This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cunningham, C. Articles by Eder, J. P. Search for Related Content PubMed PubMed Citation Articles by Cunningham, C. Articles by Eder, J. P., Jr.

Phase I and Pharmacokinetic Study of the Dolastatin-15 Analogue Tasidotin (ILX651) Administered Intravenously on Days 1, 3, and 5 Every 3 Weeks in Patients with Advanced Solid Tumors

Authors' Affiliations: ¹ Tyler Cancer Center, Tyler, Texas; ² Dana-Farber Cancer Institute, ³ Massachusetts General Hospital, Boston, Massachusetts; and ⁴ Genzyme Corp., San Antonio, Texas

Requests for reprints: Peter L. Bonate, Genzyme Corp., 4545 Horizon Hill Boulevard, San Antonio, TX 78229. Phone: 210-949-6662; Fax: 210-949-6219; E-mail: peter.bonate{at}genzyme.com.

Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of tasidotin (ILX651), a dolastatin-15 analogue, when administered on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors.

Patients and Methods: Thirty-two patients were treated with 92 courses of tasidotin through seven dose levels determined by a modified Fibonacci scheme ranging from 3.9 to 45.7 mg/m². Pharmacokinetic samples were collected during the first course.

Results: Neutropenia was the principal DLT at the 45.7 mg/m²/d dose level. In addition, one patient also experienced grade 3 neutropenia complicated with grade 3 esophageal candidiasis and grade 3 dehydration. Only 1 of 11 patients treated at the MTD, 34.4 mg/m², experienced dose-limiting neutropenia. Other common, drug-related toxicities included mild to moderate fatigue, anemia, nausea, anorexia, emesis, alopecia, and diarrhea. The best observed antitumor response consisted of stable disease and was noted in 10 patients (31%); the median duration on study for those patients with stable disease was 99.5 days compared with 37.5 days for those patients with progressive disease. Tasidotin plasma concentrations declined biphasically with an effective half-life of 55 minutes, and 11% was excreted unchanged in the urine.

Conclusion: The recommended dose for phase II studies and the MTD when tasidotin is administered on days 1, 3, and 5 every 3 weeks is 34.4 mg/m². The favorable toxicity profile of tasidotin compared with other antitubulin agents, including other dolastatin analogues, and its novel mechanism of action support further disease-directed evaluation of this agent.

This article has been cited by other articles:

				A. Ray, T. Okouneva, T. Manna, H. P. Miller, S. Schmid, L. Arthaud, R. Luduena, M. A. Jordan, and L. Wilson Mechanism of Action of the Microtubule-Targeted Antimitotic Depsipeptide Tasidotin (Formerly ILX651) and Its Major Metabolite Tasidotin C-Carboxylate Cancer Res., April 15, 2007; 67(8): 3767 - 3776. [Abstract] [Full Text] [PDF]

				A. C. Mita, L. A. Hammond, P. L. Bonate, G. Weiss, H. McCreery, S. Syed, M. Garrison, Q. S.C. Chu, J. S. DeBono, C. B. Jones, et al. Phase I and Pharmacokinetic Study of Tasidotin Hydrochloride (ILX651), a Third-Generation Dolastatin-15 Analogue, Administered Weekly for 3 Weeks Every 28 Days in Patients with Advanced Solid Tumors Clin. Cancer Res., September 1, 2006; 12(17): 5207 - 5215. [Abstract] [Full Text] [PDF]