This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by de Jonge, M. J.A. Articles by Verweij, J. Search for Related Content PubMed PubMed Citation Articles by de Jonge, M. J.A. Articles by Verweij, J. Social Bookmarking                            What's this?

Phase I and Pharmacologic Study of Oral ZD9331, A Novel Nonpolyglutamated Thymidylate Synthase Inhibitor, in Adult Patients With Solid Tumors

From the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, Rotterdam, and Department of Medical Oncology, University Medical Center St Radboud Nijmegen, Nijmegen, the Netherlands; and Institute of Cancer Research, Surrey, and AstraZeneca, Alderley Park, United Kingdom.

Address reprint requests to M.J.A. de Jonge, MD, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email: jonge{at}onch.azr.nl

PURPOSE: To assess the toxicity profile and dose-limiting toxicities (DLTs), to determine the maximum-tolerated dose, and to study the pharmacokinetics of ZD9331 when administered orally to patients with advanced solid tumors.

PATIENTS AND METHODS: Patients were treated with oral ZD9331 given once daily (od) or twice daily (bid) for 5, 7, or 10 days; cycles were repeated every 21 days at doses ranging from 2.5 to 40 mg. For pharmacokinetic analysis, plasma sampling was performed during the first course and assayed using a validated liquid chromatographic–tandem mass spectrometry assay. Plasma levels of 2'-deoxyuridine were measured as a surrogate marker for TS inhibition.

RESULTS: Forty-two patients received a total of 166 courses. The DLTs were myelosuppression and skin rash. Dose escalation of oral ZD9331 from 2.5 to 40 mg, as a single daily dose, resulted in a less than proportional increase in the plasma area under the concentration-time curve of ZD9331. The plasma drug exposure per cycle for the schedules 20 mg od for 5 days, 10 mg od for 10 days, and 10 mg bid for 5 days, all resulting in a total dose per cycle of 100 mg, were comparable. One partial response was noted in a patient with gastric cancer.

CONCLUSION: DLTs in this phase I study of oral ZD9331 were myelosuppression and skin toxicity. The recommended dose for phase II studies of oral ZD9331 is 20 mg od for 5 consecutive days, every 3 weeks.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. Perumal, R. G. Pillai, H. Barthel, J. Leyton, J. R. Latigo, M. Forster, F. Mitchell, A. L. Jackman, and E. O. Aboagye Redistribution of Nucleoside Transporters to the Cell Membrane Provides a Novel Approach for Imaging Thymidylate Synthase Inhibition by Positron Emission Tomography. Cancer Res., September 1, 2006; 66(17): 8558 - 8564. [Abstract] [Full Text] [PDF]

				G. Beutel, H. Glen, P. Schoffski, J. Chick, S. Gill, J. Cassidy, and C. Twelves Phase I Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor in Patients with Refractory Solid Tumors Clin. Cancer Res., August 1, 2005; 11(15): 5487 - 5495. [Abstract] [Full Text] [PDF]

				C. Rees, P. Beale, J. M. Trigo, F. Mitchell, A. Jackman, R. Smith, E. Douglass, and I. Judson Phase I Trial of ZD9331, a Nonpolyglutamatable Thymidylate Synthase Inhibitor, Given as a 5-Day Continuous Infusion to Patients with Refractory Solid Malignancies Clin. Cancer Res., June 1, 2003; 9(6): 2049 - 2055. [Abstract] [Full Text] [PDF]

				M. B. Sawyer, M. J. Ratain, D. Bertucci, R. P. Smith, R. L. Schilsky, N. J. Vogelzang, K. Shulman, E. C. Douglass, and G. F. Fleming Phase I Study of an Oral Formulation of ZD9331 Administered Daily for 28 Days J. Clin. Oncol., May 1, 2003; 21(9): 1859 - 1865. [Abstract] [Full Text] [PDF]

				R. Plummer, C. Rees, A. Hughes, P. Beale, M. Highley, J. Trigo, S. Gokul, I. Judson, H. Calvert, A. Jackman, et al. A Phase I Trial of ZD9331, a Water-Soluble, Nonpolyglutamatable, Thymidylate Synthase Inhibitor Clin. Cancer Res., April 1, 2003; 9(4): 1313 - 1322. [Abstract] [Full Text] [PDF]

				S. D. Baker, J. Verweij, E. K. Rowinsky, R. C. Donehower, J. H. M. Schellens, L. B. Grochow, and A. Sparreboom Role of Body Surface Area in Dosing of Investigational Anticancer Agents in Adults, 1991-2001 J Natl Cancer Inst, December 18, 2002; 94(24): 1883 - 1888. [Abstract] [Full Text] [PDF]