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


  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
  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
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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 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