A phase I study of the oral combination of CI-994, a putative histone deacetylase inhibitor, and capecitabine

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/m(2)/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/m(2)/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 (C-max) of CI-994. Conclusions: The recommended phase II dose is 6 mg/m(2) (or 10 mg) of CI-994 in combination with capecitabine 2000 mg/m(2)/day for 2 weeks of a 3-week cycle.