Treatment > Temozolomide Clinical Trials

Meeting Abstract

Rapid depletion of O6-alkylguanine DNA alkyltransferase with twice daily oral temozolomide (SCH 52365) in patients with advanced cancer

V Batra, M Dugan, SL Gerson, J Haaga, L Liu, S Majka, P Reidenberg, J Schupp, TP Spiro, P Statkevich, JK Willson

Temozolomide (TMZ) is a well tolerated, orally active methylating imidotetrazine undergoing phase II trials in malignant glioma and malignant melanoma. 
TMZ is converted to monomethyl triazenoimidazole carboxamide (MTIC) which forms cytotoxic O6-methylguanine [O6-mG] DNA adducts. 
O6-alkylguanine DNA alkyltransferase (AGT) removes O6-mG adducts by self-inactivation. 
AGT depletion results in persistent O6-mG adducts and TMZ cytotoxicity. 
Since many human tumors have high AGT, optimizing the schedule of TMZ to maximize AGT depletion may improve the effectiveness of the drug. 
This phase I dose escalation trial was designed to rapidly deplete AGT and prevent its regeneration. 
A bolus dose of 200 mg/m2 orally was followed by nine q12 hr oral doses of 50 mg/m2, 75 mg/m2, or 100 mg/m2 (total doses of 650 mg/m2, 875 mg/m2, and 1100 mg/m2). 
No dose limiting toxicity was observed at the first two dose levels and 4 of 7 patients remain on study after 2-5 cycles. 
Blood mononuclear cell (BMC) AGT depletion was used as a pharmacodynamic measure of biochemical modulation of tumor AGT. 
Rapid, dose-dependent AGT depletion was noted. 
The bolus dose depleted BMC AGT by a mean of 80% in all patients. 
90% depletion of BMC AGT occurred by day 3 at the 650 mg/m2 dose and by day 2 at the 875 mg/m2 dose. Pharmacokinetic parameters revealed a Cmax of about 12 ug/ml, a t1/2 of 1.67 hr and an AUC of 30.6 ug x hr/ml after the 200 mg/m2 bolus, consistent with prior studies. 
As expected, Cmax and AUC were proportionally less during the maintenance dose. 
At the third dose level, tumor biopsies before and on day 5 showed greater than 90% depletion of AGT. 
Thus, a novel 5 day bid oral dosing of TMZ rapidly depletes AGT and prevents its regeneration. 
This mechanism based approach may increase the potency of TMZ as an anticancer drug.

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