Sarcoma Oncology Center, Santa Monica, CA 90403, USA.
Lancet Oncol. 2013 Aug;14(9):901-8. doi: 10.1016/S1470-2045(13)70277-8. Epub 2013 Jul 16.
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.
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.
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).
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.
Amgen.
骨巨细胞瘤（GCTB）是一种非常罕见、侵袭性和进行性的溶骨性肿瘤，目前尚无标准的药物治疗或化疗方法。我们报告了在 GCTB 患者中使用地舒单抗的 2 期研究的中期安全性和疗效结果。
我们进行了一项国际性、开放性、平行分组、2 期试验，纳入了组织学确诊的 GCTB 和影像学可测量的活动性疾病患者。符合条件的患者为影像学至少有一处成熟长骨存在至少一种成熟长骨且至少 12 岁且体重至少 45kg 的成年人或骨骼成熟的青少年。我们将患者分为三组——手术无法挽救的 GCTB 患者（队列 1）、手术相关严重发病率的可挽救 GCTB 患者（队列 2）和从先前的 GCTB 地舒单抗研究中转诊的患者（队列 3）。队列 1 和 2 的患者每 4 周接受 120mg 皮下注射地舒单抗，第 1 周期第 8 天和第 15 天给予负荷剂量；队列 3 的患者继续使用之前研究中的方案。每 4 周评估研究者确定的疾病状态和临床获益。我们的主要终点是地舒单抗在不良事件和实验室异常方面的安全性特征。预先指定的次要终点是队列 1 中的疾病进展时间和队列 2 中 6 个月时无需任何手术的患者比例。安全性分析包括接受至少一剂地舒单抗的所有患者。疗效分析包括接受至少一剂地舒单抗的所有合格患者。本研究在 ClinicalTrials.gov 注册，标识符为 NCT00680992。
2008 年 9 月 9 日至 2011 年 3 月 25 日期间，共纳入 282 例患者，包括 10 例青少年。在可进行安全性分析的 281 例患者中，3 例（1%）发生下颌骨坏死，15 例（5%）发生低钙血症。最常见的 3-4 级不良事件是低磷血症，9 例（3%）患者发生，3 例（1%）患者发生贫血、背痛和四肢疼痛。25 例（9%）患者报告发生严重不良事件。无治疗相关死亡报告。根据研究者对疾病状态的评估，在中位随访 13 个月（IQR 5.8-21.0）后，队列 1 中 169 例可分析患者中有 163 例（96%）无疾病进展。队列 2 中，100 例可分析患者中有 74 例（74%）无需手术，26 例接受手术的患者中有 16 例（62%）手术方式比计划的更轻微。队列 2 的中位随访时间为 9.2 个月（IQR 4.2-12.9）。
不良事件与地舒单抗已知的安全性特征一致。地舒单抗与肿瘤反应相关，并减少了 GCTB 患者需要进行严重发病率手术的可能性。地舒单抗为 GCTB 患者提供了一种新的治疗选择。
安进公司。
