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Phase I Study of an Oral Formulation of ZD9331 Administered Daily for 28 Days

Michael B. Sawyer, Mark J. Ratain, Donna Bertucci, Robert P. Smith, Richard L. Schilsky, Nicholas J. Vogelzang, Keith Shulman, Edwin C. Douglass, Gini F. Fleming

From the Committee on Clinical Pharmacology, Department of Medicine, Cancer Research Center, and Section of Hematology/Oncology, University of Chicago; Committee on Clinical Pharmacology and Cancer Research Center, Chicago, IL; AstraZeneca Pharmaceuticals, Macclesfield, UK, and Wilmington, DE.

Address reprint requests to Mark J Ratain, MD, 5841 S Maryland Ave, MC2115, Chicago, IL 60637; email: mratain{at}medicine.bsd.uchicago.edu.

Purpose: To define the maximum-tolerated dose and dose-limiting toxicities (DLTs) of an oral formulation of ZD9331, a novel thymidylate synthase inhibitor that is not a substrate for folylpolyglutamate synthase.

Patients and Methods: Patients had Cancer and Leukemia Group B performance status 2 and refractory solid tumors. Initially, patients received ZD9331 daily for 2 weeks, with the duration of treatment escalated to a maximum of 4 weeks, followed by a 2-week rest period. Once the maximum-tolerated duration of treatment was determined, the dose of ZD9331 was increased until DLT occurred.

Results: Fifty-five patients were enrolled at eight dose levels. The DLTs were thrombocytopenia and neutropenia. At 3 mg/d, two of 19 patients developed DLT; one patient had grade 3 thrombocytopenia and grade 4 neutropenia, and the other patient had grade 3 thrombocytopenia only. Anemia was common, with a median hemoglobin nadir of 75% of baseline, before recovery or transfusion. The apparent oral clearance of ZD9931 was 11.6 ± 6.3 mL/min. Dose-limiting myelosuppression was associated with both an increased 24-hour ZD9931 concentration and blood urea nitrogen.

Conclusion: The recommended phase II dose on this schedule is 3 mg/d for 4 weeks, followed by a 2-week rest period. ZD9331 seems to have a manageable toxicity profile, although it should be used with caution in patients with renal impairment.

Supported in part by AstraZeneca and grant no. CA 14599 from the National Cancer Institute, National Institutes of Health.

Michael B. Sawyer was the Gordon E. Richards Fellow of the Canadian Cancer Society.

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