Phase I study of an oral formulation of ZD9331 administered daily for 28 days.
OBJECTIVE
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.


METHODS
Patients had Cancer and Leukemia Group B performance status < or = 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.


CONCLUSIONS
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.
Sawyer
Michael B
MB
Committe on Clinical Pharmacology, Department of Medicine, Cancer Research Center and Section of Hematology/Oncology, University of Chicago, IL USA.
Ratain
Mark J
MJ
Bertucci
Donna
D
Smith
Robert P
RP
Schilsky
Richard L
RL
Vogelzang
Nicholas J
NJ
Shulman
Keith
K
Douglass
Edwin C
EC
Fleming
Gini F
GF
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects*; D013921:Thrombocytopenia / Q000139:chemically induced
D000970:Antineoplastic Agents; D011799:Quinazolines; C094299:ZD 9331