CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases (CARBON): study protocol for a phase IB/IIA randomised controlled trial

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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.

Electronic supplementary material

The online version of this article (10.1186/s13063-019-3643-6) contains supplementary material, which is available to authorized users.

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Most cited references 9

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Molecular biology of bone metastasis.

Theresa Guise, L Kingsley, Pierrick Fournier … (2007)

Metastasis is a final stage of tumor progression. Breast and prostate cancer cells preferentially metastasize to bone, wherein they cause incurable osteolytic and osteoblastic lesions. The bone matrix is rich in factors, such as transforming growth factor-beta and insulin-like growth factors, which are released into the tumor microenvironment by osteolysis. These factors stimulate the growth of tumor cells and alter their phenotype, thus promoting a vicious cycle of metastasis and bone pathology. Physical factors within the bone microenvironment, including low oxygen levels, acidic pH, and high extracellular calcium concentrations, may also enhance tumor growth. These elements of the microenvironment are potential targets for chemotherapeutic intervention to halt tumor growth and suppress bone metastasis.

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Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model.

Øyvind S. Bruland, Knut Breistøl, Erik Larsen … (2002)

The therapeutic efficacy of the alpha-particle-emitting radionuclide (223)Ra (t(1/2) = 11.4 days) in the treatment against experimental skeletal metastases in rats was addressed. Biodistribution studies, involving measurement of (223)Ra in bone marrow samples, were performed in rats after i.v. injection. To study the therapeutic effect of (223)Ra, an experimental skeletal metastases model in nude rats was used. Animals that had received 10(6) MT-1 human breast cancer cells were treated with (223)Ra doses in the range of 6-30 kBq after 7 days. The biodistribution experiment demonstrated that (223)Ra was selectively concentrated in bone as compared with soft tissues. The femur content of (223)Ra was 800 +/- 56% of injected dose per gram tissue times gram body weight (b.w.; mean +/- SD) 1 day after the injection and 413 +/- 23% of injected dose per gram tissue times gram b.w. at 14 days. The femur:kidney ratio increased from (5.9 +/- 2.0).10(2) at 1 day to (7.2 +/- 3.0).10(2) at 14 days, whereas the femur:liver ratio increased from (6.2 +/- 0.2).10(2) to (9.1 +/- 6.6).10(2). Femur:spleen ratio increased from (8.1 +/- 0.3).10(2) at 1 day to (6.4 2.2).10(3) at 14 days. The femoral bone:marrow ratio was 6.5 +/- 2.1 after day 1 and larger than 15 at day 14. All of the tumor-bearing control animals had to be sacrificed because of tumor-induced paralysis 20-30 days after injection with tumor cells, whereas the rats treated with > or =10 kBq of (223)Ra had a significantly increased symptom-free survival (P < 0.05). Also 36% (5 of 14) of rats treated with 11 kBq and 40% (2 of 5) of rats treated with 10 kBq were alive beyond the 67-day follow-up period. No signs of bone marrow toxicity or b.w. loss were observed in the groups of treated animals. The significant antitumor effect of (223)Ra at doses that are tolerated by the bone marrow is most likely linked to the intense and highly localized radiation dose from alpha-particles at the bone surfaces. The results of this study indicate that (223)Ra should be additionally studied as a potential bone marrow-sparing treatment of cancers involving the skeleton.

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Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid.

Allan Lipton, Robert E Coleman, Michael Major … (2008)

For patients with bone metastases, high N-telopeptide of type I collagen (NTX) levels correlate with increased risks of skeletal-related events and death. However, the relation between NTX decreases and clinical benefits is unclear. Correlations between NTX normalization during treatment and clinical outcome were retrospectively analyzed in 3 large, phase 3 trials. Urinary NTX levels were measured at baseline and at Month 3 in patients with bone metastases from breast cancer (BC; n = 578), hormone-refractory prostate cancer (HRPC; n = 472), or nonsmall-cell lung cancer and other solid tumors (NSCLC/OST; n = 291) who received zoledronic acid or control (pamidronate for BC; placebo for HRPC and NSCLC/OST) for up to 24 months. NTX levels were characterized as normal (N; or =64 nmol/mmol creatinine). After 3 months of zoledronic acid, most N-group patients maintained normal levels; however, most E-group patients normalized their NTX levels (BC, 81%; HRPC, 70%; NSCLC/OST, 81%). In contrast, NTX levels normalized with pamidronate in 65% of BC, with placebo in 8% of HRPC, and in 17% of NSCLC/OST E-group patients. Normalized NTX correlated with improved overall survival versus persistently elevated NTX (significant for zoledronic acid-treated patients; trend for placebo-treated patients). Moreover, percentage reductions from baseline NTX levels correlated with benefits regardless of whether patients transitioned from E to N. Zoledronic acid normalizes or maintains normal NTX levels in most patients with bone metastases. Normalized NTX within 3 months of treatment, versus persistently elevated NTX, was associated with reduced risks of skeletal complications and death. (Copyright) 2008 American Cancer Society.

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Author and article information

Contributors

Rob Coleman: R.E.Coleman@sheffield.ac.uk

Janet Brown: J.E.Brown@sheffield.ac.uk

Emma Rathbone: Emma.Rathbone@cht.nhs.uk

Louise Flanagan: L.M.Flanagan@leeds.ac.uk

Amber Reid: amber-reid@hotmail.co.uk

Jessica Kendall: J.E.Kendall@leeds.ac.uk

Sacha Howell: Sacha.Howell@christie.nhs.uk

Chris Twelves: C.J.Twelves@leeds.ac.uk

Carlo Palmieri: C.Palmieri@liverpool.ac.uk

Anjana Anand: anjana.anand@nuh.nhs.uk

Iain MacPherson: Iain.MacPherson@glasgow.ac.uk

Sarah Brown: S.Brown@leeds.ac.uk

Journal

Journal ID (nlm-ta): Trials

Journal ID (iso-abbrev): Trials

Title: Trials

Publisher: BioMed Central (London )

ISSN (Electronic): 1745-6215

Publication date (Electronic): 15 January 2020

Publication date PMC-release: 15 January 2020

Publication date Collection: 2020

Volume: 21

Electronic Location Identifier: 89

Affiliations

[1 ]ISNI 0000 0004 1936 9262, GRID grid.11835.3e, The University of Sheffield, ; Sheffield, UK

[2 ]GRID grid.487190.3, Calderdale and Huddersfield NHS Foundation Trust, ; Huddersfield, UK

[3 ]ISNI 0000 0004 1936 8403, GRID grid.9909.9, Clinical Trials Research Unit, , Leeds Institute of Clinical Trials Research, University of Leeds, ; Leeds, UK

[4 ]ISNI 0000 0004 0430 9259, GRID grid.412917.8, The Christie NHS Foundation Trust, ; Manchester, UK

[5 ]GRID grid.443984.6, St James’s University Hospital, ; Leeds, UK

[6 ]ISNI 0000 0004 1936 8403, GRID grid.9909.9, Leeds Institute of Cancer Studies and Pathology, University of Leeds, ; Leeds, UK

[7 ]ISNI 0000 0004 0614 6369, GRID grid.418624.d, Clatterbridge Cancer Centre NHS Foundation Trust, ; Liverpool, UK

[8 ]ISNI 0000 0004 1936 8470, GRID grid.10025.36, University of Liverpool, ; Liverpool, UK

[9 ]ISNI 0000 0001 0440 1889, GRID grid.240404.6, Nottingham University Hospitals NHS Trust, ; Nottingham, UK

[10 ]ISNI 0000 0001 2193 314X, GRID grid.8756.c, Institute of Cancer Sciences, University of Glasgow, ; Glasgow, UK

Article

Publisher ID: 3643

DOI: 10.1186/s13063-019-3643-6

PMC ID: 6961242

PubMed ID: 31941523

SO-VID: 99a37bc9-e31e-4737-90e7-6dd86cf570a8

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 5 February 2019

Date accepted : 9 August 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100011703, Yorkshire Cancer Research;

Funded by: FundRef http://dx.doi.org/10.13039/501100000801, Bayer HealthCare;

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: radium-223,capecitabine,bone metastases,bone turnover markers,breast cancer

Data availability:

ScienceOpen disciplines: Medicine

Keywords: radium-223, capecitabine, bone metastases, bone turnover markers, breast cancer

CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases (CARBON): study protocol for a phase IB/IIA randomised controlled trial

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Abstract

Background

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Discussion

Trial registration

Electronic supplementary material

Related collections

Karger: Oncology

Most cited references 9

Molecular biology of bone metastasis.

Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model.

Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid.

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