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

2013; American Association for Cancer Research; Volume: 19; Issue: 11 Linguagem: Inglês

10.1158/1078-0432.ccr-12-3051

1557-3265

Patricia LoRusso, Pasi A. Jänne, Moacyr Oliveira, Naiyer A. Rizvi, Lisa Malburg, Vicki L. Keedy, Lorrin Yee, Catherine Copigneaux, Thore Hettmann, Chi‐Yuan Wu, Agnes Ang, Abdel‐Baset Halim, Robert A. Beckman, Darrin M. Beaupre, Jordan Berlin,

Peptidase Inhibition and Analysis

Abstract Purpose: 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 in patients with advanced solid tumor. 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, starting 3 weeks after the first dose; part 2—additional patients received 9, 14, or 20 mg/kg U3-1287 every 2 weeks, based on observed tolerability and pharmacokinetics from part 1. Recommended phase II dose, adverse event rates, pharmacokinetics, 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 every 2 weeks. The most frequent adverse events 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 or more in 19.2% in part 1 and 10 weeks or more in 25.8% in part 2. Conclusion: U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. Pharmacokinetic data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing. Clin Cancer Res; 19(11); 3078–87. ©2013 AACR.