Background

Approximately 70% of patients with metastatic breast cancer (MBC) develop bone metastases. Despite advances in systemic treatment options and the use of bone targeted agents in the management of bone metastases to reduce skeletal morbidity, there remains an unmet need for further treatment options. Radium-223 (Ra²²³) is an alpha-emitting radiopharmaceutical that is preferentially taken up into bone at sites of increased osteoblastic activity where it emits high-energy, short-range alpha-particles that could provide a targeted anti-tumour effect on bone metastases. Here we evaluate the safety, feasibility and efficacy findings of the combination of Ra²²³ with capecitabine chemotherapy in patients with MBC with bone involvement.

Methods

CARBON is a multi-centre, open-label phase IB/IIA study evaluating the combination of Ra²²³ (55 kBq/kg day 1 given on 6 weekly schedule) and capecitabine (1000 mg/m² bd days 4–17 every 21 days) in patients with bone metastases from MBC (± other disease sites). Other eligibility criteria included ECOG performance status 0–2, ≤2 lines of chemotherapy for MBC and current bisphosphonate or denosumab use for ≥ 6 weeks. The phase IB part of the trial (6 patients) was conducted to provide preliminary feasibility and safety of capecitabine + Ra²²³. Thereafter, 28 patients were randomised (2:1) to capecitabine + Ra²²³ or capecitabine alone to further characterise the safety profile and evaluate efficacy, the primary efficacy endpoint being the bone turnover marker (urinary n-telopeptide of type I collagen) change from baseline to end of cycle 5 and secondary endpoints of time to first symptomatic skeletal event, and disease progression at extra-skeletal and bone disease.

Results

In addition to bone metastases, 10/23 [44%] and 13/23 [57%] capecitabine + Ra²²³ and 2/11 [18%] and 9/11 [82%] capecitabine alone patients had soft tissue and visceral disease sites respectively. More capecitabine + Ra²²³ patients had received prior chemotherapy for MBC: 11/23 [48%] vs 2/11 [18%]. The analysis populations comprise 34 patients (23 capecitabine + Ra²²³, 11 capecitabine); 2 patients randomised to capecitabine + Ra²²³ received capecitabine alone and are included in the capecitabine arm. Median number of cycles received was 8.5 in capecitabine + Ra²²³ (range 3–12) and 12 in the capecitabine arm (range 1–12). 94/95 prescribed Ra²²³ cycles were administered. No dose limiting toxicities were seen in phase IB and no patients developed grade ≥ III diarrhoea. Gastrointestinal, haematological and palmer-planter erthyrodysesthesia adverse events were similar in both arms. Although formal statistical comparisons were not made, changes in bone turnover markers, the times to extra-skeletal progression and bone disease progression, and the frequency of symptomatic skeletal events were similar across the two treatment arms.

Conclusion

Capecitabine + Ra²²³ at the planned dose was safe and feasible in MBC patients with bone metastases. However, no efficacy signals were seen that might suggest greater efficacy of the combination over capecitabine alone clinically or biochemically.

中文翻译：

---

CApecitabine 加 Radium-223 (Xofigo™) 治疗骨转移的乳腺癌患者的 IB 期和随机 IIA 期试验：CARBON 试验结果

背景

大约 70% 的转移性乳腺癌 (MBC) 患者会发生骨转移。尽管在全身治疗方案方面取得了进展，并且在骨转移的管理中使用了骨靶向药物以降低骨骼发病率，但对进一步治疗方案的需求仍未得到满足。镭 223 (Ra ²²³ ) 是一种发射 α 的放射性药物，优先在成骨细胞活性增加的部位被吸收到骨骼中，在那里它会发射高能、短程 α 粒子，可以对骨骼提供有针对性的抗肿瘤作用转移。^{在这里，我们评估了 Ra 223}与卡培他滨化疗联合治疗伴骨受累的 MBC 患者的安全性、可行性和有效性。

方法

CARBON 是一项多中心、开放标签的 IB/IIA 期研究，评估 Ra ²²³（55 kBq/kg 第 1 天，每周给药 6 次）和卡培他滨（1000 mg/m ² bd，每 21 天给药一次，第 4-17 天）的组合) 患有 MBC 骨转移的患者（± 其他疾病部位）。其他资格标准包括 ECOG 体能状态 0-2、≤2 线的 MBC 化疗和目前使用双膦酸盐或狄诺塞麦 ≥ 6 周。进行试验的 IB 期部分（6 名患者）以提供卡培他滨 + Ra ²²³的初步可行性和安全性。此后，28 名患者被随机分配 (2:1) 至卡培他滨 + Ra ²²³或单独使用卡培他滨以进一步表征安全性并评估疗效，主要疗效终点是骨转换标志物（I 型胶原的尿 n-端肽）从基线到第 5 周期结束的变化，次要终点是到第一次症状性骨骼事件的时间，以及骨骼外和骨骼疾病的疾病进展。

结果

除骨转移外，10/23 [44%] 和 13/23 [57%] 卡培他滨 + Ra ²²³和 2/11 [18%] 和 9/11 [82%] 卡培他滨单药患者有软组织和内脏疾病网站分别。更多卡培他滨 + Ra ^{223 名}患者曾接受过 MBC 化疗：11/23 [48%] 对比 2/11 [18%]。分析人群包括 34 名患者（23 名卡培他滨 + Ra ^223，11名卡培他滨）；2 名随机接受卡培他滨 + Ra ²²³治疗的患者单独接受卡培他滨治疗，并被纳入卡培他滨组。^{卡培他滨 + Ra 223} （范围 3-12）接受的周期中位数为 8.5 ，卡培他滨组为 12（范围 1-12）。94/95 规定的 Ra ²²³进行了周期。IB 期未见剂量限制性毒性，也无患者出现 ≥ III 级腹泻。两组的胃肠道、血液学和帕默-普兰特 erthyrodysthesia 不良事件相似。虽然没有进行正式的统计比较，但骨转换标志物的变化、骨骼外进展和骨病进展的时间以及有症状的骨骼事件的频率在两个治疗组中是相似的。

结论

计划剂量的卡培他滨 + Ra ^{223在 MBC 骨转移患者中是安全可行的。}然而，没有观察到可能表明该组合在临床或生化方面比单独使用卡培他滨具有更大疗效的疗效信号。