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Phase 1 trial of temozolomide plus irinotecan plus O 6 ‐benzylguanine in adults with recurrent malignant glioma
Author(s) -
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.
Publication year - 2009
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.24336
Subject(s) - medicine , irinotecan , neutropenia , temozolomide , leukopenia , bolus (digestion) , glioma , gastroenterology , toxicity , phases of clinical research , pharmacology , surgery , chemotherapy , cancer , colorectal cancer , cancer research
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 O 6 ‐benzylguanine (O 6 ‐BG). METHODS: All 3 drugs, CPT‐11, TMZ, and O 6 ‐BG, were administered on Day 1 of a 21‐day treatment. First, patients were treated with a 1‐hour bolus infusion of O 6 ‐BG at a dose of 120 mg/m 2 followed immediately by a 48‐hour continuous infusion of O 6 ‐BG at a dose of 30 mg/m 2 /d. Second, within 60 minutes of the end of the 1‐hour bolus infusion of O 6 ‐BG, TMZ was administered orally at a dose of 355 mg/m 2 . 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/m 2 , the MTD of CPT‐11 was determined to be 120 mg/m 2 . In contrast, for Stratum 2 (no EIAEDs), when TMZ was administered at a dose of 200 mg/m 2 , the MTD of CPT‐11 was determined to be 80 mg/m 2 . CONCLUSIONS: The authors believe that the results of the current study provide the foundation for a phase 2 trial of O 6 ‐BG in combination with CPT‐11 and TMZ in patients with MG. Cancer 2009. © 2009 American Cancer Society.