Phase 2 trial of BCNU plus irinotecan in adults with malignant glioma

Abstract

In preclinical studies, BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, plus CPT-11 (irinotecan) exhibits schedule-dependent, synergistic activity against malignant glioma (MG). We previously established the maximum tolerated dose of CPT-11 when administered for 4 consecutive weeks in combination with BCNU administered on the first day of each 6-week cycle. We now report a phase 2 trial of BCNU plus CPT-11 for patients with MG. In the current study, BCNU (100 mg/m2) was administered on day 1 of each 6-week cycle. CPT-11 was administered on days 1, 8, 15, and 22 at 225 mg/m2 for patients receiving CYP3A1- or CYP3A4-inducing anticonvulsants and at 125 mg/m2 for those not on these medications. Newly diagnosed patients received up to 3 cycles before radiotherapy, while recurrent patients received up to 8 cycles. The primary end point of this study was radiographic response, while time to progression and overall survival were also assessed. Seventy-six patients were treated, including 37 with newly diagnosed tumors and 39 with recurrent disease. Fifty-six had glioblastoma multiforme, 18 had anaplastic astrocytoma, and 2 had anaplastic oligodendroglioma. Toxicities (grade > or =3) included infections (13%), thromboses (12%), diarrhea (10%), and neutropenia (7%). Interstitial pneumonitis developed in 4 patients. Five newly diagnosed patients (14%; 95% CI, 5%-29%) achieved a radiographic response (1 complete response and 4 partial responses). Five patients with recurrent MG also achieved a response (1 complete response and 4 partial responses; 13%; 95% CI, 4%-27%). More than 40% of both newly diagnosed and recurrent patients achieved stable disease. Median time to progression was 11.3 weeks for recurrent glioblastoma multiforme patients and 16.9 weeks for recurrent anaplastic astrocytoma/ anaplastic oligodendroglioma patients. We conclude that the activity of BCNU plus CPT-11 for patients with MG appears comparable to that of CPT-11 alone and may be more toxic.

Antitumor activity of CKD-602, a camptothecin derivative, in a mouse glioma model

“…24 CPT-11 and topotecan have also shown some efficacy in the treatment of glioma. [25][26][27] However, low levels of efficacy when administered as a single agent and major toxicities such as colitis and interstitial pneumonia potentially limit their use for this purpose. 28,29 CKD-602 is a potent topoisomerase 1 inhibitor that does not have the poor water solubility and toxicity of its parent drug, camptothecin.…”

Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme

“…Using a combination of irinotecan and carmustine, Reardon et al 21 reported objective responses (one CR and four PRs) and a median TTP of 11.3 weeks in patients with recurrent malignant gliomas (including 28 with recurrent GBM), concluding that the combination was comparable in activity to single-agent irinotecan but with more frequent toxic effects. In contrast, another phase II trial of the same combination in patients with recurrent GBM on EIACs who had failed temozolomide was reported to have 9 PR and 21 SD, with a PFS-6 rate of 30.3% and a median TTP of 17 weeks.…”

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

“…However, a phase II trial employing such a combination resulted in comparable results to that of CPT-11 alone and increased toxicity [68]. Similarly, ACNU, another nitrosourea given alone or in combination with teniposide or cytarabine in patients with GBM after TMZ failure resulted in limited activity and considerable toxicity [69].…”