Condition category
Cancer
Date applied
17/02/2016
Date assigned
17/02/2016
Last edited
27/10/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Public

Primary contact

Miss Amber Reid

ORCID ID

Contact details

Clinical Trials Research Unit (CTRU)
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom

Additional identifiers

EudraCT number

2015-003979-29

ClinicalTrials.gov number

Protocol/serial number

20654

Study information

Scientific title

A randomized phase IB/IIA study of CApecitabine plus Radium-223 (Xofigo) in breast cancer patients with BONe metastases (CARBON): an open-label interventional study

Acronym

CARBON

Study hypothesis

In advanced breast cancer, most patients with bone involvement also have metastases in other organs. Thus, a bone-targeted treatment alone is unlikely to be relevant to the majority of patients. Combination strategies with established systemic breast cancer treatments are needed. This is an open-label study which comprises an initial safety phase to establish the feasibility and safety of combining radium-223 at the licensed dose and to the same maximum recommended total dose, but given on a 6 weekly schedule to enable combination with oral capecitabine administered with the usual two weeks on and one week off treatment schedule. The safety phase, if treatment proves to be safe and feasible, will be followed by a randomised extension phase to further characterise the safety profile and provide preliminary information on efficacy.

Ethics approval

London - Fulham Research Ethics Committee, 03/02/2016, ref: 16/LO/0052

Study design

Interventional; Design type: Treatment

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Topic: Cancer; Subtopic: Breast Cancer; Disease: Bone, Breast

Intervention

Patients in the initial safety phase will receive capecitabine plus radium-223. Patients in the randomised extension phase will be randomised to receive either oral capecitabine alone or capecitabine plus radium-223 (added 07/03/2016).

Usual hospital stock of capecitabine 500mg and 150mg tablets will be used and supplied as trial specific stock according to standard operating procedures within the treating centre. Patients should swallow capecitabine tablets with water 30 min after a meal twice a day. Standard care should be followed regarding missed and vomited doses

Radium-223 50 kBq/kg b.w (55 kBq/kg after implementation of NIST update) will be administered as a slow i.v. injection 6 times at 6 weekly intervals. This treatment can be administered on an outpatient basis. It will be administered on day 1 of each alternate cycle (cycles 2, 4, 6, 8, 10 and 12). A cycle is 21 days in accordance with the standard administration of capecitabine.

Follow Up Length: 12 month(s)

Intervention type

Mixed

Phase

Drug names

Primary outcome measures

As of 07/03/2016:
Initial safety phase
1. Dose limiting toxicities

Randomised extension phase
1. Frequency of CTC grade III-IV toxicities with a focus on diarrhoea as the primary dose limiting toxicity
2. Decrease in uNTX from baseline to end of cycle 5 (approximately 15 weeks post trial entry). For patients who progress prior to the end of cycle 5, the decrease in uNTX from baseline to their end of study treatment visit will be used.

Previous primary outcome measures:
To evaluate the safety and toxicity of the combination of radium-223 and capecitabine

Secondary outcome measures

As of 07/03/2016:
1. Safety endpoints
1.1. Adverse events (AEs) and serum biochemistry and haematology abnormalities graded according to the Common Toxicity Criteria for Adverse Events (CTC) version 4.03
1.2. Serious adverse events
1.3. Dose delays and reductions due to toxicity
2. Efficacy endpoints
2.1. Changes from baseline in serum bone turnover markers (B-ALP, uNTX, P1NP, CTX and 1CTP) throughout the study period
2.2. Time to occurrence of 1st symptomatic skeletal event (SSE). This is time from registration / randomisation to 1ST SSE. Patients who do not experience an SSE by the time of final analysis will be censored at the last time known to have not experienced as SSE, study withdrawal, start of new treatment or death
2.3. Time to progression of bone disease based on unequivocal progression of existing bone lesions or appearance of one or more new osteolytic bone lesions. This is time from registration/randomisation to progression in bone. Patients who do not progress in bone by time of final analysis will be censored at the last time known to have not progressed in bone, study withdrawal, start of new treatment or death
2.4. Time to progression of extraskeletal disease. This is time from registration / randomisation to progression in extraskeletal non bony sites. Patients who do not progress outside bone by time of final analysis will be censored at the last time known to have not progressed outside bone, study withdrawal, start of new treatment or death
3. Clinical benefit endpoints
3.1. Pain scores using the Brief Pain Inventory (BPI)
3.2. Quality of life using the EORTC BM-22 bone metastases module

Previous secondary outcome measures:
To evaluate the effect of radium-223 on other bone turnover markers (P1NP, CTX, 1CTP, B-ALP)

Overall trial start date

01/03/2015

Overall trial end date

31/08/2018

Reason abandoned

Eligibility

Participant inclusion criteria

1. Female patients with histological evidence of primary breast cancer
2. Bone metastases (with or without soft tissue, lymph node or visceral metastases; brain metastases allowed if stable and untreated for = 8 weeks)
3. = 2 bone lesions confirmed on imaging (plain radiographs, CT or MRI)
4. Systemic chemotherapy with capecitabine is felt to be appropriate by the treating physician due to recent progression of metastatic disease
5. Received = 2 lines of chemotherapy in the metastatic setting. Prior cytotoxic therapy must have been completed = 28 days prior to initiation of study treatment
6. Patient has been on bone targeted therapy (bisphosphonate or denosumab) for at least 3 months prior to start of study treatment and no change to bone targeted therapy is expected during the treatment phase of the study
7. ECOG performance status 0-2
8. Life expectancy = 6 months
9. Laboratory requirements:
9.1. WBC =3.0 x10 9 /l 3000/mm3
9.2. ANC =1.5 x10 9 /l1500/mm3
9.3. Platelet count =100x109/l
9.4. Haemoglobin =10.0g/dL
9.5. Total bilirubin level =1.5 times ULN in treating institution
9.6. AST and ALT = 3 times ULN in treating institution
9.7. Calculated creatinine clearance or estimated GFR > 50mls/min (Cockcroft and Gault or Wright formula may be used according to local practice)
10. Patient must be willing and able to comply with the protocol, including follow-up visits and investigations and use effective contraception if relevant throughout the study and for at least 6 months after treatment completion
11. Must be fully informed about the study and has signed the informed consent form
12. Age at least 18 years

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

Planned Sample Size: 48; UK Sample Size: 48; Description: The sample size for the initial safety phase will require a minimum of 6 and a maximum of 12 evaluable patients. This is based on the number of patients experiencing dose-limiting toxicities. A modified 3+3 approach has been used to ensure an acceptable toxicity rate, and enable dose reduction if unacceptable toxicity is observed, prior to moving to a randomised extension phase.Up to 36 treated patients will be randomised on a 1:2 basis in the randomised extension phase at the RD.

Participant exclusion criteria

1. Received an investigational drug within 4 weeks prior to the first study treatment
2. Received external beam radiotherapy within 4 weeks prior to the first study treatment
3. Presence of imminent or established spinal cord compression based on clinical findings and/or MRI
4. Presence of other currently active (diagnosis within the last 5 years) malignancy (except treated non-melanoma skin cancer (basal or squamous), carcinoma in situ of cervix and superficial bladder cancers).
5. Patients who have had severe and unexpected reactions to fluoropyrimidine therapy or have been diagnosed with dihydropyrimidine dehydrogenase deficiency
6. Received a blood transfusion or Use of erythropoietin within 4 weeks of study treatment
7. Pregnant or breast-feeding women.
8. Treatment with sorivudine or its chemically related analogues, such as brivudine
9. Treatment with phenytoin or warfarin
10. Patients with any other serious illness or medical condition, such as, but not limited to:
10.1. Any uncontrolled infection
10.2. Clinical heart failure (NYHA Heart Failure Class III or IV)
10.3. Active Crohn’s disease or ulcerative colitis
10.4. Bone marrow myelodysplasia
10.5. Uncontrolled coronary artery disease
10.6. Active peptic ulcers
10.7. Malabsorption
11. Any exclusions as per the Xofigo or Capecitabine SmPC

Recruitment start date

30/05/2016

Recruitment end date

31/08/2017

Locations

Countries of recruitment

United Kingdom

Trial participating centre

St James' University Hospital
NHS Trust The Leeds Teaching Hospitals NHS Trust Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Weston Park Hospital
Sheffield Teaching Hospitals NHS FT Whitham Road
Sheffield
S10 2SJ
United Kingdom

Sponsor information

Organisation

Sheffield Teaching Hospitals NHS Trust

Sponsor details

Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Industry

Funder name

Bayer HealthCare

Alternative name(s)

BHC

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

Germany

Funder name

Yorkshire Cancer Research

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The publication policy is to be defined by the Trial Management Group and reviewed by the Safety Review Committee, but will include the Chief Investigator and study statistician as a minimum with additional authors included according to ICMJE criteria. Publication of emerging safety data in the form of abstracts for oral or poster presentation, or journal letters is permitted. However no formal manuscript publication is permitted until the final analysis of the primary endpoint trial data has been completed. The release of any data prior to this must be approved by the independent members of the Safety Review Committee.
All publications must have the approval of the Chief Investigator. Draft manuscripts and abstracts will be made available to Bayer and YCR prior to submission for comment. The decision to publish and final responsibility for the content will rest with the Chief Investigator and the Trial Management Group.

Intention to publish date

31/08/2020

Participant level data

Not expected to be available

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

27/10/2016: Cancer Help UK lay summary link added. 07/04/2016: the recruitment start date was changed from 31/03/2016 to 30/05/2016. 07/03/2016: Significant changes were made to this study record. Changes to the intervention and outcome measures are highlighted in the record. In addition to these, the overall start date was changed from 01/03/2016 to 01/03/2015 and the overall end date was changed from 31/08/2017 to 31/08/2018. The public title was changed from "A randomized phase IB/IIA study of capecitabine plus radium-223 (Xofigo) in breast cancer patients with bone metastases (CARBON)" to "Capecitabine oral chemotherapy with radium-223 in breast cancer patients with bone metastases (CARBON)". The "Participant inclusion criteria: Gender" was changed from "Both" to "Female".