Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial
Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial
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DOI：
10.1016/s1470-2045(14)70314-6
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发表时间：
2014-08-01
期刊：
影响因子：
51.1
通讯作者：
van den Bent, Martin J.
中科院分区：
文献类型：
--
作者：
Taal, Walter;Oosterkamp, Hendrika M.;van den Bent, Martin J.
复发性胶质母细胞瘤的治疗选择很少，二线化疗对肿瘤的活性有限。尽管缺乏良好的对照试验，贝伐单抗被广泛用于治疗复发性胶质母细胞瘤。尽管如此，这种药物治疗后报告的高反应率是否转化为总体生存益处仍不清楚。我们报告的第一个随机对照的贝伐单抗在复发glioblastoma.Methods的2期临床试验的结果的BELOB试验是一个开放标签，三组，多中心的2期研究在荷兰的14家医院进行。成人患者在替莫唑胺放化疗后首次复发胶质母细胞瘤的患者（年龄≥ 18岁），通过网络程序随机分配至口服洛莫司汀110 mg/m2，每6周一次，静脉注射贝伐单抗10 mg/kg，每2周一次，或每6周一次洛莫司汀110 mg/m2和每2周一次贝伐单抗10 mg/kg联合治疗。采用最小化程序对患者随机化进行分层，分层因素为中心、东部肿瘤协作组体能状态和年龄。主要结果是9个月时的总生存率，按意向治疗进行分析。安全性分析计划在联合治疗组的前10名患者完成两个6周周期后进行。该试验在荷兰试验注册中心（www.trialregister.nl，编号NTR 1929）注册。结果在2009年12月11日至2011年11月10日期间，153名患者入组。预先计划的安全性分析是在8例患者接受治疗后进行的，因为血液学不良事件（3例患者出现3级血小板减少症，2例患者出现4级血小板减少症）降低了贝伐珠单抗的剂量强度;此后联合治疗组的洛莫司汀剂量降至90 mg/m2。因此，除了8名患者被随机分配接受贝伐珠单抗联合洛莫司汀110 mg/m2外，51名患者被分配接受贝伐珠单抗单药治疗，47名患者接受洛莫司汀单药治疗，47名患者接受贝伐珠单抗联合洛莫司汀90 mg/m2。在这些患者中，贝伐单抗单药组50例，洛莫司汀单药组46例，贝伐单抗和洛莫司汀90 mg/m2组44例符合分析条件。9-月总生存率为43%洛莫司汀组（95% CI 29-57），贝伐单抗组38%（25-51），贝伐单抗+洛莫司汀90 mg/m2组59%（43-72），贝伐单抗+洛莫司汀110 mg/m2组87%（39-98），贝伐单抗和洛莫司汀联合组为63%（49-75）。在联合组中洛莫司汀剂量减少后，联合治疗耐受性良好。最常见的3级或更严重的毒性是高血压（贝伐单抗组50例患者中有13例[26%]，洛莫司汀组46例患者中有3例[7%]，贝伐单抗和洛莫司汀90 mg/m2组44例患者中有11例[25%]），疲乏（二[4%]，四[9%]和八[18%]）和感染（三[6%]，两[4%]和五[11%]）。在该分析时，144/148（97%）的患者已经死亡，3名（2%）仍在治疗中。然而，单用贝伐珠单抗组的结果并不能证明进一步研究这种治疗是合理的。
Background Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma.Methods The BELOB trial was an open-label, three-group, multicentre phase 2 study undertaken in 14 hospitals in the Netherlands. Adult patients (>= 18 years of age) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy were randomly allocated by a web-based program to treatment with oral lomustine 110 mg/m(2) once every 6 weeks, intravenous bevacizumab 10 mg/kg once every 2 weeks, or combination treatment with lomustine 110 mg/m(2) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Randomisation of patients was stratified with a minimisation procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analysed by intention to treat. A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group. This trial is registered with the Nederlands Trial Register (www.trialregister.nl, number NTR1929).Findings Between Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled. The preplanned safety analysis was done after eight patients had been treated, because of haematological adverse events (three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia) which reduced bevacizumab dose intensity; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m(2). Thus, in addition to the eight patients who were randomly assigned to receive bevacizumab plus lomustine 110 mg/m(2), 51 patients were assigned to receive bevacizumab alone, 47 to receive lomustine alone, and 47 to receive bevacizumab plus lomustine 90 mg/m(2). Of these patients, 50 in the bevacizumab alone group, 46 in the lomustine alone group, and 44 in the bevacizumab and lomustine 90 mg/m(2) group were eligible for analyses. 9-month overall survival was 43% (95% CI 29-57) in the lomustine group, 38% (25-51) in the bevacizumab group, 59% (43-72) in the bevacizumab and lomustine 90 mg/m(2) group, 87% (39-98) in the bevacizumab and lomustine 110 mg/m(2) group, and 63% (49-75) for the combined bevacizumab and lomustine groups. After the reduction in lomustine dose in the combination group, the combined treatment was well tolerated. The most frequent grade 3 or worse toxicities were hypertension (13 [26%] of 50 patients in the bevacizumab group, three [7%] of 46 in the lomustine group, and 11 [25%] of 44 in the bevacizumab and lomustine 90 mg/m(2) group), fatigue (two [4%], four [9%], and eight [18%]), and infections (three [6%], two [4%], and five [11%]). At the time of this analysis, 144/148 (97%) of patients had died and three (2%) were still on treatment.Interpretation The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment.