Study aims and objectives
The purpose of this study is to determine the safety profile and clinical relevance of the combination of radium-223 and capecitabine in breast cancer patients with bone metastases. The study protocol and this manuscript have been written in accordance with Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.
Primary objectives
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To evaluate the safety and toxicity of the combination of radium-223 and capecitabine
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To preliminarily estimate if multiple intravenous (i.v.) injections of radium-223 plus capecitabine will have any clinically relevant effect on uNTX in breast cancer patients with bone metastases, with or without other sites of disease
The sample size calculation is based solely on the primary toxicity endpoint. Primary analysis of the uNTX endpoint is focussed on estimation only, i.e. no formal hypothesis testing will be carried out for the purpose of decision making. No formal comparisons will be made.
Secondary objectives
To evaluate the effect of radium-223 on other bone turnover markers (N-terminal propeptide of procollagen type-1 (P1NP), serum C-telopeptide (CTX), pyridinoline cross-linked carboxyterminal telopeptide (1CTP), B-ALP)
To evaluate pain scores and quality of life
To evaluate time to first SSE – defined as any of: use of external-beam radiotherapy to relieve skeletal symptoms; new symptomatic pathological vertebral or non-vertebral bone fracture; spinal cord compression; tumour-related orthopaedic surgical intervention
To evaluate time to progression of bone disease and time to progression of extraskeletal disease
Study design
The trial is designed as a randomised, controlled, open-label, multi-centre, phase IB/IIA study. It comprises an initial safety phase to establish the feasibility and safety of combining radium-223 at the recommended dose of 55 kBq/kg given on a 6-weekly schedule to enable combination with orally administered capecitabine administered with the standard of care schedule (2 weeks of capecitabine followed by 1 week off treatment). Recruitment to the initial safety phase utilises a 3 + 3 design. If the treatment in the initial safety phase proves to be feasible and safe, the randomised extension phase will open to recruitment. The extension phase of the study aims to characterise the safety profile and provide preliminary estimation of efficacy.
The participant pathway can be seen schematically in Fig. 1 and a populated Standard Protocol Items: Recommendations Figure is also provided in Fig. 2.
Study population
Patients are eligible if they have histological evidence of primary breast cancer with imaging evidence of bone metastases (with or without soft tissue, lymph node or visceral metastases; brain metastases allowed if stable and untreated for ≥ 8 weeks) and systemic chemotherapy with capecitabine is felt to be appropriate by the treating physician. They must have received no more than two lines of chemotherapy in the metastatic setting and prior cytotoxic therapy must have been completed 28 days or more prior to initiation of study treatment. They must have an Eastern Co-operative Oncology Group (ECOG) performance status 0–2 and a life expectancy of 6 or more months. Patients are required to have appropriate haematological and biochemical parameters, to be aged 18 years or over and be able and willing to consent and comply with study treatment, visits and required investigations.
Patients are excluded from the study if they are pregnant or breast feeding; received an investigational drug within 4 weeks prior to the first study treatment; received external-beam radiotherapy within 4 weeks prior to the first study treatment; they have the presence of imminent or established spinal cord compression based on clinical findings and/or magnetic resonance imaging (MRI); 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 the cervix and superficial bladder cancers). Patients are also excluded if they have had severe and unexpected reactions to fluoropyrimidine therapy or have been diagnosed with dihydropyrimidine dehydrogenase deficiency; received a blood transfusion or erythropoietin within 4 weeks of study treatment; are hypersensitive to capecitabine or any of its excipients; have received treatment with sorivudine or its chemically related analogues, such as brivudine; and are receiving treatment with phenytoin or warfarin. Patients with any other serious illness or medical condition will be excluded, such as, but not limited to: any uncontrolled infection, clinical heart failure (NYHA Heart Failure Class III or IV), active Crohn’s disease or ulcerative colitis, bone marrow myelodysplasia, uncontrolled coronary artery disease, active peptic ulcers, malabsorption.
Sample size
Approximately 48 participants will be recruited across both phases of the trial.
Initial safety phase
A minimum of six and a maximum of 12 evaluable participants will be recruited into the initial safety phase. This is based on the number of participants experiencing Dose Limiting Toxicities (DLTs), using a modified 3 + 3 approach (see Fig. 3).
Extension phase
An additional 36 participants will be recruited to the extension phase, and will be randomised on a 1:2 ratio to receive either:
Orally administered capecitabine alone 1000 mg/m2 twice a day (bd) or, capecitabine 850 or 1000 mg/m2 bd (as determined in the initial safety phase) plus radium-223 55 kBq/kg by i.v. injection on day 1 of cycle (2, 4, 6, 8, 10 and 12) of capecitabine for a total of six injections.
The sample size for the extension phase is based upon the primary toxicity endpoint of grade-III/IV toxicity. With 24 participants in the capecitabine plus radium-223 arm, this provides approximately 80% power to exclude a grade-III/IV diarrhoea rate of 25% from the upper limit of a one-sided 85% CI, assuming a rate of approximately 10% with capecitabine alone. If no more than 3/24 participants experience grade-III/IV diarrhoea the upper limit of the one-sided 85% CI will exclude 25%.
The control arm is included to provide concurrent standard of care data for interpretation only. No formal comparisons between arms will be made.
Recruitment
Participants are recruited from NHS hospitals throughout the UK which are approved to participate in this study having obtained requisite ethical and management approval. There are four centres open to recruitment; Weston Park Hospital in Sheffield, St James’s Hospital in Leeds, The Christie Hospital in Manchester and the Clatterbridge Cancer Centre in Liverpool. These centres have been selected based on their proven track record in delivering early phase studies and experience with radium-223. Further centres may be considered if the recruitment target is not being met. The estimated accrual for this study is two to three participants a month. Thus, participant accrual is expected to be completed within 18 months.
Study treatment
A maximum of 12 cycles of combination therapy is given unless disease progression or unacceptable toxicity are encountered. A cycle is 21 days in accordance with the standard administration of capecitabine.
A maximum of two doses of capecitabine are being investigated in this study; 850 mg/m2 bd and 1000 mg/m2 bd. The starting dose is 1000 mg/m2 bd which is in accordance with the standard administration of capecitabine. Capecitabine is delivered on days 4–17 for up to 12 cycles to provide a 3–4-day window before and after radium-223 to minimise any risk of potentiating normal tissue radiation sensitivity. After cycle 12, patients may continue with capecitabine off study as per standard of care, if they are continuing to receive clinical benefit.
Radium-223 is administered at 55 kBq/kg. This dose has been selected based on clinical data from previous studies in prostate cancer and breast cancer which have demonstrated efficacy and tolerability [14, 16,17,18]. Radium-223 is administered as a slow i.v. injection on day 1 of alternating cycles, starting at cycle 2 to provide one cycle of safety information in each participant with capecitabine alone.
Initial safety phase
The safety data for the first cohort is reviewed by the Safety Review Committee and the capecitabine dose will either be expanded to a further three participants or de-escalated to 850 mg/m2 bd depending on the frequency and severity of toxicity experienced.
Toxicity data for each subsequent cohort is reviewed prior to dose expansion after three participants have been recruited and observed for DLTs, according to Fig. 3.
DLTs are assessed during the second cycle of capecitabine treatment up to the administration of cycle 3 day 1 and will be defined as the following events:
Gastrointestinal toxicity of ≥ grade III lasting > 48 h despite adequate supportive care measures
Haematological toxicity ≥ grade IV lasting > 7 days despite adequate supportive care measures which should exclude the use of bone marrow growth factors
Gastrointestinal toxicity ≥ grade III or haematological toxicity≥ grade IV experienced by participants during the first cycle, i.e. up to the administration of cycle 2 day 1 are not classed as DLTs as they are related to the capecitabine only.
The number of participants recruited to the initial safety phase, and the dose carried forward to the randomised extension phase is determined by the number of DLTs in line with the DLT schema.
Evaluability
Participants can miss no more than 50% of doses in the first two treatment cycles in order to be evaluable for DLT in the initial safety phase. Participants missing more than 50% of doses for reasons other than toxicity without experiencing a DLT will be replaced.
Assessments
Participants are assessed clinically at baseline, on day 1 of each cycle, with additional haematology assessments during cycles 1 and 2 (days 8 and 15, respectively), at the end of study visit, and then at the 12-weekly follow-up visits.
Planar bone scintigraphy/SPECT ± computerised tomography (CT) is performed at baseline and at the end of study visit, and when clinically indicated. Chest/abdominal/pelvic CT or MRI is performed at baseline, weeks 12 and 24 after the initiation of treatment, at the of study visit and when clinically indicated.
Serum and second voided urine samples are collected to analyse changes in bone turnover markers at baseline, day 1 of alternating cycles starting at cycle 2, and at the end of the study visit.
Quality of life is assessed using EORTC QLQ-C30 and QLQ-Bone Metastases Module (QLQ-BM22) which will be completed by the participant prior to the first administration of trial treatment, day 1 of alternating cycles starting at cycle 2, and at the end of study visit.
Response is evaluated using RECIST v1.1 with comparisons to baseline evaluation.
Data collection and management
All protocol-required information is completed at sites onto paper Case Report Forms by research staff, with the exception of quality-of-life information which will be completed directly by participants. Overall trial and data management is provided by the Leeds Clinical Trials Research Unit (CTRU), including monitoring of data for quality and completeness.
The independent Safety Review Committee (SRC) meets regularly to review the safety and ethics of the study by regularly reviewing the safety data during the dose escalation and expansion phases.
Statistical analysis
Statistical analysis is the responsibility of the CARBON CTRU trial statistician. A full statistical analysis plan will be written before any formal analyses are undertaken.
During the initial safety phase, after every cohort of three participants, the CTRU trial statistician produces a summary of DLTs and AEs at each dose level, detailed safety listings and treatment compliance data for all participants in the study. The final analysis of primary endpoints and all secondary endpoints will take place when all participants have been followed up for at least 12 months.
The analysis population for the initial safety phase includes any participant who has received at least one complete cycle of capecitabine and radium-223. For the extension phase intention-to treat (ITT) population, per-protocol and safety analysis populations will be used. Statistical analysis is summarised by treatment arm.
Primary endpoint analysis
Dose Limiting Toxicities (initial safety phase)
The number of participants experiencing DLTs within the first cycle of radium-223 treatment will be presented, with descriptive summaries of the specific DLTs observed.
Frequency of CTC grade-III/IV toxicities with a focus on diarrhoea as the primary toxicity (extension phase)
The number of participants experiencing any grade-III/IV toxicity will be presented by arm, across all cycles as well as by each cycle. Toxicities should be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE).
Decrease in uNTX from baseline to end of cycle 5 (approximately 15 weeks post trial entry) (extension phase)
The proportion of participants categorised as responders (≥ 30% reduction in uNTX from baseline) at the end of cycle 5 will be presented by arm.
Secondary endpoint analysis
Safety endpoints
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The number of Serious Adverse Events (SAEs), Serious Adverse Reactions (SARs) and Serious Unexpected Adverse Reactions (SUSARs) will be summarised descriptively by arm, causality, seriousness and body system
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The worst AE for each participant will be summarised by arm, overall and by treatment cycle. The proportion of participants experiencing each toxicity will be summarised by maximum NCI CTCAE (V4.03) grade by arm
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Dose delays and reductions will be summarised by arm overall and by treatment cycle
Efficacy endpoints
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Descriptive and graphical summaries of the changes in serum bone turnover markers will be presented by arm. Multi-level repeated-measures modelling will also be used to estimate differences between the two treatment arms over time
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Time to occurrence of first symptomatic skeletal event (SSE) will be calculated using the Kaplan-Meier method. Median time to first SSE will be presented with corresponding 95% CIs for each arm
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Time to progression of bone disease will be calculated using the Kaplan-Meier method. Median time to progression of bone disease will be presented, with corresponding 95% CIs for each arm
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Time to progression of extraskeletal disease will be calculated using the Kaplan-Meier method. Median time to progression of extraskeletal disease will be presented, with corresponding 95% CIs for each arm
Clinical benefit endpoints
Study organisation and administration
The CARBON study is funded by Bayer Healthcare, supported by Yorkshire Cancer Research (YCR) through the YCR Centre for Early Phase Clinical Trials, and is sponsored by the University of Leeds. Additional support is also provided by the National Institute for Health Research (NIHR) through the use of the Clinical Research Network (CRN). Trial supervision will be established according to the principles of Good Clinical Practice and in line with the relevant Research Governance Framework within the UK and through adherence with CTRU standard operating procedures. A Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist has been prepared for this manuscript (Additional file 1).
The trial is registered (ISRCTN92755158 and EudraCT number 2015–003979-29).