Phase I study of JM-216 (an oral platinum analogue) in combination with paclitaxel in patients with advanced malignancies

This phase I study was conducted to determine the dose limiting toxicity, maximum tolerated doses, and recommended phase II doses of the combination of JM-216 and paclitaxel. Patients received paclitaxel intravenously over one hour on day 1 of each cycle. Oral JM-216 was administered on days 1-5 starting after the paclitaxel infusion. Cycles were repeated every 21 days. Patients were accrued at nine different dosing combinations. JM-216 doses ranged from 10-80 mg/m2/day and were combined with paclitaxel doses of 150, 175, or 200 mg/m2. Forty-three patients were treated with 146 cycles of therapy. Dose-limiting toxicity, consisting of febrile neutropenia and grade 3 thrombocytopenia, was encountered in 2 patients at the seventh dose level (JM-216 80 mg/m2/day + paclitaxel 175 mg/m2). Two intermediate dose levels were explored. The first level (JM-216 70 mg/m2/day + paclitaxel 175 mg/m2) produced dose-limiting thrombocytopenia in 1 of 6 patients. However, two additional patients also demonstrated delayed recovery from thrombocytopenia following treatment. As a result, a second intermediate dose level (JM-216 60 mg/m2/day + paclitaxel 200 mg/m2) was filled with six patients. No dose-limiting toxicities were reported in any patients at this dose level. The combination of oral JM-216 and paclitaxel is well-tolerated with minimal non-hematologic and reversible hematologic toxicity. The recommended dose for phase II study is JM-216 60 mg/m2/day for 5 days and paclitaxel 200 mg/m2 on day 1 repeated every 21 days. Higher doses of JM-216 are associated with more severe thrombocytopenia and delayed hematologic recovery resulting in subsequent dosing delays.