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Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01103323
First received: April 8, 2010
Last updated: May 28, 2015
Last verified: May 2015
Results First Received: October 19, 2012  
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: Metastatic Colorectal Cancer
Interventions: Drug: Regorafenib (Stivarga, BAY73-4506)
Drug: Placebo
Other: Best Supportive Care (BSC)

  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
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506)+BSC Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Placebo+BSC Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). Period 1 is placebo and placebo-regorafenib with placebo period only before unblinding. Period 2 is placebo-regorafenib with regorafenib period only.

Participant Flow for 2 periods

Period 1:   Without/Before Drug Switch
    Regorafenib (Stivarga, BAY73-4506)+BSC   Placebo+BSC
STARTED   505   255 
Participants Received Treatment   500   253 
COMPLETED   429   237 
NOT COMPLETED   76   18 
Adverse Event                50                7 
Withdrawal by Subject                17                5 
Protocol Violation                2                0 
Physician Decision                2                0 
did not receive study treatment                5                2 
Switch to Regorafenib                0                4 

Period 2:   Switched From Placebo to Regorafenib
    Regorafenib (Stivarga, BAY73-4506)+BSC   Placebo+BSC
STARTED   0   4 [1] 
COMPLETED   0   3 
NOT COMPLETED   0   1 
Adverse Event                0                1 
[1] Participants in the placebo+BSC group switched to Regorafenib treatment after unblinding.



  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
Regorafenib (Stivarga, BAY73-4506)+BSC Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Placebo+BSC Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Total Total of all reporting groups

Baseline Measures
   Regorafenib (Stivarga, BAY73-4506)+BSC   Placebo+BSC   Total 
Overall Participants Analyzed 
[Units: Participants]
 505   255   760 
Age [1] 
[Units: Years]
Mean (Full Range)
 60.7 
 (22 to 82) 
 60.1 
 (25 to 85) 
 60.5 
 (22 to 85) 
[1] The age of the patient in years at enrollment in the study.
Gender 
[Units: Participants]
     
Female   194   102   296 
Male   311   153   464 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) before treatment [1] 
[Units: Participants]
     
 265   146   411 
 240   109   349 
[1] ECOG PS is a scale that measures how cancer affects the daily life of a patient on an ordinal scale from grade 0 (best) to grade 5 (worst). 0=Fully active without restriction; 1= Restricted in physically strenuous activity; 2= Ambulatory, capable of all selfcare; 3= Capable of limited selfcare; 4= Completely disabled; 5= Dead
KRAS mutation [1] 
[Units: Participants]
     
No   205   94   299 
Yes   273   157   430 
Unknown   27   4   31 
[1] KRAS - Kirsten rat sarcoma viral oncogene homolog (protein), member of the RAS family of GTPases (guanosine triphosphate hydrolases)


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Overall Survival   [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis (IA). ]

2.  Secondary:   Progression-free Survival (Based on Investigator’s Assessment)   [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

3.  Secondary:   Objective Tumor Response   [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

4.  Secondary:   Disease Control   [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

5.  Secondary:   Tumor Response   [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]


  Serious Adverse Events


  Other Adverse Events
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Time Frame AE was collected up to 30 days after end of study treatment (per protocol) over a period of approximately 3.7 years.
Additional Description Disseminated Intravascular Coagulation (DIC), International Normalized Ratio (INR), Cardiac Troponin T (cTnT), Gastroihntestina (GI), Not Otherwise Specified (NOS), Aspartate Aminotransferase (AST), Genitourinary (GU), Alanine Aminotransferase (ALT), Acute Respiratory Distress Syndrome (ARDS), Absolute Neutrophil Count (ANC)

Frequency Threshold
Threshold above which other adverse events are reported   5  

Reporting Groups
  Description
Regorafenib (BAY73-4506)+BSC Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Placebo+BSC Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). It is for placebo period only before unblinding.
Placebo - Regorafenib After Unblinding Participants in the placebo+BSC group switched to treatment with Regorafenib after unblinding. It is for Regorafenib treatment period only

Other Adverse Events
    Regorafenib (BAY73-4506)+BSC   Placebo+BSC   Placebo - Regorafenib After Unblinding
Total, other (not including serious) adverse events       
# participants affected / at risk   489/500 (97.80%)   229/253 (90.51%)   4/4 (100.00%) 
Blood and lymphatic system disorders       
Edema: Limb * 1       
# participants affected / at risk   49/500 (9.80%)   16/253 (6.32%)   0/4 (0.00%) 
# events   57   19   0 
Hemoglobin * 1       
# participants affected / at risk   76/500 (15.20%)   29/253 (11.46%)   0/4 (0.00%) 
# events   142   46   0 
Platelets * 1       
# participants affected / at risk   79/500 (15.80%)   6/253 (2.37%)   1/4 (25.00%) 
# events   136   9   2 
Cardiac disorders       
Hypertension * 1       
# participants affected / at risk   155/500 (31.00%)   21/253 (8.30%)   1/4 (25.00%) 
# events   213   23   1 
Endocrine disorders       
Hypothyroidism * 1       
# participants affected / at risk   27/500 (5.40%)   1/253 (0.40%)   1/4 (25.00%) 
# events   29   1   1 
Eye disorders       
Ocular - Other * 1       
# participants affected / at risk   5/500 (1.00%)   0/253 (0.00%)   1/4 (25.00%) 
# events   5   0   1 
Gastrointestinal disorders       
Anorexia * 1       
# participants affected / at risk   239/500 (47.80%)   73/253 (28.85%)   0/4 (0.00%) 
# events   388   96   0 
Ascites * 1       
# participants affected / at risk   23/500 (4.60%)   6/253 (2.37%)   1/4 (25.00%) 
# events   24   8   1 
Constipation * 1       
# participants affected / at risk   119/500 (23.80%)   48/253 (18.97%)   0/4 (0.00%) 
# events   147   58   0 
Diarrhea * 1       
# participants affected / at risk   218/500 (43.60%)   44/253 (17.39%)   2/4 (50.00%) 
# events   514   57   2 
Fistula, GI, Colon/Cecum/Appendix * 1       
# participants affected / at risk   0/500 (0.00%)   0/253 (0.00%)   1/4 (25.00%) 
# events   0   0   1 
Mucositis (functional/symptomatic), Oral cavity * 1       
# participants affected / at risk   145/500 (29.00%)   12/253 (4.74%)   0/4 (0.00%) 
# events   267   12   0 
Nausea * 1       
# participants affected / at risk   115/500 (23.00%)   55/253 (21.74%)   1/4 (25.00%) 
# events   162   67   1 
Taste alteration * 1       
# participants affected / at risk   39/500 (7.80%)   6/253 (2.37%)   0/4 (0.00%) 
# events   44   6   0 
Vomiting * 1       
# participants affected / at risk   85/500 (17.00%)   41/253 (16.21%)   1/4 (25.00%) 
# events   144   50   3 
General disorders       
Constitutional symptoms - Other * 1       
# participants affected / at risk   30/500 (6.00%)   17/253 (6.72%)   0/4 (0.00%) 
# events   33   19   0 
Fatigue * 1       
# participants affected / at risk   318/500 (63.60%)   115/253 (45.45%)   0/4 (0.00%) 
# events   612   168   0 
Fever * 1       
# participants affected / at risk   136/500 (27.20%)   40/253 (15.81%)   2/4 (50.00%) 
# events   189   48   3 
Flu-like syndrome * 1       
# participants affected / at risk   27/500 (5.40%)   6/253 (2.37%)   1/4 (25.00%) 
# events   30   8   1 
Insomnia * 1       
# participants affected / at risk   39/500 (7.80%)   14/253 (5.53%)   0/4 (0.00%) 
# events   43   15   0 
Pain, Abdomen NOS * 1       
# participants affected / at risk   121/500 (24.20%)   47/253 (18.58%)   0/4 (0.00%) 
# events   239   53   0 
Pain, Back * 1       
# participants affected / at risk   79/500 (15.80%)   25/253 (9.88%)   0/4 (0.00%) 
# events   114   27   0 
Pain, Buttock * 1       
# participants affected / at risk   4/500 (0.80%)   0/253 (0.00%)   1/4 (25.00%) 
# events   5   0   1 
Pain, Chest/Thorax NOS * 1       
# participants affected / at risk   26/500 (5.20%)   12/253 (4.74%)   0/4 (0.00%) 
# events   29   14   0 
Pain, Extremity - limb * 1       
# participants affected / at risk   51/500 (10.20%)   14/253 (5.53%)   0/4 (0.00%) 
# events   83   19   0 
Pain, Head/Headache * 1       
# participants affected / at risk   50/500 (10.00%)   18/253 (7.11%)   0/4 (0.00%) 
# events   65   23   0 
Pain, Joint * 1       
# participants affected / at risk   32/500 (6.40%)   13/253 (5.14%)   0/4 (0.00%) 
# events   34   14   0 
Pain, Muscle * 1       
# participants affected / at risk   50/500 (10.00%)   14/253 (5.53%)   0/4 (0.00%) 
# events   64   16   0 
Pain, Throat/Pharynx/Larynx * 1       
# participants affected / at risk   9/500 (1.80%)   1/253 (0.40%)   1/4 (25.00%) 
# events   12   1   1 
Weight loss * 1       
# participants affected / at risk   167/500 (33.40%)   30/253 (11.86%)   2/4 (50.00%) 
# events   240   34   7 
Hepatobiliary disorders       
Hepatobiliary - Other * 1       
# participants affected / at risk   8/500 (1.60%)   4/253 (1.58%)   1/4 (25.00%) 
# events   9   4   3 
Metabolism and nutrition disorders       
ALT * 1       
# participants affected / at risk   28/500 (5.60%)   7/253 (2.77%)   0/4 (0.00%) 
# events   53   8   0 
AST * 1       
# participants affected / at risk   37/500 (7.40%)   12/253 (4.74%)   0/4 (0.00%) 
# events   72   13   0 
Alkaline phosphatase * 1       
# participants affected / at risk   35/500 (7.00%)   8/253 (3.16%)   0/4 (0.00%) 
# events   49   12   0 
Bilirubin (Hyperbilirubinemia) * 1       
# participants affected / at risk   97/500 (19.40%)   22/253 (8.70%)   1/4 (25.00%) 
# events   160   37   3 
Creatinine * 1       
# participants affected / at risk   15/500 (3.00%)   7/253 (2.77%)   1/4 (25.00%) 
# events   19   8   2 
GFR * 1       
# participants affected / at risk   4/500 (0.80%)   1/253 (0.40%)   1/4 (25.00%) 
# events   9   2   1 
Hyperuricemia * 1       
# participants affected / at risk   12/500 (2.40%)   1/253 (0.40%)   1/4 (25.00%) 
# events   13   1   1 
Hypocalcemia * 1       
# participants affected / at risk   34/500 (6.80%)   1/253 (0.40%)   0/4 (0.00%) 
# events   57   1   0 
Hypokalemia * 1       
# participants affected / at risk   50/500 (10.00%)   6/253 (2.37%)   0/4 (0.00%) 
# events   84   7   0 
Hyponatremia * 1       
# participants affected / at risk   32/500 (6.40%)   6/253 (2.37%)   0/4 (0.00%) 
# events   43   10   0 
Hypophosphatemia * 1       
# participants affected / at risk   32/500 (6.40%)   2/253 (0.79%)   1/4 (25.00%) 
# events   62   3   2 
Lipase * 1       
# participants affected / at risk   32/500 (6.40%)   3/253 (1.19%)   0/4 (0.00%) 
# events   74   4   0 
Metabolic/Lab - Other * 1       
# participants affected / at risk   42/500 (8.40%)   8/253 (3.16%)   0/4 (0.00%) 
# events   69   15   0 
Proteinuria * 1       
# participants affected / at risk   40/500 (8.00%)   6/253 (2.37%)   0/4 (0.00%) 
# events   109   11   0 
Nervous system disorders       
Dizziness * 1       
# participants affected / at risk   28/500 (5.60%)   13/253 (5.14%)   0/4 (0.00%) 
# events   31   13   0 
Neuropathy: sensory * 1       
# participants affected / at risk   51/500 (10.20%)   25/253 (9.88%)   0/4 (0.00%) 
# events   68   27   0 
Respiratory, thoracic and mediastinal disorders       
Cough * 1       
# participants affected / at risk   56/500 (11.20%)   28/253 (11.07%)   1/4 (25.00%) 
# events   77   32   1 
Dyspnea (Shortness of breath) * 1       
# participants affected / at risk   89/500 (17.80%)   34/253 (13.44%)   0/4 (0.00%) 
# events   110   46   0 
Voice changes * 1       
# participants affected / at risk   160/500 (32.00%)   16/253 (6.32%)   1/4 (25.00%) 
# events   211   17   1 
Skin and subcutaneous tissue disorders       
Alopecia * 1       
# participants affected / at risk   39/500 (7.80%)   4/253 (1.58%)   0/4 (0.00%) 
# events   43   4   0 
Cheilitis * 1       
# participants affected / at risk   4/500 (0.80%)   0/253 (0.00%)   1/4 (25.00%) 
# events   4   0   3 
Dermatology - Other * 1       
# participants affected / at risk   30/500 (6.00%)   7/253 (2.77%)   0/4 (0.00%) 
# events   45   10   0 
Dry skin * 1       
# participants affected / at risk   50/500 (10.00%)   10/253 (3.95%)   0/4 (0.00%) 
# events   59   11   0 
Hand-foot skin reaction * 1       
# participants affected / at risk   235/500 (47.00%)   19/253 (7.51%)   1/4 (25.00%) 
# events   720   21   3 
Pruritus * 1       
# participants affected / at risk   29/500 (5.80%)   11/253 (4.35%)   0/4 (0.00%) 
# events   39   11   0 
Rash/Desquamation * 1       
# participants affected / at risk   145/500 (29.00%)   13/253 (5.14%)   1/4 (25.00%) 
# events   211   17   2 
Vascular disorders       
Hemorrhage pulmonary, Nose * 1       
# participants affected / at risk   45/500 (9.00%)   6/253 (2.37%)   0/4 (0.00%) 
# events   55   6   0 
* Events were collected by non-systematic assessment
1 Term from vocabulary, NCI-CTCAE v.3.0



  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
At 2nd IA, pre-specified O’Brien-Fleming-type efficacy boundary was crossed. DMC concluded OS result positive and after positive risk benefit assessment, recommended unblinding of study. OS from 2nd IA are the final formal and definitive results.


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

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01103323     History of Changes
Other Study ID Numbers: 14387
2009-012787-14 ( EudraCT Number )
Study First Received: April 8, 2010
Results First Received: October 19, 2012
Last Updated: May 28, 2015
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: National Institute of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Czech Republic: State Institute for Drug Control
Hungary: National Institute of Pharmacy
Australia: Department of Health and Ageing Therapeutic Goods Administration
China: Food and Drug Administration
Japan: Pharmaceuticals and Medical Devices Agency
Brazil: National Health Surveillance Agency
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Switzerland: Swissmedic
Canada: Health Canada
Spain: Spanish Agency of Medicines
Portugal: National Pharmacy and Medicines Institute
Turkey: Ministry of Health
Israel: Ministry of Health
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Belgium: Federal Agency for Medicinal Products and Health Products
United States: Food and Drug Administration