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Phase
1 study of temozolomide plus irinotecan (CPT-11) in adults with recurrent
malignant glioma
M.
A. Badruddoja, D. Reardon, R. Beason, A. Friedman, J. A. Quinn, J. Rich, J.
Sampson, V. Stafford-Fox, D. D. Bigner, H. S. Friedman
Duke
University Medical Center, Durham, NC; Pharmacia & Upjohn, Kalamazoo, MI;
Schering Corporation, Kenilworth, NJ
Previous
phase II studies have validated the efficacy of temozolomide (TMZ) and
irinotecan (CPT-11) as single agents for the treatment of malignant glioma (MG).
Pre-clinical studies demonstrate that TMZ synergizes the cytotoxic activity of
CPT-11 against human malignant glioma xenografts (Patel Clin Ca Res 6: 4154,
2000).
The current phase I study is designed to determine the maximum tolerated dose (MTD)
and dose limiting toxicity (DLT) of CPT-11 when combined with TMZ administered
at 200 mg/m2/dose x 5 days every 6 weeks.
A treatment cycle consists of 4 weekly infusions of CPT-11 over 6 weeks.
CPT-11 is escalated in successive cohorts of 3-6 patients.
Patients are stratified based on concurrent use of CYP3A4 enzyme-inducing
anticonvulsants (EIAC).
Each stratum is escalated independently.
To date fifty-nine patients have been enrolled, 36 patients in the EIAC stratum
(GBM=29, AA= 6 and, AO=1) and 22 patients in the non-EIAC stratum (GBM=17, AA=5,
AO=0).
There have been two DLTs to date.
One patient (80mg/m2-EIAC) experienced grade 4 neutropenia and an additional
patient (80mg/m2, non-EIAC) experienced grade 4 pancytopenia.
To date 1 patient has had a complete response after 7 cycles, 2 have had partial
response after 5 cycles, and 39 patients have had stable disease for 1-6 cycles.
We have not reached the MTD of CPT-11 and continue to accrue patients in the 100
mg/m2 non-EIAC and at the 175 mg/m2 EIAC strata, respectively.
The combination of TMZ plus CPT-11 appears to be well tolerated.
Preliminary responses, even at low CPT-11 dose levels, suggests the combination
may be more efficacious than each agent alone.
© Copyright 2003
American Society of
Clinical Oncology All rights reserved worldwide
Source: http://www.asco.org/ac/1,1003,_12-002489-00_18-002003-00_19-00102176-00_29-00A,00.asp?cat=CNS+Tumors&parent=
Central+Nervous+System+Tumors&returnpid=2325&SubCat_ID=4 |
