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Phase 1 trial of irinotecan (CPT-11) in patients with
recurrent malignant glioma: a North American Brain Tumor Consortium study
Prados MD, Yung WK, Jaeckle KA, Robins HI, Mehta MP, Fine HA, Wen PY,
Cloughesy TF, Chang SM, Nicholas MK, Schiff D, Greenberg HS, Junck L, Fink KL,
Hess KR, Kuhn J; North American Brain Tumor Consortium study.
Department of Neurological Surgery, University of California at San Francisco,
San Francisco, CA 94143, USA. pradosm@neurosurg.ucsf.edu
This study was conducted to determine the maximum tolerated dose and
dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to
adults with progressive malignant glioma who were treated with enzyme inducing
antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with
those in patients not on EIAED therapy treated at the recommended phase 2 dose
for other cancers.
The CPT-11 dose was 350 mg/m(2) i.v. every 3 weeks and
remained fixed in patients not on EIAED therapy, but the dose was escalated by
50-mg/m(2) increments in patients on EIAED therapy.
CPT-11 and its metabolites
SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic
acid)-1-piperidine]-carbonyloxycamptothecin) were characterized in both groups.
Patients on EIAEDs received 350 to 800 mg/m(2) of CPT-11.
Dose-limiting toxicity
was due to grade 3 diarrhea despite maximal doses of loperamide.
The systemic
levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group.
There was a moderate-to-fair relationship between CPT-11 dose and the area under
the curve (AUC) for CPT-11 and APC over the 2, but no relationship dosage range
of 350 to 800 mg/m between CPT-11 dose and the AUC for SN-38 or SN-38G.
At the
750-mg/m(2) dose, the AUC for CPT-11 (21.6 microg x h/ml) matched the AUC (21.6
microg x h/ml) in the non-EIAED group treated with 350 mg/m(2) of CPT-11.
We
conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is
750 mg/m(2) when given every 3 weeks.
A phase 2 study of patients with recurrent
malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is
stratified according to the use of EIAEDs.
PMID: 14769140 [PubMed - indexed for MEDLINE]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14769140
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