Temozolomide in Patients With Advanced Cancer
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 was administered as a single oral dose every 28 days. Doses were escalated to 750 or 1000 mg/m. 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. 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, 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.
Conclusion: Temozolomide 750 mg/m 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-alkylguanine DNA alkyltransferase.

Temozolomide (Temodar; Schering-Plough Research Institute, Kenilworth, NJ), an imidazotetrazine derivative, is a cytotoxic alkylating agent with anticancer activity in patients with recurrent and refractory high-grade glioma and metastatic melanoma. Unlike the first-generation imidazotetrazine derivative dacarbazine, which is converted enzymatically to the active metabolite 5-(3-methyltriazeno)-imidazole-4-carboxamide (MTIC), temozolomide is degraded chemically to MTIC in an irreversible, pH-dependent process; MTIC is further degraded to 5-aminoimidazole-4-carboxamide. Both temozolomide and MTIC alkylate and form N-methylguanine, O-methylguanine, and O-methyladenine adducts. The formation of the O-methylguanine adduct has been hypothesized to be the main cytotoxic pathway for temozolomide. Resistance arises with the reversal of the DNA adducts by a DNA repair protein such as O-alkylguanine DNA alkyltransferase (AGT) or by DNA mismatch repair deficiency.

Temozolomide has demonstrated activity at 150–200 mg/m/day when administered once/day for 5 days, repeated every 4 weeks. The principal toxicity noted in these studies was myelosuppression, both neutropenia and thrombocytopenia. Continuous daily schedules of 75–100 mg/m/day for up to 3–7 weeks have shown less myelotoxicity, but an improvement in efficacy remains to be shown.

After oral administration, temozolomide is completely (bioavailability 1.09, range 0.67–1.36) and rapidly absorbed. Temozolomide is eliminated principally from plasma, by chemical conversion to MTIC, with minimal excretion as unchanged drug in the urine. When pharmacokinetic parameters (mean ± SD) were determined on day 1 of a once-daily, 5-day regimen, the apparent volume of distribution was 28 ± 11 L, terminal half-life 1.8 ± 0.4 hours, and apparent oral clearance 12 ± 4 L/hour. In a subsequent phase I trial with a once-daily, 5-day regimen, the terminal half-life range was 1.3–2.0 hours (mean 1.8 hrs) with no accumulation between days 1 and 5. No difference in apparent oral clearance was noted between days 1 and 5 within the cohorts; however, patients who had prior treatment with a nitrosourea had a statistically significant lower clearance than that of patients without prior treatment. The active metabolite MTIC was detected in plasma within 1 hour of temozolomide administration, had a terminal half-life of 1.5 hours, and had total systemic exposure of 2.2% of temozolomide. In another phase I trial with a once-daily, 5-day regimen, the average terminal half-life and apparent oral clearance were 1.8 hours and 6.9 L/hour/m, respectively. Body surface area–based dosing for temozolomide reduces interpatient variability in drug exposure by up to 35%, which was confirmed in a population pharmacokinetic analysis. On an extended continuous oral schedule, the terminal half-life and apparent oral clearance of temozolomide were consistent with those of other pharmacokinetic studies, and no plasma accumulation of temozolomide was noted during 7 weeks of administration.

Alternate regimens for administration of temozolomide are being investigated. This study was conducted to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic behavior, and potential antitumor activity of temozolomide administered as a single dose every 28 days in minimally pretreated patients.