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Phase 1 trial of temozolomide plus irinotecan plus O6‐benzylguanine in adults with recurrent malignant glioma

BACKGROUND: The current study was a phase 1 clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG). The trial was designed to determine the maximum tolerated dose (MTD) and toxicity of irinotecan (CPT‐11) when administered with temozolomide (TMZ) and O6‐benzylg...

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Published in:Cancer 2009-07, Vol.115 (13), p.2964-2970
Main Authors: Quinn, Jennifer A., Jiang, Sara Xiaoyin, Reardon, David A., Desjardins, Annick, Vredenburgh, James J., Gururangan, Sridharan, Sampson, John H., McLendon, Roger E., Herndon, James E., Friedman, Henry S.
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Language:English
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Summary:BACKGROUND: The current study was a phase 1 clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG). The trial was designed to determine the maximum tolerated dose (MTD) and toxicity of irinotecan (CPT‐11) when administered with temozolomide (TMZ) and O6‐benzylguanine (O6‐BG). METHODS: All 3 drugs, CPT‐11, TMZ, and O6‐BG, were administered on Day 1 of a 21‐day treatment. First, patients were treated with a 1‐hour bolus infusion of O6‐BG at a dose of 120 mg/m2 followed immediately by a 48‐hour continuous infusion of O6‐BG at a dose of 30 mg/m2/d. Second, within 60 minutes of the end of the 1‐hour bolus infusion of O6‐BG, TMZ was administered orally at a dose of 355 mg/m2. Third, 1 hour after administration of TMZ, CPT‐11 was infused over 90 minutes. Patients were accrued to 1 of 2 strata based on CYP3A1‐ and CYP3A4‐inducing antiepileptic drug (EIAED) use; dose escalation was conducted independently within these strata. RESULTS: Fifty‐five patients were enrolled. In both strata, the dose‐limiting toxicities were hematologic and included grade 4 neutropenia, febrile neutropenia, leukopenia, and/or thrombocytopenia. For Stratum 1 (EIAEDs), when TMZ was administered at a dose of 355 mg/m2, the MTD of CPT‐11 was determined to be 120 mg/m2. In contrast, for Stratum 2 (no EIAEDs), when TMZ was administered at a dose of 200 mg/m2, the MTD of CPT‐11 was determined to be 80 mg/m2. CONCLUSIONS: The authors believe that the results of the current study provide the foundation for a phase 2 trial of O6‐BG in combination with CPT‐11 and TMZ in patients with MG. Cancer 2009. © 2009 American Cancer Society. This is a phase 1 trial of temozolomide plus irinotecan plus O6‐benzylguanine in patients who are receiving and those who are not receiving enzyme‐inducing anticonvulsants. The authors believe this study provides the foundation for a phase 2 trial of these 3 agents.
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.24336