Centre Léon Bérard, Department of Medicine, French Sarcoma Group, European Organisation for Research and Treatment of Cancer, University Claude Bernard Lyon I, Lyon, France.
State Medical Centre, Budapest, Hungary.
Lancet Oncol. 2015 May;16(5):531-40. doi: 10.1016/S1470-2045(15)70102-6. Epub 2015 Apr 8.
Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas.
We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0-2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m(2) plus cisplatin 75 mg/m(2) or intravenous infusion of placebo plus cisplatin 75 mg/m(2) every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517.
Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9-33·2) in the placebo group and 30·5 months (20·7-37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45-2·69] vs 1·41 [1·38-1·58] months; hazard ratio 0·76 [95% CI 0·59-0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group.
The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas.
Sanofi.
奥马珠单抗（AVE8062）破坏已建立的肿瘤的脉管系统，并在与顺铂联合使用时显示出临床前协同抗肿瘤活性。在这项 3 期试验中，我们旨在评估奥马珠单抗联合顺铂与安慰剂联合顺铂在晚期软组织肉瘤患者中的疗效和安全性。
我们在 10 个国家的 44 个中心进行了这项多中心、随机、双盲、安慰剂对照的 3 期研究。年龄在 18 岁及以上、转移性软组织肉瘤、东部合作肿瘤组（ECOG）表现状态为 0-2，且先前接受过蒽环类药物和异环磷酰胺治疗的患者，按 1:1 比例随机分配（1:1）接受奥马珠单抗 25mg/m2加顺铂 75mg/m2 或安慰剂加顺铂 75mg/m2静脉输注，每 3 周一次。患者通过交互式语音应答系统，按照区组随机化方案（区组大小为 4）进行分组，并根据组织学亚型进行分层。患者、医务人员、研究人员以及处理和分析数据的人员均对治疗分组进行了盲法处理。我们的主要终点是意向治疗人群的中位无进展生存期。对至少接受过一次研究药物治疗的所有随机患者进行安全性分析。该试验现已结束，在 ClinicalTrials.gov 上注册，编号为 NCT00699517。
2008 年 6 月 13 日至 2012 年 4 月 26 日，我们随机分配了 355 名患者接受奥马珠单抗联合顺铂（n=176）或安慰剂联合顺铂（n=179）治疗。安慰剂组的中位随访时间为 27.9 个月（IQR 20.9-33.2），奥马珠单抗组为 30.5 个月（20.7-37.6）。与安慰剂组相比，奥马珠单抗组的无进展生存期略有但显著改善（中位 1.54 个月[95%CI 1.45-2.69] vs 1.41[1.38-1.58]个月；风险比 0.76[95%CI 0.59-0.98]；p=0.0302）。奥马珠单抗组发生 3 级或 4 级不良事件的频率高于安慰剂组，包括中性粒细胞减少症（奥马珠单抗组 34 例[19%]，安慰剂组 14 例[8%]）和血小板减少症（奥马珠单抗组 15 例[8%]，安慰剂组 6 例[3%]）。奥马珠单抗组有 18 例患者和安慰剂组有 10 例患者因不良事件导致死亡。
奥马珠单抗联合顺铂显著改善了无进展生存期；然而，在晚期软组织肉瘤患者中，它并没有显示出足够的临床获益，不能支持其作为一种治疗选择。需要预测性生物标志物来合理地开发用于软组织肉瘤的肿瘤血管破坏药物。
赛诺菲。
