Treatment > Temozolomide Clinical Trials

Meeting Abstract

Protracted Cyclic Administration of Temozolomide Is Feasible; a Phase I, Pharmacokinetic and Pharmacodynamic Study

D Cutler, Louis Denis, R Drengler, S Eckhardt, Jose Figueroa, C Geyer, L Reyderman, Eric Rowinsky, A Tolcher, Daniel Von Hoff

Temozolomide (TMZ; Temodal), an imidazotetrazine alkylating agent, is approved for treatment of malignant glioma and in clinical development for malignant melanoma and other advanced cancers. 
The recommended initial oral dosing schedule is 150 mg/m² daily x 5 every 28 days. 
The DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGAT) has been implicated in conferring resistance to TMZ and alkylating agents. 
Preclinical studies have demonstrated progressive depletion of AGAT with prolonged exposure to TMZ, which serves as the rationale to evaluate TMZ on protracted schedules. 
This phase I study explores the feasibility and pharmacokinetic (PK) profile of cyclic daily dosing of TMZ on days 1-7 and days 15-21 every 28 days. 
Correlated pharmacodynamic (PD) effects include toxicity and weekly AGAT levels in peripheral blood mononuclear cells (PBMC). 
Thus far, 21 patients (pts) with advanced solid malignancies have received a total of 42 courses of TMZ at escalating dose levels [50 – 75 – 100 – 125 – 150 and 175 mg/m² daily]. 
At the 175 mg/m² dose-level, dose-limiting (grade 4) thrombocytopenia was observed in 1 heavily-pretreated pt and grade 3 in 1 minimally-pretreated pt. 
Accrual is ongoing to determine the maximally tolerated dose (MTD). 
Preliminary PK parameters on Day 1 and Day 15 indicate that TMZ was rapidly absorbed (Tmax range [0.83 to 1.67 hr]) and eliminated (T1/2 range [1.75 to 1.99 hr]). 
TMZ did not accumulate following multiple dose administration and mean [%CV] values for Cmax and AUC include: {table} Depletion of PBMC AGAT was a function of dose and duration of TMZ exposure. 
In conclusion, this protracted cyclic TMZ schedule is feasible and, at near MTD, permits a 3.2-fold greater drug exposure than conventional dosing [2450 vs 750 mg/m² q 28 days], possibly resulting in therapeutic advantage.

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