The objective of the trial is to establish the maximum tolerated dose (MTD) and safety profile of Cloretazine (VNP40101M) in combination with Temodar (temozolomide) and then to study this dose in an expanded number of patients. Cohorts of 3-6 patients receive escalating doses of Cloretazine until the MTD is determined (Phase I). In Phase II, response rates, progression-free survival and overall survival will be evaluated in addition to the safety profile. Patients receive oral temozolomide on days 1-7 and intravenous Cloretazine over 15-30 minutes two hours after the last dose of temozolomide on day seven. Treatment repeats every seven weeks in the absence of disease progression or unacceptable toxicity.
Correlative studies conducted as part of the trial will measure: the level of O6 alkylguanine DNA alkyltransferase (AGT) expression in peripheral blood monocytes before treatment with temozolomide and just prior to the administration of Cloretazine; the status of O6- methylguanine-methyltransferase (MGMT) methylation as well as other methylation patterns in plasma from patients treated with this regimen relative to outcome; and Cloretazine in the cerebral spinal fluid and serum/plasma in Phase II.
Dr Raizer said: “One of the mechanisms of resistance in malignant gliomas is AGT. We are hoping that we can deplete the level of AGT with Temodar and that the combination of agents will improve anti-tumor responses and outcomes. To date there is no standard therapy for malignant gliomas that recur; if we can increase progression- free and overall survival with this combination, we will be able to help patients.”
Ann Cahill, vice president, clinical development, said: “Despite decades of research, there has been little progress in the treatment of malignant gliomas which recur after primary therapy. We are pleased to support Dr Raizer’s study of Cloretazine in this patient population.”