Preclinical Characterization And First-In-Human Study Of Mm-141, A Dual Antibody Inhibitor Of Igf-1r And Erbb3

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PABackground: MM-141 is a tetravalent bi-specific monoclonal antibody that binds IGF-1R and ErbB3, oncogenic receptors commonly co-expressed in solid tumors. In preclinical models, MM-141 blocks both ligand-dependent and -independent PI3K/AKT/mTOR signaling initiated through IGF-1R and ErbB3 complexes and potentiates the activity of gemcitabine, paclitaxel, nab-paclitaxel, docetaxel, irinotecan, tamoxifen, and everolimus. A multi-arm phase I study is ongoing, with continuing patient enrollment in Arm B (MM-141 in combination with everolimus). Monotherapy Arm A and combination Arm C (MM-141 with nab-paclitaxel and gemcitabine) are completed.Methods: Tumor expression of IGF-1R and ErbB3 was measured by immunohistochemistry. In vitro expression and degradation of IGF-1R and ErbB3 in pancreatic cell line models post-treatment were measured by immunoblotting and ubiquitination, respectively. The phase I dose-escalation study evaluated safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of MM-141 as monotherapy (Arm A, n = 15) and in combination with everolimus (Arm B) or with nab-paclitaxel and gemcitabine (Arm C, n = 11). Pre- and post-treatment biopsies were acquired where mandated. Patients in the monotherapy Arm A received MM-141 at 6, 12, 20 mg/kg weekly or 40 mg/kg biweekly. Patients in the dose-escalation portion of Arm C received MM-141 at a weekly dose of 12 or 20 mg/kg in combination with weekly nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) on a schedule of 3 weeks on, 1 week off. Enrollment in Arm B (MM-141 in combination with everolimus) is ongoing. Patient serum free IGF-1 levels were detected using an in-house developed CLIA validated ELISA-based assay.Results: Here we report common co-expression of IGF-1R and ErbB3 in solid tumors. In stage IV metastatic pancreatic cancer, co-expression of IGF-1R and ErbB3 was associated with decreased patient survival. In preclinical models, increased expression of IGF-1R and ErbB3 desensitized tumors to gemcitabine and paclitaxel. However, co-treatment with MM-141 reversed this acquired resistance through blockade of growth factor binding and induction of IGF-1R and ErbB3 degradation. In the monotherapy arm of a phase I study, no dose-limiting toxicities were observed at any of the studied dose levels. The safety, tolerability, PK and PD profile of MM-141 support 2.8g bi-weekly MM-141 phase II recommended dose. The analysis of pre- and post-treatment biopsies confirmed that levels of IGF-1R and ErbB3 were decreased following MM-141 administration.In Arm C, the observed safety profile of MM-141 in combination with nab-paclitaxel and gemcitabine was comparable to expected toxicities reported with the chemotherapy combination when used alone. Retrospective analysis of serum free IGF-1 levels in breast cancer patients (Arm B) demonstrated that patients with elevated levels of this potential biomarker remained on study longer and received a greater number of doses of MM-141.Conclusion: These data support continued development of MM-141 in biomarker-selected patient populations and the upcoming phase II study of MM-141 in combination with nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer patients with detectable free IGF-1 serum levels.Citation Format: Alexey A. Lugovskoy, Michel Curley, Jason Baum, Sharlene Adams, Sergio Iadevaia, Victoria Rimkunas, Adam Camblin, Lin Nie, Gege Tan, Bryan Johnson, Sara Mathews, Kerry Horgan, Chrystal U. Louis, Akos G. Czibere, Monica Arnedos, Jean-Charles Soria, Rastilav Bahleda, Anthony Shields, Patricia M. LoRusso, Mansoor Saleh, Steven J. Isakoff. Preclinical characterization and first-in-human study of MM-141, a dual antibody inhibitor of IGF-1R and ErbB3. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT237. doi:10.1158/1538-7445.AM2015-CT237