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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01234337




Registration number
NCT01234337
Ethics application status
Date submitted
4/10/2010
Date registered
4/11/2010
Date last updated
6/11/2018

Titles & IDs
Public title
Phase III Trial Comparing Capecitabine in Combination With Sorafenib or Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer
Scientific title
A Phase III Randomized, Double Blind, Placebo-controlled Trial Comparing Capecitabine Plus Sorafenib Versus Capecitabine Plus Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer
Secondary ID [1] 0 0
2010-018501-10
Secondary ID [2] 0 0
12444
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Sorafenib (Nexavar, BAY43-9006)
Treatment: Drugs - Placebo
Treatment: Drugs - Capecitabine

Experimental: Sorafenib (Nexavar, BAY43-9006) + Capecitabine - Capecitabine was administered orally at a dose of 1,000 milligram per square meter (mg/m\^2) twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Sorafenib was administered orally at a dose of 600 mg (200 mg in the morning, 400 mg in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m\^2 twice daily and sorafenib dose to a total daily dose of 800 mg for that subject.

Placebo comparator: Placebo + Capecitabine - Capecitabine was administered orally at a dose of 1,000 mg/m\^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Placebo matching to sorafenib was administered orally, 3 tablets (1 tablet in the morning, 2 tablets in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m\^2 twice daily and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that subject.


Treatment: Drugs: Sorafenib (Nexavar, BAY43-9006)
Capecitabine was administered orally at a dose of 1,000 milligram per square meter (mg/m\^2) twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Sorafenib was administered orally at a dose of 600 mg (200 mg in the morning, 400 mg in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m\^2 twice daily and sorafenib dose to a total daily dose of 800 mg for that subject.

Treatment: Drugs: Placebo
Capecitabine was administered orally at a dose of 1,000 mg/m\^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Placebo matching to sorafenib was administered orally, 3 tablets (1 tablet in the morning, 2 tablets in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m\^2 twice daily and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that subject.

Treatment: Drugs: Capecitabine
Capecitabine was administered orally at a dose of 1,000 milligram per square meter (mg/m\^2) twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle.days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m\^2 twice daily,
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free Survival (PFS) Assessed by the Independent Review Panel According to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1
Timepoint [1] 0 0
From randomization of the first participant until approximately 3 years or until disease radiological progression
Secondary outcome [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
From randomization of the first participant until approximately 3 years later
Secondary outcome [2] 0 0
Time to Progression (TTP) by Central Review
Timepoint [2] 0 0
From randomization of the first participant until approximately 3 years later or until disease radiological progression
Secondary outcome [3] 0 0
Objective Response Rate (ORR) by Central Review
Timepoint [3] 0 0
From randomization of the first participant until approximately 3 years later or until disease radiological progression
Secondary outcome [4] 0 0
Disease Control Rate (DCR) by Central Review
Timepoint [4] 0 0
From randomization of the first participant until approximately 3 years later or until disease radiological progression
Secondary outcome [5] 0 0
Duration of Response (DOR) by Central Reader
Timepoint [5] 0 0
From randomization of the first participant until approximately 3 years later or until disease radiological progression

Eligibility
Key inclusion criteria
* Age is >=18 years
* Subject has histologically or cytologically confirmed HER2-negative adenocarcinoma of the breast. HER2 status should be determined by an accredited laboratory
* Subject has locally advanced or metastatic disease; locally advanced disease must not be amenable to resection with curative intent. Must have measurable or non-measurable disease (according to RECIST [Response Evaluation Criteria for Solid Tumors] 1.1)
* All computer tomography (CT; with contrast) and magnetic resonance imaging (MRI) used to document disease must have been done <= 4 weeks before randomization. Bone scans (if clinically indicated) must have been done <= 12 weeks prior to randomization
* Subject must have received up to two prior chemotherapy regimens (adjuvant/neo-adjuvant treatments are considered one regimen), and no more than one prior regimen for advanced and/or metastatic disease. Chemotherapy regimens include both targeted and biologic therapy
* Prior regimens must have included an anthracycline (eg, doxorubicin, epirubicin) and a taxane (eg, paclitaxel, docetaxel), either in combination or in separate regimens, in either the neo-adjuvant/adjuvant or the metastatic setting or both, as either monotherapy or as part of a combination with another agent. Sequential regimens will count as a single regimen; multiple neo-adjuvant / adjuvant regimens will count as a single regimen
* Subjects are either resistant to or have failed prior taxane and anthracycline OR Resistant to or have failed prior taxane AND for whom further anthracycline therapy is not indicated (for example, intolerance or cumulative doses of doxorubicin or doxorubicin equivalents [for example, epirubicin)
* Subjects who relapse beyond 12 months after the last taxane or anthracycline dose given in the adjuvant, neo-adjuvant, or metastatic setting are eligible. Further therapy with the agent(s) for a subsequent regimen must have been considered and ruled out, for example due to prior toxicity or intolerance, or based on the local standard of practice
* Prior experimental chemotherapy treatment is allowed, provided it is given in combination with at least one drug approved for the treatment of breast cancer (excluding drugs that target VEGF [Vascular Endothelial Growth Factor] or VEGFR [Vascular Endothelial Growth Factor Receptor], eg, bevacizumab, brivanib, sunitinib, vatalinib).
* Prior hormonal therapy for locally advanced or metastatic breast cancer is allowed. Subjects who are refractory to hormonal therapy are allowed.
* Prior neo-adjuvant or adjuvant chemotherapy is allowed.
* Subject must have discontinued prior chemotherapy (including both targeted and biologic therapies), prior therapeutic radiation therapy, or prior hormonal therapy for locally advanced or metastatic disease >= 4 weeks (28 days) before randomization. Start of study treatment is allowed within less than 28 days of the prior therapy provided that 5 half-lives of the prior treatment drug(s) have elapsed
* ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1
* Adequate bone marrow, liver and renal function within 7 days prior to randomization
* All acute toxic effects of any prior treatment have resolved to NCI-CTCAE (National Cancer Institute-Common Terminology Criteria for Adverse Events) v4.0 Grade 1 or less
* Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to randomization
* Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF (Informed Consent Form) until at least 30 days after the last dose of study drug.
* Subject must be able to swallow and retain oral medication
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* HER2 positive breast cancer
* Unknown hormone receptor status (estrogen and progesterone receptor).
* Subjects with bilateral breast cancer or a history of two distinct breast cancers.
* Subjects with inflammatory breast carcinoma.
* Subjects who have received no prior taxane and anthracycline for the treatment of breast cancer (either in adjuvant, neo-adjuvant or metastatic setting).
* Prior use of sorafenib or capecitabine
* Subjects considered by the treating investigator to be appropriate candidates for hormonal therapy as current treatment for locally advanced/metastatic breast cancer
* Subjects with locally advanced disease who are considered by the treating investigator to be appropriate candidates for radiation therapy as current treatment for locally advanced breast cancer
* Subjects with active brain metastases or leptomeningeal disease.
* Subjects with seizure disorder requiring medication.
* Radiation to any lesions <= 4 weeks prior to randomization. Palliative radiation to bone metastasis for pain control is permitted with provisions
* Major surgery, open biopsy, or significant traumatic injury <= 4 weeks
* Evidence or history of bleeding diathesis or coagulopathy. Uncontrolled hypertension, active or clinically significant cardiac disease. Subject with thrombotic, embolic, venus or arterial events
* Subjects with any hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or higher within 4 weeks before randomization
* Subjects with an infection of NCI-CTCAE v4.0 > Grade 2
* Subjects with a history of human immunodeficiency virus infection or current chronic or active hepatitis B or C infection.
* Subjects who have used strong CYP3A4 inducers (eg, phenytoin, carbamazepine, phenobarbital, St. John's Wort [Hypericum perforatum], dexamethasone at a dose of greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days before randomization.
* Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology from breast cancer
* Subjects with a history DHPD (Dihydropyrimidine dehydrogenase) reaction to fluropyrimidine or history of known or suspected allergy or hypersensitivity to any of the study drugs
* Presence of a non-healing wound, non-healing ulcer, or bone fracture
* Women pregnant or breast feeding
* Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
21/02/2011
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
20/10/2017
Sample size
Target
Accrual to date
Final
537
Recruitment in Australia
Recruitment state(s)
ACT,NSW,SA,VIC,WA
Recruitment hospital [1] 0 0
- Garran
Recruitment hospital [2] 0 0
- Liverpool
Recruitment hospital [3] 0 0
- Waratah
Recruitment hospital [4] 0 0
- Adelaide
Recruitment hospital [5] 0 0
- Bendigo
Recruitment hospital [6] 0 0
- Frankston
Recruitment hospital [7] 0 0
- Perth
Recruitment postcode(s) [1] 0 0
2605 - Garran
Recruitment postcode(s) [2] 0 0
2170 - Liverpool
Recruitment postcode(s) [3] 0 0
2298 - Waratah
Recruitment postcode(s) [4] 0 0
5000 - Adelaide
Recruitment postcode(s) [5] 0 0
3550 - Bendigo
Recruitment postcode(s) [6] 0 0
- Frankston
Recruitment postcode(s) [7] 0 0
6000 - Perth
Recruitment outside Australia
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United States of America
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California
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Florida
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Illinois
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Indiana
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Kentucky
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Massachusetts
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Mississippi
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Missouri
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North Carolina
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Pennsylvania
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Tennessee
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Texas
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Vermont
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Wisconsin
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Argentina
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Buenos Aires
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Argentina
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Ciudad Auton. De Buenos Aires
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Wien
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Liège
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Brugge
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Bruxelles - Brussel
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Edegem
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Liaoning
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Nymburk
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Praha 10
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Hessen
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Ioannina
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Patras
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Hungary
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Budapest
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Nyiregyhaza
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Pecs
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Szentes
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Szolnok
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Ireland
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Cork
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Dublin
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Beer Sheva
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Haifa
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Israel
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Jerusalem
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Israel
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Petah Tikva
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Israel
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Ramat Gan
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Italy
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Emilia-Romagna
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Italy
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Lazio
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Italy
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Lombardia
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Italy
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Marche
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Italy
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Sicilia
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Italy
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Toscana
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Japan
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Aichi
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Ehime
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Osaka
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Japan
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Saitama
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Tokyo
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Chiba
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Japan
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Fukuoka
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Japan
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Kagoshima
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Poland
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Gdansk
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Poland
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Gdynia
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Poland
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Poznan
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Puerto Rico
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San Juan
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Russian Federation
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Chelyabinsk
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Russian Federation
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Kazan
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South Africa
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Eastern Cape
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South Africa
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Gauteng
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Spain
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A Coruña
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Spain
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Barcelona
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Spain
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Castellón
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Spain
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Illes Baleares
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Spain
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Tarragona
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Spain
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Lleida
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Spain
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Madrid
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Spain
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Palma de Mallorca
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Spain
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Sevilla
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Spain
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Valencia
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Sweden
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Stockholm
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United Kingdom
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Cornwall
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United Kingdom
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Nottinghamshire
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United Kingdom
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London
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United Kingdom
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Manchester
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United Kingdom
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Northwood

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Bayer
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Onyx Therapeutics, Inc.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
The objective of this phase-III trial is to compare the efficacy and safety of sorafenib in combination with capecitabine versus capecitabine in combination with placebo in the treatment of subjects with locally advanced or metastatic HER2-negative breast cancer who are resistant to or have failed prior taxane and an anthracycline or for whom further anthracycline therapy is not indicated. After signing consent there can be up to 28 days before starting the treatment during which time a number of tests will be carried out which will include tumor evaluations and medical history. The following tests and evaluations will have to be done within 7 days of the start of treatment,on Day 1 of every cycle and at the end of study: Electrocardiogram, blood tests, patient quality of life questionnaires and a complete physical exam and vital signs. Treatment will be given in 21 day cycles with sorafenib/placebo to be taken every day for 21 days and capecitabine to be taken for the first 14 days. Patients will come in weekly for the first 6 weeks and then on Day1 for every cycle after the first 2 cycles. During the weekly visits the subjects will be check for any side effects and blood draws will happen for the study on Day 1 of each cycle. Subjects will be followed for overall survival.
Trial website
https://clinicaltrials.gov/study/NCT01234337
Trial related presentations / publications
Baselga J, Costa F, Gomez H, Hudis CA, Rapoport B, Roche H, Schwartzberg LS, Petrenciuc O, Shan M, Gradishar WJ. A phase 3 tRial comparing capecitabinE in combination with SorafenIb or pLacebo for treatment of locally advanced or metastatIc HER2-Negative breast CancEr (the RESILIENCE study): study protocol for a randomized controlled trial. Trials. 2013 Jul 22;14:228. doi: 10.1186/1745-6215-14-228.
Baselga J, Zamagni C, Gomez P, Bermejo B, Nagai SE, Melichar B, Chan A, Mangel L, Bergh J, Costa F, Gomez HL, Gradishar WJ, Hudis CA, Rapoport BL, Roche H, Maeda P, Huang L, Meinhardt G, Zhang J, Schwartzberg LS. RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer. Clin Breast Cancer. 2017 Dec;17(8):585-594.e4. doi: 10.1016/j.clbc.2017.05.006. Epub 2017 May 22.
Public notes

Contacts
Principal investigator
Name 0 0
Bayer Study Director
Address 0 0
Bayer
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01234337