Abstract
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 (Ra(223)) 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 Ra(223) 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 Ra(223) (55 kBq/kg day 1 given on 6 weekly schedule) and capecitabine (1000 mg/m(2) 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 + Ra(223). Thereafter, 28 patients were randomised (2:1) to capecitabine + Ra(223) 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 + Ra(223) and 2/11 [18%] and 9/11 [82%] capecitabine alone patients had soft tissue and visceral disease sites respectively. More capecitabine + Ra(223) patients had received prior chemotherapy for MBC: 11/23 [48%] vs 2/11 [18%]. The analysis populations comprise 34 patients (23 capecitabine + Ra(223), 11 capecitabine); 2 patients randomised to capecitabine + Ra(223) received capecitabine alone and are included in the capecitabine arm. Median number of cycles received was 8.5 in capecitabine + Ra(223) (range 3-12) and 12 in the capecitabine arm (range 1-12). 94/95 prescribed Ra(223) 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 + Ra(223) 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.