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

651 Background: MM-111 (111) inhibits ligand activated HER3 signaling in HER2+ tumors. This study evaluated the safety of 111 combined with standard of care (SOC) HER2-targeting regimens (Rx): capecitabine (X) + cisplatin (C) + trastuzumab (T) (Arm 1); lapatinib (L) +/- trastuzumab (Arm 2); paclitaxel (P) + trastuzumab (Arm 3); lapatinib + paclitaxel + trastuzumab (Arm 4); docetaxel (D) + trastuzumab (Arm 5). Methods: This was a multi-arm Phase 1, dose escalation study of 111 in combination with SOC regimens to evaluate safety, pharmacokinetics (PK), and anti-tumor activity. Patients were required to have documented advanced HER2-positive cancer and adequate organ function. Each arm was designed to run as a separate Phase 1 study to address safety and tolerability and utilized a “3 + 3” design with standard dosing of the SOC regimen. 111 was dosed weekly at 10 mg/kg and escalated up to 20 mg/kg where possible. For Arm 5, 111 was dosed q3w starting at 30mg/kg and escalated up to 40mg/kg. Results: A total of 86 patients (11 bladder, 46 breast, 15 gastro-esophageal, 14 other cancers) were enrolled and treated across all five arms. Dose-limiting toxicities (DLTs) included anemia, acute renal failure (assessed as cisplatin-related), chest pain, decreased appetite, diarrhea, febrile neutropenia, hyperuricemia, hypokalemia, hyponatremia, hypophosphatemia, mucosal inflammation, nausea, neutropenia, stomatitis, thrombocytopenia, and vomiting. An MTD was not reached in Arms 2-5; Arm 1 required a capecitabine dose reduction. Conclusions: Treatment with 111 and SOC HER2-directed regimens was feasible. The Recommended 111 Phase 2 doses are 20mg/kg QW and 40mg/Q3W. Additional safety, PK and preliminary activity data will be provided. Clinical trial information: NCT01304784.Patient outcomes summary. Arm Rx (Dose) Units 111 and T (mg/kg) X, D, C and P (mg/m2) Arm 1 X (1000) C (80) T (4/2) 111 (5-10) Arm 2 T (4/2) L (1000) 111 (10-20) Arm 3 P (80) T (4/2) 111 (10-20) Arm 4 P (80) L (750) T (4/2) 111 (10-20) Arm 5 D (75) T (8/6) 111 (30-40) N (safety population) 17 31* 23 9 6 DLT 6 4 1 1 0 SAE 5 12 6 4 1 N (evaluable population) 14 24 21 9 6 CR; PR; SD 1 CR;3 PR;6 SD 4 PR;10 SD 6 PR;7 SD 4 PR; 3 SD 1 PR; 2 SD *10 patients did not receive T.