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

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 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/m(2) over 1 h on days 1, 3, and 5, along with a continuous infusion of O(6)-BG at 30 mg/m(2)/day. TMZ was administered at the end of the first bolus infusion of O(6)-BG and then every 24 h for 5 days during the continuous infusion of O(6)-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/m(2) on day 1 and 50 mg/m(2)/day on days 2-5; schedule 2, 50 mg/m(2)/day on days 1-5; and schedule 3, 50 mg/m(2)/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 O(6)-BG was schedule 1. This study provides the foundation for a phase II trial of O(6)-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

“…Concurrent administration of O 6 BG restores tumor cell sensitivity to alkylating agents such as TMZ, which was previously investigated as a strategy to improve TMZ efficacy in recurrent GBM patients (5,6). However, early phase studies revealed that O 6 BG/TMZ administration caused severe off-target myelosuppression.…”

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

“…In all cases, dose limitation was myelosuppression manifested as neutropenia, leukopenia, and thrombocytopenia [86,89,91,93,94]. That O 6 -BG exacerbated this toxicity provides strong circumstantial evidence for MGMT being a major resistance mechanism, at least in the corresponding normal human bone marrow stem cells.…”

“…Using an O 6 -BG dose of 100 mg/m 2 [86] or 120 mg/m 2 [90], the maximal tolerated dose of carmustine was 40 mg/m 2 , which is considerably lower than the dose of 120 mg/m 2 without the MGMT inhibitor. Using bolus infusion of O 6 -BG (120 mg/m 2 ,1 h) on days 1, 3, and 5, combined with a continuous infusion of O 6 -BG at 30 mg/m 2 /day, the maximal tolerated dose of temozolomide was 200 mg/m 2 on day 1 and 50 mg/m 2 /day on days 2-5 [91]. The total dose (400 mg/m 2 ) was only slightly less than the maximum tolerated dose of a single temozolomide application without MGMT inhibitor, which was 472 mg/m 2 [89].…”

Strategies to Improve the Killing of Tumors Using Temozolomide: Targeting the DNA Repair Protein MGMT

“…Since one molecule of MGMT removes only one alkyl molecule, an excess of DNA adducts at the O 6 -position could completely deplete MGMT [29,30]. The stoichiometric and irreversible transfer of adducts to internal cysteine residues at position 145 prevents GC AT transitions or [41,43,44] Melanoma in vivo [38,39] Pediatric/solid tumors Phase I [45] Glioblastoma A clinical trial [40] Lomeguatrib TMZ Melanoma A clinical trial [52] Prostate, CNS, colorectal cancer A clinical trial [53] Acute leukemia in vitro [49] Pancreatic Phase I [50] Breast cancer in vitro/in vivo [48] Ovarian cancer in vitro [47] Antiepileptic drugs…”