Phase I dose-finding study of a new taxane, RPR 109881A, administered as aone-hour intravenous infusion days 1 and 8 to patients with advanced solidtumors

Purpose: To define the maximum-tolerated dose, recommended phase II dose (R D), dose-limiting toxicity (DLT), and pharmacokinetics of a novel taxane, R PR 109881A, administered on days 1 and 8 of a 21-day cycle. Patients and Methods: Twenty-nine patients were enrolled and treated accord ing to a modified continual reassessment method from a starting dose of 7.5 mg/m(2) to 52.5 mg/m(2). Detailed pharmacokinetic analyses of blood and ur ine were performed on days 1 and 8 of the first cycle. Toxicity was monitor ed weekly. Results: DLT consisting of grade 3 or 4 diarrhea was seen in three of six p atients at 52.5 mg/m(2). Grade 3 or 4 granulocytopenia was also seen in fiv e of six patients treated at this dose (four of six in the first cycle). At the next lower dose level, 45 mg/m(2) toxicity was moderate, with only one of 12 patients experiencing severe diarrhea and grade 4 granulocytopenia w ith associated infection. Drug concentrations were consistent with a three- compartment open model. The total-body clearance suggests a linear dose-con centration relationship. RPR 109881A has a high clearance (mean, 42.6 L/h/m (2)), a large volume of distribution (mean, 952 L/m(2)), and a long termina l half-life (mean, 24 hours). There wets no drug accumulation between days 1 and 8. One partial response was seen in a patient with renal cell carcino ma. Conclusion: The RD of RPR 109881A given as a 1-hour infusion on days 1 and 8 of a 21-day cycle is 45 mg/m(2). At this dose the drug is well tolerated and should be further studied. J Clin Oncol 18:4098-4108. (C) 2000 by Ameri can Society of Clinical Oncology.