Temozolomide in Patients with Advanced Cancer: Phase I and Pharmacokinetic Study

Michelle A. Rudek, Ross C. Donehower, Paul Statkevich, Vijay K. Batra, David L. Cutler, Sharyn D. Baker

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Study Objective. To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and potential antitumor activity of temozolomide administered as a single dose every 28 days. Design. Open label, phase I, dose-escalation trial. Setting. University-affiliated cancer center. Patients. Eleven patients aged 33-73 years with a documented solid tumor or lymphoma who failed therapy of proven efficacy for their disease or had a disease for which no conventional therapy was available. Intervention. Temozolomide 500 mg/m 2 was administered as a single oral dose every 28 days. Doses were escalated to 750 or 1000 mg/m2. No intrapatient dose escalation was allowed. At least two patients were enrolled at each dose level. Patients who did not have progressive disease and did not experience a dose-limiting toxicity, or experienced a dose-limiting toxicity but were eligible for dose reduction, were eligible to continue on the study. Measurements and Main Results: Pharmacokinetic analysis was performed for temozolomide and its active metabolite, 5-(3-methyltriazeno)-imidazole-4-carboxamide (MTIC). Neutropenia and thrombocytopenia were dose limiting at 1000 mg/m2. Temozolomide was absorbed rapidly (mean time to maximum concentration 1.4 hrs) and eliminated, with average half-life and apparent oral systemic clearance values of 1.8 hours and 97 ml/minute/m2, respectively. Mean systemic exposure to MTIC was 3.7% of temozolomide. No objective responses were observed. The maximum tolerated dose of temozolomide was 750 mg/m2. Conclusion. Temozolomide 750 mg/m2 administered orally every 28 days was well tolerated. Alternate temozolomide dosing schedules such as continuous daily administration may enhance antitumor activity through sustained depletion of the DNA repair protein O6-alkylguanine DNA alkyltransferase.

Original languageEnglish (US)
Pages (from-to)16-25
Number of pages10
Issue number1
StatePublished - Jan 2004


  • Alkylating agents
  • Imidazotetrazine
  • MTIC
  • Pharmacokinetics
  • Phase I
  • Temozolomide

ASJC Scopus subject areas

  • Pharmacology (medical)


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