Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial
Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial
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DOI：
10.1016/s0140-6736(20)32554-x
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发表时间：
2021-01-23
期刊：
影响因子：
168.9
通讯作者：
Oza, Amit M.
中科院分区：
文献类型：
--
作者：
Lheureux, Stephanie;Cristea, Mihaela C.;Oza, Amit M.
Weel（WEE 1hu）抑制剂adavosertib和吉西他滨在早期临床试验中显示出临床前协同作用和有希望的活性。我们的目的是确定这种组合在卵巢cancer.Methods患者的疗效，在这个双盲，随机，安慰剂对照，2期试验，妇女可测量复发铂耐药或铂难治性高级别浆液性卵巢癌从11个学术中心在美国和加拿大招募。如果女性年龄在18岁或以上，东部肿瘤协作组的体能状态为0-2，预期寿命超过3个月，器官和骨髓功能正常，则有资格参加。非高级别浆液性组织学卵巢癌女性有资格入组非随机探索性队列。高级别浆液性卵巢癌的合格参与者被随机分配（21），采用区组随机化（区组大小为3和6），无分层，接受静脉吉西他滨（1000 mg/m2，第1、8和15天）与口服adavosertib（175 mg）或相同的安慰剂，每日一次，第1、2、8、9、15和16天，28天为一个周期，直至疾病进展或出现不可接受的毒性。患者和每例患者的护理团队均对治疗分配设盲。主要终点是无进展生存期。安全性和疗效分析人群包括至少接受一剂治疗的所有患者。结果2014年9月22日至2018年5月30日期间，共有124名女性入组，其中99名患有高级别浆液性卵巢癌，随机分配至adavosertib+吉西他滨组（65名[66%]）或安慰剂+吉西他滨组（34名[34%]）。ClinicalTrials.gov 25名患有非高级别浆液性卵巢癌的女性被纳入探索性队列。随机分组后，发现5例高级别浆液性卵巢癌患者不合格（实验组4例，对照组1例），未接受治疗。所有治疗患者（n=119）的中位年龄为62岁（IQR 54-67）。adavosertib+吉西他滨组的无进展生存期更长（adavosertib+吉西他滨组的中位生存期为4.6个月[95% CI 3.6-6.4]，安慰剂+吉西他滨组为3.0个月[1.8-3.8];风险比0.55 [95% CI 0.35-0.90];对数秩p=0.015）。最常见的3级或更严重不良事件为血液学（阿达沃塞替+吉西他滨组61例受试者中38例[62%]中性粒细胞减少，安慰剂+吉西他滨组33例受试者中10例[30%]中性粒细胞减少;阿达沃塞替+吉西他滨组61例受试者中19例[31%]血小板减少，安慰剂+吉西他滨组33例受试者中2例16%1）。无治疗相关死亡;两名患者（高级别浆液性卵巢癌队列中每组各1例）在研究药物治疗期间死亡（来自实验组中的败血症和来自对照组中的疾病进展）。解释观察到的Weel抑制剂与吉西他滨组合的临床功效支持正在进行的DNA损伤反应药物在高级别浆液性卵巢癌中的评估，具有高复制应激的TP 53突变肿瘤类型。这种治疗方法可能适用于具有高复制压力的其他肿瘤类型;需要更大规模的验证性研究。版权所有（C）2021爱思唯尔有限公司保留所有权利。
Background The Weel (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer.Methods In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (21), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m 2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9,15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual.Findings Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54-67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4.6 months [95% CI 3.6-6.4] with adavosertib plus gemcitabine vs 3.0 months [1.8-3.8] with placebo plus gemcitabine; hazard ratio 0.55 [95% CI 0.35-0.90]; log-rank p=0.015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two 16%1 of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group).Interpretation The observed clinical efficacy of a Weel inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required. Copyright (C) 2021 Elsevier Ltd. All rights reserved.