Treatment > Temozolomide Clinical Trials

Meeting Abstract

Protracted Daily Administration of Temozolomide Is Feasible: A Phase I and Pharmacokinetic - 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) is a new imidazotetrazine alkylating agent approved for treatment of malignant glioma and in clinical development for other advanced malignancies. 
The recommended initial oral dosing schedule is 150 mg/m² daily x 5 q 28 days. 
The DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGAT) has been implicated in conferring resistance to TMZ. 
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 PK profile of continuous daily dosing of TMZ for 21 days q 28 days. Correlated PD effects include weekly AGAT levels in peripheral blood mononuclear cells (PBMC). 
Thus far, 34 patients (pts) with advanced solid malignancies have received a total of 64 courses of TMZ at escalating dose levels [50 – 75 – 100 – 125 and 150 mg/m² daily]. 
Thrombocytopenia was the principal toxicity; grade 4 thrombocytopenia consistently occurred in minimally-pretreated (MP) pts at doses >125 mg/m² daily and in heavily-pretreated (HP) pts at doses > 100 mg/m2 daily. 
The maximally tolerated dose (MTD) based on 2 courses for MP pts was defined at 100 mg/m² daily. 
Accrual is ongoing to define the MTD for HP pts. 
Preliminary PK parameters on Day 1 and Day 21 indicate that TMZ was rapidly absorbed (T_max range [1.25 to 1.5 hr]) and eliminated (T_1/2 range [1.5 to 2.6 hr]). 
TMZ did not accumulate following multiple dose administrations and mean [%CV] values for C_max and AUC include: {table} Progressive depletion of PBMC AGAT was dose related. 
In conclusion, protracted daily dosing of TMZ is feasible and, at the defined MTD for MP pts, permits a 2.8-fold greater drug exposure than conventional dosing [2100 vs 750 mg/m² q 28 days], possibly resulting in therapeutic advantage.

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