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
  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
  Show 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) ]

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 ]

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
  Hide Other 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).

Frequency Threshold
Threshold above which other adverse events are reported   5%  

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

Other Adverse Events
    Regorafenib (Double Blind Only)     Placebo ( Double Blind Only)     Regorafenib, Open Label Only (Regorafenib Continued)     Placebo, Open Label Only (Switch to Regorafenib)  
Total, other (not including serious) adverse events          
# participants affected / at risk     131/132     60/66     31/41     55/56  
Blood and lymphatic system disorders          
Anemia * 1        
# participants affected / at risk     14/132 (10.61%)     4/66 (6.06%)     2/41 (4.88%)     7/56 (12.50%)  
Endocrine disorders          
Hypothyroidism * 1        
# participants affected / at risk     19/132 (14.39%)     2/66 (3.03%)     2/41 (4.88%)     4/56 (7.14%)  
Gastrointestinal disorders          
Abdominal pain * 1        
# participants affected / at risk     33/132 (25.00%)     10/66 (15.15%)     6/41 (14.63%)     11/56 (19.64%)  
Constipation * 1        
# participants affected / at risk     36/132 (27.27%)     15/66 (22.73%)     7/41 (17.07%)     12/56 (21.43%)  
Diarrhea * 1        
# participants affected / at risk     60/132 (45.45%)     6/66 (9.09%)     8/41 (19.51%)     15/56 (26.79%)  
Dyspepsia * 1        
# participants affected / at risk     7/132 (5.30%)     2/66 (3.03%)     2/41 (4.88%)     2/56 (3.57%)  
Dry mouth * 1        
# participants affected / at risk     8/132 (6.06%)     3/66 (4.55%)     0/41 (0.00%)     3/56 (5.36%)  
Mucositis oral * 1        
# participants affected / at risk     54/132 (40.91%)     5/66 (7.58%)     2/41 (4.88%)     17/56 (30.36%)  
Nausea * 1        
# participants affected / at risk     26/132 (19.70%)     8/66 (12.12%)     6/41 (14.63%)     13/56 (23.21%)  
Gastrointestinal disorders - Other * 1        
# participants affected / at risk     8/132 (6.06%)     3/66 (4.55%)     0/41 (0.00%)     1/56 (1.79%)  
Vomiting * 1        
# participants affected / at risk     22/132 (16.67%)     5/66 (7.58%)     4/41 (9.76%)     3/56 (5.36%)  
General disorders          
Edema limbs * 1        
# participants affected / at risk     6/132 (4.55%)     7/66 (10.61%)     3/41 (7.32%)     8/56 (14.29%)  
Fatigue * 1        
# participants affected / at risk     66/132 (50.00%)     25/66 (37.88%)     5/41 (12.20%)     22/56 (39.29%)  
Fever * 1        
# participants affected / at risk     28/132 (21.21%)     7/66 (10.61%)     3/41 (7.32%)     9/56 (16.07%)  
Flu like symptoms * 1        
# participants affected / at risk     7/132 (5.30%)     1/66 (1.52%)     2/41 (4.88%)     1/56 (1.79%)  
Pain * 1        
# participants affected / at risk     20/132 (15.15%)     13/66 (19.70%)     3/41 (7.32%)     11/56 (19.64%)  
Infections and infestations          
Infections and infestations - Other * 1        
# participants affected / at risk     8/132 (6.06%)     0/66 (0.00%)     3/41 (7.32%)     2/56 (3.57%)  
Rash pustular * 1        
# participants affected / at risk     9/132 (6.82%)     0/66 (0.00%)     0/41 (0.00%)     2/56 (3.57%)  
Upper respiratory infection * 1        
# participants affected / at risk     12/132 (9.09%)     0/66 (0.00%)     1/41 (2.44%)     4/56 (7.14%)  
Urinary tract infection * 1        
# participants affected / at risk     7/132 (5.30%)     2/66 (3.03%)     2/41 (4.88%)     1/56 (1.79%)  
Investigations          
Alanine aminotransferase increased * 1        
# participants affected / at risk     9/132 (6.82%)     1/66 (1.52%)     4/41 (9.76%)     5/56 (8.93%)  
Alkaline phosphatase increased * 1        
# participants affected / at risk     6/132 (4.55%)     3/66 (4.55%)     3/41 (7.32%)     2/56 (3.57%)  
Aspartate aminotransferase increased * 1        
# participants affected / at risk     12/132 (9.09%)     3/66 (4.55%)     5/41 (12.20%)     8/56 (14.29%)  
Blood bilirubin increased * 1        
# participants affected / at risk     13/132 (9.85%)     2/66 (3.03%)     2/41 (4.88%)     7/56 (12.50%)  
Neutrophil count decreased * 1        
# participants affected / at risk     6/132 (4.55%)     3/66 (4.55%)     2/41 (4.88%)     4/56 (7.14%)  
Investigations - Other * 1        
# participants affected / at risk     6/132 (4.55%)     3/66 (4.55%)     3/41 (7.32%)     1/56 (1.79%)  
Platelet count decreased * 1        
# participants affected / at risk     8/132 (6.06%)     0/66 (0.00%)     0/41 (0.00%)     3/56 (5.36%)  
Weight loss * 1        
# participants affected / at risk     18/132 (13.64%)     5/66 (7.58%)     2/41 (4.88%)     5/56 (8.93%)  
Metabolism and nutrition disorders          
Anorexia * 1        
# participants affected / at risk     40/132 (30.30%)     14/66 (21.21%)     5/41 (12.20%)     13/56 (23.21%)  
Hypoalbuminemia * 1        
# participants affected / at risk     6/132 (4.55%)     0/66 (0.00%)     1/41 (2.44%)     3/56 (5.36%)  
Hypokalemia * 1        
# participants affected / at risk     5/132 (3.79%)     2/66 (3.03%)     0/41 (0.00%)     7/56 (12.50%)  
Hyponatremia * 1        
# participants affected / at risk     4/132 (3.03%)     3/66 (4.55%)     0/41 (0.00%)     3/56 (5.36%)  
Hypophosphatemia * 1        
# participants affected / at risk     7/132 (5.30%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Hyperglycemia * 1        
# participants affected / at risk     5/132 (3.79%)     4/66 (6.06%)     1/41 (2.44%)     3/56 (5.36%)  
Musculoskeletal and connective tissue disorders          
Back pain * 1        
# participants affected / at risk     12/132 (9.09%)     3/66 (4.55%)     2/41 (4.88%)     1/56 (1.79%)  
Myalgia * 1        
# participants affected / at risk     21/132 (15.91%)     8/66 (12.12%)     3/41 (7.32%)     9/56 (16.07%)  
Pain in extremity * 1        
# participants affected / at risk     14/132 (10.61%)     3/66 (4.55%)     1/41 (2.44%)     3/56 (5.36%)  
Nervous system disorders          
Dysgeusia * 1        
# participants affected / at risk     11/132 (8.33%)     2/66 (3.03%)     0/41 (0.00%)     3/56 (5.36%)  
Headache * 1        
# participants affected / at risk     20/132 (15.15%)     6/66 (9.09%)     2/41 (4.88%)     8/56 (14.29%)  
Peripheral sensory neuropathy * 1        
# participants affected / at risk     8/132 (6.06%)     1/66 (1.52%)     1/41 (2.44%)     2/56 (3.57%)  
Renal and urinary disorders          
Proteinuria * 1        
# participants affected / at risk     10/132 (7.58%)     1/66 (1.52%)     8/41 (19.51%)     5/56 (8.93%)  
Respiratory, thoracic and mediastinal disorders          
Cough * 1        
# participants affected / at risk     11/132 (8.33%)     6/66 (9.09%)     1/41 (2.44%)     8/56 (14.29%)  
Dyspnea * 1        
# participants affected / at risk     8/132 (6.06%)     3/66 (4.55%)     2/41 (4.88%)     4/56 (7.14%)  
Epistaxis * 1        
# participants affected / at risk     3/132 (2.27%)     0/66 (0.00%)     2/41 (4.88%)     3/56 (5.36%)  
Hoarseness * 1        
# participants affected / at risk     32/132 (24.24%)     4/66 (6.06%)     2/41 (4.88%)     9/56 (16.07%)  
Voice alteration * 1        
# participants affected / at risk     16/132 (12.12%)     2/66 (3.03%)     0/41 (0.00%)     8/56 (14.29%)  
Skin and subcutaneous tissue disorders          
Alopecia * 1        
# participants affected / at risk     32/132 (24.24%)     1/66 (1.52%)     5/41 (12.20%)     16/56 (28.57%)  
Dry skin * 1        
# participants affected / at risk     8/132 (6.06%)     0/66 (0.00%)     1/41 (2.44%)     1/56 (1.79%)  
Erythema multiforme * 1        
# participants affected / at risk     7/132 (5.30%)     1/66 (1.52%)     0/41 (0.00%)     1/56 (1.79%)  
Erythroderma * 1        
# participants affected / at risk     5/132 (3.79%)     0/66 (0.00%)     0/41 (0.00%)     3/56 (5.36%)  
Skin and subcutaneous tissue disorders - Other * 1        
# participants affected / at risk     11/132 (8.33%)     1/66 (1.52%)     3/41 (7.32%)     5/56 (8.93%)  
Pain of skin * 1        
# participants affected / at risk     8/132 (6.06%)     1/66 (1.52%)     0/41 (0.00%)     1/56 (1.79%)  
Palmar-plantar erythrodysesthesia syndrome * 1        
# participants affected / at risk     75/132 (56.82%)     9/66 (13.64%)     12/41 (29.27%)     33/56 (58.93%)  
Pruritus * 1        
# participants affected / at risk     11/132 (8.33%)     8/66 (12.12%)     2/41 (4.88%)     4/56 (7.14%)  
Rash acneiform * 1        
# participants affected / at risk     7/132 (5.30%)     0/66 (0.00%)     0/41 (0.00%)     1/56 (1.79%)  
Rash maculo-papular * 1        
# participants affected / at risk     24/132 (18.18%)     2/66 (3.03%)     3/41 (7.32%)     6/56 (10.71%)  
Vascular disorders          
Hypertension * 1        
# participants affected / at risk     77/132 (58.33%)     18/66 (27.27%)     9/41 (21.95%)     29/56 (51.79%)  
* Events were collected by non-systematic assessment
1 Term from vocabulary, NCI-CTCAE v.4.0



  Limitations and Caveats
  Hide 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.


  More Information