Study of Regorafenib as a 3rd-line or Beyond Treatment for Gastrointestinal Stromal Tumors (GIST) (GRID)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01271712
First received: December 17, 2010
Last updated: February 19, 2014
Last verified: February 2014
Results First Received: May 24, 2013  
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: Gastrointestinal Stromal Tumors
Interventions: Drug: Regorafenib (Stivarga, BAY73-4506)
Drug: Placebo
Drug: Best supportive care

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
A total of 240 participants with metastatic and/or unresectable GIST whose disease had progressed despite prior treatments with at least imatinib and sunitinib were screened; 199 were randomized. Patients must have shown objective disease progression or intolerance to imatinib, as well as disease progression while on sunitinib treatment.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants were randomized in a 2:1 ratio to receive either regorafenib (133 patients) or placebo (66 patients). Randomization was stratified according 3rd vs. 4th line of therapy (at least 50% of patients were to be 3rd line), and geographical region (Asia vs.rest of world).

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo First, Then Option of Open Label Regorafenib Treatment Double blind phase: participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks. Open Label phase: participants on placebo who switched to Regorafenib, received Regorafenib 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks.

Participant Flow for 4 periods

Period 1:   Double Blind Treatment
    Regorafenib (Stivarga, BAY73-4506)     Placebo First, Then Option of Open Label Regorafenib Treatment  
STARTED     133     66  
Participants Received Treatment     132     66  
COMPLETED     41 [1]   56 [2]
NOT COMPLETED     92     10  
Death                 2                 0  
Lack of Efficacy                 1                 0  
Adverse Event                 8                 4  
Progressive disease                 21                 3  
Withdrawal by Subject                 4                 0  
Non compliance with study drug                 2                 0  
Ongoing in double-blind treatment                 53                 3  
receive no study drug                 1                 0  
[1] 41 participants started open-label treatment with regorafenib
[2] 56 participants started open-label treatment with regorafenib

Period 2:   Open Label Treatment
    Regorafenib (Stivarga, BAY73-4506)     Placebo First, Then Option of Open Label Regorafenib Treatment  
STARTED     41     56  
Participants Received Treatment     41     56  
COMPLETED     0     0  
NOT COMPLETED     41     56  
Death                 1                 1  
Withdrawal by Subject                 0                 5  
Physician Decision                 2                 0  
Adverse Event                 2                 4  
Progressive disease                 12                 13  
Ongoing with open-label treatment                 24                 33  

Period 3:   Safety Follow-up
    Regorafenib (Stivarga, BAY73-4506)     Placebo First, Then Option of Open Label Regorafenib Treatment  
STARTED     36 [1]   7 [1]
COMPLETED     27     4  
NOT COMPLETED     9     3  
Death                 4                 2  
Withdrawal by Subject                 1                 1  
Protocol Violation                 1                 0  
Ongoing with open-label treatment                 3                 0  
[1] All participants who discontinued study drug entered 30-day Safety Follow-up

Period 4:   Survival Follow-up
    Regorafenib (Stivarga, BAY73-4506)     Placebo First, Then Option of Open Label Regorafenib Treatment  
STARTED     27 [1]   4 [1]
COMPLETED     0     0  
NOT COMPLETED     27     4  
Death                 13                 3  
Ongoing with open-label treatment                 14                 1  
[1] All participants entered Survival Follow-up 30 days after discontinuation of study drug



  Baseline Characteristics
  Hide Baseline Characteristics

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 (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Total Total of all reporting groups

Baseline Measures
    Regorafenib (Stivarga, BAY73-4506)     Placebo     Total  
Number of Participants  
[units: participants]
  133     66     199  
Age  
[units: Years]
Mean ± Standard Deviation
  58.2  ± 12.5     58.1  ± 13.9     58.2  ± 12.9  
Gender  
[units: Participants]
     
Female     48     24     72  
Male     85     42     127  
ECOG Performance Status (PS)] [1]
[units: Participants]
     
PS 0     73     37     110  
PS 1     60     29     89  
PS 2     0     0     0  
Missing     0     0     0  
Prior anti-cancer drug group [2]
[units: Participants]
     
3rd line     74     39     113  
4th line and beyond     59     27     86  
[1] ECOG = Eastern cooperative oncology group PS levels are 0 (Fully active, able to carry on all pre-disease performance), 1 (ambulatory and able to carry out work of a light or sedentary), 2 (Ambulatory and capable of all selfcare but unable to carry out any work activities), 3 (Capable of only limited selfcare, confined to bed or chair more than 50% of awake time), 4 (Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair) and 5 (death).
[2] 3rd line: 3rd in sequence of multiple therapies: imatinib (1st); sunitinib (2nd). 4th line and beyond: 4th in sequence of multiple therapies: imatinib (1st); sunitinib (2nd); other (3rd).



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Progression-free Survival   [ Time Frame: From randomization of the first subject until approximately 144 progression-free survival events had occurred (study duration approximately one year) ]

Measure Type Primary
Measure Title Progression-free Survival
Measure Description Progression-free Survival (PFS) was defined as the time from date of randomization to radiological disease progression or death due to any cause, whichever occurs first. PFS was based on central radiological assessment using modified RECIST (Response Evaluation Criteria in Solid Tumors) v.1.1. Progression is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study; or unequivocal progression of existing non-target lesions; or appearance of new lesions. Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation. Results are based on central evaluation.
Time Frame From randomization of the first subject until approximately 144 progression-free survival events had occurred (study duration approximately one year)  
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.
Full Analysis Set (FAS) - defined as all randomized participants.

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  133     66  
Progression-free Survival  
[units: Days]
Median ( 95% Confidence Interval )
  147  
  ( 122 to 173 )  
  28  
  ( 28 to 32 )  


Statistical Analysis 1 for Progression-free Survival
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.000001
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The two treatment groups were compared using a stratified log rank test with a one-sided alpha of 0.01 stratified by (3rd vs 4th-line; and geographical region). The null hypothesis that both treatment arms have the same PFS distribution was tested against the alternative hypothesis that the distribution of PFS in the regorafenib arm is different from the control arm according to a proportional hazards relation between the treatment arms.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  stratified
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.

Statistical Analysis 2 for Progression-free Survival
Groups [1] All groups
Method [2] Regression, Cox
Hazard Ratio (HR) [3] 0.268
95% Confidence Interval ( 0.185 to 0.388 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Hazard ratio and its 95% CI (Confidence Interval) was based on stratified Cox Regression Model
[2] Other relevant method information, such as adjustments or degrees of freedom:
  stratified
[3] Other relevant estimation information:
  regorafenib over placebo



2.  Secondary:   Overall Survival   [ Time Frame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately one year ]

Measure Type Secondary
Measure Title Overall Survival
Measure Description Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their date of last contact. Since the median value could not be estimated due to censored data, the number of participants with events is presented.
Time Frame From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately one year  
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.
Full Analysis Set (FAS)

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  133     66  
Overall Survival  
[units: Percentage of participants]
  21.8     25.8  


Statistical Analysis 1 for Overall Survival
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.198896
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  stratified
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.

Statistical Analysis 2 for Overall Survival
Groups [1] All groups
Method [2] Regression, Cox
Hazard Ratio (HR) [3] 0.772
95% Confidence Interval ( 0.423 to 1.408 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Hazard ratio and its 95% CI was based on stratified Cox Regression Model
[2] Other relevant method information, such as adjustments or degrees of freedom:
  stratified
[3] Other relevant estimation information:
  regorafenib over control



3.  Secondary:   Time to Progression (TTP)   [ Time Frame: From randomization of the first subject until until date of database cutoff (26 Jan 2012); study duration approximately 1 year ]

Measure Type Secondary
Measure Title Time to Progression (TTP)
Measure Description Time to progression (TTP) was defined as the time from date of randomization to disease progression (based on central radiological assessment using modified RECIST [Response Evaluation Criteria in Solid Tumors] v.1.1). Progression is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study; or unequivocal progression of existing non-target lesions; or appearance of new lesions. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation. Results are based on central evaluation.
Time Frame From randomization of the first subject until until date of database cutoff (26 Jan 2012); study duration approximately 1 year  
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.
Full Analysis Set (FAS)

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  133     66  
Time to Progression (TTP)  
[units: Days]
Median ( 95% Confidence Interval )
  165  
  ( 125 to 174 )  
  28  
  ( 28 to 34 )  


Statistical Analysis 1 for Time to Progression (TTP)
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.000001
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  stratified
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.

Statistical Analysis 2 for Time to Progression (TTP)
Groups [1] All groups
Method [2] Regression, Cox
Hazard Ratio (HR) [3] 0.248
95% Confidence Interval ( 0.170 to 0.364 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  stratified
[3] Other relevant estimation information:
  No text entered.



4.  Secondary:   Tumor Response   [ Time Frame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year ]

Measure Type Secondary
Measure Title Tumor Response
Measure Description Tumor Response of a subject was defined as the best tumor response (Complete Response [CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).], Partial Response [PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.], Stable Disease [SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.], or Progressive Disease [PD: at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study or unequivocal progression of existing non-target lesions, or appearance of new lesions.]) observed during the trial period and assessed according to RECIST v1.1 criteria. Results are based on central evaluation.
Time Frame From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year  
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.
Full Analysis Set (FAS)

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  133     66  
Tumor Response  
[units: Percentage of Participants]
Number ( 95% Confidence Interval )
   
Complete Response (CR)     0  
  ( 0 to 0 )  
  0  
  ( 0 to 0 )  
Partial Response (PR)     4.5  
  ( 1.7 to 9.6 )  
  1.5  
  ( 0 to 8.2 )  
Stable Disease (SD)     71.4  
  ( 63.0 to 78.9 )  
  33.3  
  ( 22.2 to 46.0 )  
Progressive Disease (PD)     21.1  
  ( 14.5 to 29.0 )  
  63.6  
  ( 50.9 to 75.1 )  
Not Assessable     3.0  
  ( 0.8 to 7.5 )  
  1.5  
  ( 0 to 8.2 )  

No statistical analysis provided for Tumor Response



5.  Secondary:   Objective Response Rate   [ Time Frame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year. ]

Measure Type Secondary
Measure Title Objective Response Rate
Measure Description Objective response rate was defined as the percentage of subjects whose best response was Complete Response (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Results are based on central evaluation.
Time Frame From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year.  
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.
Full Analysis Set (FAS)

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  133     66  
Objective Response Rate  
[units: Percentage of Participants]
Number ( 95% Confidence Interval )
  4.5  
  ( 1.7 to 9.6 )  
  1.5  
  ( 0.0 to 8.2 )  

No statistical analysis provided for Objective Response Rate



6.  Secondary:   Disease Control Rate (DCR)   [ Time Frame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year ]

Measure Type Secondary
Measure Title Disease Control Rate (DCR)
Measure Description Disease Control Rate (DCR) was defined as the percentage of subjects whose best response was Complete Response (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).), Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.), or Stable Disease (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to RECIST v1.1 criteria. SD had to be maintained for at least 12 weeks from the first demonstration of that rating. Results are based on central evaluation.
Time Frame From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year  
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.
Full Analysis Set (FAS)

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  133     66  
Disease Control Rate (DCR)  
[units: Percentage of Participants]
Number ( 95% Confidence Interval )
  52.6  
  ( 43.8 to 61.3 )  
  9.1  
  ( 3.4 to 18.7 )  

No statistical analysis provided for Disease Control Rate (DCR)



7.  Secondary:   Duration of Response (DOR)   [ Time Frame: From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year ]

Measure Type Secondary
Measure Title Duration of Response (DOR)
Measure Description Duration of Response was defined as the time from date of first response (Complete Response [CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).] or Partial Response [PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.]) to the date when Progressive Disease (PD: at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study or unequivocal progression of existing non-target lesions, or appearance of new lesions.) is first documented, or to the date of death, whichever occurs first, according to RECIST v1.1. Subjects still having CR or PR and have not died at the time of analysis were censored at their last date of tumor evaluation. Duration of response defined for responders only, i.e CR or PR. Results are based on central evaluation.
Time Frame From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year  
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.
Full Analysis Set with response participants

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  6     1  
Duration of Response (DOR)  
[units: Days]
Median ( 95% Confidence Interval )
  99  
  ( 42 to NA ) [1]
  30  
  ( NA to NA ) [2]
[1] A complete confidence interval (CI) cannot be calculated because there are too few patients in the data set.
[2] CI cannot be calculated because there is only 1 patient in the data set.

No statistical analysis provided for Duration of Response (DOR)




  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame From randomization of the first subject until date of database cutoff (26 Jan 2012).
Additional Description Acronyms used: International Normalized Ratio (INR).

Reporting Groups
  Description
Regorafenib (Double Blind Only) Regorafenib (Double Blind study phase only): Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo ( Double Blind Only) Placebo (Double Blind study phase only): Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Regorafenib, Open Label Only (Regorafenib Continued) Continue Regorafenib (Open Label study phase only): Participants continue to receive Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Placebo, Open Label Only (Switch to Regorafenib) Switch to Regorafenib (Open Label study phase only): Participants switched to Open label Regorafenib treatment from Placebo. Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks

Serious Adverse Events
    Regorafenib (Double Blind Only)     Placebo ( Double Blind Only)     Regorafenib, Open Label Only (Regorafenib Continued)     Placebo, Open Label Only (Switch to Regorafenib)  
Total, serious adverse events          
# participants affected / at risk     38/132 (28.79%)     14/66 (21.21%)     9/41 (21.95%)     20/56 (35.71%)  
Blood and lymphatic system disorders          
Anemia * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Cardiac disorders          
Acute coronary syndrome * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Cardiac arrest * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Cardiac disorders - Other * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Ear and labyrinth disorders          
Vertigo * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     1/41 (2.44%)     0/56 (0.00%)  
Gastrointestinal disorders          
Abdominal pain * 1        
# participants affected / at risk     5/132 (3.79%)     1/66 (1.52%)     0/41 (0.00%)     1/56 (1.79%)  
Ascites * 1        
# participants affected / at risk     3/132 (2.27%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Colonic fistula * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Colonic obstruction * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Colonic perforation * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Constipation * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Diarrhea * 1        
# participants affected / at risk     2/132 (1.52%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Gastric hemorrhage * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Intra-abdominal hemorrhage * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     1/41 (2.44%)     0/56 (0.00%)  
Ileus * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Lower gastrointestinal hemorrhage * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Nausea * 1        
# participants affected / at risk     1/132 (0.76%)     1/66 (1.52%)     0/41 (0.00%)     1/56 (1.79%)  
Obstruction gastric * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     1/41 (2.44%)     0/56 (0.00%)  
Gastrointestinal disorders - Other * 1        
# participants affected / at risk     1/132 (0.76%)     1/66 (1.52%)     0/41 (0.00%)     0/56 (0.00%)  
Peritoneal necrosis * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Retroperitoneal hemorrhage * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Upper gastrointestinal hemorrhage * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Vomiting * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
General disorders          
Death NOS * 1        
# participants affected / at risk     1/132 (0.76%)     2/66 (3.03%)     0/41 (0.00%)     0/56 (0.00%)  
Fatigue * 1        
# participants affected / at risk     2/132 (1.52%)     2/66 (3.03%)     0/41 (0.00%)     2/56 (3.57%)  
Fever * 1        
# participants affected / at risk     3/132 (2.27%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Malaise * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Multi-organ failure * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Non-cardiac chest pain * 1        
# participants affected / at risk     0/132 (0.00%)     1/66 (1.52%)     0/41 (0.00%)     0/56 (0.00%)  
General disorders and administration site conditions - Other * 1        
# participants affected / at risk     1/132 (0.76%)     1/66 (1.52%)     0/41 (0.00%)     1/56 (1.79%)  
Pain * 1        
# participants affected / at risk     1/132 (0.76%)     2/66 (3.03%)     0/41 (0.00%)     1/56 (1.79%)  
Hepatobiliary disorders          
Bile duct stenosis * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Cholecystitis * 1        
# participants affected / at risk     0/132 (0.00%)     1/66 (1.52%)     0/41 (0.00%)     0/56 (0.00%)  
Hepatic failure * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     1/41 (2.44%)     0/56 (0.00%)  
Hepatic hemorrhage * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     1/41 (2.44%)     0/56 (0.00%)  
Hepatobiliary disorders - Other * 1        
# participants affected / at risk     1/132 (0.76%)     1/66 (1.52%)     0/41 (0.00%)     0/56 (0.00%)  
Portal vein thrombosis * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Infections and infestations          
Abdominal infection * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Catheter related infection * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Enterocolitis infectious * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     2/56 (3.57%)  
Lung infection * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Infections and infestations - Other * 1        
# participants affected / at risk     2/132 (1.52%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Sepsis * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     1/41 (2.44%)     0/56 (0.00%)  
Upper respiratory infection * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Urinary tract infection * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Wound infection * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Investigations          
Alanine aminotransferase increased * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     2/56 (3.57%)  
Aspartate aminotransferase increased * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Blood bilirubin increased * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     1/41 (2.44%)     1/56 (1.79%)  
Creatinine increased * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
INR increased * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Neutrophil count decreased * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Investigations - Other * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Platelet count decreased * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Metabolism and nutrition disorders          
Acidosis * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Dehydration * 1        
# participants affected / at risk     3/132 (2.27%)     1/66 (1.52%)     0/41 (0.00%)     0/56 (0.00%)  
Hyperglycemia * 1        
# participants affected / at risk     0/132 (0.00%)     1/66 (1.52%)     0/41 (0.00%)     0/56 (0.00%)  
Hyperkalemia * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Musculoskeletal and connective tissue disorders          
Back pain * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     2/56 (3.57%)  
Generalized muscle weakness * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Muscle weakness right-sided * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)          
Tumor pain * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     2/56 (3.57%)  
Nervous system disorders          
Hypoglossal nerve disorder * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Nervous system disorders - Other * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Paresthesia * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Reversible posterior leukoencephalopathy syndrome * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Somnolence * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Psychiatric disorders          
Confusion * 1        
# participants affected / at risk     0/132 (0.00%)     1/66 (1.52%)     0/41 (0.00%)     0/56 (0.00%)  
Mania * 1        
# participants affected / at risk     0/132 (0.00%)     1/66 (1.52%)     0/41 (0.00%)     0/56 (0.00%)  
Psychiatric disorders - Other * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Renal and urinary disorders          
Acute kidney injury * 1        
# participants affected / at risk     2/132 (1.52%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Renal and urinary disorders - Other * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Respiratory, thoracic and mediastinal disorders          
Adult respiratory distress syndrome * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     1/41 (2.44%)     0/56 (0.00%)  
Dyspnea * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Pneumonitis * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Skin and subcutaneous tissue disorders          
Rash maculo-papular * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Surgical and medical procedures          
Surgical and medical procedures - Other * 1        
# participants affected / at risk     0/132 (0.00%)     0/66 (0.00%)     2/41 (4.88%)     0/56 (0.00%)  
Vascular disorders          
Hypertension * 1        
# participants affected / at risk     1/132 (0.76%)     0/66 (0.00%)     0/41 (0.00%)     0/56 (0.00%)  
Thromboembolic event * 1        
# participants affected / at risk     2/132 (1.52%)     0/66 (0.00%)     1/41 (2.44%)     1/56 (1.79%)  
* Events were collected by non-systematic assessment
1 Term from vocabulary, NCI-CTCAE v.4.0




  Other Adverse Events


  More Information
  Hide More Information

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 Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.


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
Overall survival results are confounded by the fact that 85% of the participants initially randomized to placebo switched to open-label regorafenib.  


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:

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01271712     History of Changes
Other Study ID Numbers: 14874, 2009-017957-37
Study First Received: December 17, 2010
Results First Received: May 24, 2013
Last Updated: February 19, 2014
Health Authority: United States: Food and Drug Administration
Austria:AGES-PharmMed LCM
Belgium:Agence Fédérale des Médicaments et des Produits de Santé
Canada: Health Canada
China: Food and Drug Administration
Finland: Finnish Medicines Agency
France: Agence française de sécurité sanitaire des produits de santé (Afssaps)
Germany: Federal Institute for Drugs and Medical Devices
Israel: Ministry of Health
Italy: Agenzia Italiana del Farmaco
Japan: Pharmaceuticals and Medical Devices Agency
Netherlands: College ter Beoordeling van Geneesmiddelen Medicines Evaluation Board
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Singapore: Health Sciences Authority
South Korea: Korea Food and Drug Administration
Spain: Agencia Española de Medicamentos y Productos Sanitarios
United Kingdom: Medicines and Healthcare Products Regulatory Agency