A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: A North American Brain Tumor Consortium study1

Abstract

The purpose of this study was to determine the response to CPT-11 administered every three weeks to adults with progressive malignant glioma, treated with or without enzyme-inducing antiepileptic drug (EIAED) therapy, at the recommended phase 2 dose determined from a previous phase 1 study. Adult patients age 18 or older with a KPS of 60 or higher who had measurable recurrent grade III anaplastic glioma (AG) or grade IV glioblastoma multiforme (GBM) were eligible. No more than one prior chemotherapy was allowed, either as adjuvant therapy or for recurrent disease. The CPT-11 dose was 350 mg/m(2) i.v. every three weeks in patients not on EIAED and 750 mg/m(2) in patients on EIAED therapy. Patients with stable or responding disease could be treated until tumor progression or a total of 12 months of therapy. The primary end point of the study was to determine whether CPT-11 could significantly delay tumor progression, using the rate of six-month progression-free survival (PFS-6). The trial was sized to be able to discriminate between a 15% and 35% rate for the GBM group alone and between a 20% and 40% rate for the entire cohort. There were 51 eligible patients, including 38 GBM and 13 AG patients, enrolled. The median age was 52 and 42 years, respectively. PFS-6 for the entire cohort was 17.6%. PFS-6 was 15.7% (95% confidence interval [CI], 0.07-0.31) for the GBM patients and 23% (95% CI, 0.07-0.52) for AG patients. Toxicity for the group included diarrhea and myelosuppression. We conclude that the recommended phase 2 dose of CPT-11 for patients with or without EIAED was ineffective on this schedule, in this patient population.

Non-methylated MGMT as Predictive Factor in Newly Diagnosed Glioblastoma Multiforme Treated with Bevacizumab Concurrent with Radiotherapy Followed by Adjuvant Bevacizumab plus Irinotecan versus Temozolomide Concurrent with Radiotherapy Followed by Adjuvant Temozolomide

“…Irinotecan active metabolite (100-1000 times more active inhibitor of topoisomerse) is 7-ethyl-10-hydroxycamptothecin (SN-38). Gliomas cells can convert irinotecan to SN-38 directly which decrease proliferation with resultant apoptosis [17]. So our trial was to test the role of bevacizumab with irinotecan versus temozolomide in non-methylated MGMT newly diagnosed glioblastoma multiforme.…”

An algorithm for chemotherapy treatment of recurrent glioma patients after temozolomide failure in the general oncology setting

“…However, Prados et al failed to show such an association but the CPT-11 dose in patients that received EIAEDs was 750 mg/m2, lower to the maximum of 1700 mg/m2 that was used in the previous study [46].…”

Convection-enhanced delivery of SN-38-loaded polymeric micelles (NK012) enables consistent distribution of SN-38 and is effective against rodent intracranial brain tumor models

“…Irinotecan hydrochloride (CPT-11), a prodrug of SN-38, has shown some antitumor activities in patients with recurrent glioblastoma, with response rates of 0-17% in several trials (Friedman et al, 1999;Chamberlain, 2002;Cloughesy et al, 2003;Prados et al, 2006). The activity of CPT-11 depends on the conversion ratio of CPT-11 to SN-38.…”