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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:
ClinicalTrials.gov Identifier:
NCT01271712
First Posted: January 7, 2011
Last Update Posted: October 5, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Bayer
Results First Submitted: May 24, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, 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   91 [1]   58 [2] 
NOT COMPLETED   42   8 
Death                2                0 
Lack of Efficacy                1                0 
Adverse Event                9                4 
Progressive disease                23                3 
Withdrawal by Subject                4                1 
Non compliance with study drug                2                0 
receive no study drug                1                0 
[1] 91 participants started open-label treatment with regorafenib
[2] 58 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   91   58 
COMPLETED   0   0 
NOT COMPLETED   91   58 
Death                6                5 
Withdrawal by Subject                6                11 
Physician Decision                2                0 
Adverse Event                12                8 
Progressive disease                56                31 
Ongoing with open-label treatment                6                1 
Non-compliance with study drug                1                0 
Protocol Violation                0                1 
Switching to other therapy                2                1 

Period 3:   Safety Follow-up
    Regorafenib (Stivarga, BAY73-4506)   Placebo First, Then Option of Open Label Regorafenib Treatment
STARTED   118 [1]   52 [1] 
COMPLETED   97   37 
NOT COMPLETED   21   15 
Death                11                7 
Withdrawal by Subject                4                2 
Protocol Violation                1                1 
Ongoing safety follow-up                3                4 
No follow-up                1                1 
Progressive disease                1                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   100 [1]   39 [1] 
COMPLETED   85 [2]   33 [3] 
NOT COMPLETED   15   6 
Ongoing survival follow-up                15                6 
[1] All participants entered Survival Follow-up immediately after safety follow-up
[2] 85 participants died and completed survival follow-up.
[3] 33 participants died and completed survival follow-up.



  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 
Overall Participants Analyzed 
[Units: Participants]
 133   66   199 
Age 
[Units: Years]
Mean (Standard Deviation)
 58.2  (12.5)   58.1  (13.9)   58.2  (12.9) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      48  36.1%      24  36.4%      72  36.2% 
Male      85  63.9%      42  63.6%      127  63.8% 
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 
[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).
Prior anti-cancer drug group [1] 
[Units: Participants]
     
3rd line   74   39   113 
4th line and beyond   59   27   86 
[1] 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 (08 Jun 2015) ]
  Hide Outcome Measure 2

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. Median OS was not observed at the time of PFS analysis and first analysis of OS, therefore only the proportion of death events was reported in the results posting system. This approach was maintained for the subsequent updates in the results posting system.
Time Frame From randomization of the first subject until date of database cutoff (08 Jun 2015)  

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). 58 (87.9%) patients in placebo group and 91 (68.4%) patients in regorafenib had started open-label treatment with regorafenib before time of final database cutoff 08 Jun 2015

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 
Participants Analyzed 
[Units: Participants]
 133   66 
Overall Survival 
[Units: Percentage of patients with death]
 82.0   80.3 


Statistical Analysis 1 for Overall Survival
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.285777
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  stratified
[4] 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
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Regression, Cox
Hazard Ratio (HR) [4] 0.909
95% Confidence Interval 0.653 to 1.265
[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] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  stratified
[4] Other relevant estimation information:
  regorafenib over control. 58 (87.9%) patients in placebo group and 91 (68.4%) patients in regorafenib had started open-label treatment with regorafenib before time of final database cutoff 08 Jun 2015.



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 (08 Jun 2015).
Additional Description At primary completion (cutoff 26JAN2012) blinded patients who received either regorafenib or placebo were reported in “Regorafenib (DoubleBlindOnly)” and “Placebo (DoubleBlindOnly)” respectively; patients who received regorafenib after unblinding were reported in "Regorafenib, OpenLabelOnly(RegorafenibCont.)" and "Placebo, OpenLabelOnly(Switch to Regorafenib)". This safety update (cutoff 08JUN2015) was reported in “Treated with Regorafenib at any time” and “Treated with Regorafenib for>1 year”.

Reporting Groups
  Description
Regorafenib (Double Blind 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. Data cut-off date 26 JAN 2012.
Placebo (Double Blind 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. Data cut-off date 26 JAN 2012.
Placebo, Open Label Only (Switch to Regorafenib) 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. Data cut-off date 08 JUN 2015.
Treated With Regorafenib at Any Time Treated with Regorafenib at any time (including placebo switched to regorafenib): At any time, 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. Data cut-off date 08 JUN 2015.
Treated With Regorafenib for > 1 Year Treated with Regorafenib for > 1 year (including placebo switched to regorafenib): For more than a year, 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. Data cut-off date 08 JUN 2015.

Serious Adverse Events
    Regorafenib (Double Blind Only)   Placebo (Double Blind Only)   Placebo, Open Label Only (Switch to Regorafenib)   Treated With Regorafenib at Any Time   Treated With Regorafenib for > 1 Year
Total, Serious Adverse Events           
# participants affected / at risk   23/41 (56.10%)   8/8 (100.00%)   31/58 (53.45%)   103/190 (54.21%)   39/75 (52.00%) 
Blood and lymphatic system disorders           
Anemia * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   2/190 (1.05%)   0/75 (0.00%) 
# events   0   0   2   3   0 
Cardiac disorders           
Acute coronary syndrome * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   7/190 (3.68%)   6/75 (8.00%) 
# events   0   0   0   7   6 
Atrial fibrillation * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   1   1   1 
Cardiac arrest * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Chest pain - cardiac * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   2   2 
Conduction disorder * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Heart failure * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Cardiac disorders - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   0   1   0 
Congenital, familial and genetic disorders           
Congenital, familial and genetic disorders - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   0   1   0 
Ear and labyrinth disorders           
Vertigo * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   0   1   0 
Eye disorders           
Eye disorders - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   1   1   1 
Gastrointestinal disorders           
Abdominal pain * 1           
# participants affected / at risk   5/41 (12.20%)   0/8 (0.00%)   2/58 (3.45%)   9/190 (4.74%)   1/75 (1.33%) 
# events   5   0   2   10   1 
Anal fistula * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Ascites * 1           
# participants affected / at risk   3/41 (7.32%)   0/8 (0.00%)   0/58 (0.00%)   3/190 (1.58%)   0/75 (0.00%) 
# events   4   0   0   4   0 
Colonic fistula * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Colonic obstruction * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   2   2   0 
Colonic perforation * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   0   2   4   2 
Constipation * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   2/190 (1.05%)   2/75 (2.67%) 
# events   0   0   1   2   2 
Diarrhea * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   3/190 (1.58%)   2/75 (2.67%) 
# events   1   0   0   4   3 
Gastric hemorrhage * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   1/58 (1.72%)   2/190 (1.05%)   0/75 (0.00%) 
# events   1   0   1   2   0 
Intra-abdominal hemorrhage * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   3/190 (1.58%)   0/75 (0.00%) 
# events   1   0   0   3   0 
Ileus * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   1/58 (1.72%)   2/190 (1.05%)   0/75 (0.00%) 
# events   1   0   1   2   0 
Lower gastrointestinal hemorrhage * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Nausea * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   1/58 (1.72%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   1   1   2   1 
Obstruction gastric * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   0   1   0 
Gastrointestinal disorders - Other * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Peritoneal necrosis * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Retroperitoneal hemorrhage * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   0   1   0 
Small intestinal obstruction * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   2   2 
Upper gastrointestinal hemorrhage * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   0   1   0 
Vomiting * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   0   1   2   1 
General disorders           
Death NOS * 1           
# participants affected / at risk   1/41 (2.44%)   2/8 (25.00%)   1/58 (1.72%)   3/190 (1.58%)   2/75 (2.67%) 
# events   1   2   1   3   2 
Edema limbs * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   2   2   0 
Fatigue * 1           
# participants affected / at risk   2/41 (4.88%)   1/8 (12.50%)   2/58 (3.45%)   5/190 (2.63%)   2/75 (2.67%) 
# events   4   2   2   7   2 
Fever * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   2/58 (3.45%)   5/190 (2.63%)   2/75 (2.67%) 
# events   1   0   2   5   2 
Malaise * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Multi-organ failure * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   2/190 (1.05%)   0/75 (0.00%) 
# events   0   0   1   2   0 
Non-cardiac chest pain * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   0/58 (0.00%)   0/190 (0.00%)   0/75 (0.00%) 
# events   0   1   0   0   0 
General disorders and administration site conditions - Other * 1           
# participants affected / at risk   1/41 (2.44%)   1/8 (12.50%)   2/58 (3.45%)   5/190 (2.63%)   3/75 (4.00%) 
# events   1   1   3   6   3 
Pain * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   2/58 (3.45%)   3/190 (1.58%)   1/75 (1.33%) 
# events   1   0   3   4   1 
Hepatobiliary disorders           
Bile duct stenosis * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   0   1   2   1 
Cholecystitis * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Hepatic failure * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   1/58 (1.72%)   3/190 (1.58%)   0/75 (0.00%) 
# events   2   0   1   4   0 
Hepatic hemorrhage * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   0   0   3   1 
Hepatobiliary disorders - Other * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   1/58 (1.72%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   1   1   2   1 
Portal vein thrombosis * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   1   1   0 
Infections and infestations           
Abdominal infection * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   2/190 (1.05%)   0/75 (0.00%) 
# events   1   0   0   2   0 
Bronchial infection * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   0   0   3   2 
Catheter related infection * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   2   2   0 
Enterocolitis infectious * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   0   3   3   2 
Lung infection * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   0   1   2   1 
Infections and infestations - Other * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   4/58 (6.90%)   8/190 (4.21%)   3/75 (4.00%) 
# events   1   0   4   9   4 
Sepsis * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   3/190 (1.58%)   1/75 (1.33%) 
# events   0   0   2   3   1 
Upper respiratory infection * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   3/190 (1.58%)   3/75 (4.00%) 
# events   0   0   0   3   3 
Urinary tract infection * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Wound infection * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Injury, poisoning and procedural complications           
Fracture * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   3/190 (1.58%)   2/75 (2.67%) 
# events   0   0   2   4   3 
Hip fracture * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   1   1   1 
Investigations           
Alanine aminotransferase increased * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   3/190 (1.58%)   1/75 (1.33%) 
# events   0   0   2   6   3 
Aspartate aminotransferase increased * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   1   1   0 
Blood bilirubin increased * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   3/190 (1.58%)   1/75 (1.33%) 
# events   0   0   2   3   1 
Creatinine increased * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   2   0   0   2   0 
INR increased * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Neutrophil count decreased * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   1   1   0 
Investigations - Other * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   2/190 (1.05%)   0/75 (0.00%) 
# events   1   0   0   2   0 
Platelet count decreased * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   2   2   0 
Metabolism and nutrition disorders           
Acidosis * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Anorexia * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Dehydration * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   0/58 (0.00%)   3/190 (1.58%)   3/75 (4.00%) 
# events   0   1   0   3   3 
Hyperglycemia * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   0/58 (0.00%)   0/190 (0.00%)   0/75 (0.00%) 
# events   0   1   0   0   0 
Hyperkalemia * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   3   0   0   3   0 
Musculoskeletal and connective tissue disorders           
Back pain * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   0   2   2   1 
Generalized muscle weakness * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Musculoskeletal and connective tissue disorder - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   1   1   1 
Muscle weakness right-sided * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   3/58 (5.17%)   6/190 (3.16%)   3/75 (4.00%) 
# events   1   0   3   6   3 
Tumor pain * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   3/190 (1.58%)   1/75 (1.33%) 
# events   0   0   4   5   1 
Nervous system disorders           
Amnesia * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Hypoglossal nerve disorder * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Intracranial hemorrhage * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Nervous system disorders - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   2/190 (1.05%)   0/75 (0.00%) 
# events   0   0   2   2   0 
Paresthesia * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Reversible posterior leukoencephalopathy syndrome * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Somnolence * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Stroke * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   2/190 (1.05%)   2/75 (2.67%) 
# events   0   0   1   2   2 
Transient ischemic attacks * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Psychiatric disorders           
Confusion * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   1   1   1 
Mania * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   0/58 (0.00%)   0/190 (0.00%)   0/75 (0.00%) 
# events   0   4   0   0   0 
Psychiatric disorders - Other * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Renal and urinary disorders           
Acute kidney injury * 1           
# participants affected / at risk   2/41 (4.88%)   0/8 (0.00%)   1/58 (1.72%)   3/190 (1.58%)   0/75 (0.00%) 
# events   2   0   2   4   0 
Renal and urinary disorders - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   3/190 (1.58%)   1/75 (1.33%) 
# events   0   0   0   4   2 
Renal colic * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Urinary retention * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   2/190 (1.05%)   1/75 (1.33%) 
# events   1   0   0   2   1 
Respiratory, thoracic and mediastinal disorders           
Adult respiratory distress syndrome * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   0   1   0 
Dyspnea * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   2/190 (1.05%)   0/75 (0.00%) 
# events   1   0   0   2   0 
Pleural effusion * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Pneumonitis * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Respiratory failure * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Skin and subcutaneous tissue disorders           
Rash maculo-papular * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   1   1   1 
Surgical and medical procedures           
Surgical and medical procedures - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   4/190 (2.11%)   2/75 (2.67%) 
# events   0   0   1   4   2 
Vascular disorders           
Hypertension * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   1   0   0   1   0 
Vascular disorders - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   0/75 (0.00%) 
# events   0   0   0   1   0 
Peripheral ischemia * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   0/58 (0.00%)   1/190 (0.53%)   1/75 (1.33%) 
# events   0   0   0   1   1 
Thromboembolic event * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   1/58 (1.72%)   4/190 (2.11%)   0/75 (0.00%) 
# events   1   0   2   5   0 
* Events were collected by non-systematic assessment
1 Term from vocabulary, NCI-CTCAE (4.0)




  Other Adverse Events


  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.


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