A phase 1 trial of xentuzumab, an IGF-neutralizing antibody, in Japanese patients with advanced solid tumors

Summary

Xentuzumab is an insulin-like growth factor (IGF) ligand-neutralizing antibody. This phase 1 trial assessed xentuzumab in Japanese patients with solid tumors. Patients aged ?20 years old with solid tumors that were refractory or not amenable to standard therapy were enrolled. Patients received xentuzumab intravenously at a starting dose of 750 mg/week. Dose escalation used a 3+3 design with dose de-escalation. The primary endpoint was to determine the maximum tolerated dose (MTD) of xentuzumab. Safety, pharmacokinetics, pharmacodynamics and anti-tumor activity were also assessed. Fifteen patients received xentuzumab in the dose escalation part (750 mg/week [n = 6]; 1000 mg/week [n = 3]; 1400 mg/week [n = 6]). There were no dose-limiting toxicities at any dose; MTD of xentuzumab was not reached. Xentuzumab 1000 mg/week was recommended as the relevant biological dose. Six further patients received xentuzumab 1000 mg/week in an expansion cohort. Of 21 patients, 13 (61.9%) experienced a drug-related adverse event, most commonly fatigue (23.8%), neutropenia (19.0%), diarrhea, nausea, white blood cell count decreased, and muscle spasms (14.3% each). No relevant deviations from dose linearity of xentuzumab exposure were observed during dose escalation. Total IGF-1 and IGF-2 levels increased, and bioactive IGF levels decreased, from baseline to 24 hours after the first infusion in cycle 1. Partial response was observed in two (9.5%) patients with desmoid-type fibromatosis. Disease control was achieved in six (28.6%) patients (median duration 42.4 months). Xentuzumab monotherapy was well tolerated in Japanese patients and showed evidence of anti-tumor activity.