A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study
A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study
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DOI：
10.1186/s12885-016-2174-8
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发表时间：
2016-02-24
期刊：
影响因子：
3.8
通讯作者：
Valle, Juan W.
中科院分区：
文献类型：
--
作者：
Bridgewater, John;Lopes, Andre;Valle, Juan W.
背景：顺铂和吉西他滨 (CisGem) 联合治疗是晚期胆道癌 (ABC) 患者的标准治疗方法。 Selumetinib (AZD6244, ARRY-142886) 有效且选择性地抑制 MEK1/2（一种细胞内激酶），并在 ABC 中显示出活性。 ABC-04 试验的目的是确定 ABC 患者中司美替尼联合 CisGem 的推荐剂量。方法：符合条件的患者年龄 >= 18 岁，具有组织学或细胞学证实的不可切除的复发或转移性胆道癌、胆囊癌或壶腹癌，WHO 体能状态 0-2 级，以及足够的主要器官功能。患者可能之前接受过手术、放疗或辅助化疗，但之前没有接受过 CisGem 治疗，也没有针对局部晚期或转移性疾病进行过化疗。患者在 21 天周期的第 1 天和第 8 天静脉注射顺铂 25 mg/m(2) 加吉西他滨 1000 mg/m2。每天服用司美替尼胶囊。患者接受最多 8 个周期的 CisGem 治疗，并可以接受司美替尼治疗直至疾病进展。使用剂量递减方案来确定司美替尼的推荐剂量。第一剂量水平为 75 mg bd。以 3 人为一组招募患者，并在第一个治疗周期期间评估剂量限制毒性 (DLT)。结果：招募了 13 名患者，其中 12 名患者可进行 DLT 评估（1 名患者未开始治疗）。所有可评估的患者均接受司美替尼 75 mg bd 的起始剂量，其中一名患者出现 DLT（心源性胸痛）。服用司美替尼的中位天数（根据剂量中断天数进行调整）为 171.5（IQR：75.5 至 344）。两名患者在注册后 14 个月和 19 个月仍在接受治疗。第 1 周期中有 3 例暂时中断司美替尼，1 例永久中断司美替尼。8 名患者可评估客观缓解 (RECIST v1.1)：3 名患者部分缓解，5 名患者疾病稳定。中位 PFS 为 6.4 个月（IQR 5.2 至 13.7）。与司美替尼相关的毒性主要与水肿和皮疹有关，1-2 级且可控制。药代动力学分析显示，与CisGem联用时，司美替尼的AUC(0-无穷大)、AUC(0-8)和Cmax分别增加12%、11%和30%，而司美替尼N-去甲基代谢物的Cmax下降40%。没有证据表明司美替尼单独或与CisGem联合用药时司美替尼或司美替尼N-去甲基代谢物的Cmax时间不同。结论：司美替尼与CisGem联用时的推荐剂量为75 mg bd。转化研究正在进行中，以确定可以预测结果的生物标志物（ClinicalTrials.gov 标识符：NCT01242605，2010 年 7 月 6 日）。
Background: Combined treatment with cisplatin and gemcitabine (CisGem) is the standard of care for patients with advanced biliary tract cancer (ABC). Selumetinib (AZD6244, ARRY-142886) potently and selectively inhibits MEK1/2, an intracellular kinase and has shown activity in ABC. The objective of the ABC-04 trial was to establish the recommended dose of selumetinib in combination with CisGem in patients with ABC.Methods: Eligible patients were >= 18 years, had histologically or cytologically-confirmed unresectable recurrent or metastatic biliary tract, gallbladder or ampullary carcinoma, WHO performance status 0-2, and adequate major organ function. Patients may have had prior surgery, radiotherapy or adjuvant chemotherapy, but no prior CisGem and no prior chemotherapy for locally advanced or metastatic disease. Patients received cisplatin 25 mg/m(2) plus gemcitabine 1000 mg/m2 intravenously on days 1 and 8 of a 21-day cycle. Selumetinib capsules were taken daily. Patients received up to 8 cycles of CisGem and could receive selumetinib until disease progression. A dose de-escalation scheme was used to determine the recommended dose of selumetinib. The first dose level was 75 mg bd. Patients were recruited in cohorts of 3 and assessed for dose limiting toxicity (DLT) during the first cycle of treatment.Results: Thirteen patients were recruited, of whom 12 were evaluable for DLT (1 did not start treatment). All evaluable patients received the starting dose of selumetinib 75 mg bd and one patient experienced a DLT (cardiac chest pain). The median number of days selumetinib was taken (adjusted for the number of days of dose interruptions) was 171.5 (IQR: 75.5 to 344). Two patients remained on treatment at 14 and 19 months post registration. There were 3 temporary and 1 permanent interruptions of selumetinib in cycle 1. Eight patients were evaluable for objective response (RECIST v1.1): 3 had a partial response and 5 stable disease. The median PFS was 6.4 months (IQR 5.2 to 13.7). Toxicities related to selumetinib were mostly related to oedema and rash, grade 1-2 and manageable. Pharmacokinetic analysis showed that the AUC(0-infinity), AUC(0-8) and Cmax of selumetinib increased by 12, 11 and 30 % respectively when it was administered with CisGem, while Cmax for the N-desmethyl metabolite of selumetinib decreased by 40 %. There was no evidence that the time of Cmax for selumetinib or N-desmethyl metabolite of selumetinib were different when selumetinib was administered alone or with CisGem.Conclusion: The recommended dose of selumetinib when combined with CisGem was 75 mg bd. Translational studies are underway to identify biomarkers that may predict outcome (ClinicalTrials.gov identifier: NCT01242605 July 6th 2010).