A phase I trial of 1,3-bis(2-chloroethyl)-1-nitrosourea plus temozolomide: A North American Brain Tumor Consortium study
A phase I trial of 1,3-bis(2-chloroethyl)-1-nitrosourea plus temozolomide: A North American Brain Tumor Consortium study
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DOI：
10.1093/neuonc/2.1.34
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发表时间：
2000-01-01
期刊：
影响因子：
15.9
通讯作者：
Prados, MD
中科院分区：
文献类型：
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作者：
Schold, SC;Kuhn, JG;Prados, MD
北美脑肿瘤联盟进行了一项1，3-双（2-氯乙基）-1-亚硝基脲（BCNU）和替莫唑胺联合治疗的I期试验。合格性包括患有被认为对标准疗法难治的癌症类型的患者。不允许进行既往亚硝基脲治疗。在两种治疗方案中有平行的剂量递增，在18个月期间入组了45例患者。替莫唑胺继BCNU（A组）后的最大耐受剂量（MTD）为替莫唑胺550 mg/m2/p.o，BCNU 150 mg/m2/i. v），而替莫唑胺先于BCNU时（B组）的MTD为替莫唑胺400 mg/m2/p.o，BCNU 100 mg/m2/i. v。毒性主要为血液学毒性，尽管有三例肺毒性，其中一例可能代表亚硝基脲诱导的肺纤维化增强。替莫唑胺的半衰期为1.86（+/-0.31）h，剂量与峰浓度呈中度相关，剂量与血药浓度-时间曲线呈强相关。替莫唑胺的药代动力学参数不受治疗方案的影响，因此方案之间MTD的差异可能是由于生物学而不是药代动力学序列相互作用。在43名可评价应答的患者中有9名部分应答，包括25名组织学诊断为胶质母细胞瘤的患者中的5名，该方案II期试验的推荐剂量和时间表为BCNU 150 mg/m2/i. v.，随后2小时内给予替莫唑胺550 mg/m2/p.o.。每6周重复一次。我们还建议在治疗期间进行筛查和定期肺功能检查，以评估亚硝基脲诱导的肺纤维化可能的增强作用。
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/m(2)/p.o, and BCNU at 150 mg/m(2)/i.v.), whereas the MTD when temozolomide 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 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/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 periodic pulmonary function testing during treatment to assess the possible potentiation of nitrosourea-induced pulmonary fibrosis.