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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.

Abstract Background A substantial proportion of breast cancer patients develop metastatic disease, with over 450,000 deaths globally per year. Bone is the most common first site of metastatic disease accounting for 40% of all first recurrence and 70% of patients with advanced disease develop skeletal involvement. Treatment of bone metastases currently focusses on symptom relief and prevention and treatment of skeletal complications. However, there remains a need for further treatment options for patients with bone metastases. Combining systemic therapy with a bone-targeted agent, such as radium-223, may provide an effective treatment with minimal additional side effects. Methods/design CARBON is a UK-based, open-label, multi-centre study which comprises an initial safety phase to establish the feasibility and safety of combining radium-223 given on a 6-weekly schedule in combination with orally administered capecitabine followed by a randomised extension phase to further characterise the safety profile and provide preliminary estimation of efficacy. Discussion The CARBON study is important as the results will be the first to assess radium-223 with chemotherapy in advanced breast cancer. If the results find acceptable rates of toxicity with a decrease in bone turnover markers, further work will be necessary in a phase II/III setting to assess the efficacy and clinical benefit. Trial registration ISRCTN, ISRCTN92755158, Registered on 17 February 2016.