Lheureux S, Oza A M, Laurie S A, Halford R, Jonker D, Chen E, Keller D, Bourade V, Wang L, Doyle L, Siu L L, Goel R
Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada M5G2M9.
Department of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada K1H8M5.
Br J Cancer. 2015 Dec 1;113(11):1534-40. doi: 10.1038/bjc.2015.343. Epub 2015 Nov 10.
Eribulin mesylate is a synthetic microtubule inhibitor that showed cytotoxic synergy in combination with gemcitabine preclinically. This combination was assessed in a Phase I dose-finding trial in patients diagnosed with advanced solid tumours who had received up to two prior chemotherapy regimens for metastatic disease (CP cohort).
Dose escalation was performed in a 3+3 design to identify the recommended phase II dose (RP2D). Two additional expansion cohorts in women with gynaecologic cancers at the RP2D (G), and further dose escalation of metastatic chemotherapy-naive patients (CN), were evaluated.
45 patients were treated: 21 (CP), 10 (G) and 14 (CN). The initial combination of eribulin and gemcitabine was administered on days 1, 8, and 15 of a 28-day cycle; however, due to 2 out of 6 dose-limiting haematological toxicities at the first dose level, a reduced dose-intense schedule was assessed. The RP2D was defined at 1.0 mg m(-2) eribulin and 1000 mg m(-2) gemcitabine day 1 and 8 q3 weeks. No other significant toxicities were observed in the G expansion cohort. Neutropenia prevented further dose escalation in the CN cohort. Objective responses were seen in all three cohorts - 2/21 (CP), 1/10 (G) and 2/14 (CN).
The combination of eribulin and gemcitabine was well tolerated at the RP2D.
甲磺酸艾瑞布林是一种合成微管抑制剂，临床前研究显示其与吉西他滨联合具有细胞毒性协同作用。在一项I期剂量探索试验中，对诊断为晚期实体瘤且已接受最多两种转移性疾病既往化疗方案的患者（CP队列）评估了这种联合用药。
采用3+3设计进行剂量递增，以确定推荐的II期剂量（RP2D）。对另外两个队列进行了评估，一个是在RP2D剂量水平下纳入的妇科癌症女性患者队列（G），另一个是对未接受过转移性化疗的患者进一步进行剂量递增（CN）。
共治疗45例患者，其中21例（CP队列）、10例（G队列）和14例（CN队列）。艾瑞布林和吉西他滨的初始联合用药方案为在28天周期的第1、8和15天给药；然而，由于在第一个剂量水平出现6例剂量限制性血液学毒性中的2例，对剂量强度降低的给药方案进行了评估。RP2D确定为艾瑞布林1.0 mg m(-2)、吉西他滨1000 mg m(-2)，于第1天和第8天给药，每3周一次。在G扩展队列中未观察到其他显著毒性。中性粒细胞减少症阻止了CN队列的进一步剂量递增。在所有三个队列中均观察到客观缓解，CP队列2/21例、G队列1/10例、CN队列2/14例。
艾瑞布林和吉西他滨联合用药在RP2D剂量下耐受性良好。
