Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study
Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study
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DOI：
10.1016/s1470-2045(10)70010-3
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发表时间：
2010-03-01
期刊：
影响因子：
51.1
通讯作者：
Jun, Susie
中科院分区：
文献类型：
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作者：
Thomas, David;Henshaw, Robert;Jun, Susie
骨巨细胞瘤（GCT）是一种原发性溶骨性骨肿瘤，具有低转移潜力，并与大量骨骼疾病相关。GCT富含破骨细胞样巨细胞，并含有表达RANK配体（RANKL）的单核（基质）细胞，RANKL是破骨细胞激活的关键介质。我们研究了denosumab（一种抗RANKL的全人源单克隆抗体）对GCT患者肿瘤细胞存活和生长的潜在治疗效果。方法在这项开放标签的单组研究中，37例复发性或不可切除的GCT患者入组，每月（每28天）皮下注射denosumab 120 mg，在第1个月的第8天和第15天给药。主要终点是肿瘤反应，定义为至少90%的巨细胞消除或目标病变在第25周内无放射学进展。研究招募截止；患者的治疗和随访正在进行中。该研究已在Clinical Trials.gov注册，编号NCT00396279。结果2例患者的组织学或影像学资料不足，无法进行疗效评估。35例可评估患者中有30例（86%;95% Cl 70-95）有肿瘤反应：20例中有20例通过组织学评估，15例中有10例通过放射学评估。37例患者中有33例报告了不良事件；最常见的是四肢疼痛（n=7），背部疼痛（n=4）和头痛（n=4）。5例患者出现3-5级不良事件，其中只有1例（人绒毛膜促性腺激素浓度3级升高，与妊娠无关）被认为可能与治疗有关。报告了5个严重的不良事件，尽管没有一个被认为与治疗有关。进一步研究denosumab作为GCT的治疗是有必要的。
Background Giant-cell tumour (GCT) of bone is a primary osteolytic bone tumour with low metastatic potential and is associated with substantial skeletal morbidity. GCT is rich in osteoclast-like giant cells and contains mononuclear (stromal) cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. We investigated the potential therapeutic effect of denosumab, a fully human monoclonal antibody against RANKL, on tumour-cell survival and growth in patients with GCT.Methods In this open-label, single-group study, 37 patients with recurrent or unresectable GCT were enrolled and received subcutaneous denosumab 120 mg monthly (every 28 days), with loading doses on days 8 and 15 of month 1. The primary endpoint was tumour response, defined as elimination of at least 90% of giant cells or no radiological progression of the target lesion up to week 25. Study recruitment is closed; patient treatment and follow-up are ongoing. The study is registered with Clinical Trials.gov, NCT00396279.Findings Two patients had insufficient histology or radiology data for efficacy assessment. 30 of 35 (86%; 95% Cl 70-95) of evaluable patients had a tumour response: 20 of 20 assessed by histology and 10 of 15 assessed by radiology. Adverse events were reported in 33 of 37 patients; the most common being pain in an extremity (n=7), back pain (n=4), and headache (n=4). Five patients had grade 3-5 adverse events, only one of which (grade 3 increase in human chorionic gonadotropin concentration not related to pregnancy) was deemed to be possibly treatment related. Five serious adverse events were reported although none were deemed treatment related.Interpretation Further investigation of denosumab as a therapy for GCT is warranted.