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Phase I and Pharmacokinetic Study of Taxotere (RP 56976) Administered as a 24-Hour Infusion

CRC Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow G11 6NT, Scotland [D. B., A. S., J. C., M. A. G., G. A. C., P. W., S. B. K., D. J. K.], and Rhône-Poulenc Rorer, Recherche-Developpement, 92165 Antony Cedex, France [V. A., N. Le B.]

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.

¹ To whom requests for reprints should be addressed, at CRC Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, Scotland.

Received 7/ 7/92. Accepted 11/11/92.

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