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

Abstract

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.

• Authors: Maja J A de Jonge, Cornelis J A Punt, Alex Sparreboom, André S T Planting, M E W J Peters, Jacqueline van De Schraaf, Ann Jackman, Rob Smith, Pieter H M de Mulder, Jaap Verweij
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 20 Issue 7 Pg. 1923-31 (Apr 01 2002) ISSN: 0732-183X [Print] United States
• PMID: 11919253 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Quinazolines
• ZD 9331
• Thymidylate Synthase

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, chemistry, pharmacokinetics)
• Area Under Curve
• Bone Marrow (drug effects)
• Chromatography, Liquid
• Drug Eruptions (etiology)
• Female
• Humans
• Male
• Mass Spectrometry
• Middle Aged
• Neoplasms (blood, drug therapy)
• Quinazolines (administration & dosage, adverse effects, chemistry, pharmacokinetics)
• Thymidylate Synthase (antagonists & inhibitors)
• Treatment Outcome