A phase I trial of 1,3-bis(2-chloroethyl)-1-nitrosourea plus temozolomide:A North American Brain Tumor Consortium study

The North American Brain Tumor Consortium conducted a phase I trial of the combination 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide. E ligibility included a patient with a cancer type that was considered refrac tory to standard therapy. Prior nitrosourea treatments were not permitted. There were parallel dose escalations in two treatment schedules, Forty-five patients were enrolled during an 18-month period. The maximum tolerated do ses (MTDs) when temozolomide followed BCNU (Arm A) were temozolomide at 550 mg/m(2)/p.o, and BCNU at 150 mg/m(2)/i.v.), whereas the MTD when temozolom ide preceded BCNU (Arm B) was temozolomide at 400 mg/m(2)/p.o, and BCNU at 100 mg/m(2)/i.v. Toxicity was predominantly hematologic, although there wer e three instances of pulmonary toxicity, which in one case could have repre sented potentiation of nitrosourea-induced pulmonary fibrosis. The half-lif e of temozolomide was 1.86 (+/-0.31) h, There was a moderate relationship b etween dose and peak concentration and a strong relationship between dose a nd plasma concentration time curve. Pharmacokinetic parameters of temozolom ide were unaffected by the treatment schedule, so the difference in MTD bet ween the schedules is likely due to a biologic rather than a pharmacokineti c sequence interaction, There were 9 partial responses among 43 patients ev aluable for response, including 5 of 25 with a histologic diagnosis of glio blastoma, The recommended dose and schedule for phase II trials of this reg imen are BCNU 150 mg/m(2)/i.v. followed in 2 h by temozolomide 550 mg/m(2)/ p.o. repeated every 6 weeks. We are also recommending screening and periodi c pulmonary function testing during treatment to assess the possible potent iation of nitrosourea-induced pulmonary fibrosis.