A PHASE-I AND PHARMACOLOGY STUDY OF AN ORAL PLATINUM COMPLEX, JM216 - DOSE-DEPENDENT PHARMACOKINETICS WITH SINGLE-DOSE ADMINISTRATION

JM216 [bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV)] is an oral platinum complex with in vivo activity against murine and human tumor models and a lack of nephro- and neurotoxicity in rodents. During a phase I study of a single-dose schedule, JM216 was given in dry-filled hard gelatin capsules by mouth without hydration or diuresis. In all, 37 patients were given a total of 88 courses at doses ranging from 60 to 700 mg/m(2). The study was stopped before the MTD was reached because of nonlinear pharmacokinetics. Myelosuppression was manifest by leucopenia or thrombocytopenia and showed marked variability at 420-700 mg/m(2). Vomiting was mild and controllable by antiemetics in approximately 50% of courses. The onset of vomiting was delayed to 4 h after during ingestion, There was no nephro-, oto- or neurotoxicity. A partial response was recorded in a patient with recurrent ovarian cancer, and significant falls in plasma tumour markers (CA125) were seen in two further cases. Plasma pharmacokinetics were linear and showed moderate interpatient variability at dose levels of less than or equal to 120 mg/m(2). At dose levels of greater than or equal to 200 mg/m(2), C-max and AUC increased less than proportionally to dose. This was associated with greater interpatient pharmacokinetic variability and reduced urinary platinum recovery. A significant sigmoidal relationship existed between ultrafilterable plasma AUC and the percentage of reduction in platelet count (r(2) = 0.78). Nonlinear absorption was a limitation to this single-dose schedule of oral NM216; however, little nonhaematological toxicity was seen at doses associated with myelosuppression and antitumour activity. Clinical studies of divided dose schedules using doses within the range of pharmacokinetic linearity (less than or equal to 120 mg/m(2)) are now being investigated.