A phase I study of the trinuclear platinum compound, BBR 3464, in combination with protracted venous infusional 5-fluorouracil in patients with advanced cancer

Purpose. BBR 3464 is a novel trinuclear platinum anticancer agent with a broad spectrum of preclinical antitumour activity. A phase I, open-label dose-escalating study was performed to determine the maximum tolerated dose (MTD) of BBR 3464 administered in combination with protracted venous infusional (PVI) 5-fluorouracil (5-FU) for up to six courses in patients with locally advanced and/or metastatic cancer. Methods. Dose escalation was based on observation of toxicity at each dose level. BBR 3464 (0.6 mg/m(2) escalated to 0.75 mg/m(2)) was studied in combination with PVI 5-FU (200 mg/m(2) per day). Results. Entered into the study were 14 patients. The most frequent toxicities were nausea, neutropenia, fatigue and diarrhoea. The protocol-defined MTD was not determined as 11/14 patients experienced grade 3 or 4 neutropenia that interrupted the planned administration of PVI 5-FU on day 15 (of 21). Although these events were not dose-limiting, as defined in the protocol, they imposed limitations on the dose of PVI 5-FU administered. Antitumour activity was observed: a partial response in one patient (7%) with invasive breast cancer. Stable disease was confirmed in three patients (21%). These four patients all completed the planned six courses of combined therapy. Conclusions. In light of the lack of septic events associated with the recorded neutropenia, it may be possible to safely continue PVI 5-FU despite the grade 3 or 4 neutropenia or modify the PVI schedule and administer therapy on days 1-15 of the 21-day cycle, but these modifications were not considered in this study.