Phase III Trial Comparing Capecitabine in Combination With Sorafenib or Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Onyx Therapeutics, Inc.
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01234337
First received: October 4, 2010
Last updated: May 6, 2016
Last verified: May 2016
Results First Received: May 10, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Breast Cancer
Interventions: Drug: Sorafenib(Nexavar, BAY43-9006)
Drug: Placebo
Drug: Capecitabine

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
At 154 sites in 22 countries, participants with histologically or cytologically confirmed human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the breast, and locally advanced or metastatic disease, were screened.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of 707 participants screened, 537 participants were randomized and 527 participants received at least 1 dose of study treatment. The reasons for 170 screen failures were adverse event in 21 participants, disease progression, recurrence or relapse in 2, consent withdrawn in 16, death in 4, and protocol violation in 127 participants.

Reporting Groups
  Description
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 + 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.

Participant Flow:   Overall Study
    Sorafenib(Nexavar, BAY43-9006) + Capecitabine     Placebo + Capecitabine  
STARTED     266     271  
Participants Received Treatment     260     267  
COMPLETED     169     207  
NOT COMPLETED     97     64  
Adverse Event                 55                 20  
Ongoing                 16                 24  
InvestigatorDecision notProtocolDriven                 4                 3  
Non-compliant with study medication                 3                 2  
Randomized but not Treated                 6                 4  
Lost to Follow-up                 0                 1  
Protocol Violation                 2                 3  
Withdrawal by Subject                 11                 7  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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 + 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.
Total Total of all reporting groups

Baseline Measures
    Sorafenib(Nexavar, BAY43-9006) + Capecitabine     Placebo + Capecitabine     Total  
Number of Participants  
[units: participants]
  266     271     537  
Age  
[units: years]
Mean (Standard Deviation)
  53.3  (10.2)     54.4  (10.9)     53.9  (10.6)  
Gender  
[units: Participants]
     
Female     265     268     533  
Male     1     3     4  
Race/Ethnicity, Customized  
[units: Participants]
     
White     205     212     417  
Black     7     4     11  
Asian     50     50     100  
Hispanic     4     5     9  
Region of Enrollment [1]
[units: Participants]
     
Europe     166     168     334  
North America     23     26     49  
Other     77     77     154  
Eastern Cooperative Oncology Group (ECOG) [2]
[units: Participants]
     
ECOG status=0     152     161     313  
ECOG status=1     114     110     224  
ECOG status=2     0     0     0  
ECOG status=3     0     0     0  
ECOG status=4     0     0     0  
Number of Prior Chemotherapies for Metastatic Disease [3]
[units: Participants]
     
Prior chemotherapies=0     114     118     232  
Prior chemotherapies=1     152     153     305  
Hormone Receptor Status [4]
[units: Participants]
     
Negative     83     84     167  
Positive     183     187     370  
Visceral Disease at Baseline  
[units: Participants]
     
Missing     1     1     2  
No     66     57     123  
Yes     199     213     412  
[1] Other countries in the below category included Argentina, Australia, China, Israel and Japan.
[2] ECOG status 0=Fully active, able to carry on all pre-disease performance without restriction; 1=Restricted in physically strenuous activity but ambulatory, able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2=Ambulatory, capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
[3] Assessed by Interactive voice response system (IVRS). Participants with more than 1 actual number of prior chemotherapies were combined with participants with 1 prior chemotherapy.
[4] The hormone receptor status was assessed by IVRS, and considered as follows: in case, the tumor expressed estrogen and/or progesterone receptor, the participant was considered to have positive hormone receptor status. Otherwise, if both receptors were not expressed, then participant was considered to have a negative hormone receptor status.



  Outcome Measures
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1.  Primary:   Progression-free Survival (PFS) Assessed by the Independent Review Panel According to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1   [ Time Frame: From randomization of the first participant until approximately 3 years or until disease radiological progression ]

2.  Secondary:   Overall Survival (OS)   [ Time Frame: From randomization of the first participant until approximately 3 years later ]

3.  Secondary:   Time to Progression (TTP) by Central Review   [ Time Frame: From randomization of the first participant until approximately 3 years later or until disease radiological progression ]

4.  Secondary:   Objective Response Rate (ORR) by Central Review   [ Time Frame: From randomization of the first participant until approximately 3 years later or until disease radiological progression ]

5.  Secondary:   Disease Control Rate (DCR) by Central Review   [ Time Frame: From randomization of the first participant until approximately 3 years later or until disease radiological progression ]

6.  Secondary:   Duration of Response (DOR) by Central Reader   [ Time Frame: From randomization of the first participant until approximately 3 years later or until disease radiological progression ]

7.  Other Pre-specified:   Patient Reported Outcomes: Functional Assessment of Cancer Therapy-Breast Symptom Index (8 Item) (FBSI-8)   [ Time Frame: 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) ]

8.  Other Pre-specified:   Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score   [ Time Frame: 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) ]

9.  Other Pre-specified:   Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score   [ Time Frame: 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) ]

10.  Other Pre-specified:   Maximum Observed Drug Concentration (Cmax) of Capecitabine and 5-fluorouracil   [ Time Frame: Pre-dose and 0.5, 1, 2, and 4 hours after capecitabine dosing at Cycle 2, Day 14 ]

11.  Other Pre-specified:   Area Under Curve From Time Zero to Last Quantifiable Concentration (AUC[0-tlast]) of Capecitabine and 5-fluorouracil   [ Time Frame: Pre-dose and 0.5, 1, 2, and 4 hours after capecitabine dosing at Cycle 2, Day 14 ]

12.  Other Pre-specified:   Number of Participants With Treatment-emergent Grade 3 and 4 Laboratory Abnormalities   [ Time Frame: From the start of study treatment up to 30 days after the last dose ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Results of exploratory analysis of biomarkers are anticipated in the month of February, 2016.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Therapeutic Area Head
Organization: BAYER
e-mail: clinical-trials-contact@bayerhealthcare.com


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01234337     History of Changes
Other Study ID Numbers: 12444
2010-018501-10 ( EudraCT Number )
Study First Received: October 4, 2010
Results First Received: May 10, 2015
Last Updated: May 6, 2016
Health Authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Australia: Department of Health and Ageing Therapeutic Goods Administration
Austria : Federal Ministry for Labour, Health, and Social Affairs
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Brazil: Ministry of Health
Canada: Health Canada
Chile: Comisión Nacional de Investigación Científica y Tecnológica
China: Ministry of Health
Czech Republic: State Institute for Drug Control
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Greece: Ministry of Health and Welfare
Hungary: National Institute of Pharmacy
Ireland: Irish Medicines Board
Israel: Israeli Health Ministry Pharmaceutical Administration
Italy: National Monitoring Centre for Clinical Trials - Ministry of Health
Japan: Ministry of Health, Labor and Welfare
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: Ministry of Health of the Russian Federation
South Africa: Medicines Control Council
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration