Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial
Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial
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DOI：
10.1016/s1470-2045(19)30215-3
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发表时间：
2019-07-01
期刊：
影响因子：
51.1
通讯作者：
Bliss, Judith M.
中科院分区：
文献类型：
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作者：
Judson, Ian;Morden, James P.;Bliss, Judith M.
背景：肺泡状软组织肉瘤是一种对化疗无效的罕见软组织肉瘤。在非随机研究中，酪氨酸激酶抑制剂头孢拉尼在ASPS中显示出显著的活性。头孢拉尼在肺泡软组织肉瘤(CASPS)中的研究旨在区分头孢拉尼的疗效和ASPS的内在惰性。方法在这项双盲、安慰剂对照、随机、2期试验中，我们从英国(n=7)、西班牙(n=3)和澳大利亚(n=2)的12家医院招募了参与者。如果患者年龄为16岁或以上；在过去6个月内进展的转移性ASPS；ECOG功能状态为0-1；预期寿命超过12周；以及足够的骨髓、肝和肾功能，则符合条件。参与者必须在试验进入前4周内没有接受抗癌治疗，除了姑息性放射治疗。参与者被随机分配(2：1)，通过使用计算机生成的随机排列块将其分配给头孢拉尼(30 mg口服，每天一次)或匹配的安慰剂片剂，为期24周。治疗是用数字编码的瓶子提供的，将参与者和临床医生分配给分配。如果参与者的进展是由实体肿瘤的反应评估标准(1.1版)定义的，那么他们在24周或更早的时候是非盲目的；服用安慰剂的人交叉使用头孢拉尼，所有参与者继续治疗，直到进展或死亡。主要终点是靶标记物病变直径总和在基线和24周之间的百分比变化，如果进展更早，在可评估的人群中进行评估(所有随机分配的参与者在第24周[如果进展更早]进行扫描，测量靶标记物病变)。对所有接受至少一剂研究药物的参与者进行安全性评估。这项研究在ClinicalTrials.gov注册，编号NCT01337401；欧洲临床试验数据库，编号EudraCT2010-021163-33；以及ISRCTN注册，编号ISRCTN63733470招募已经完成并正在进行中。结果，在2011年7月15日至2016年7月29日招募的48名参与者中，所有人被随机分配到头孢拉尼(n=32)或安慰剂(n=16)。女性23例(48%)，年龄中位数为31岁(IQR 27-45)。在这些分析的数据截止时(2018年4月11日)，中位随访时间为34.3个月(IQR 23.7-55.6)。头孢拉尼组的4名参与者不能评估主要终点(1名没有开始治疗，3名在24周时没有进行扫描)。在可评估人群中，靶标记物病变直径总和的中位百分比变化在头孢拉尼组为-8.3%(IQR26.5至5.9%)，而安慰剂组为13.4%(IQR1.1至21.3%)(单侧p=0.0010)。头孢拉尼最常见的3级不良反应是高血压(6例[19%])和腹泻(2例[6%])。报告了12例患者的15例严重不良反应，其中12例发生在开放标签头孢拉尼上，最常见的症状是脱水(n=2)、呕吐(n=2)和蛋白尿(n=2)。1例患者在接受开放标签头孢拉尼治疗41天后可能发生与治疗相关的死亡(颅内出血)，患者被分配到隐蔽期服用安慰剂。考虑到ASPS的高转移率和较差的长期预后，加上常规化疗的无效，我们发现头孢拉尼在这种疾病中具有显著的临床活性，是朝着这些年轻患者的长期疾病控制目标迈出的重要一步。未来在ASPS的临床试验也可能涉及免疫检查点抑制剂。
Background Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS.Methods In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2: 1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing.Findings Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34.3 months (IQR 23.7-55.6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was-8.3% (IQR-26.5 to 5.9) with cediranib versus 13.4% (IQR 1.1 to 21.3) with placebo (one-sided p=0.0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase.Interpretation Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors.