Phase I Study of U3-1287, a Fully Human Anti-HER3 Monoclonal Antibody, in Patients With Advanced Solid Tumors

Abstract

Purpose:Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for other HER family members, and its expression is associated with poor prognosis. This first-in-human study of U3-1287 (NCT00730470), a fully human anti-HER3 monoclonal antibody, evaluated its safety, tolerability, and pharmacokinetics (PKs) in advanced solid tumor patients. 

Experimental Design: The study was conducted in 2 parts: part 1-sequential cohorts received escalating doses (0.3-20 mg/kg) of U3-1287 every 2 weeks (q2w), starting 3 weeks after the first dose; part 2-additional patients received 9, 14, or 20 mg/kg U3-1287 q2w, based on observed tolerability and PKs from part 1. Recommended phase II dose, adverse event (AE) rates, PKs, and tumor response were determined. Results: Fifty-seven patients (part 1: 26; part 2: 31) received U3-1287. As no dose-limiting toxicities were reported, the maximum tolerated dose was not reached. The maximum administered dose was 20 mg/kg q2w. The most frequent AEs related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea (10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient developed anti-U3-1287 antibodies. In these heavily pretreated patients, stable disease was maintained ≥ 9 weeks in 19.2% in part 1 and ≥ 10 weeks in 25.8% in part 2. 

Conclusions: U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. PK data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing.