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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: May 20, 2014
Last verified: May 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
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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
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
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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 (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
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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) ]
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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 ]
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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 ]

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 ]

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. ]

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 ]

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 ]


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


  More Information