Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial
Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial
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DOI：
10.1016/s1470-2045(14)71136-2
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发表时间：
2015-01-01
期刊：
影响因子：
51.1
通讯作者：
Aglietta, Massimo
中科院分区：
文献类型：
--
作者：
Grignani, Giovanni;Palmerini, Emanuela;Aglietta, Massimo
背景先前的研究结果显示索拉非尼在治疗不可切除的晚期和转移性骨肉瘤患者中有希望但短期的活性。这种治疗失败归因于mTOR途径，因此可以通过添加mTOR抑制剂来克服。我们的目的是研究索拉非尼联合依维莫司在标准治疗后进展为不能手术的高级别骨肉瘤患者中的活性。方法：我们在三个意大利肉瘤组中心进行了这项非随机2期试验。我们招募了在标准治疗（甲氨蝶呤、顺铂和阿霉素，加或不加异环磷酰胺）后进展为复发或不可切除的骨肉瘤的成人（bb0 = 18岁）。患者接受800mg索拉非尼加5mg依维莫司，每天一次，直到疾病进展或不可接受的毒性作用。主要终点为6个月无进展生存期（PFS）。所有分析均为意向治疗。该试验已在ClinicalTrials.gov注册，注册号NCT01804374。我们在2011年6月16日至2013年6月4日期间招募了38名患者。38例患者中有17例（45%;95% CI 28-61）在6个月时无进展。38例患者中有25例（66%）毒性作用导致剂量减少或短暂中断，或两者兼而有之，2例（5%）患者永久停药。最常见的3-4级不良事件是6例（16%）患者淋巴细胞减少和低磷血症，5例（13%）患者手足综合征，4例（11%）患者血小板减少，2例（5%）患者疲劳、口腔黏膜炎、腹泻和贫血。1例（3%）患者为3级气胸，需要经胸引流，并在疾病进展时复发。据报道，在这两种情况下，这都是与研究药物相关的严重不良事件。在试验期间未报告其他严重不良事件。没有与治疗相关的死亡。尽管索拉非尼和依维莫司联合治疗晚期或不可切除骨肉瘤患者显示出进一步治疗的活性，但它没有达到预先设定的6个月PFS达到50%或更高的目标。
Background Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment.Methods We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (>= 18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374.Findings We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths.Interpretation Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater.