Phase II study of combination BCNU and temozolomide (TMZ) prior to radiotherapy in newly diagnosed anaplastic oligodendroglial tumors

Abstract

2068 Background: Chemosensitivity of oligodendroglial tumors has been widely demonstrated also no standard treatment has been defined to date. Combination of BCNU and TMZ offers the potential advantage of combining the two most efficient drugs in high grade glioma, and have been described to overcome chemoresistance in part by depleting O-6 methylguanine-DNA methyl transferase (MGMT). Our objective was to assess the clinical activity of the combination of BCNU and TMZ administered prior to radiotherapy, and to determine the predictive value of 1p/19q codeletion and MGMT status on response for patients (pts) with newly diagnosed anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA). Methods: To be eligible in this ongoing multicentric phase II study, pts must present a newly diagnosed AO or AOA, with measurable disease after initial surgery. Pts are given BCNU 150 mg/m2 on day 1 and TMZ 110 mg/m2 on day one to day 5 of every 42-day cycle, up to 6 cycles before radiotherapy unless progression. MRI is performed every two cycles. Primary endpoint is objective response rate (Macdonald criteria). Secondary endpoints include progression-free survival, overall survival and predictive value of response for 1p and 19q deletions and MGMT status. Results: To date, 36 pts have been enrolled out of a planned accrual of 50 pts. For interim analysis which included centralised review of histology (WHO 2007) and imaging of the first 23 patients, 21 pts are evaluable and meet inclusion criterias: median age is 55 years; median KPS is 80; histology (WHO 2007) is AO grade III (6 pts), AOA grade III (9 pts), AOA grade IV (6). Median PFS is 16 months [CI 2.6 - 29.4]. Response include CR: 2(10%) and PR: 5(24%), SD: 5(24%), PD: 9(43%). Responses (RC+RP) were of 3/6 (50%) in AO grade III, 3/9 (33%) in AOA grade III, and 1/6 (17%) in AOA grade IV. Toxicity is acceptable. Molecular analysis is in progress. Conclusions: Interim analysis of this phase II study suggests that BCNU and TMZ is active in anaplastic oligodendroglial tumors and confirms heterogeneity of this population. Impact of molecular markers will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology, Lilly Oncology, Schering-Plough