Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study
Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study
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DOI：
10.1016/s1470-2045(13)70277-8
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发表时间：
2013-08-01
期刊：
影响因子：
51.1
通讯作者：
Jacobs, Ira
中科院分区：
文献类型：
--
作者：
Chawla, Sant;Henshaw, Robert;Jacobs, Ira
背景骨巨细胞瘤(GCTB)是一种非常罕见、侵袭性和进展性的溶骨肿瘤，目前尚无标准的药物治疗或化疗方法。我们报告了Denosumab在GCTB患者中的第二阶段研究的中期安全性和有效性结果。方法我们对组织学证实的GCTB和放射学可测量的活动性疾病患者进行了一项国际性、开放标签、平行分组的第二阶段试验。符合条件的患者是成年人或骨骼成熟的青少年，他们至少12岁，体重至少45公斤，有至少一个成熟的长骨的放射证据。我们将患者分为三组--那些无法手术挽救的GCTB患者(队列1)，那些可挽救的GCTB患者，他们的手术与严重的并发症相关(队列2)，以及那些从先前的研究中转移到GCTB的患者(队列3)。队列1和2的患者在第一个周期的第8天和第15天接受每4周120毫克的皮下注射地诺单抗，负荷剂量为第1周期的第8天和第15天；队列3的患者继续使用先前研究的方案。每4周评估一次由调查者确定的疾病状态和临床益处。我们的主要终点是根据不良事件和实验室异常情况来评价地诺舒单抗的安全性。预先指定的次级终点是队列1中疾病进展的时间和队列2中6个月时未进行任何手术的患者的比例。安全性分析包括所有接受至少一剂地诺单抗的患者。疗效分析包括所有符合条件的患者，他们至少接受了一剂地诺单抗。这项研究在ClinicalTrials.gov注册，编号为NCT00680992。研究对象为2008年9月9日至2011年3月25日期间的282名患者，其中包括10名青少年。在可进行安全性分析的281例患者中，3例(1%)出现颌骨坏死，15例(5%)出现低钙血症。最常见的3-4级不良事件是9例(3%)患者出现低磷血症，以及3例患者(1%)出现贫血、背痛和四肢疼痛。有25例(9%)患者报告了严重不良事件。没有与治疗相关的死亡报告。根据研究人员对疾病状况的评估，在队列1的169名可分析患者中，有163名(96%)在13个月的中位随访期(IQR 5.8-21.0)后没有疾病进展。在队列2中，100名可分析患者中有74名(74%)没有接受手术，26名接受手术的患者中有16名(62%)接受了比计划更少的手术。队列2的中位随访期为9.2个月(IQR 4.2-12.9)。解释不良事件与已知的地诺单抗的安全性相一致。地诺舒单抗与肿瘤反应相关，减少了GCTB患者病理性手术的需要。Denosumab代表了GCTB患者的一种新的治疗选择。
Background Giant cell tumour of bone (GCTB) is a very rare, aggressive, and progressive osteolytic tumour for which no standard medicinal treatment or chemotherapy exists. We report interim safety and efficacy results from a phase 2 study of denosumab in patients with GCTB.Methods We did an international, open-label, parallel-group, phase 2 trial of patients with histologically confirmed GCTB and radiographically measurable active disease. Eligible patients were adults or skeletally mature adolescents with radiographic evidence of at least one mature long bone who were at least 12 years old and weighed at least 45 kg. We divided patients into three cohorts-those with surgically unsalvageable GCTB (cohort 1), those with salvageable GCTB whose surgery was associated with severe morbidity (cohort 2), and those who transferred from a previous study of denosumab for GCTB (cohort 3). Patients in cohorts 1 and 2 received 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle; those in cohort 3 continued the regimen from the previous study. Investigator-determined disease status and clinical benefit were assessed every 4 weeks. Our primary endpoint was the safety profile of denosumab in terms of adverse events and laboratory abnormalities. Prespecified secondary endpoints were time to disease progression in cohort 1 and the proportion of patients without any surgery at 6 months in cohort 2. Safety analyses included all patients who received at least one dose of denosumab. Efficacy analyses included all eligible patients who received at least one dose of denosumab. This study is registered with ClinicalTrials.gov, identifier NCT00680992.Findings 282 patients, including ten adolescents, were included between Sept 9, 2008, and March 25, 2011. Of the 281 patients analysable for safety, three (1%) had osteonecrosis of the jaw and 15 (5%) hypocalcaemia. The most common grade 3-4 adverse events were hypophosphataemia, which occurred in nine (3%) patients, and anaemia, back pain, and pain in extremities, each of which occurred in three patients (1%). Serious adverse events were reported in 25 (9%) patients. No treatment-related deaths were reported. On the basis of investigators' assessment of disease status, 163 of 169 (96%) analysable patients in cohort 1 had no disease progression after median follow-up of 13 months (IQR 5.8-21.0). In cohort 2, 74 of 100 (74%) analysable patients had no surgery and 16 of 26 (62%) patients who had surgery underwent a less morbid procedure than planned. Median follow-up in cohort 2 was 9.2 months (IQR 4.2-12.9).Interpretation Adverse events were consistent with the known safety profile of denosumab. Denosumab was associated with tumour responses and reduced the need for morbid surgery in patients with GCTB. Denosumab represents a new treatment option for patients with GCTB.