甲苯达唑联合洛莫司汀或替莫唑胺治疗复发性胶质母细胞瘤患者：一项随机开放标签的II期试验。
Mebendazole plus lomustine or temozolomide in patients with recurrent glioblastoma: A randomised open-label phase II trial.
作者信息
Patil Vijay M, Menon Nandini, Chatterjee Abhishek, Tonse Raees, Choudhari Amit, Mahajan Abhishek, Puranik Ameya D, Epari Sridhar, Jadhav Monica, Pathak Shruti, Peelay Zoya, Walavalkar Rutuja, Muthuluri Hemanth K, Ravi Krishna Madala, Chandrasekharan Arun, Pande Nikhil, Gupta Tejpal, Banavali Shripad, Jalali Rakesh
机构信息
Department of Medical Oncology, Tata Memorial Center, Mumbai, India.
Homi Bhabha National Institute (HBNI), Mumbai, India.
出版信息
EClinicalMedicine. 2022 May 27;49:101449. doi: 10.1016/j.eclinm.2022.101449. eCollection 2022 Jul.
BACKGROUND
Recurrent glioblastoma (GBM) has dismal outcomes and limited treatment options. Mebendazole (MBZ) has activity in glioma both and , and is well tolerated in combination with lomustine (CCNU) and temozolomide (TMZ). In this study, we sought to determine whether the addition of MBZ to CCNU or TMZ would improve overall survival (OS) in recurrent GBM.
METHODS
In this phase II randomized open-label trial, adult patients with ECOG PS 0-3, with recurrent GBM who were not eligible for re-radiation, were randomized 1:1 to the CCNU-MBZ and TMZ-MBZ arms. CCNU was administered at 110 mg/m every 6 weeks with MBZ 800 mg thrice daily and TMZ was administered at 200 mg/m once daily on days 1-5 of a 28 days cycle with MBZ 1600 mg thrice daily. The primary endpoint was OS at 9 months. A 9-month OS of 55% or more in any arm was hypothesized to warrant further evaluation and a value below 35% was too low to warrant further investigation. OS was analyzed using intention to treat (ITT) and per-protocol (PP) analyses. Per-protocol analysis was used for safety analysis. Clinical Trials Registry-India number, CTRI/2018/01/011542.
FINDINGS
Participants were recruited from 14 March 2019 to 18 June 2021, 44 patients were randomised on each arm. At 17.4 months, 68 events for OS analysis had occurred, 33 in the TMZ-MBZ and 35 in the CCNU-MBZ arm. The 9-month OS was 36.6% (95% CI 22.3-51.0) and 45% (95% CI 29.6-59.2) in the TMZ-MBZ and CCNU-MBZ arms respectively, in the ITT population. ECOG PS was the only independent prognostic factor impacting OS (HR-0.48, 95% CI 0.27-0.85; = 0.012). Grade 3-5 adverse events were seen in 8 (18.6%; = 43) and 4 (9.5%; = 42) patients in the TMZ-MBZ and CCNU-MBZ arms respectively. There were no treatment related deaths.
INTERPRETATION
The addition of MBZ to TMZ or CCNU failed to achieve the pre-set benchmark of 55% 9-month OS. This was probably due to 28.6% of patients having poor PS of 2-3.
FUNDING
Brain Tumor Foundation (BTF) of India, Indian Cooperative Oncology Network (ICON), and India Cancer Research Consortium (ICRC) under ICMR (Indian Council of Medical Research).
背景
复发性胶质母细胞瘤（GBM）预后不佳且治疗选择有限。甲苯咪唑（MBZ）在胶质瘤中具有活性，并且与洛莫司汀（CCNU）和替莫唑胺（TMZ）联合使用时耐受性良好。在本研究中，我们试图确定在CCNU或TMZ中添加MBZ是否会改善复发性GBM的总生存期（OS）。
方法
在这项II期随机开放标签试验中，ECOG体能状态为0 - 3、患有复发性GBM且不符合再次放疗条件的成年患者，以1:1的比例随机分配至CCNU - MBZ组和TMZ - MBZ组。CCNU每6周以110mg/m给药，同时MBZ每日三次，每次800mg；TMZ在28天周期的第1 - 5天以200mg/m每日一次给药，同时MBZ每日三次，每次1600mg。主要终点是9个月时的总生存期。假设任何一组9个月总生存期达到55%或更高则值得进一步评估，而低于35%则过低不值得进一步研究。使用意向性分析（ITT）和符合方案分析（PP）对总生存期进行分析。符合方案分析用于安全性分析。印度临床试验注册编号，CTRI/2018/01/011542。
研究结果
从2019年3月14日至2021年6月18日招募参与者，每组随机分配44例患者。在17.4个月时，发生了68例用于总生存期分析的事件，TMZ - MBZ组33例，CCNU - MBZ组35例。在ITT人群中，TMZ - MBZ组和CCNU - MBZ组9个月总生存期分别为36.6%（95%CI 22.3 - 51.0）和45%（95%CI 29.6 - 59.2）。ECOG体能状态是影响总生存期的唯一独立预后因素（HR - 0.48，95%CI 0.27 - 0.85；P = 0.012）。TMZ - MBZ组和CCNU - MBZ组分别有8例（18.6%；n = 43）和4例（9.5%；n = 42）患者出现3 - 5级不良事件。没有与治疗相关的死亡。
解读
在TMZ或CCNU中添加MBZ未能达到预设的9个月总生存期55%的基准。这可能是由于28.6%的患者体能状态较差，为2 - 3级。
资助
印度脑肿瘤基金会（BTF）、印度合作肿瘤学网络（ICON）以及印度医学研究理事会（ICMR）下属的印度癌症研究联盟（ICRC）。
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