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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01103323
First received: April 8, 2010
Last updated: January 23, 2014
Last verified: January 2014
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

  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) Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Participant Flow:   Overall Study
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
STARTED     505     255  
Participants Received Treatment     500     253  
COMPLETED     386     232  
NOT COMPLETED     119     23  
Adverse Event                 42                 7  
Withdrawal by Subject                 16                 5  
Protocol Violation                 2                 0  
Physician Decision                 2                 0  
ongoing with treatment                 52                 9  
did not receive study treatment                 5                 2  



  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) Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Total Total of all reporting groups

Baseline Measures
    Regorafenib (Stivarga, BAY73-4506)     Placebo     Total  
Number of Participants  
[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 )  
Gender  
[units: Participants]
     
Female     194     102     296  
Male     311     153     464  
Eastern Cooperative Oncology Group (ECOG) performance status (PS) before treatment [2]
[units: Participants]
     
0     265     146     411  
1     240     109     349  
KRAS mutation [3]
[units: Participants]
     
No     205     94     299  
Yes     273     157     430  
Unknown     27     4     31  
[1] The age of the patient in years at enrollment in the study.
[2] 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
[3] KRAS - Kirsten rat sarcoma viral oncogene homolog (protein), member of the RAS family of GTPases (guanosine triphosphate hydrolases)



  Outcome Measures
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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 (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]
  Hide Outcome Measure 2

Measure Type Secondary
Measure Title Progression-free Survival (Based on Investigator’s Assessment)
Measure Description Progression-free survival was defined as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical) or death due to any cause, if death occurred before progression was documented.
Time Frame From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.  
Safety Issue No  

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.
ITT

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  505     255  
Progression-free Survival (Based on Investigator’s Assessment)  
[units: Days]
Median ( 95% Confidence Interval )
  59  
  ( 57 to 65 )  
  52  
  ( 51 to 53 )  


Statistical Analysis 1 for Progression-free Survival (Based on Investigator’s Assessment)
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.000001
Hazard Ratio (HR) [4] 0.494
95% Confidence Interval ( 0.419 to 0.582 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Two treatment groups compared using a stratified log-rank test, stratified by same stratification factors as randomization. Hazard ratio (Regorafenib / Placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Comparison based on pre-specified alpha level of 0.025 (1-sided).
[4] Other relevant estimation information:
  Hazard ratio (Regorafenib / Placebo)



3.  Secondary:   Objective Tumor Response   [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 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 (19May2012 - 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 (19May2012 - 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 No text entered.
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 (Stivarga, BAY73-4506) Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Other Adverse Events
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Total, other (not including serious) adverse events      
# participants affected / at risk     489/500     228/253  
Blood and lymphatic system disorders      
Edema: Limb * 1    
# participants affected / at risk     46/500 (9.20%)     16/253 (6.32%)  
# events     53     19  
Hemoglobin * 1    
# participants affected / at risk     70/500 (14.00%)     28/253 (11.07%)  
# events     127     45  
Platelets * 1    
# participants affected / at risk     77/500 (15.40%)     6/253 (2.37%)  
# events     125     9  
Cardiac disorders      
Hypertension * 1    
# participants affected / at risk     152/500 (30.40%)     20/253 (7.91%)  
# events     207     22  
Gastrointestinal disorders      
Anorexia * 1    
# participants affected / at risk     234/500 (46.80%)     72/253 (28.46%)  
# events     352     95  
Constipation * 1    
# participants affected / at risk     119/500 (23.80%)     48/253 (18.97%)  
# events     146     58  
Diarrhea * 1    
# participants affected / at risk     214/500 (42.80%)     44/253 (17.39%)  
# events     436     57  
Mucositis (Functional/Symptomatic), Oral Cavity * 1    
# participants affected / at risk     144/500 (28.80%)     12/253 (4.74%)  
# events     257     12  
Nausea * 1    
# participants affected / at risk     112/500 (22.40%)     55/253 (21.74%)  
# events     149     67  
Taste Alteration * 1    
# participants affected / at risk     37/500 (7.40%)     6/253 (2.37%)  
# events     40     6  
Vomiting * 1    
# participants affected / at risk     80/500 (16.00%)     41/253 (16.21%)  
# events     112     50  
General disorders      
Constitutional Symptoms - Other * 1    
# participants affected / at risk     29/500 (5.80%)     17/253 (6.72%)  
# events     36     19  
Fatigue * 1    
# participants affected / at risk     316/500 (63.20%)     116/253 (45.85%)  
# events     584     168  
Fever * 1    
# participants affected / at risk     133/500 (26.60%)     39/253 (15.42%)  
# events     183     47  
Flu-Like Syndrome * 1    
# participants affected / at risk     25/500 (5.00%)     6/253 (2.37%)  
# events     28     8  
Insomnia * 1    
# participants affected / at risk     39/500 (7.80%)     14/253 (5.53%)  
# events     43     15  
Pain, Abdomen NOS * 1    
# participants affected / at risk     118/500 (23.60%)     47/253 (18.58%)  
# events     194     53  
Pain, Back * 1    
# participants affected / at risk     74/500 (14.80%)     24/253 (9.49%)  
# events     107     26  
Pain, Extremity - Limb * 1    
# participants affected / at risk     47/500 (9.40%)     14/253 (5.53%)  
# events     77     19  
Pain, Head/Headache * 1    
# participants affected / at risk     50/500 (10.00%)     18/253 (7.11%)  
# events     63     23  
Pain, Joint * 1    
# participants affected / at risk     31/500 (6.20%)     13/253 (5.14%)  
# events     32     14  
Pain, Muscle * 1    
# participants affected / at risk     49/500 (9.80%)     14/253 (5.53%)  
# events     63     16  
Weight Loss * 1    
# participants affected / at risk     162/500 (32.40%)     28/253 (11.07%)  
# events     220     32  
Metabolism and nutrition disorders      
ALT * 1    
# participants affected / at risk     27/500 (5.40%)     5/253 (1.98%)  
# events     49     5  
AST * 1    
# participants affected / at risk     35/500 (7.00%)     9/253 (3.56%)  
# events     67     9  
Alkaline Phosphatase * 1    
# participants affected / at risk     32/500 (6.40%)     8/253 (3.16%)  
# events     44     12  
Bilirubin (Hyperbilirubinemia) * 1    
# participants affected / at risk     95/500 (19.00%)     22/253 (8.70%)  
# events     156     37  
Hypocalcemia * 1    
# participants affected / at risk     33/500 (6.60%)     1/253 (0.40%)  
# events     51     1  
Hypokalemia * 1    
# participants affected / at risk     46/500 (9.20%)     5/253 (1.98%)  
# events     58     6  
Hyponatremia * 1    
# participants affected / at risk     29/500 (5.80%)     6/253 (2.37%)  
# events     40     10  
Hypophosphatemia * 1    
# participants affected / at risk     32/500 (6.40%)     2/253 (0.79%)  
# events     55     3  
Lipase * 1    
# participants affected / at risk     31/500 (6.20%)     3/253 (1.19%)  
# events     70     4  
Metabolic/Lab - Other * 1    
# participants affected / at risk     37/500 (7.40%)     8/253 (3.16%)  
# events     60     14  
Proteinuria * 1    
# participants affected / at risk     40/500 (8.00%)     6/253 (2.37%)  
# events     89     11  
Nervous system disorders      
Dizziness * 1    
# participants affected / at risk     26/500 (5.20%)     13/253 (5.14%)  
# events     29     13  
Neuropathy: Sensory * 1    
# participants affected / at risk     50/500 (10.00%)     25/253 (9.88%)  
# events     66     27  
Respiratory, thoracic and mediastinal disorders      
Cough * 1    
# participants affected / at risk     55/500 (11.00%)     28/253 (11.07%)  
# events     76     32  
Dyspnea (Shortness Of Breath) * 1    
# participants affected / at risk     85/500 (17.00%)     33/253 (13.04%)  
# events     103     45  
Voice Changes * 1    
# participants affected / at risk     160/500 (32.00%)     16/253 (6.32%)  
# events     205     17  
Skin and subcutaneous tissue disorders      
Alopecia * 1    
# participants affected / at risk     39/500 (7.80%)     4/253 (1.58%)  
# events     43     4  
Dermatology - Other * 1    
# participants affected / at risk     29/500 (5.80%)     6/253 (2.37%)  
# events     43     8  
Dry Skin * 1    
# participants affected / at risk     50/500 (10.00%)     10/253 (3.95%)  
# events     59     11  
Hand-Foot Skin Reaction * 1    
# participants affected / at risk     234/500 (46.80%)     19/253 (7.51%)  
# events     685     21  
Pruritus * 1    
# participants affected / at risk     27/500 (5.40%)     11/253 (4.35%)  
# events     36     11  
Rash/Desquamation * 1    
# participants affected / at risk     142/500 (28.40%)     13/253 (5.14%)  
# events     207     17  
Vascular disorders      
Hemorrhage Pulmonary, Nose * 1    
# participants affected / at risk     45/500 (9.00%)     6/253 (2.37%)  
# events     54     6  
* Events were collected by non-systematic assessment
1 Term from vocabulary, NCI-CTCAE v.3.0



  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.


Limitations and Caveats
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.  


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


Publications of Results:

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01103323     History of Changes
Other Study ID Numbers: 14387, 2009-012787-14
Study First Received: April 8, 2010
Results First Received: October 19, 2012
Last Updated: January 23, 2014
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