Phase III Trial Comparing Capecitabine in Combination With Sorafenib or Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer
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
2 other identifiers
interventional
537
22 countries
151
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 Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3 breast-cancer
Started Feb 2011
Typical duration for phase_3 breast-cancer
151 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
October 4, 2010
CompletedFirst Posted
Study publicly available on registry
November 4, 2010
CompletedStudy Start
First participant enrolled
February 21, 2011
CompletedPrimary Completion
Last participant's last visit for primary outcome
May 12, 2014
CompletedResults Posted
Study results publicly available
September 3, 2015
CompletedStudy Completion
Last participant's last visit for all outcomes
October 20, 2017
CompletedNovember 6, 2018
October 1, 2018
3.2 years
October 4, 2010
May 10, 2015
October 8, 2018
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Progression-free Survival (PFS) Assessed by the Independent Review Panel According to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1
PFS was defined as the time from date of randomization to disease progression, radiological or death due to any cause, whichever occurs first. Per RECIST version 1.1, progressive disease was determined when there was at least 20% increase in the sum of diameters of the target lesions, taking as a reference the smallest sum on study (this included the baseline sum if that was the smallest sum on trial). In addition to a relative increase of 20%, the sum had demonstrated an absolute increase of at least 5 mm. Appearance of new lesions and unequivocal progression of existing non-target lesions was also interpreted as progressive disease. Participants without progression or death at the time of analysis were censored at their last date of evaluable tumor evaluation. Median and other 95% confidence intervals (CIs) computed using Kaplan-Meier estimates.
From randomization of the first participant until approximately 3 years or until disease radiological progression
Secondary Outcomes (5)
Overall Survival (OS)
From randomization of the first participant until approximately 3 years later
Time to Progression (TTP) by Central Review
From randomization of the first participant until approximately 3 years later or until disease radiological progression
Objective Response Rate (ORR) by Central Review
From randomization of the first participant until approximately 3 years later or until disease radiological progression
Disease Control Rate (DCR) by Central Review
From randomization of the first participant until approximately 3 years later or until disease radiological progression
Duration of Response (DOR) by Central Reader
From randomization of the first participant until approximately 3 years later or until disease radiological progression
Other Outcomes (6)
Patient Reported Outcomes: Functional Assessment of Cancer Therapy-Breast Symptom Index (8 Item) (FBSI-8)
Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 16, 19, 22, 25, 28, 31, 34, 37, and end of treatment (EOT, 21 days after last dose of study drug)
Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score
Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 16, 19, 22, 25, 28, and EOT (21 days after last dose of study drug)
Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score
Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 16, 19, 22, 25, 28, and EOT (21 days after last dose of study drug)
- +3 more other outcomes
Study Arms (2)
Sorafenib (Nexavar, BAY43-9006) + Capecitabine
EXPERIMENTALCapecitabine 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 + Capecitabine
PLACEBO COMPARATORCapecitabine 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.
Interventions
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.
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.
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,
Eligibility Criteria
You may qualify if:
- 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
- +3 more criteria
You may not qualify if:
- 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
- +7 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Bayerlead
- Onyx Therapeutics, Inc.collaborator
Study Sites (153)
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Greenbrae, California, 94904-2007, United States
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Sylmar, California, 91342, United States
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West Palm Beach, Florida, 33407, United States
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Joliet, Illinois, 60435, United States
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Evansville, Indiana, 47713, United States
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Louisville, Kentucky, 40207, United States
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Boston, Massachusetts, 02114, United States
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Boston, Massachusetts, 02115-6084, United States
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Jackson, Mississippi, 39202, United States
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Springfield, Missouri, 65804, United States
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Albuquerque, New Mexico, 87131, United States
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Lake Success, New York, 11042, United States
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Durham, North Carolina, 27710, United States
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Philadelphia, Pennsylvania, 19104, United States
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Bristol, Tennessee, 37620, United States
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Memphis, Tennessee, 38120, United States
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El Paso, Texas, 79905, United States
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Burlington, Vermont, 05405, United States
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Madison, Wisconsin, 53792, United States
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Mar del Plata, Buenos Aires, B7600CTO, Argentina
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Buenos Aires, Ciudad Auton. de Buenos Aires, C1280AEB, Argentina
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Buenos Aires, Ciudad Auton. de Buenos Aires, C1425AWC, Argentina
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Garran, Australian Capital Territory, 2605, Australia
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Liverpool, New South Wales, 2170, Australia
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Waratah, New South Wales, 2298, Australia
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Adelaide, South Australia, 5000, Australia
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Bendigo, Victoria, 3550, Australia
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Frankston, Victoria, Australia
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Perth, Western Australia, 6000, Australia
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Linz, Upper Austria, 4010, Austria
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Vienna, 1100, Austria
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Liège, Liège, 4000, Belgium
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Bruges, 8000, Belgium
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Bruxelles - Brussel, 1000, Belgium
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Edegem, 2650, Belgium
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Hasselt, 3500, Belgium
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Montreal, Quebec, H2L 4M1, Canada
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Montreal, Quebec, H3G 1A4, Canada
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Shenyang, Liaoning, 110001, China
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Beijing, 100021, China
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Beijing, 100071, China
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Nanning, 530021, China
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Shanghai, 200030, China
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Tianjin, 300060, China
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Xi'an, 710032, China
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České Budějovice, 370 01, Czechia
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Nová Ves pod Pleší, 262 04, Czechia
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Nymburk, 288 02, Czechia
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Olomouc, 775 20, Czechia
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Prague, 10034, Czechia
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Prague, 128 08, Czechia
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Prague, 150 06, Czechia
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Prague, 150 30, Czechia
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Clermont-Ferrand, 63011, France
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Lille, 59020, France
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Nantes, 44805, France
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Saint-Cloud, 92210, France
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Toulouse, 31052, France
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Erlangen, Bavaria, 91054, Germany
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Frankfurt am Main, Hesse, 60389, Germany
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Offenbach, Hesse, 63069, Germany
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Cologne, North Rhine-Westphalia, 50931, Germany
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Cologne, North Rhine-Westphalia, 51067, Germany
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Mainz, Rhineland-Palatinate, 55131, Germany
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Leipzig, Saxony, 04103, Germany
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Stendal, Saxony-Anhalt, 39576, Germany
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Berlin, 13589, Germany
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Athens, 11528, Greece
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Heraklion, 711 10, Greece
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Ioannina, 45500, Greece
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Larissa, 41100, Greece
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Pátrai, 26500, Greece
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Budapest, 1032, Hungary
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Nyíregyháza, H-4400, Hungary
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Pécs, 7624, Hungary
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Szentes, 6600, Hungary
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Szolnok, H-5004, Hungary
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Cork, Ireland
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Dublin, 7, Ireland
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Dublin, 9, Ireland
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Dublin, DUBLIN 4, Ireland
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Dublin, DUBLIN 8, Ireland
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Galway, Ireland
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Beersheba, 8410101, Israel
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Haifa, 3109601, Israel
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Haifa, 35152, Israel
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Jerusalem, 9112001, Israel
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Jerusalem, 9372212, Israel
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Petah Tikva, 4941492, Israel
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Ramat Gan, 5266202, Israel
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Bologna, Emilia-Romagna, 40138, Italy
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Forlì-Cesena, Emilia-Romagna, 47014, Italy
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Modena, Emilia-Romagna, 41124, Italy
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Ravenna, Emilia-Romagna, 48121, Italy
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Rome, Lazio, 00161, Italy
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Cremona, Lombardy, 26100, Italy
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Milan, Lombardy, 20089, Italy
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Monza-Brianza, Lombardy, 20900, Italy
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Palermo, Sicily, 90127, Italy
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Ancona, The Marches, 60126, Italy
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Pisa, Tuscany, 56126, Italy
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Nagoya, Aichi-ken, 464-8681, Japan
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Matsuyama, Ehime, 791-0280, Japan
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Suita, Osaka, 565-0871, Japan
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Hidaka, Saitama, 350-1298, Japan
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Kita-Adachigun, Saitama, 362-0806, Japan
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Bunkyo, Tokyo, 113-8677, Japan
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Koto-ku, Tokyo, 135-8550, Japan
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Chiba, 260-8717, Japan
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Fukuoka, 811-1395, Japan
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Kagoshima, 892-0833, Japan
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Osaka, 540-0006, Japan
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Gdansk, 80-952, Poland
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Gdynia, 81-519, Poland
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Poznan, 61-485, Poland
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San Juan, 00918, Puerto Rico
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Chelyabinsk, 454087, Russia
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Kazan', 420029, Russia
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Port Elizabeth, Eastern Cape, 6045, South Africa
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Johannesburg, Gauteng, 2196, South Africa
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Pretoria, Gauteng, 0081, South Africa
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Pretoria, Gauteng, 0084, South Africa
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Pretoria, Gauteng, 0181, South Africa
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Santiago de Compostela, A Coruña, 15706, Spain
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Sabadell, Barcelona, 08208, Spain
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Terrassa, Barcelona, 08221, Spain
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Castellon, Castellón, 12002, Spain
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Palma de Mallorca, Illes Baleares, 07120, Spain
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Reus, Tarragona, 43204, Spain
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A Coruña, 15006, Spain
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Barcelona, 08003, Spain
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Barcelona, 08025, Spain
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Barcelona, 08035, Spain
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Barcelona, 08036, Spain
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Lleida, 25198, Spain
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Madrid, 28033, Spain
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Madrid, 28034, Spain
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Madrid, 28040, Spain
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Madrid, 28041, Spain
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Madrid, 28050, Spain
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Palma de Mallorca, 07198, Spain
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Seville, 41013, Spain
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Seville, 41071, Spain
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Valencia, 46009, Spain
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Valencia, 46010, Spain
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Valencia, 46014, Spain
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Stockholm, 118 83, Sweden
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Stockholm, 171 76, Sweden
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Truro, Cornwall, TR1 3LJ, United Kingdom
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Nottingham, Nottinghamshire, NG5 1PB, United Kingdom
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London, NW3 2QG, United Kingdom
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Manchester, M20 4BX, United Kingdom
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Northwood, HA6 2RN, United Kingdom
Related Publications (2)
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.
PMID: 23876062RESULTBaselga 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.
PMID: 28830796RESULT
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Limitations and Caveats
Results of exploratory analysis of biomarkers are anticipated in the month of February, 2016.
Results Point of Contact
- Title
- Therapeutic Area Head
- Organization
- BAYER
Study Officials
- STUDY DIRECTOR
Bayer Study Director
Bayer
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
October 4, 2010
First Posted
November 4, 2010
Study Start
February 21, 2011
Primary Completion
May 12, 2014
Study Completion
October 20, 2017
Last Updated
November 6, 2018
Results First Posted
September 3, 2015
Record last verified: 2018-10