Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial.
Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial.
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DOI：
10.1016/s1470-2045(13)70049-4
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发表时间：
2013-04
期刊：
影响因子：
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通讯作者：
Maki RG
中科院分区：
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作者：
Schwartz GK;Tap WD;Qin LX;Livingston MB;Undevia SD;Chmielowski B;Agulnik M;Schuetze SM;Reed DR;Okuno SH;Ludwig JA;Keedy V;Rietschel P;Kraft AS;Adkins D;Van Tine BA;Brockstein B;Yim V;Bitas C;Abdullah A;Antonescu CR;Condy M;Dickson MA;Vasudeva SD;Ho AL;Doyle LA;Chen HX;Maki RG
临床前研究表明，通过抑制胰岛素样生长因子-1受体（IGF-1 R）和mTOR，具有协同抗肿瘤活性。IGF-1 R的表达似乎对这种作用至关重要。我们通过免疫组织化学法根据IGF-1 R表达研究了IGF-1 R抗体cixutumumab和mTOR抑制剂temsirolimus联合治疗化疗难治性骨和软组织肉瘤患者的安全性和有效性。我们在美国19个癌症中心进行了一项多中心、开放标签、2期研究。根据免疫组化IGF-1 R表达，将年龄至少16岁、经组织学确诊为骨或软组织肉瘤的患者分配至3个治疗组之一：IGF-1 R阳性软组织肉瘤（A组）、IGF-1 R阳性骨肉瘤（B组）或IGF-1 R阴性骨和软组织肉瘤（C组）。患者每周接受一次cixutumumab（6 mg/kg，静脉内）和替西罗莫司（25 mg，静脉内固定剂量）治疗，为期6周。每组均采用Simon最优两阶段设计，主要终点为每个治疗组前54例患者的12周意向治疗分析无进展生存期（PFS），虽然患者仍在接受治疗，但本试验已完成入组，这是最终分析。本研究注册于ClinicalTrials.gov，编号NCT 01016015。在2009年11月18日至2012年4月11日期间，对388例患者进行了IGF-1 R表达筛查，每组54例。（31%;单侧95% CI下限21%;双侧90% CI 21-43），IGF-1 R阳性骨肉瘤组54例中有19例（35%;单侧95% CI下限24%;双侧90% CI 24-47），IGF-1 R阴性组54例患者中有21例（39%，单侧95% CI下限28%;双侧90% CI 28-51）在12周时无进展。2011年4月6日，对方案进行了修订，在IGF-1 R阳性软组织肉瘤组中增加了3例患者（共57例患者），在IGF-1 R阴性组中增加了9例患者（共63例患者）。研究期间报告了2546起不良事件，其中214起（8%）为3-4级。174例接受治疗的患者中最常见的3-4级毒性为16例（9%）患者的贫血、18例（10%）患者的高血糖、16例（9%）患者的低磷酸盐血症、25例（14%）患者的淋巴细胞减少症、19例（11%）患者的口腔粘膜炎和19例（11%）患者的血小板减少症。cixutumumab和temsirolimus的组合在肉瘤患者中显示出临床活性，并为未来的试验奠定了基础。然而，免疫组化检测的IGF-1 R表达并不能预测联合治疗后的临床结果。国家癌症研究所和生存周期基金，纪念斯隆-凯特琳癌症中心。
Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3–4. The most common grade 3–4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. National Cancer Institute and Cycle for Survival Fund, Memorial Sloan-Kettering Cancer Center.