title: A phase I trial of 1,3-bis(2-chloroethyl)-1-nitrosourea plus temozolomide: a North American Brain Tumor Consortium study.
abstract: The North American Brain Tumor Consortium conducted a phase I trial of the combination 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide. Eligibility included a patient with a cancer type that was considered refractory 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 doses (MTDs) when temozolomide followed BCNU (Arm A) were temozolomide at 550 mg/m2/p.o. and BCNU at 150 mg/m2/i.v.), whereas the MTD when temozolomide preceded BCNU (Arm B) was temozolomide at 400 mg/m2/p.o. and BCNU at 100 mg/m2/i.v. Toxicity was predominantly hematologic, although there were three instances of pulmonary toxicity, which in one case could have represented potentiation of nitrosourea-induced pulmonary fibrosis. The half-life of temozolomide was 1.86 (+/-0.31) h. There was a moderate relationship between dose and peak concentration and a strong relationship between dose and plasma concentration time curve. Pharmacokinetic parameters of temozolomide were unaffected by the treatment schedule, so the difference in MTD between the schedules is likely due to a biologic rather than a pharmacokinetic sequence interaction. There were 9 partial responses among 43 patients evaluable for response, including 5 of 25 with a histologic diagnosis of glioblastoma. The recommended dose and schedule for phase II trials of this regimen are BCNU 150 mg/m2/i.v. followed in 2 h by temozolomide 550 mg/m2/p.o. repeated every 6 weeks. We are also recommending screening and periodic pulmonary function testing during treatment to assess the possible potentiation of nitrosourea-induced pulmonary fibrosis.
authors: University of Texas Southwestern Medical Center, Dallas 75214, USA.
authors: S C
authors: SC
authors: Schold
authors: J G
authors: JG
authors: Kuhn
authors: S M
authors: SM
authors: Chang
authors: M E
authors: ME
authors: Bosik
authors: H I
authors: HI
authors: Robins
authors: M P
authors: MP
authors: Mehta
authors: A M
authors: AM
authors: Spence
authors: D
authors: D
authors: Fulton
authors: K L
authors: KL
authors: Fink
authors: M D
authors: MD
authors: Prados
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000097:blood; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy*; D002330:Carmustine / Q000008:administration & dosage*; D003606:Dacarbazine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D020714:Maximum Tolerated Dose; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D002330:Carmustine; D000077204:Temozolomide