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

Abstract

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.