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

Abstract

PURPOSE:

To define the maximum-tolerated dose, recommended phase II dose (RD), dose-limiting toxicity (DLT), and pharmacokinetics of a novel taxane, RPR 109881A, administered on days 1 and 8 of a 21-day cycle.

PATIENTS AND METHODS:

Twenty-nine patients were enrolled and treated according 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 urine were performed on days 1 and 8 of the first cycle. Toxicity was monitored weekly.

RESULTS:

DLT consisting of grade 3 or 4 diarrhea was seen in three of six patients at 52.5 mg/m(2). Grade 3 or 4 granulocytopenia was also seen in five 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 with associated infection. Drug concentrations were consistent with a three-compartment open model. The total-body clearance suggests a linear dose-concentration 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 terminal half-life (mean, 24 hours). There was no drug accumulation between days 1 and 8. One partial response was seen in a patient with renal cell carcinoma.

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.

• Authors: K A Gelmon, J Latreille, A Tolcher, L Génier, B Fisher, D Forand, S D'Aloisio, L Vernillet, L Daigneault, A Lebecq, M Besenval, E Eisenhauer
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 18 Issue 24 Pg. 4098-108 (Dec 15 2000) ISSN: 0732-183X [Print] United States
• PMID: 11118471 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• RPR 109881A
• Taxoids
• Paclitaxel

Topics

• Adult
• Aged
• Agranulocytosis (chemically induced)
• Antineoplastic Agents, Phytogenic (administration & dosage, adverse effects, pharmacokinetics)
• Diarrhea (chemically induced)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Paclitaxel (administration & dosage, adverse effects, analogs & derivatives)
• Taxoids