Temozolomide (TMZ) and lomustine (CCNU) in high grade glioma (HGG) patients: Phase I study

Abstract

1577 Background: TMZ has activity in HHG and same new combinations are being studied to evaluate an increase of this activity. The combination of TMZ and nitrosureas were evaluated preclinically. These experimental results indicated synergistic killing when TMZ is combined with nitrosureas in resistant human glioma cell lines. Based on these finding, as primary endpoint, this phase I study was performed to determine the maximum tolerated dose (MTD), safety and feasibility of new treatment schedule of temozolomide when administered with a fixed dose of CCNU, and secondary, was evaluated the preliminary data of efficacy. Methods: Recurrent HHG patients (10 with glioblastoma multiforme and two with anaplastic astrocytoma) were treated with oral TMZ 75 mg/mq for 21 or 28 consecutive days or TMZ 100 mg/mq for 28 consecutive days together with orally CCNU 100 mg/mq on day 1 every 6 weeks. This schedule was approved by ethics committe and a informed consent was obtained for all subjects. Results: Eleven patients received a total of 35 courses of TMZ/CCNU. The main toxicities of the regimen consisted of vomiting, costipation, neutropenia and thrombocytopenia. The myelotoxicity was dose-limiting in two of six new patients treated with TMZ 100 mg/mq x 28 days plus CCNU 100 mg/mq d1 dose level. None dose-limiting toxicity was evaluated in 15 courses in the patients at the lower dose level. Preliminary data about toxicity are ongoing. For ongoing phase II clinical trial we recommended safe dose is TMZ 75 mg/mq for 28 consecutive days and CCNU 100 mg/mq d 1 every 6 ws. Conclusions: The schedule didn't reduce the TMZ dose-intensity and the addition of CCNU didn't substantially modify the tolerability of TMZ respect to standard single-agent TMZ. The preliminary results about TTP disease seem to be very promising. No significant financial relationships to disclose.