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Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors

2011; Elsevier BV; Volume: 23; Issue: 2 Linguagem: Inglês

10.1093/annonc/mdr137

1569-8041

Jean‐Charles Soria, Javier Cortés, Christophe Massard, Jean‐Pierre Armand, Daniele Andreis, Stanislas Ropert, Eva Revilla Lopez, Aurélie Catteau, J S James, Jean‐François Marier, Martin Béliveau, Robert E. Martell, José Baselga,

Colorectal Cancer Treatments and Studies

PurposeWe studied the safety, tolerability, and recommended dose of BMS-599626, an orally bioavailable inhibitor of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases.Patients and methodsPatients with advanced solid tumors that expressed epidermal growth factor receptor (EGFR) and/or HER-2 were recruited and enrolled in a phase I, open-label, dose escalation trial of oral BMS-599626 starting at 100 mg/day given once daily for at least 28 days.ResultsForty-five patients received BMS-599626 (100–660 mg/day). Dose-limiting toxic effects were reported at 660 mg/day (grade 3 elevation of hepatic transaminases [two patients] and QTc interval prolongation [one patient]), therefore the recommended maximum tolerated dose was 600 mg/day. The most frequent drug-related toxic effects were diarrhea (30% of patients), anorexia (13%), asthenia (30%), and cutaneous toxic effects, including skin rash (30%). Pharmacokinetic analysis demonstrated Cmax and exposure to BMS-599626 in patients increased with dose. Eleven patients had stable disease and received BMS-599626 for ≥4 months. Serial skin and tumor biopsies taken before and after treatment revealed expected changes in pharmacodynamic biomarkers, indicating that the EGFR and HER-2 pathways were affected. Positron emission tomography imaging showed a metabolic response in 2 of 10 patients evaluated.ConclusionBMS-599626 was generally well tolerated, with disease stabilization across a range of tumor types and doses.