title: Phase I and pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion.
abstract: N-Debenzoyl-N-tert-butoxycarbonyl-10-deacytyl taxol (Taxotere, RP 56976) is a semisynthetic analogue of taxol, prepared from a noncytotoxic precursor extracted from the needles of the European yew tree (Taxus baccata L.). It has a broad spectrum of antitumor activity against a variety of transplantable tumors in mice. In vitro cytotoxicity assays suggest that it is 2-5-fold more potent than taxol. In this phase I study Taxotere was administered by 24 h i.v. infusion at 3-week intervals. Thirty patients with solid tumors refractory to conventional therapy were treated; 70 courses of Taxotere were administered at doses ranging from 10 to 90 mg/m2. Grade 4 neutropenia and grade 3 mucositis were dose limiting but reversible at 90 mg/m2. The pattern and grade of toxicity at this dose were similar in 3 heavily pretreated patients compared with 7 patients who had received a maximum of one previous chemotherapy regimen. Alopecia occurred at 55 mg/m2 and above. Other mild toxicities included phlebitis, diarrhea, emesis, and sensory peripheral neuropathy, but these were neither dose-limiting nor clearly dose-related. One patient treated at 70 mg/m2 had an anaphylactoid reaction following the second dose of Taxotere. No cardiovascular toxicity was observed. No partial or complete responses were documented. Plasma concentrations of Taxotere were determined by high-performance liquid chromatography, and end-of-fusion levels at the maximum tolerated dose exceeded drug concentrations which are cytotoxic in vitro. The maximum tolerated dose for Taxotere administered as a 24-h infusion is 90 mg/m2.
authors.affiliation: CRC Department of Medical Oncology, Beatson Oncology Centre, Glasgow, Scotland.
authors.forename: D
authors.initials: D
authors.lastname: Bissett
authors.forename: A
authors.initials: A
authors.lastname: Setanoians
authors.forename: J
authors.initials: J
authors.lastname: Cassidy
authors.forename: M A
authors.initials: MA
authors.lastname: Graham
authors.forename: G A
authors.initials: GA
authors.lastname: Chadwick
authors.forename: P
authors.initials: P
authors.lastname: Wilson
authors.forename: V
authors.initials: V
authors.lastname: Auzannet
authors.forename: N
authors.initials: N
authors.lastname: Le Bail
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerr
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000494:pharmacology*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D043823:Taxoids
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel