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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: December 12, 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
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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 
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) ]

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 ]
  Hide Outcome Measure 4

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  

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 
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. ]

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 (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”.

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

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.

Other 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, Other (not including serious) Adverse Events           
# participants affected / at risk   40/41 (97.56%)   7/8 (87.50%)   58/58 (100.00%)   189/190 (99.47%)   75/75 (100.00%) 
Blood and lymphatic system disorders           
Anemia * 1           
# participants affected / at risk   4/41 (9.76%)   0/8 (0.00%)   11/58 (18.97%)   32/190 (16.84%)   14/75 (18.67%) 
# events   7   0   25   72   30 
Blood and lymphatic system disorders - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   6/190 (3.16%)   4/75 (5.33%) 
# events   0   0   9   17   9 
Ear and labyrinth disorders           
Hearing impaired * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   1/58 (1.72%)   7/190 (3.68%)   5/75 (6.67%) 
# events   1   0   1   7   5 
Ear and labyrinth disorders - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   4/58 (6.90%)   7/190 (3.68%)   4/75 (5.33%) 
# events   0   0   4   7   4 
Endocrine disorders           
Hypothyroidism * 1           
# participants affected / at risk   4/41 (9.76%)   0/8 (0.00%)   6/58 (10.34%)   37/190 (19.47%)   23/75 (30.67%) 
# events   4   0   6   48   30 
Eye disorders           
Blurred vision * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   6/190 (3.16%)   6/75 (8.00%) 
# events   0   0   2   6   6 
Eye disorders - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   6/190 (3.16%)   4/75 (5.33%) 
# events   0   0   1   6   4 
Gastrointestinal disorders           
Abdominal pain * 1           
# participants affected / at risk   14/41 (34.15%)   0/8 (0.00%)   16/58 (27.59%)   61/190 (32.11%)   25/75 (33.33%) 
# events   18   0   23   118   56 
Ascites * 1           
# participants affected / at risk   2/41 (4.88%)   1/8 (12.50%)   2/58 (3.45%)   6/190 (3.16%)   1/75 (1.33%) 
# events   2   1   2   8   3 
Bloating * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   7/190 (3.68%)   6/75 (8.00%) 
# events   0   0   1   10   9 
Constipation * 1           
# participants affected / at risk   10/41 (24.39%)   5/8 (62.50%)   16/58 (27.59%)   63/190 (33.16%)   28/75 (37.33%) 
# events   14   6   30   100   51 
Diarrhea * 1           
# participants affected / at risk   15/41 (36.59%)   1/8 (12.50%)   24/58 (41.38%)   96/190 (50.53%)   53/75 (70.67%) 
# events   20   1   66   350   278 
Dyspepsia * 1           
# participants affected / at risk   4/41 (9.76%)   1/8 (12.50%)   6/58 (10.34%)   19/190 (10.00%)   11/75 (14.67%) 
# events   4   2   9   38   29 
Dry mouth * 1           
# participants affected / at risk   5/41 (12.20%)   0/8 (0.00%)   5/58 (8.62%)   15/190 (7.89%)   5/75 (6.67%) 
# events   5   0   6   16   6 
Flatulence * 1           
# participants affected / at risk   4/41 (9.76%)   0/8 (0.00%)   3/58 (5.17%)   10/190 (5.26%)   5/75 (6.67%) 
# events   4   0   3   11   6 
Mucositis oral * 1           
# participants affected / at risk   14/41 (34.15%)   2/8 (25.00%)   21/58 (36.21%)   81/190 (42.63%)   38/75 (50.67%) 
# events   18   3   48   174   111 
Nausea * 1           
# participants affected / at risk   9/41 (21.95%)   3/8 (37.50%)   18/58 (31.03%)   61/190 (32.11%)   32/75 (42.67%) 
# events   12   4   32   109   65 
Gastrointestinal disorders - Other * 1           
# participants affected / at risk   4/41 (9.76%)   0/8 (0.00%)   4/58 (6.90%)   16/190 (8.42%)   10/75 (13.33%) 
# events   4   0   7   20   14 
Stomach pain * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   7/190 (3.68%)   5/75 (6.67%) 
# events   0   0   2   7   5 
Vomiting * 1           
# participants affected / at risk   10/41 (24.39%)   3/8 (37.50%)   12/58 (20.69%)   48/190 (25.26%)   21/75 (28.00%) 
# events   11   5   24   85   54 
General disorders           
Chills * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   4/58 (6.90%)   11/190 (5.79%)   8/75 (10.67%) 
# events   1   0   4   19   16 
Edema limbs * 1           
# participants affected / at risk   3/41 (7.32%)   3/8 (37.50%)   11/58 (18.97%)   33/190 (17.37%)   17/75 (22.67%) 
# events   4   3   20   71   52 
Fatigue * 1           
# participants affected / at risk   18/41 (43.90%)   3/8 (37.50%)   32/58 (55.17%)   104/190 (54.74%)   46/75 (61.33%) 
# events   32   4   83   250   136 
Fever * 1           
# participants affected / at risk   10/41 (24.39%)   1/8 (12.50%)   18/58 (31.03%)   52/190 (27.37%)   25/75 (33.33%) 
# events   17   1   24   83   46 
Flu like symptoms * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   3/58 (5.17%)   17/190 (8.95%)   13/75 (17.33%) 
# events   1   0   3   21   16 
Localized edema * 1           
# participants affected / at risk   2/41 (4.88%)   1/8 (12.50%)   3/58 (5.17%)   7/190 (3.68%)   4/75 (5.33%) 
# events   2   1   5   9   6 
Non-cardiac chest pain * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   7/190 (3.68%)   6/75 (8.00%) 
# events   0   0   1   8   7 
General disorders and administration site conditions - Other * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   4/58 (6.90%)   10/190 (5.26%)   5/75 (6.67%) 
# events   1   0   5   11   6 
Pain * 1           
# participants affected / at risk   5/41 (12.20%)   1/8 (12.50%)   18/58 (31.03%)   53/190 (27.89%)   27/75 (36.00%) 
# events   8   1   43   110   68 
Immune system disorders           
Allergic reaction * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   4/190 (2.11%)   4/75 (5.33%) 
# events   0   0   1   4   4 
Infections and infestations           
Bronchial infection * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   4/58 (6.90%)   10/190 (5.26%)   8/75 (10.67%) 
# events   0   0   4   11   9 
Infections and infestations - Other * 1           
# participants affected / at risk   2/41 (4.88%)   0/8 (0.00%)   5/58 (8.62%)   21/190 (11.05%)   13/75 (17.33%) 
# events   3   0   7   38   25 
Rash pustular * 1           
# participants affected / at risk   2/41 (4.88%)   0/8 (0.00%)   2/58 (3.45%)   13/190 (6.84%)   10/75 (13.33%) 
# events   2   0   16   48   41 
Sinusitis * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   1/58 (1.72%)   6/190 (3.16%)   5/75 (6.67%) 
# events   1   0   1   6   5 
Skin infection * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   3/58 (5.17%)   6/190 (3.16%)   4/75 (5.33%) 
# events   0   0   4   7   4 
Tooth infection * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   5/190 (2.63%)   4/75 (5.33%) 
# events   0   0   1   5   4 
Upper respiratory infection * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   9/58 (15.52%)   25/190 (13.16%)   20/75 (26.67%) 
# events   0   0   12   37   32 
Urinary tract infection * 1           
# participants affected / at risk   2/41 (4.88%)   0/8 (0.00%)   2/58 (3.45%)   12/190 (6.32%)   6/75 (8.00%) 
# events   3   0   4   17   9 
Investigations           
Alanine aminotransferase increased * 1           
# participants affected / at risk   4/41 (9.76%)   1/8 (12.50%)   6/58 (10.34%)   20/190 (10.53%)   4/75 (5.33%) 
# events   9   2   15   41   10 
Alkaline phosphatase increased * 1           
# participants affected / at risk   1/41 (2.44%)   1/8 (12.50%)   3/58 (5.17%)   11/190 (5.79%)   3/75 (4.00%) 
# events   1   1   6   21   4 
Aspartate aminotransferase increased * 1           
# participants affected / at risk   4/41 (9.76%)   2/8 (25.00%)   8/58 (13.79%)   23/190 (12.11%)   6/75 (8.00%) 
# events   9   2   15   58   24 
Blood bilirubin increased * 1           
# participants affected / at risk   4/41 (9.76%)   1/8 (12.50%)   9/58 (15.52%)   22/190 (11.58%)   7/75 (9.33%) 
# events   6   3   15   52   27 
GGT increased * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   2/58 (3.45%)   4/190 (2.11%)   1/75 (1.33%) 
# events   0   2   2   4   1 
Lipase increased * 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   11   19   14 
Neutrophil count decreased * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   6/58 (10.34%)   13/190 (6.84%)   6/75 (8.00%) 
# events   0   0   8   25   12 
Investigations - Other * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   14/190 (7.37%)   10/75 (13.33%) 
# events   0   0   14   49   28 
Platelet count decreased * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   6/58 (10.34%)   15/190 (7.89%)   10/75 (13.33%) 
# events   5   0   25   46   34 
White blood cell decreased * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   6/190 (3.16%)   4/75 (5.33%) 
# events   0   0   2   17   15 
Weight gain * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   2/58 (3.45%)   3/190 (1.58%)   2/75 (2.67%) 
# events   0   1   3   4   3 
Weight loss * 1           
# participants affected / at risk   4/41 (9.76%)   2/8 (25.00%)   11/58 (18.97%)   40/190 (21.05%)   22/75 (29.33%) 
# events   5   2   20   72   44 
Metabolism and nutrition disorders           
Anorexia * 1           
# participants affected / at risk   15/41 (36.59%)   3/8 (37.50%)   20/58 (34.48%)   76/190 (40.00%)   31/75 (41.33%) 
# events   21   5   42   133   71 
Dehydration * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   5/58 (8.62%)   6/190 (3.16%)   4/75 (5.33%) 
# events   0   1   5   8   6 
Hypoalbuminemia * 1           
# participants affected / at risk   2/41 (4.88%)   0/8 (0.00%)   3/58 (5.17%)   9/190 (4.74%)   2/75 (2.67%) 
# events   2   0   3   10   2 
Hypocalcemia * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   3/58 (5.17%)   9/190 (4.74%)   4/75 (5.33%) 
# events   2   0   8   15   4 
Hypokalemia * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   12/58 (20.69%)   20/190 (10.53%)   13/75 (17.33%) 
# events   0   0   18   31   22 
Hyponatremia * 1           
# participants affected / at risk   0/41 (0.00%)   2/8 (25.00%)   3/58 (5.17%)   8/190 (4.21%)   2/75 (2.67%) 
# events   0   2   4   11   2 
Hypophosphatemia * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   1/58 (1.72%)   10/190 (5.26%)   5/75 (6.67%) 
# events   1   0   1   13   7 
Hypercalcemia * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   3/58 (5.17%)   4/190 (2.11%)   4/75 (5.33%) 
# events   0   1   3   4   4 
Hyperglycemia * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   5/58 (8.62%)   13/190 (6.84%)   9/75 (12.00%) 
# events   3   0   5   18   10 
Hyperuricemia * 1           
# participants affected / at risk   1/41 (2.44%)   1/8 (12.50%)   2/58 (3.45%)   7/190 (3.68%)   2/75 (2.67%) 
# events   1   1   2   7   2 
Musculoskeletal and connective tissue disorders           
Arthralgia * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   4/58 (6.90%)   14/190 (7.37%)   8/75 (10.67%) 
# events   1   0   7   20   14 
Back pain * 1           
# participants affected / at risk   2/41 (4.88%)   1/8 (12.50%)   4/58 (6.90%)   21/190 (11.05%)   14/75 (18.67%) 
# events   2   1   6   29   20 
Bone pain * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   5/190 (2.63%)   5/75 (6.67%) 
# events   0   0   3   9   9 
Flank pain * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   5/190 (2.63%)   4/75 (5.33%) 
# events   0   0   1   5   4 
Generalized muscle weakness * 1           
# participants affected / at risk   1/41 (2.44%)   1/8 (12.50%)   4/58 (6.90%)   6/190 (3.16%)   3/75 (4.00%) 
# events   1   1   7   14   11 
Myalgia * 1           
# participants affected / at risk   5/41 (12.20%)   3/8 (37.50%)   10/58 (17.24%)   33/190 (17.37%)   16/75 (21.33%) 
# events   5   3   17   75   48 
Neck pain * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   0/58 (0.00%)   2/190 (1.05%)   1/75 (1.33%) 
# events   0   1   0   2   1 
Musculoskeletal and connective tissue disorder - Other * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   4/58 (6.90%)   14/190 (7.37%)   10/75 (13.33%) 
# events   1   0   5   17   12 
Pain in extremity * 1           
# participants affected / at risk   5/41 (12.20%)   1/8 (12.50%)   7/58 (12.07%)   28/190 (14.74%)   17/75 (22.67%) 
# events   5   2   15   51   37 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Tumor pain * 1           
# participants affected / at risk   1/41 (2.44%)   1/8 (12.50%)   3/58 (5.17%)   7/190 (3.68%)   2/75 (2.67%) 
# events   2   1   4   9   2 
Nervous system disorders           
Dizziness * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   1/58 (1.72%)   6/190 (3.16%)   6/75 (8.00%) 
# events   0   1   1   16   16 
Dysgeusia * 1           
# participants affected / at risk   2/41 (4.88%)   0/8 (0.00%)   4/58 (6.90%)   17/190 (8.95%)   9/75 (12.00%) 
# events   2   0   4   19   11 
Headache * 1           
# participants affected / at risk   4/41 (9.76%)   0/8 (0.00%)   11/58 (18.97%)   37/190 (19.47%)   23/75 (30.67%) 
# events   4   0   21   66   49 
Paresthesia * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   3/58 (5.17%)   11/190 (5.79%)   9/75 (12.00%) 
# events   0   0   5   19   13 
Peripheral sensory neuropathy * 1           
# participants affected / at risk   5/41 (12.20%)   0/8 (0.00%)   4/58 (6.90%)   16/190 (8.42%)   6/75 (8.00%) 
# events   7   0   8   22   7 
Somnolence * 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 
Psychiatric disorders           
Anxiety * 1           
# participants affected / at risk   4/41 (9.76%)   0/8 (0.00%)   3/58 (5.17%)   9/190 (4.74%)   4/75 (5.33%) 
# events   4   0   4   10   5 
Confusion * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   1/58 (1.72%)   2/190 (1.05%)   0/75 (0.00%) 
# events   0   1   1   2   0 
Depression * 1           
# participants affected / at risk   2/41 (4.88%)   0/8 (0.00%)   2/58 (3.45%)   10/190 (5.26%)   4/75 (5.33%) 
# events   2   0   2   11   5 
Insomnia * 1           
# participants affected / at risk   3/41 (7.32%)   1/8 (12.50%)   3/58 (5.17%)   21/190 (11.05%)   14/75 (18.67%) 
# events   3   1   4   22   15 
Renal and urinary disorders           
Hematuria * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   3/58 (5.17%)   7/190 (3.68%)   3/75 (4.00%) 
# events   1   0   3   9   3 
Renal and urinary disorders - Other * 1           
# participants affected / at risk   3/41 (7.32%)   0/8 (0.00%)   0/58 (0.00%)   9/190 (4.74%)   3/75 (4.00%) 
# events   3   0   0   11   4 
Proteinuria * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   6/58 (10.34%)   22/190 (11.58%)   8/75 (10.67%) 
# events   0   0   11   57   20 
Urinary frequency * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   2/58 (3.45%)   7/190 (3.68%)   4/75 (5.33%) 
# events   0   0   2   8   5 
Respiratory, thoracic and mediastinal disorders           
Cough * 1           
# participants affected / at risk   1/41 (2.44%)   1/8 (12.50%)   11/58 (18.97%)   27/190 (14.21%)   15/75 (20.00%) 
# events   1   1   18   44   32 
Dyspnea * 1           
# participants affected / at risk   4/41 (9.76%)   0/8 (0.00%)   7/58 (12.07%)   22/190 (11.58%)   11/75 (14.67%) 
# events   6   0   9   32   16 
Epistaxis * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   4/58 (6.90%)   10/190 (5.26%)   7/75 (9.33%) 
# events   0   0   6   15   10 
Hiccups * 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 
Hoarseness * 1           
# participants affected / at risk   8/41 (19.51%)   0/8 (0.00%)   9/58 (15.52%)   42/190 (22.11%)   17/75 (22.67%) 
# events   8   0   11   71   36 
Pneumonitis * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   3/58 (5.17%)   5/190 (2.63%)   4/75 (5.33%) 
# events   0   0   3   5   4 
Voice alteration * 1           
# participants affected / at risk   2/41 (4.88%)   1/8 (12.50%)   11/58 (18.97%)   28/190 (14.74%)   14/75 (18.67%) 
# events   2   1   12   32   17 
Skin and subcutaneous tissue disorders           
Alopecia * 1           
# participants affected / at risk   7/41 (17.07%)   0/8 (0.00%)   21/58 (36.21%)   62/190 (32.63%)   33/75 (44.00%) 
# events   9   0   26   84   49 
Dry skin * 1           
# participants affected / at risk   2/41 (4.88%)   0/8 (0.00%)   2/58 (3.45%)   13/190 (6.84%)   7/75 (9.33%) 
# events   3   0   3   15   8 
Erythema multiforme * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   1/58 (1.72%)   10/190 (5.26%)   7/75 (9.33%) 
# events   1   0   3   17   12 
Erythroderma * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   4/58 (6.90%)   9/190 (4.74%)   6/75 (8.00%) 
# events   0   0   5   11   6 
Hyperhidrosis * 1           
# participants affected / at risk   0/41 (0.00%)   1/8 (12.50%)   2/58 (3.45%)   6/190 (3.16%)   4/75 (5.33%) 
# events   0   2   2   11   9 
Skin and subcutaneous tissue disorders - Other * 1           
# participants affected / at risk   3/41 (7.32%)   0/8 (0.00%)   7/58 (12.07%)   27/190 (14.21%)   17/75 (22.67%) 
# events   3   0   10   41   28 
Pain of skin * 1           
# participants affected / at risk   0/41 (0.00%)   0/8 (0.00%)   1/58 (1.72%)   9/190 (4.74%)   6/75 (8.00%) 
# events   0   0   1   38   35 
Palmar-plantar erythrodysesthesia syndrome * 1           
# participants affected / at risk   17/41 (41.46%)   1/8 (12.50%)   39/58 (67.24%)   126/190 (66.32%)   58/75 (77.33%) 
# events   37   1   151   664   453 
Pruritus * 1           
# participants affected / at risk   4/41 (9.76%)   1/8 (12.50%)   7/58 (12.07%)   20/190 (10.53%)   10/75 (13.33%) 
# events   4   2   8   27   15 
Rash acneiform * 1           
# participants affected / at risk   2/41 (4.88%)   0/8 (0.00%)   3/58 (5.17%)   11/190 (5.79%)   6/75 (8.00%) 
# events   2   0   3   11   6 
Rash maculo-papular * 1           
# participants affected / at risk   6/41 (14.63%)   0/8 (0.00%)   8/58 (13.79%)   32/190 (16.84%)   16/75 (21.33%) 
# events   7   0   10   71   26 
Vascular disorders           
Hypotension * 1           
# participants affected / at risk   1/41 (2.44%)   0/8 (0.00%)   1/58 (1.72%)   7/190 (3.68%)   4/75 (5.33%) 
# events   1   0   1   8   5 
Hypertension * 1           
# participants affected / at risk   18/41 (43.90%)   3/8 (37.50%)   37/58 (63.79%)   123/190 (64.74%)   61/75 (81.33%) 
# events   32   3   97   575   430 
Thromboembolic event * 1           
# participants affected / at risk   0/41 (0.00%)   2/8 (25.00%)   1/58 (1.72%)   5/190 (2.63%)   4/75 (5.33%) 
# events   0   2   1   6   4 
* Events were collected by non-systematic assessment
1 Term from vocabulary, NCI-CTCAE (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.


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