© 2004 European Society for Medical Oncology
Original article |
A phase I study of the oral combination of CI-994, a putative histone deacetylase inhibitor, and capecitabine
1 Section of Hematology/Oncology, Department of Medicine, 2 Cancer Research Center, 3 Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL; 4 Pfizer Inc., Ann Arbor, MI, USA
* Correspondence to: Dr H. L. Kindler, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637, USA. Tel: +1-773-702-0360; Fax: +1-773-702-0963; Email: hkindler{at}medicine.bsd.uchicago.edu
Background: This study was conducted to determine the toxicity profile, maximum tolerated dose (MTD) and pharmacokinetics of the putative histone deacetylase inhibitor CI-994 in combination with capecitabine.
Patients and methods: Fifty-four patients were treated according to three different dosing schemes in which the capecitabine dose was fixed and the CI-994 dose was escalated. Capecitabine was administered in twice daily divided doses, and CI-994 was given as a single daily dose. In schedule A, 26 patients were treated with capecitabine 1650 mg/m2/day and CI-994 for 2 weeks of a 3-week cycle. In schedule B, six patients received capecitabine 1650 mg/m2/day for two 3-week cycles and CI-994 for 5 of 6 weeks. In schedule C, 22 patients were treated with capecitabine 2000 mg/m2/day and CI-994 for 2 of 3 weeks.
Results: At the MTD, the principal dose-limiting toxicity was thrombocytopenia. The pharmacokinetics of CI-994 were unaltered by capecitabine, and there was no correlation between body surface area and major pharmacokinetic parameters. Platelet count nadir was best predicted by the observed maximal concentration (Cmax) of CI-994.
Conclusions: The recommended phase II dose is 6 mg/m2 (or 10 mg) of CI-994 in combination with capecitabine 2000 mg/m2/day for 2 weeks of a 3-week cycle.
Key words: capecitabine, CI-994, dose-limiting toxicity, histone deacetylase inhibitor, pharmacokinetics, phase I study
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