O1-080 - Phase I and Dose Finding Study of U3-1287, a Human Monoclonal Antibody Targeting HER3, in Japanese Patients with Advanced Solid Tumors

Abstract

ABSTRACT Background HER3 is a key dimerization partner for HER-family members that activates oncogenic signaling pathways lead to cell survival and proliferation. U3-1287 is a fully human anti-HER3 monoclonal antibody that has demonstrated anticancer activity in preclinical models. In a preceding US phase I study, the tolerability of U3-1287 was evaluated up to the dose of 20 mg/kg without dose-limiting toxic effects (DLTs). In this study, we evaluated the tolerability, pharmacokinetics (PK) and potential antitumor activities of U3-1287 in Japanese patients with solid tumors up to the dose of 18 mg/kg. Methods Patients with advanced solid tumors that were well known to express HER3 were eligible (e.g. lung, breast, colorectal, cervical, esophageal, and sarcoma). Patients received U3-1287 9 or 18 mg/kg intravenously every 3 weeks (q3w). The incidence of anti-U3-1287 antibodies (HAHA), tumor response and U3-1287 related biomarkers were also evaluated. Results Nine patients, three at 9 mg/kg and six at 18 mg/kg, were enrolled. Five patients were male, all patients had ECOG PS ≤ 1 and median (range) age was 67 (50–69) years. Primary tumor types were lung (2), colorectal (2), esophageal (2), breast (1), cervical (1) and sarcoma (1). U3-1287-related AEs reported in ≥2 patients were ALT increase (3 patients), platelet count decrease, diarrhea, stomatitis, cheilitis, rash maculo-papular and AST increase (2 each). No DLTs were observed. Plasma disappearance of U3-1287 was bi-phasic and terminal half-life at the dose of 18 mg/kg was approximately 9 days. The PK profile was similar to the US phase I study. Four patients had a best response of stable disease. All patients tested negative for HAHA formation. Conclusions U3-1287 was well tolerated up to 18 mg/kg in Japanese patients with solid tumors. These data support a dosing regimen of 18 mg/kg q3w in future studies.