: Employed by Merrimack. Stock Ownership. All other authors have declared no conflicts of interest.