Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma

JA Quinn, SX Jiang, DA Reardon, A Desjardins… - Neuro …, 2009 - academic.oup.com
JA Quinn, SX Jiang, DA Reardon, A Desjardins, JJ Vredenburgh, JN Rich, S Gururangan…
Neuro-oncology, 2009academic.oup.com
This phase I clinical trial conducted with patients who had recurrent or progressive
malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and
toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with
O 6-benzylguanine (O 6-BG). Both TMZ and O 6-BG were administered on days 1–5 of a 28-
day treatment cycle. A bolus infusion of O 6-BG was administered at 120 mg/m2 over 1 h on
days 1, 3, and 5, along with a continuous infusion of O 6-BG at 30 mg/m2/day. TMZ was …
Abstract
This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O6-benzylguanine (O6-BG). Both TMZ and O6-BG were administered on days 1–5 of a 28-day treatment cycle. A bolus infusion of O6-BG was administered at 120 mg/m2 over 1 h on days 1, 3, and 5, along with a continuous infusion of O6-BG at 30 mg/m2/day. TMZ was administered at the end of the first bolus infusion of O6-BG and then every 24 h for 5 days during the continuous infusion of O6-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m2 on day 1 and 50 mg/m2/day on days 2–5; schedule 2, 50 mg/m2/day on days 1–5; and schedule 3, 50 mg/m2/day on days 1–5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O6-BG was schedule 1. This study provides the foundation for a phase II trial of O6-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.
Oxford University Press