Phase I and pharmacologic study of oral ZD9331, a novel nonpolyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
de Jonge
Maja J A
MJ
Department of Medical Oncology, Rotterdam Cancer Institute, University Hospital, Rotterdam, the Netherlands. jonge@onch.azr.nl
Punt
Cornelis J A
CJ
Sparreboom
Alex
A
Planting
André S T
AS
Peters
M E W J
ME
van De Schraaf
Jacqueline
J
Jackman
Ann
A
Smith
Rob
R
de Mulder
Pieter H M
PH
Verweij
Jaap
J
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D001853:Bone Marrow / Q000187:drug effects*; D002853:Chromatography, Liquid; D003875:Drug Eruptions / Q000209:etiology*; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011799:Quinazolines; C094299:ZD 9331; D013940:Thymidylate Synthase