A Study of Whole Brain Radiation Therapy and Capecitabine in Breast Cancer Participants With Newly Diagnosed Brain Metastasis

Study Overview
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Brief Summary
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This open-label, randomized, parallel arm study will evaluate the effect of capecitabine administered concurrently with WBRT and as maintenance therapy in participants with breast cancer and newly diagnosed brain metastases. Participants will be randomized to receive either capecitabine with 10 days standard WBRT, or WBRT alone. Maintenance therapy will follow with capecitabine or another systemic therapy in the WBRT only group.

Official Title
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XERAD: Open-Label, Phase II, Randomized, Comparative, Multicentre Trial of Concurrent Whole Brain Radiation Therapy (WBRT) and Capecitabine (Xeloda®) Followed by Maintenance Capecitabine Compared With Standard WBRT in Breast Cancer Patients With Newly Diagnosed Brain Metastasis

Conditions
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Breast Cancer

Intervention / Treatment
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* Radiation: WBRT
* Drug: Capecitabine
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with histologically confirmed breast cancer with known human epidermal receptor-2 (HER2) and hormone status Newly diagnosed CNS metastasis with at least one brain lesion measuring greater than or equal to (>/=) 1 centimeter (cm) or two lesions measuring >/= 0.5 to less than (<) 1 cm in longest dimension Participant not eligible for or refusing surgery or stereotactic radiosurgery Eastern cooperative oncology group (EOCG) performance status 0 to 2 Exclusion Criteria: Prior treatment of brain metastases Leptomeningeal disease Known contra-indication to radiotherapy or magnetic resonance imaging (MRI) or capecitabine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: WBRT Followed by Standard of Care<br>Participants will receive 3000 centi-Gray (cGy) WBRT in 10 single daily fractions over 12 to 14 days (300 cGy / fraction) followed by standard of care therapy at the discretion of the treating oncologist starting no earlier than 2 weeks after completion of WBRT. The participants will be followed during the treatment until the halting of standard of care for any reason (central nervous system [CNS] or extra-cranial tumor progression, unacceptable toxicity, change of therapeutic strategy, withdrawal of participant consent, or death). | Radiation: WBRT<br>* 3000 cGy WBRT in 10 single daily fractions over 12 to 14 days (300 cGy / fraction).<br>Drug: Standard of Care<br>* The choice of standard of care will be at the discretion of the treating oncologist. The protocol does not specify any particular standard of care treatment.<br>|
| Experimental: WBRT+Capecitabine Followed by Capecitabine Maintenance<br>Participants will receive 3000 cGy WBRT in 10 single daily fractions over 12 to 14 days (300 cGy / fraction) concurrent with capecitabine 825 milligrams per square meter (mg/m^2) orally twice daily, Days 1-14 of a 21 day cycle for 1 cycle followed by capecitabine 1000 mg/m^2 orally twice daily Days 1-14 every 21 days starting with Cycle 2, one week after completion of WBRT and continuing until the halting of capecitabine for any reason (CNS or extra-cranial progression, unacceptable toxicity, withdrawal of participant consent or death). | Radiation: WBRT<br>* 3000 cGy WBRT in 10 single daily fractions over 12 to 14 days (300 cGy / fraction).<br>Drug: Capecitabine<br>* 825 mg/m^2 orally twice daily, Days 1-14 of a 21 day cycle for 1 cycle followed by 1000 mg/m^2 orally twice daily Days 1-14 every 21 days starting with Cycle 2.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Best Objective Central Nervous System (CNS) Response, Assessed by Centralized Independent Expert According to Magnetic Resonance Imaging (MRI) - Intent-to-Treat (ITT) Population | Best objective CNS response was defined as having complete response (CR) or partial response (PR) for CNS metastasis, assessed by contrast-enhanced MRI using response evaluation criteria in solid tumors (RECIST). CR: disappearance of all CNS lesions. PR: greater than or equal to (>/=) 30 percent (%) decrease in sum of longest diameters (LD) of CNS lesions taking as reference the baseline sum LD. | Baseline until disease progression (PD), unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first (up to approximately 1 year 5.5 months overall) | 
| Percentage of Participants With Best Objective CNS Response, Assessed by Centralized Independent Expert According to MRI - Per-Protocol (PP) Population | Best objective CNS response was defined as having CR or PR for CNS metastasis, assessed by contrast-enhanced MRI using RECIST. CR: disappearance of all CNS lesions. PR: >/=30% decrease in sum of LD of CNS lesions taking as reference the baseline sum LD. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first (up to approximately 1 year 5.5 months overall) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective CNS Response at 4 Weeks After Completion of WBRT, Assessed by Centralized Independent Expert According to MRI | Objective CNS response was defined as having CR or PR for CNS metastasis, assessed by contrast-enhanced MRI using RECIST. CR: disappearance of all CNS lesions. PR: >/=30% decrease in sum of LD of CNS lesions taking as reference the baseline sum LD. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first up to 4 weeks after completion of WBRT (up to approximately 7 weeks) | 
| Percentage of Participants With Best Objective CNS Response, Assessed by Investigator According to MRI | Best objective CNS response was defined as having CR or PR for CNS metastasis, assessed by contrast-enhanced MRI using RECIST. CR: disappearance of all CNS lesions. PR: >/=30% decrease in sum of LD of CNS lesions taking as reference the baseline sum LD. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first (up to approximately 1 year 5.5 months overall) | 
| Percentage of Participants With Objective CNS Response at 4 Weeks After Completion of WBRT, Assessed by Centralized Independent Expert According to MRI in 3 Dimension | Objective CNS response was defined as having CR or PR for CNS metastasis, assessed by 3 dimensional MRI using RECIST. CR: disappearance of all CNS lesions. PR: >/=30% decrease in sum of LD of CNS lesions taking as reference the baseline sum LD. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first up to 4 weeks after completion of WBRT (up to approximately 7 weeks) | 
| Percentage of Participants With Clinical Benefit, Assessed by Investigator According to MRI | Clinical benefit was defined as having CR, PR, or stable disease (SD), assessed by contrast-enhanced MRI using RECIST. CR: disappearance of all CNS lesions. PR: >/=30 % decrease in sum of LD of CNS lesions taking as reference the baseline sum LD. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) taking as reference smallest sum LD since treatment started. PD: a 20% or greater increase in the sum of the LD of CNS lesions taking as reference the smallest sum LD recorded since the treatment started or appearance of one or more CNS lesions and/or unequivocal progression of existing CNS lesions. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first (up to approximately 1 year 5.5 months overall) | 
| Percentage of Participants With Objective CNS Response at 4 Weeks After Completion of WBRT, Assessed by Investigator According to MRI | Objective CNS response was defined as having CR or PR for CNS metastasis, assessed by contrast-enhanced MRI using RECIST. CR: disappearance of all CNS lesions. PR: >/=30 % decrease in sum of LD of CNS lesions taking as reference the baseline sum LD. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first up to 4 weeks after completion of WBRT (up to approximately 7 weeks) | 
| Duration of CNS Response, Assessed by Investigator According to MRI | Duration of CNS response was defined as the time from first documented cranial CR or PR (whichever was recorded first) until the first date CNS recurrence or progression was documented as assessed by contrast-enhanced MRI according to RECIST criteria but without exam for response confirmation. CR: disappearance of all CNS lesions. PR: >/=30 % decrease in sum of LD of CNS lesions taking as reference the baseline sum LD. PD: a 20% or greater increase in the sum of the LD of CNS lesions taking as reference the smallest sum LD recorded since the treatment started or appearance of one or more CNS lesions and/or unequivocal progression of existing CNS lesions. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first (up to approximately 1 year 5.5 months overall) | 
| Time to CNS Progression, Assessed by Investigator According to MRI | Time to CNS progression was defined as the time from start of study treatment to first documentation of PD or death due to CNS metastasis. PD was assessed by contrast-enhanced MRI according to RECIST. PD: a 20% or greater increase in the sum of the LD of CNS lesions taking as reference the smallest sum LD recorded since the treatment started or appearance of one or more CNS lesions and/or unequivocal progression of existing CNS lesions. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first (up to approximately 1 year 5.5 months overall) | 
| Percentage of Participants With Best Objective Extra-cranial Disease Response, Assessed by Investigator According to Computed Tomography (CT) | Best objective extra-cranial response was defined as having CR or PR for extra-cranial lesions, assessed by CT using RECIST. CR: disappearance of all extra-cranial lesions. PR: >/=30 % decrease in sum of LD of extra-cranial lesions taking as reference the baseline sum LD. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first (up to approximately 1 year 5.5 months overall) | 
| Percentage of Participants With Objective Extra-cranial Disease Response at 4 Weeks After Completion of WBRT, Assessed by Investigator According to CT | Objective extra-cranial response was defined as having CR or PR for extra-cranial lesions, assessed by CT using RECIST. CR: disappearance of all extra-cranial lesions. PR: >/=30 % decrease in sum of LD of extra-cranial lesions taking as reference the baseline sum LD. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first up to 4 weeks after completion of WBRT (up to approximately 7 weeks) | 
| Time to Extra-cranial Disease Progression, Assessed by Investigator According to CT | Time to extra-cranial progression was defined as the time from start of study treatment to first documentation of PD or death due to extra-cranial lesions. PD was assessed by CT according to RECIST. PD: a 20% or greater increase in the sum of the LD of extra-cranial lesions taking as reference the smallest sum LD recorded since the treatment started or appearance of one or more extra-cranial lesions and/or unequivocal progression of existing extra-cranial lesions. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first (up to approximately 1 year 5.5 months overall) | 
| Time to Progression, Assessed by Investigator According to MRI and CT | Time to progression was defined as the time from start of study treatment to first documentation of PD or death due to tumor (CNS or extra-cranial). PD was assessed by MRI or CT according to RECIST. PD: a 20% or greater increase in the sum of the LD of CNS or extra-cranial lesions taking as reference the smallest sum LD recorded since the treatment started or appearance of one or more CNS or extra-cranial lesions and/or unequivocal progression of existing CNS or extra-cranial lesions. | Baseline until PD, unacceptable toxicity, withdrawal of consent, change of therapeutic strategy (for arm WBRT Followed by Standard of Care only), or death, whichever occurred first (up to approximately 1 year 5.5 months overall) | 
| Overall Survival (OS) | OS was defined as the time from the start of study treatment to date of death due to any cause. OS was assessed using Kaplan-Meier analysis. | Baseline until death (up to approximately 1 year 5.5 months overall) | 
| Absolute Change From Baseline in Mini Mental State (MMS) Total Score | MMS was an 11-question measure that tested five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. Four items were scored on a scale of 0 to 1; 1 item was scored on a scale of 0 to 2; 3 items were scored on a scale of 0 to 3; and 3 items were scored on a scale of 0 to 5. MMS total score was obtained by adding the scores of all individual items and ranged from 0 to 30, where higher scores indicate better cognitive state. | Baseline, Up to end of Treatment (up to 10.6 months overall) |