First-in-human study of MM-141: A novel tetravalent monoclonal antibody targeting IGF-1R and ErbB3.

Abstract

384 Background: MM-141 is a novel tetravalent bispecific monoclonal antibody that binds IGF-1R and ErbB3 and blocks both ligand dependent and independent IGF-1R/ErbB3/PI3K/AKT/mTOR signaling. MM-141 potentiated gemcitabine, nab-paclitaxel, docetaxel, irinotecan, tamoxifen, and everolimus in preclinical models. A multi-arm Phase 1 study is ongoing and the monotherapy dose-escalation portion of the study is completed. Hepatocellular carcinoma (HCC) patients were enrolled to an expansion cohort of Arm A to receive MM-141 as a monotherapy. Another arm of treatment combined MM-141 with gemcitabine and nab-paclitaxel. Methods: This is a Phase 1 dose-escalation study evaluating safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of MM-141 as monotherapy (n=15) and in combination with everolimus (Arm B) or with nab-paclitaxel and gemcitabine (Arm C). Three HCC patients in the Arm A expansion cohort received MM-141 as a monotherapy at a weekly dose of 20 mg/kg. These patients underwent mandatory pre-treatment and optional post-treatment biopsies. Patients in the dose-escalation portion of Arm C received MM-141 at a weekly dose of 12 or 20 mg/kg or a bi-weekly dose of 40 mg/kg in combination with gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2). Results: 15 patients with advanced solid tumors were enrolled into the dose escalation portion of Arm A. No dose-limiting toxicities were observed at any of the studied doses. The safety, tolerability, PK and PD profile support weekly and bi-weekly MM-141 dosing. The Arm A expansion enrolled 3 patients with sorafenib-refractory HCC. The analysis of pre- and post-treatment biopsies confirmed that IGF-1R and ErbB3 are expressed in patients previously exposed to sorafenib, and their levels are decreased after MM-141 exposure. Arm C, combining MM-141, gemcitabine, and nab-paclitaxel in a “3+3” dose-escalation design is on-going. Conclusions: MM-141 was well tolerated as a monotherapy and translational analysis of pharmacodynamic parameters suggest appropriate target engagement. Combination data with gemcitabine/nab-paclitaxel will be presented and preparations for a randomized Phase 2 study in front-line pancreatic cancer are underway. Clinical trial information: NCT01733004.