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

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/m 2 . 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/m 2 . 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/m 2 , 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/m 2 . Conclusion. Temozolomide 750 mg/m 2 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 O 6 ‐alkylguanine DNA alkyltransferase.