Phase I study of oral CI-994 in combination with gemcitabine in treatment of patients with advanced cancer

PURPOSE The purpose of this study was to determine the maximum tolerated dose, pharmacokinetic profile, and evidence of antitumor activity of CI-994 used in combination with gemcitabine. METHODS This was a dose escalation trial in which gemcitabine (1000 mg/ m 2 ) was given as a 30-minute infusion on days 1, 8, and 15 of a 28-day cycle. CI-994 was taken orally on consecutive days 1-21 at escalating doses of 2, 4, 6, and 8 mg/m 2 per cohort (three patients/cohort). Plasma samples were collected on days 1 and 15 of course 1 and analyzed for CI-994 pharmacokinetic assessment. RESULTS Twenty patients with advanced cancer received a total of 76 courses of treatment. Dose-limiting toxicity occurred at the 8-mg/ m 2 dose. Four of seven patients experienced thrombocytopenia during the first cycle. Grade 4 thrombocytopenia was observed in three of 10 (30%) courses at 8 mg/m 2 . In contrast, only two of 28 (7%) courses at 6 mg/m 2 were associated with grade 4 thrombocytopenia. Pharmacokinetic analysis indicated that absorption of CI-994 was rapid, with peak plasma concentrations occurring at the first sample 2 hours after dosing. Two patients achieved a minor response, 12 had stable disease (median duration, 105 days), four had progressive disease, and two were not evaluable. CONCLUSIONS The 6-mg/m 2 dose of CI-994 (p.o. x 21 days) was defined as the maximum tolerated dose that could safely be administered in combination with gemcitabine (1000 mg/m 2 i.v. on days 1, 8, and 15) during a 28-day cycle.