Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex

Objectives: To define the maximum tolerated dose (MTD), the toxicity and ph armacokinetic profile of BBR3464, a novel triplatinum complex. Patients and methods: Fourteen patients with advanced solid tumors not resp onsive to previous antitumor treatments received BBR 3464 on a daily x 5 sc hedule every twenty-eighth day. The drug was given as a one-hour infusion w ith pre-and post-treatment hydration (500 ml in one hour) and no antiemetic prophylaxis. The starting dose was 0.03 mg/m(2)/day. A modified accelerate d titration escalation design was used. Total and free platinum (Pt) concen trations in plasma and urine were assessed by ICP-MS on days 1 and 5 of the first cycle. Results: Dose was escalated four times up to 0.17 mg/m(2)/day. Short-lastin g neutropenia and diarrhea of late onset were dose-limiting and defined the MTD at 0.12 mg/m(2). Nausea and vomiting were rare, neither neuro- nor ren al toxic effects were observed. BBR3464 showed a rapid distribution phase o f 1 hour and a terminal half-life of several days. At 0.17 mg/m(2) plasma C max and AUC on day 5 were higher than on day 1, indicating drug accumulatio n. Approximately 10% of the equivalent dose of BBR3464 (2.2%-13.4%) was rec overed in a 24-hour urine collection. Conclusions: The higher than expected incidence of neutropenia and GI toxic ity might be related to the prolonged half-life and accumulation of total a nd free Pt after daily administrations. Lack of nephrotoxicity and the low urinary excretion support the use of the drug without hydration. The single intermittent schedule has been selected for clinical development.