Abstract 2774: Complete results from a phase Ia dose-escalation and dose-expansion study of single-agent MetMAb, a monovalent antagonist antibody to the receptor MET, administered intravenously in patients with locally advanced or metastatic solid tumors
Authors: Ravi Salgia, Amy C. Peterson, John Bothos, Steve Eppler, Wei Yu, Priti Hegde, Bob Yauch, Jiping Zha, Mark J. Ratain, David Geary, Elayne Wesolowsky, Marjorie LaRosiliere, Premal Patel, Rebecca Moss
Journal: Cancer Research (2010)

Abstract COMPLETE RESULTS FROM A PHASE Ia DOSE-ESCALATION AND DOSE-EXPANSION STUDY OF SINGLE-AGENT MetMAb, A MONOVALENT ANTAGONIST ANTIBODY TO THE RECEPTOR MET, ADMINISTERED INTRAVENOUSLY IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS Background: The receptor tyrosine kinase Met and/or its ligand, the hepatocyte growth factor (HGF), are frequently over-expressed in cancers and their levels are closely related to cancer progression and prognosis. Aberrant activation of HGF/Met pathway can enhance invasion, proliferation, and survival. MetMAb was uniquely engineered as a recombinant, humanized, monovalent (one-armed) monoclonal antibody to act as an antagonist of HGF-induced Met signaling. Materials and Methods: This was a 3+3 open label, Phase Ia, dose escalation study in patients with advanced solid malignancies and consisted of two stages: a dose escalation stage, which tested 1, 4, 10, 20 and 30 mg/kg doses of MetMAb, and an expansion stage, which tested a recommended phase 2 dose (RP2D) of 15 mg/kg of MetMAb. Patients received MetMAb IV every 21 days. Pre- and post- dose serum was collected for evaluation of pharmacodynamic (PD) biomarkers that could be affected by inhibition of Met signaling. In addition, archival tissue was obtained for exploratory diagnostic assessments. Results: We present here the complete results from the Phase Ia study, in which 34 patients were treated with MetMAb as a single-agent – 21 patients in the dose-escalation phase and 13 patients in the expansion stage. MetMAb was generally well tolerated at all dose-cohorts up to the maximum administered dose (MAD) of 30 mg/kg. No Gr4 drug-related toxicities were observed. One Gr3 and dose-limiting toxicity (DLT) of pyrexia was observed at 4 mg/kg; other Gr3 drug-related toxicities included: abdominal pain, increased aspartate aminotransferase, hyponatremia and peripheral edema. In the dose expansion stage, the most frequent drug-related toxicities included fatigue (39%) and peripheral edema (54%). An objective complete response was observed in one patient with gastric carcinoma after 4 cycles of treatment (and patient continues to exhibit no evidence of disease); analysis of the patient's archived tumor showed findings characteristic of an HGF/cMet autocrine tumor. At the RP2D, MetMAb has a half-life and clearance approximating 11 days and 7 (±2.0) mL/day/kg, respectively. Conclusions: This Phase Ia study represents a first in human trial of a monovalent antibody. MetMAb, when administered as a single-agent, is generally safe and well tolerated. The combination of MetMAb plus bevacizumab is being investigated, and a Phase II study testing MetMAb in combination with erlotinib in NSCLC is currently ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2774.