PHASE-I CLINICAL-TRIAL OF CIS-DICHLORO-TRANS-DIHYDROXY-BIS-ISOPROPYLAMINE PLATINUM(IV) (CHIP)

Abstract

Cis-Dichloro-trans-dihydroxy-bis-isopropylamine platinum(IV) (CHIP), a 2nd-generation Pt complex with little or no nephrotoxicity in preclinical studies, has undergone phase I clinical testing and initial pharmacokinetic evaluation in 26 patients with solid tumors who received 40 courses of treatment. Doses of 20-350 mg/m2 were evaluated as single 2-h infusions given every 3 wk for 2 doses, 2 l of pretreatment hydration (but no diuretics) in all but 5 patients. Nausea and vomiting was almost universal but was severe in only 3 courses. The dose-limiting toxic effect was myelosuppression, with a median wbc [white blood cell] count nadir of 2500/mm3 and a median platelet count nadir of 32,000/mm3 at the maximum tolerated dose of 350 mg/m2. No increase in serum creatinine or decrease in creatinine clearance was seen. No pretreatment hydration was given in 5 of the 7 patients treated at 350 mg/m2. Two cases of hypersensitivity were seen. No hearing loss was observed, and no other toxic effects were noted. Plasma decay of total Pt was biexponential with a prolonged .beta. phase. Recovery of Pt in the urine was rapid up to 8-10 h and slow thereafter. Recoveries were incomplete and variable (16.5-62% of the dose at 48 h).