Phase I study of amatuximab, a novel monoclonal antibody to mesothelin, in Japanese patients with advanced solid tumors

Abstract

Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5%) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4%) and pyrexia (23.5%). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).

Figures

Fig. 1

Serum concentration of amatuximab in cycle 1. n = 7 in 50 and 200 mg/m2, n = 3 in 100 mg/m2 dose group on cycle 1 day 1. n = 5 in 50 mg/m2, n = 3 in 100 mg/m2, n = 6 in 200 mg/m2 dose group on cycle 1 day 22. Error bars show standard deviation. Abbreviations: SD = standard deviation

Fig. 2

Individual serum concentrations in cycle 1. (a) 50 mg/m2 dose group (n = 7). (b) 100 mg/m2 dose group (n = 3). (c) 200 mg/m2 dose group (n = 7). Red line: HACA-positive patients who showed a decrease in the serum concentration in cycle 1

Fig. 3

Relationship between dose and pharmacokinetic parameters of Cmax and AUC(0–24) on cycle 1 day 1. (a) Cmax. (b) AUC(0–24). Abbreviations: AUC = area under the concentration curve; AUC(0–24) = AUC from zero to 24 h; Cmax = maximum serum concentration; JP = Japan; US = United States