Abstract PS14-02: A randomised phase IB/IIA study of CApecitabine plus Radium-223 in breast cancer patients with BONe metastases (CARBON) - Safety and preliminary efficacy findings

Background: Bone metastases (BMs) occur in approximately 70% of patients (pts) with metastatic breast cancer (MBC). Despite significant advances in the management of BMs with bone-targeted agents and the associated reduction in skeletal-related events, there remains an unmet need for further treatment options to improve median overall survival beyond 2-3 years. Radium-223 [R] dichloride is an alpha-emitting radiopharmaceutical that is avidly taken up, like calcium, into the bone where it emits high-energy, short-range alpha-particles resulting in a targeted anti-tumour effect on BMs. Combining R with current systemic therapy could potentially enhance efficacy in MBC with BMs. Methods: CARBON is a UK, open-label, multi-centre phase IB/IIA study evaluating the combination of capecitabine [C] (1000mg/m2 bd days 4-17, 12x21 day cycles) with R 55kBq/kg day 1 given on a 6-weekly schedule in pts with BMs from MBC (+/- other sites of disease) with ≥2 bone lesions on radionuclide bone scan and/or ≥1 lesion confirmed on plain radiographs, CT or MRI. Other eligibility criteria included ECOG PS 0-2, ≤ 2 lines of chemotherapy for MBC and current use of a bisphosphonate / denosumab for ≥6 weeks. To establish the feasibility and safety of C+R the phase IB opened in August 2016 registering 6 pts; the primary endpoint was dose-limiting toxicities (DLTs), defined as ≥grade 3 gastrointestinal toxicity lasting >48 hours or ≥grade 4 haematological toxicity lasting >7 days. Subsequently, between April 2017 and March 2019 28 pts were randomised (2:1) to C+R vs C in phase IIa to further characterise the safety profile, with frequency of CTC grade 3-4 toxicities and diarrhoea as primary endpoints. Preliminary evaluation of efficacy through assessment of bone turnover marker changes from baseline to end of cycle 5 and time to progression in bone and overall was made. Results: Baseline clinico-pathologic characteristics and prior treatments were well balanced between the arms; 13 C+R and 9 C pts had visceral metastases. There were 0 DLTs in the 6 phase IB pts, therefore the same C+R dose and schedule was studied in phase IIA. 2 pts randomised to C+R received C alone and are included in the C arm. The safety population consists of 34 pts (23 C+R, 11 C). Median number of cycles received was 8.5 (range 3-12) in C+R arm and 12 (range 1-12) in C arm. 38/307 (12%) treatment cycles were delayed (25 [13%] C+R arm, 13 [12%] C arm). 11 (48%) C+R and 6 (55%) C pts had a permanent C dose reduction. 94/95 (99%) prescribed R cycles were administered. 9 (39%) C+R and 9 (82%) C pts completed all 12 cycles. Other reasons for discontinuation were: progressive disease in 12 (52%) C+R and 0 in C pts; toxicity in 1 (4%) C+R and 1 (9%) C pt; clinician decision in 1 (9%) C pt; progressive disease and toxicity in 1 (4%) C+R pt. Only 25/575 (4%) reported AEs were grade 3-4 (n=21 in 11 [48%] C+R pts, n=4 in 4 [36%] C pts) with 0 episodes of grade 3-4 diarrhoea. Table 1 shows maximum grades of diarrhoea and haematological AEs experienced by arm. 18 SAEs occurred (n=11 in 8 C+R pts, n=7 in 2 C pts). 8 (44%) SAEs were grade 3 (C+R: 6, C: 2); none were related to diarrhoea. There were 0 SUSARs. Conclusion: In the first completed trial evaluating R with chemotherapy in MBC pts, the combination of C+R is safe and well-tolerated. Preliminary efficacy analyses including bone markers are ongoing and will be presented at the meeting. The creation of the data was supported in part by Bayer Plc and Yorkshire Cancer Research. Citation Format: Matthew Winter, Jessica Kendall, Sarah Brown, Emma Rathbone, Caroline Wilson, Sacha Howell, Chris Twelves, Carlo Palmieri, Anjana Anand, Iain MacPherson, Rob Coleman, Janet Brown. A randomised phase IB/IIA study of CApecitabine plus Radium-223 in breast cancer patients with BONe metastases (CARBON) - Safety and preliminary efficacy findings [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-02.