Morgan Robert J, Synold Timothy W, Longmate Jeffrey A, Quinn David I, Gandara David, Lenz Heinz-Josef, Ruel Christopher, Xi Bixin, Lewis Michael D, Colevas A Dimitrios, Doroshow James, Newman Edward M
Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA.
Department of Cancer Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
Cancer Chemother Pharmacol. 2015 Nov;76(5):897-907. doi: 10.1007/s00280-015-2868-7. Epub 2015 Sep 11.
The California Cancer Consortium completed a phase I trial of E7389 (eribulin mesylate), an analog of the marine natural product halichondrin B. This trial was to determine the pharmacodynamics, pharmacokinetics, and MTD of E7389 administered by bolus injection weekly for 3 weeks out of four.
This trial included a rapid titration design. Real-time pharmacokinetics were utilized to guide dose escalation. Initially, single-patient cohorts were enrolled with intra- and inter-patient dose doubling. The second phase was a standard 3 + 3 dose escalation schedule. At the MTD, a cohort of patients was enrolled for target validation studies (separate manuscript). The starting dose was 0.125 mg/m(2), and doses were doubled within and between patients in the first phase. Blood and urine sampling for E7389 pharmacokinetics was performed on doses 1 and 3 of cycle 1. Levels were determined using a LC/MS/MS assay.
Forty patients were entered. Thirty-eight were evaluable for toxicity and 35 for response. The rapid escalation ended with a grade 3 elevation of alkaline phosphatase at 0.5 mg/m(2)/week. The second phase ended at 2.0 mg/m(2)/week with dose-limiting toxicities of grades 3 and 4 febrile neutropenia. Other toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m(2)/week. Responses included four partial responses (lung cancer [2], urothelial [1], and melanoma [1]).
E7389 was well tolerated in this trial with the major toxicity being myelosuppression. PD shows that E7389 induces significant morphologic changes (bundle formation) in the microtubules of peripheral blood mononuclear cells and tumor cells in vivo. The data suggest that lower intra-tumoral levels of β-tubulin III or higher intra-tumoral levels of MAP4 may correlate with response to E7389, while lower intra-tumoral levels of stathmin may be associated with progression. PK data reveal that E7389 exhibits a tri-exponential elimination from the plasma of patients receiving a rapid i.v. infusion. At sub-toxic doses, plasma concentrations of E7389 are maintained well above the levels required for activity in vitro for >72 h.
加利福尼亚癌症联盟完成了一项关于E7389（甲磺酸艾瑞布林）的I期试验，E7389是海洋天然产物软海绵素B的类似物。该试验旨在确定每周静脉推注一次、四周内连续三周给药的E7389的药效学、药代动力学和最大耐受剂量（MTD）。
该试验采用快速滴定设计。利用实时药代动力学指导剂量递增。最初，纳入单患者队列，患者内和患者间剂量加倍。第二阶段采用标准的3+3剂量递增方案。在最大耐受剂量时，纳入一组患者进行靶点验证研究（单独成文）。起始剂量为0.125mg/m²，在第一阶段患者内和患者间剂量加倍。在第1周期的第1剂和第3剂给药后采集血液和尿液样本用于E7389药代动力学研究。采用液相色谱/串联质谱法测定血药浓度。
共纳入40例患者。38例可进行毒性评估，35例可进行疗效评估。快速递增阶段在剂量为0.5mg/m²/周时以3级碱性磷酸酶升高结束。第二阶段在剂量为2.0mg/m²/周时结束，出现3级和4级发热性中性粒细胞减少的剂量限制性毒性。其他毒性包括低血糖、低磷血症和疲劳。最大耐受剂量为1.4mg/m²/周。疗效包括4例部分缓解（肺癌[2例]、尿路上皮癌[1例]和黑色素瘤[1例]）。
在本试验中E7389耐受性良好，主要毒性为骨髓抑制。药效学研究表明，E7389在体内可诱导外周血单核细胞和肿瘤细胞微管发生显著形态学改变（束状形成）。数据表明，肿瘤内较低水平的β-微管蛋白III或较高水平的微管相关蛋白4（MAP4）可能与对E7389的反应相关，而肿瘤内较低水平的Stathmin可能与疾病进展相关。药代动力学数据显示，接受快速静脉输注的患者血浆中E7389呈现三指数消除。在亚毒性剂量下，E7389的血浆浓度在>72小时内维持在远高于体外活性所需的水平之上。
