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.

Abstract

PURPOSE:

We 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 METHODS:

Patients 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.

RESULTS:

Forty-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 C(max) 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.

CONCLUSION:

BMS-599626 was generally well tolerated, with disease stabilization across a range of tumor types and doses.

• Authors: J-C Soria, J Cortes, C Massard, J-P Armand, D De Andreis, S Ropert, E Lopez, A Catteau, J James, J-F Marier, M Beliveau, R E Martell, J Baselga
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 23 Issue 2 Pg. 463-71 (Feb 2012) ISSN: 1569-8041 [Electronic] England
• PMID: 21576284 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Antineoplastic Agents
• Carbamates
• Protein Kinase Inhibitors
• Triazines
• (4-((1-(3-fluorophenyl)methyl)-1H-indazol-5-ylamino)-5-methylpyrrolo(2,1-f)(1,2,4)triazin-6-yl)carbamic acid 3-morpholinylmethyl ester
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents (pharmacokinetics)
• Carbamates (pharmacokinetics)
• ErbB Receptors (antagonists & inhibitors)
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (pharmacokinetics)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Triazines (pharmacokinetics)