Randomized phase 2 study of carbopl

Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma
Kathryn M. Field, 
John Simes,
Abstract
Background The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy.

Methods This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0–2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS).

Results One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64–1.33, P = .66). ORR was 14% (combination) versus 6% (monotherapy) (P = .18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82–1.69, P = .38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately.

Conclusions Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies.

Clinical trials registration nr ACTRN12610000915055.

Key words
bevacizumab
 
carboplatin
 
glioblastoma
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Glioblastoma (GBM) has a universally poor prognosis. Its incidence is low compared with other malignancies, but with one of the highest average years of life lost for any malignancy,1–3 it carries a high morbidity and mortality burden and a high social burden for the cancer sufferer and carer. There is no standard management for recurrent disease. Traditionally used chemotherapy drugs have included carboplatin, lomustine, carmustine, and temozolomide in various schedules, with typical response rates less than 20%, 6-month progression-free survival (6PFS) around 15%, and overall survival (OS) generally less than 6 months, although results across studies are somewhat heterogeneous.4–6

In recent years, the vascular endothelial growth factor (VEGF) inhibitor bevacizumab has emerged as a promising agent, effective both as monotherapy and in combination with traditional chemotherapy drugs, in early-phase clinical trials in the setting of recurrent GBM. Encouraging results from phase 2 studies in recurrent disease were reported in 2007 and 2009, with response rates up to 50% and progression-free survival (PFS) up to 9 months, representing a substantial improvement on historical data for chemotherapy alone.7,8 This led to US FDA approval in 2009 for use of bevacizumab in recurrent GBM and widespread uptake of the drug on that continent.9

Despite this, there remain several unanswered questions, which include the use of bevacizumab as monotherapy versus in combination with chemotherapy, the potential utility of continuing bevacizumab beyond disease progression, and comparison of the recently developed Response Assessment in Neuro-Oncology (RANO) guidelines10 with the Macdonald criteria used to interpret MRI changes in earlier studies.11 RANO criteria place emphasis on fluid attenuated inversion recovery (FLAIR) sequence abnormalities, which were not considered in the traditional Macdonald criteria and may be more relevant in the setting of antiangiogenic agents (eg, bevacizumab) that may affect T1 contrast enhancement. In addition, the effect of bevacizumab on quality of life (QOL) and neurocognitive function (NCF) has been questioned, with limited existing information at the time of study design and now controversial findings in the first-line setting for bevacizumab use in GBM.12–14

We report the primary endpoint for Part 1 of “A randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma multiforme” (CABARET) in which we compared the effect of bevacizumab plus carboplatin with bevacizumab monotherapy on progression-free survival (PFS) in patients with recurrent GBM. At the time of protocol development, carboplatin was a commonly used second-line chemotherapy drug for recurrent GBM in Australia based on previous studies showing modest benefit, with response or stabilization of disease i

結果 (中文) 1:

随机卡铂和贝伐单抗治疗复发胶质母细胞瘤的第二阶段研究凯思琳 · 米大的场地，约翰 · 梅斯摘要背景优化使用贝伐单抗治疗复发胶质母细胞瘤 (GBM)，包括单或合用治疗方法的选择尚不确定。本研究的目的是比较联合贝伐单抗单药治疗。这是一个 2 部分随机的阶段 2 的方法研究。资格标准纳入经常性 GBM 后放疗和替莫唑胺，大紫荆勋贤，没有其他化疗和东部合作肿瘤小组性能状态 0-2。(部分 1) 的主要目标是确定贝伐单抗加卡铂方案与贝伐单抗单药治疗对无进展生存 (PFS) 在神经肿瘤学条件中使用改性的反应评估的影响。贝伐单抗给出了每 2 个星期，10 毫克/公斤;和卡铂每隔 4 周，(AUC 5)。对进展，患者能够继续随机继续或停止贝伐单抗 (部分 2)。次要终点包括客观的放射反应率 (ORR)、 生活质量、 毒性和总生存期 (OS)。结果一两百二十二个患者 (年龄中位数，55y) 从 18 澳大利亚网站入选到部分 1。平均随访 32 个月，对治疗时间中位数为 3.3 个月。中位数 PFS 被每个手臂 3.5 个月 (危害比 [HR]: 0.92，95 %ci: 0.64 — — 1.33，P =.66 明显奥尔是 14%(组合) 6%(单一疗法) (P = 18 级明显中位数 OS 是 6.9 (组合) 对 7.5 个月 (单一疗法) (HR: 1.18，95 %ci: 0.82-1.69，P = 38 明显贝伐单抗相关不良事件的发生率类似于先前的文献，没有新的毒性信号。毒性较高，结合臂。第一部分 2 数据 (n = 48) 将单独报告。结论加卡铂导致更多毒性没有额外的临床益处。贝伐单抗治疗复发 GBM 患者的临床结果不如那些在以前报告的研究。临床试验注册 nr ACTRN12610000915055。关键词贝伐单抗 卡铂 胶质母细胞瘤以前的 SectionNext 节Glioblastoma (GBM) has a universally poor prognosis. Its incidence is low compared with other malignancies, but with one of the highest average years of life lost for any malignancy,1–3 it carries a high morbidity and mortality burden and a high social burden for the cancer sufferer and carer. There is no standard management for recurrent disease. Traditionally used chemotherapy drugs have included carboplatin, lomustine, carmustine, and temozolomide in various schedules, with typical response rates less than 20%, 6-month progression-free survival (6PFS) around 15%, and overall survival (OS) generally less than 6 months, although results across studies are somewhat heterogeneous.4–6In recent years, the vascular endothelial growth factor (VEGF) inhibitor bevacizumab has emerged as a promising agent, effective both as monotherapy and in combination with traditional chemotherapy drugs, in early-phase clinical trials in the setting of recurrent GBM. Encouraging results from phase 2 studies in recurrent disease were reported in 2007 and 2009, with response rates up to 50% and progression-free survival (PFS) up to 9 months, representing a substantial improvement on historical data for chemotherapy alone.7,8 This led to US FDA approval in 2009 for use of bevacizumab in recurrent GBM and widespread uptake of the drug on that continent.9Despite this, there remain several unanswered questions, which include the use of bevacizumab as monotherapy versus in combination with chemotherapy, the potential utility of continuing bevacizumab beyond disease progression, and comparison of the recently developed Response Assessment in Neuro-Oncology (RANO) guidelines10 with the Macdonald criteria used to interpret MRI changes in earlier studies.11 RANO criteria place emphasis on fluid attenuated inversion recovery (FLAIR) sequence abnormalities, which were not considered in the traditional Macdonald criteria and may be more relevant in the setting of antiangiogenic agents (eg, bevacizumab) that may affect T1 contrast enhancement. In addition, the effect of bevacizumab on quality of life (QOL) and neurocognitive function (NCF) has been questioned, with limited existing information at the time of study design and now controversial findings in the first-line setting for bevacizumab use in GBM.12–14We report the primary endpoint for Part 1 of “A randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma multiforme” (CABARET) in which we compared the effect of bevacizumab plus carboplatin with bevacizumab monotherapy on progression-free survival (PFS) in patients with recurrent GBM. At the time of protocol development, carboplatin was a commonly used second-line chemotherapy drug for recurrent GBM in Australia based on previous studies showing modest benefit, with response or stabilization of disease i

結果 (中文) 3:

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