PHASE-I AND PHARMACOKINETIC STUDY OF AN ORAL PLATINUM COMPLEX GIVEN DAILY FOR 5 DAYS IN PATIENTS WITH CANCER

Purpose: We aimed to determine the maximum-tolerated dose (MTD) clinic al toxicities, pharmacokinetics, and pharmacodynamics of oral JM216 gi ven once daily for 5 days to cancer patients. Patients and Methods Pat ients who fulfilled standard phase I trial criteria were enrolled. Ora l JM216 was given at doses based on patient body-surface area, on an e mpty stomach, once daily for 5 consecutive days, as 10-, 50-, and 200- mg hard gelatin capsules and with oral antiemetics. The pharmacokineti cs of platinum were studied on days 1 and 5 of the first treatment cou rse using atomic absorption spectrophotometry (AAS). Results: Thirty-t wo patients received 94 courses of oral JM216 at doses that ranged fro m 30 to 140 mg/m(2) body-surface area for 5 consecutive days. The MTD was 140 mg/m(2)/d, The dose-limiting toxicities were thrombocytopenia and neutropenia. Hematotoxicity was reversible (nadir, 17 to 21 days; recovery, 28 days), non-cumulative, and dependent on the dose and hist ory of previous therapy. There were two instances of neutropenic sepsi s. Two-thirds of patients experienced mild nausea, vomiting, or diarrh ea. There was no ototoxicity, neurotoxicity, nephrotoxicity, or object ive tumor responses. There was ct significant correlation between JM21 6 dose and the day 1 and 5 plasma ultrafiltrate area under the concent ration-time curve (AUG; r = .78), which indicates linear pharmacokinet ics. There was considerable intersubject pharmacokinetic and pharmacod ynamic variability, but a significant sigmoidal relationship between t he plasma ultrafiltrate AUC and severity of thrombocytopenia (R-2 = .8 3). Conclusion: We recommend JM216 doses of 100 and 120 mg/m(2)/d x 5 for previously treated and untreated patients, respectively, for phase II trials. (C) 1997 by American Society of Clinical Oncology.