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 (1,000 mg/m2) 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/m2 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-limitingtoxicity occurred at the 8-mg/ m2 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/m2. In contrast, only two of 28 (7%) courses at 6 mg/m2 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/m2 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 (1,000 mg/m2 i.v. on days 1, 8, and 15) during a 28-day cycle.