Greystoke A, Blagden S, Thomas A L, Scott E, Attard G, Molife R, Vidal L, Pacey S, Sarkar D, Jenner A, De-Bono J S, Steward W
Drug Development Unit, Royal Marsden Hospital, Sutton, UK.
Ann Oncol. 2006 Aug;17(8):1313-9. doi: 10.1093/annonc/mdl097. Epub 2006 May 25.
TZT-1027 is a tubulin-binding drug and synthetic derivative of dolastatin-10 with cytotoxic and antivascular activity in vitro and in vivo. Studies have demonstrated anti-tumour activity in several tumour types.
Patients were treated with escalating doses of TZT-1027 and carboplatin at doses from 1.6 to 2.0 mg/m2 and AUC 4 and 5 respectively. For pharmacokinetic analysis, plasma sampling was done during the first course using a high-performance liquid chromatographic assay.
14 patients received a total of 55 cycles at three dose levels. Dose limiting toxicities (DLTs) were first observed with 1.6 mg/m2 TZT-1027 and carboplatin AUC 5; 1 patient had grade 4 neutropenia and a delay in day 8 treatment occurred in two patients (gr 2 fatigue, gr 3 diarrhoea). At TZT-1027 2 mg/m2 and carboplatin AUC 5, one patient experienced grade 3 paralytic ileus. The most frequent toxicities were neutropenia, anaemia, fatigue, constipation, infection and vomiting. Peripheral neuropathy was reported in 36% of patients. One patient (pancreatic adenocarcinoma) achieved a partial response lasting 181 days. Pharmacokinetic analysis did not demonstrate any interaction between TZT-1027 and carboplatin.
The recommended phase II dose is TZT-1027 1.6 mg/m2 and carboplatin AUC 5. No evidence of a PK interaction between these agents was observed.
TZT - 1027是一种微管结合药物，是多拉司他汀 - 10的合成衍生物，在体外和体内均具有细胞毒性和抗血管生成活性。研究已证实其在多种肿瘤类型中具有抗肿瘤活性。
患者接受递增剂量的TZT - 1027和卡铂治疗，TZT - 1027剂量为1.6至2.0 mg/m²，卡铂剂量分别为AUC 4和5。为进行药代动力学分析，在第一个疗程期间使用高效液相色谱分析法进行血浆采样。
14例患者在三个剂量水平共接受了55个周期的治疗。在TZT - 1027剂量为1.6 mg/m²和卡铂AUC 5时首次观察到剂量限制性毒性（DLT）；1例患者出现4级中性粒细胞减少，2例患者（2级疲劳、3级腹泻）在第8天出现治疗延迟。在TZT - 1027剂量为2 mg/m²和卡铂AUC 5时，1例患者出现3级麻痹性肠梗阻。最常见的毒性反应为中性粒细胞减少、贫血、疲劳、便秘、感染和呕吐。36%的患者报告有周围神经病变。1例患者（胰腺腺癌）获得了持续181天的部分缓解。药代动力学分析未显示TZT - 1027与卡铂之间存在任何相互作用。
推荐的II期剂量为TZT - 1027 1.6 mg/m²和卡铂AUC 5。未观察到这些药物之间存在药代动力学相互作用的证据。
