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Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy

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ClinicalTrials.gov Identifier: NCT01103323
Recruitment Status : Completed
First Posted : April 14, 2010
Results First Posted : November 19, 2012
Last Update Posted : June 24, 2015
Sponsor:
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Metastatic Colorectal Cancer
Interventions Drug: Regorafenib (Stivarga, BAY73-4506)
Drug: Placebo
Other: Best Supportive Care (BSC)
Enrollment 760
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Regorafenib (Stivarga, BAY73-4506)+BSC Placebo+BSC
Hide Arm/Group Description Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). Period 1 is placebo and placebo-regorafenib with placebo period only before unblinding. Period 2 is placebo-regorafenib with regorafenib period only.
Period Title: Without/Before Drug Switch
Started 505 255
Participants Received Treatment 500 253
Completed 429 237
Not Completed 76 18
Reason Not Completed
Adverse Event             50             7
Withdrawal by Subject             17             5
Protocol Violation             2             0
Physician Decision             2             0
did not receive study treatment             5             2
Switch to Regorafenib             0             4
Period Title: Switched From Placebo to Regorafenib
Started 0 4 [1]
Completed 0 3
Not Completed 0 1
Reason Not Completed
Adverse Event             0             1
[1]
Participants in the placebo+BSC group switched to Regorafenib treatment after unblinding.
Arm/Group Title Regorafenib (Stivarga, BAY73-4506)+BSC Placebo+BSC Total
Hide Arm/Group Description Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). Total of all reporting groups
Overall Number of Baseline Participants 505 255 760
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous   [1] 
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 505 participants 255 participants 760 participants
60.7
(22 to 82)
60.1
(25 to 85)
60.5
(22 to 85)
[1]
Measure Description: The age of the patient in years at enrollment in the study.
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 505 participants 255 participants 760 participants
Female
194
  38.4%
102
  40.0%
296
  38.9%
Male
311
  61.6%
153
  60.0%
464
  61.1%
Eastern Cooperative Oncology Group (ECOG) performance status (PS) before treatment   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 505 participants 255 participants 760 participants
0 265 146 411
1 240 109 349
[1]
Measure Description: ECOG PS is a scale that measures how cancer affects the daily life of a patient on an ordinal scale from grade 0 (best) to grade 5 (worst). 0=Fully active without restriction; 1= Restricted in physically strenuous activity; 2= Ambulatory, capable of all selfcare; 3= Capable of limited selfcare; 4= Completely disabled; 5= Dead
KRAS mutation   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 505 participants 255 participants 760 participants
No 205 94 299
Yes 273 157 430
Unknown 27 4 31
[1]
Measure Description: KRAS - Kirsten rat sarcoma viral oncogene homolog (protein), member of the RAS family of GTPases (guanosine triphosphate hydrolases)
1.Primary Outcome
Title Overall Survival
Hide Description Overall survival (OS) was defined as the time (days) from randomization to death due to any cause. Patients alive at the time of analysis were censored at the last date known to be alive. If a patient was lost to follow-up and there was no contact after randomization, this patient was censored at Day 1.
Time Frame From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis (IA).
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Hide Analysis Population Description
Intent to treat (ITT)
Arm/Group Title Regorafenib (Stivarga, BAY73-4506)+BSC Placebo+BSC
Hide Arm/Group Description:
Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)
Overall Number of Participants Analyzed 505 255
Median (95% Confidence Interval)
Unit of Measure: Days
196
(178 to 222)
151
(134 to 177)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Regorafenib (Stivarga, BAY73-4506)+BSC, Placebo+BSC
Comments Sample size based on primary efficacy endpoint of OS. The study was designed to have 90% power to detect 33.3% increase in median OS (i.e. hazard ratio of 0.75, Regorafenib / Placebo). Assuming 1-sided overall alpha of 0.025, randomization ratio of 2:1 for Regorafenib and Placebo, and 2 formal interim analyses of OS using an O’Brien-Fleming-type error spending function, a total of 582 death events were required for primary completion. Results based on 2nd planned formal IA with 432 total events.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005178
Comments According to protocol specified O'Brien-Fleming type alpha spending function and 432 death events at 2nd IA, the pre-specified alpha (false positive rate) for this analysis was 0.009279 (1-sided).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.774
Confidence Interval 95%
0.636 to 0.942
Estimation Comments Two treatment groups compared using a stratified log-rank test, stratified by same stratification factors as randomization. Hazard ratio (Regorafenib / Placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.
2.Secondary Outcome
Title Progression-free Survival (Based on Investigator’s Assessment)
Hide Description Progression-free survival was defined as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical) or death due to any cause, if death occurred before progression was documented.
Time Frame From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
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Hide Analysis Population Description
ITT
Arm/Group Title Regorafenib (Stivarga, BAY73-4506)+BSC Placebo+BSC
Hide Arm/Group Description:
Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)
Overall Number of Participants Analyzed 505 255
Median (95% Confidence Interval)
Unit of Measure: Days
59
(57 to 65)
52
(51 to 53)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Regorafenib (Stivarga, BAY73-4506)+BSC, Placebo+BSC
Comments Two treatment groups compared using a stratified log-rank test, stratified by same stratification factors as randomization. Hazard ratio (Regorafenib / Placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.000001
Comments Comparison based on pre-specified alpha level of 0.025 (1-sided).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.494
Confidence Interval 95%
0.419 to 0.582
Estimation Comments Hazard ratio (Regorafenib / Placebo)
3.Secondary Outcome
Title Objective Tumor Response
Hide Description The objective tumor response was defined as the percentage of patients with complete response (CR, tumor disappears) or partial response (PR, sum of lesion sizes decreased at least 30% from baseline) as best overall response. A best overall response was defined for all patients, using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. Patients whose best overall response was not CR or PR, and any patients with no post-baseline assessments were considered nonresponders for the analysis.
Time Frame From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT
Arm/Group Title Regorafenib (Stivarga, BAY73-4506)+BSC Placebo+BSC
Hide Arm/Group Description:
Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)
Overall Number of Participants Analyzed 505 255
Measure Type: Number
Unit of Measure: Percentage of participants
1.0 0.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Regorafenib (Stivarga, BAY73-4506)+BSC, Placebo+BSC
Comments Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.188432
Comments Comparison based on pre-specified alpha level of 0.025 (1-sided).
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value -0.60
Confidence Interval 95%
-1.74 to 0.53
Estimation Comments Difference = Placebo - Regorafenib 160 mg
4.Secondary Outcome
Title Disease Control
Hide Description Disease control was defined as the percentage of patients whose best response was not PD [sum of lesion sizes increased at least 20% from smallest sum on study or new lesions] (ie, CR [tumor disappears], PR [sum of lesion sizes decreased at least 30% from baseline] or SD (stable disease)). SD included if at least 6 weeks after randomization.
Time Frame From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT
Arm/Group Title Regorafenib (Stivarga, BAY73-4506)+BSC Placebo+BSC
Hide Arm/Group Description:
Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)
Overall Number of Participants Analyzed 505 255
Measure Type: Number
Unit of Measure: Percentage of participants
41.0 14.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Regorafenib (Stivarga, BAY73-4506)+BSC, Placebo+BSC
Comments Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.000001
Comments Comparison based on pre-specified alpha level of 0.025 (1-sided).
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value -25.94
Confidence Interval 95%
-32.06 to -19.82
Estimation Comments Difference = Placebo - Regorafenib 160 mg
5.Secondary Outcome
Title Tumor Response
Hide Description A tumor response (best overall response) was defined for all patients, using the RECIST criteria, version 1.1. Categories: complete response (CR, tumor disappears), partial response (PR, sum of lesion sizes decreased at least 30% from baseline), stable disease (SD, steady state of disease), progressive disease (PD, sum of lesion sizes increased at least 20% from smallest sum on study or new lesions). Clinical PD considered when radiographic imaging not possible.
Time Frame From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT
Arm/Group Title Regorafenib (Stivarga, BAY73-4506)+BSC Placebo+BSC
Hide Arm/Group Description:
Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).
Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)
Overall Number of Participants Analyzed 505 255
Measure Type: Number
Unit of Measure: Percentage of participants
Complete Response (CR) 0 0
Partial Response (PR) 1.0 0.4
Stable Disease (SD) 42.8 14.5
Progressive Disease (PD) 49.5 80.0
Non CR/Non PD 0.8 0.4
Not applicable 0.2 0
Not assessed 5.7 4.7
Time Frame AE was collected up to 30 days after end of study treatment (per protocol) over a period of approximately 3.7 years.
Adverse Event Reporting Description Disseminated Intravascular Coagulation (DIC), International Normalized Ratio (INR), Cardiac Troponin T (cTnT), Gastroihntestina (GI), Not Otherwise Specified (NOS), Aspartate Aminotransferase (AST), Genitourinary (GU), Alanine Aminotransferase (ALT), Acute Respiratory Distress Syndrome (ARDS), Absolute Neutrophil Count (ANC)
 
Arm/Group Title Regorafenib (BAY73-4506)+BSC Placebo+BSC Placebo - Regorafenib After Unblinding
Hide Arm/Group Description Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). It is for placebo period only before unblinding. Participants in the placebo+BSC group switched to treatment with Regorafenib after unblinding. It is for Regorafenib treatment period only
All-Cause Mortality
Regorafenib (BAY73-4506)+BSC Placebo+BSC Placebo - Regorafenib After Unblinding
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Regorafenib (BAY73-4506)+BSC Placebo+BSC Placebo - Regorafenib After Unblinding
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   232/500 (46.40%)      103/253 (40.71%)      2/4 (50.00%)    
Blood and lymphatic system disorders       
DIC * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Edema: Limb * 1  1/500 (0.20%)  1 1/253 (0.40%)  1 0/4 (0.00%)  0
Edema: Trunk/Genital * 1  0/500 (0.00%)  0 2/253 (0.79%)  4 0/4 (0.00%)  0
Edema: Viscera * 1  0/500 (0.00%)  0 1/253 (0.40%)  3 0/4 (0.00%)  0
Hemoglobin * 1  4/500 (0.80%)  8 2/253 (0.79%)  2 0/4 (0.00%)  0
INR * 1  2/500 (0.40%)  5 0/253 (0.00%)  0 0/4 (0.00%)  0
Neutrophils * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Platelets * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Thrombotic microangiopathy * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Cardiac disorders       
Cardiac arrhythmia - Other * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Cardiac ischemia/infarction * 1  6/500 (1.20%)  6 1/253 (0.40%)  2 0/4 (0.00%)  0
Hypertension * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Hypotension * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Left ventricular systolic dysfunction * 1  1/500 (0.20%)  3 0/253 (0.00%)  0 0/4 (0.00%)  0
Supraventricular arrhythmia, Atrial fibrillation * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
cTnT * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Eye disorders       
Diplopia * 1  1/500 (0.20%)  1 1/253 (0.40%)  1 0/4 (0.00%)  0
Ocular - Other * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Gastrointestinal disorders       
Anorexia * 1  5/500 (1.00%)  8 2/253 (0.79%)  2 0/4 (0.00%)  0
Ascites * 1  1/500 (0.20%)  2 2/253 (0.79%)  2 1/4 (25.00%)  1
Constipation * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Dehydration * 1  3/500 (0.60%)  3 2/253 (0.79%)  2 0/4 (0.00%)  0
Diarrhea * 1  8/500 (1.60%)  9 0/253 (0.00%)  0 0/4 (0.00%)  0
Distension * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Enteritis * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Fistula, GI, Abdomen NOS * 1  1/500 (0.20%)  2 1/253 (0.40%)  1 0/4 (0.00%)  0
Fistula, GI, Anus * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Fistula, GI, Small bowel NOS * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
GI - Other * 1  1/500 (0.20%)  1 1/253 (0.40%)  1 0/4 (0.00%)  0
Hemorrhoids * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Ileus * 1  2/500 (0.40%)  3 3/253 (1.19%)  3 0/4 (0.00%)  0
Mucositis (functional/symptomatic), Small bowel * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Necrosis, GI, Peritoneal cavity * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Obstruction, GI, Colon * 1  9/500 (1.80%)  11 6/253 (2.37%)  8 0/4 (0.00%)  0
Obstruction, GI, Ileum * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Obstruction, GI, Small bowel NOS * 1  4/500 (0.80%)  5 7/253 (2.77%)  9 0/4 (0.00%)  0
Obstruction, GI, Stomach * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Perforation, GI, Colon * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Stricture, GI, Biliary tree * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Ulcer, GI, Duodenum * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Vomiting * 1  3/500 (0.60%)  3 0/253 (0.00%)  0 1/4 (25.00%)  1
General disorders       
Constitutional symptoms - Other * 1  34/500 (6.80%)  49 23/253 (9.09%)  39 0/4 (0.00%)  0
Death not associated with CTCAE term, Disease progression NOS * 1  16/500 (3.20%)  17 6/253 (2.37%)  6 1/4 (25.00%)  1
Death not associated with CTCAE term, Multi-Organ Failure * 1  4/500 (0.80%)  4 1/253 (0.40%)  1 0/4 (0.00%)  0
Death not associated with CTCAE term, Sudden death * 1  2/500 (0.40%)  2 2/253 (0.79%)  2 0/4 (0.00%)  0
Fatigue * 1  5/500 (1.00%)  6 5/253 (1.98%)  5 0/4 (0.00%)  0
Fever * 1  17/500 (3.40%)  21 2/253 (0.79%)  2 0/4 (0.00%)  0
Pain, Abdomen NOS * 1  13/500 (2.60%)  21 2/253 (0.79%)  2 0/4 (0.00%)  0
Pain, Back * 1  4/500 (0.80%)  6 4/253 (1.58%)  5 0/4 (0.00%)  0
Pain, Buttock * 1  2/500 (0.40%)  4 0/253 (0.00%)  0 0/4 (0.00%)  0
Pain, Cardiac/Heart * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Pain, Chest wall * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Pain, Chest/Thorax NOS * 1  4/500 (0.80%)  4 1/253 (0.40%)  1 0/4 (0.00%)  0
Pain, Extremity - limb * 1  2/500 (0.40%)  6 0/253 (0.00%)  0 0/4 (0.00%)  0
Pain, Head/Headache * 1  2/500 (0.40%)  2 1/253 (0.40%)  1 0/4 (0.00%)  0
Pain, Joint * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Pain, Liver * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Pain, Neuralgia/Peripheral nerve * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Pain, Pain NOS * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Pain, Tumor pain * 1  3/500 (0.60%)  3 1/253 (0.40%)  1 0/4 (0.00%)  0
Syndromes - Other * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Tumor flare * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Weight loss * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Hepatobiliary disorders       
Cholecystitis * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Hepatobiliary - Other * 1  2/500 (0.40%)  2 1/253 (0.40%)  1 0/4 (0.00%)  0
Liver dysfunction * 1  17/500 (3.40%)  28 5/253 (1.98%)  11 0/4 (0.00%)  0
Immune system disorders       
Allergic reaction * 1  2/500 (0.40%)  4 0/253 (0.00%)  0 0/4 (0.00%)  0
Infections and infestations       
Infection (documented clinically), Abdomen NOS * 1  4/500 (0.80%)  4 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection (documented clinically), Anal/perianal * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection (documented clinically), Appendix * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection (documented clinically), Bladder (urinary) * 1  2/500 (0.40%)  2 1/253 (0.40%)  1 0/4 (0.00%)  0
Infection (documented clinically), Blood * 1  3/500 (0.60%)  5 2/253 (0.79%)  2 0/4 (0.00%)  0
Infection (documented clinically), Bronchus * 1  3/500 (0.60%)  3 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection (documented clinically), Catheter-related * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection (documented clinically), Kidney * 1  1/500 (0.20%)  1 1/253 (0.40%)  1 0/4 (0.00%)  0
Infection (documented clinically), Lung (Pneumonia) * 1  9/500 (1.80%)  11 3/253 (1.19%)  4 0/4 (0.00%)  0
Infection (documented clinically), Skin (Cellulitis) * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection (documented clinically), Soft tissue NOS * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection (documented clinically), Urinary tract NOS * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection (documented clinically), Wound * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection - Other * 1  5/500 (1.00%)  6 1/253 (0.40%)  2 0/4 (0.00%)  0
Infection with normal ANC, Blood * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Infection with normal ANC, Catheter-related * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection with normal ANC, Colon * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection with normal ANC, Gallbladder (Cholecystitis) * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection with normal ANC, Kidney * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection with normal ANC, Lung (Pneumonia) * 1  1/500 (0.20%)  1 1/253 (0.40%)  1 0/4 (0.00%)  0
Infection with normal ANC, Soft tissue NOS * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection with unknown ANC, Kidney * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Infection with unknown ANC, Lung (Pneumonia) * 1  1/500 (0.20%)  1 1/253 (0.40%)  1 0/4 (0.00%)  0
Metabolism and nutrition disorders       
AST * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Bilirubin (Hyperbilirubinemia) * 1  8/500 (1.60%)  11 3/253 (1.19%)  3 0/4 (0.00%)  0
Hypoalbuminemia * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Hypocalcemia * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Hyponatremia * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Metabolic/Lab - Other * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Fracture * 1  4/500 (0.80%)  4 2/253 (0.79%)  3 0/4 (0.00%)  0
Gait/Walking * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Muscle weakness left-sided * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Muscle weakness, Extremity - lower * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Muscle weakness, Whole body/generalized * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Musculoskeletal - Other * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Myositis * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Secondary malignancy (possibly related to cancer treatment) * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Nervous system disorders       
Ataxia * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
CNS ischemia * 1  1/500 (0.20%)  2 2/253 (0.79%)  2 0/4 (0.00%)  0
Cognitive disturbance * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Confusion * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Dizziness * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Encephalopathy * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Mood Alteration, Anxiety * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Neurology - Other * 1  3/500 (0.60%)  4 2/253 (0.79%)  2 0/4 (0.00%)  0
Neuropathy: Cranial, CN III Pupil, upper eyelid, extra ocular mov * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Neuropathy: motor * 1  3/500 (0.60%)  3 0/253 (0.00%)  0 0/4 (0.00%)  0
Seizure * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Somnolence * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Speech impairment * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Syncope (Fainting) * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Renal and urinary disorders       
Cystitis * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Fistula, GU, Bladder * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Obstruction, GU, Ureter * 1  2/500 (0.40%)  2 1/253 (0.40%)  1 0/4 (0.00%)  0
Renal - Other * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Renal failure * 1  5/500 (1.00%)  6 3/253 (1.19%)  5 0/4 (0.00%)  0
Urinary retention * 1  0/500 (0.00%)  0 2/253 (0.79%)  2 0/4 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
ARDS * 1  1/500 (0.20%)  1 1/253 (0.40%)  1 0/4 (0.00%)  0
Cough * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Dyspnea (Shortness of breath) * 1  12/500 (2.40%)  18 4/253 (1.58%)  4 0/4 (0.00%)  0
Pleural effusion * 1  1/500 (0.20%)  2 4/253 (1.58%)  4 0/4 (0.00%)  0
Pneumonitis * 1  1/500 (0.20%)  2 1/253 (0.40%)  1 0/4 (0.00%)  0
Pneumothorax * 1  2/500 (0.40%)  3 0/253 (0.00%)  0 0/4 (0.00%)  0
Pulmonary - Other * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Skin and subcutaneous tissue disorders       
Dermatology - Other * 1  1/500 (0.20%)  2 2/253 (0.79%)  3 0/4 (0.00%)  0
Erythema multiforme * 1  2/500 (0.40%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Hand-foot skin reaction * 1  1/500 (0.20%)  3 0/253 (0.00%)  0 0/4 (0.00%)  0
Rash/Desquamation * 1  4/500 (0.80%)  7 1/253 (0.40%)  1 0/4 (0.00%)  0
Wound complication, non-infectious * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Vascular disorders       
Hematoma * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Hemorrhage - Other * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Hemorrhage pulmonary, Bronchus * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Hemorrhage pulmonary, Mediastinum * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Hemorrhage, GI, Abdomen NOS * 1  2/500 (0.40%)  4 0/253 (0.00%)  0 0/4 (0.00%)  0
Hemorrhage, GI, Anus * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Hemorrhage, GI, Lower GI NOS * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Hemorrhage, GI, Rectum * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Hemorrhage, GI, Stoma * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Hemorrhage, GI, Upper GI NOS * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Hemorrhage, GI, Varices (esophageal) * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Hemorrhage, GI, Varices (rectal) * 1  1/500 (0.20%)  1 0/253 (0.00%)  0 0/4 (0.00%)  0
Hemorrhage, GU, Vagina * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
Thrombosis/Embolism (vascular access) * 1  0/500 (0.00%)  0 1/253 (0.40%)  1 0/4 (0.00%)  0
Thrombosis/Thrombus/Embolism * 1  6/500 (1.20%)  6 3/253 (1.19%)  5 0/4 (0.00%)  0
Vascular - Other * 1  1/500 (0.20%)  2 0/253 (0.00%)  0 0/4 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, NCI-CTCAE v.3.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Regorafenib (BAY73-4506)+BSC Placebo+BSC Placebo - Regorafenib After Unblinding
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   489/500 (97.80%)      229/253 (90.51%)      4/4 (100.00%)    
Blood and lymphatic system disorders       
Edema: Limb * 1  49/500 (9.80%)  57 16/253 (6.32%)  19 0/4 (0.00%)  0
Hemoglobin * 1  76/500 (15.20%)  142 29/253 (11.46%)  46 0/4 (0.00%)  0
Platelets * 1  79/500 (15.80%)  136 6/253 (2.37%)  9 1/4 (25.00%)  2
Cardiac disorders       
Hypertension * 1  155/500 (31.00%)  213 21/253 (8.30%)  23 1/4 (25.00%)  1
Endocrine disorders       
Hypothyroidism * 1  27/500 (5.40%)  29 1/253 (0.40%)  1 1/4 (25.00%)  1
Eye disorders       
Ocular - Other * 1  5/500 (1.00%)  5 0/253 (0.00%)  0 1/4 (25.00%)  1
Gastrointestinal disorders       
Anorexia * 1  239/500 (47.80%)  388 73/253 (28.85%)  96 0/4 (0.00%)  0
Ascites * 1  23/500 (4.60%)  24 6/253 (2.37%)  8 1/4 (25.00%)  1
Constipation * 1  119/500 (23.80%)  147 48/253 (18.97%)  58 0/4 (0.00%)  0
Diarrhea * 1  218/500 (43.60%)  514 44/253 (17.39%)  57 2/4 (50.00%)  2
Fistula, GI, Colon/Cecum/Appendix * 1  0/500 (0.00%)  0 0/253 (0.00%)  0 1/4 (25.00%)  1
Mucositis (functional/symptomatic), Oral cavity * 1  145/500 (29.00%)  267 12/253 (4.74%)  12 0/4 (0.00%)  0
Nausea * 1  115/500 (23.00%)  162 55/253 (21.74%)  67 1/4 (25.00%)  1
Taste alteration * 1  39/500 (7.80%)  44 6/253 (2.37%)  6 0/4 (0.00%)  0
Vomiting * 1  85/500 (17.00%)  144 41/253 (16.21%)  50 1/4 (25.00%)  3
General disorders       
Constitutional symptoms - Other * 1  30/500 (6.00%)  33 17/253 (6.72%)  19 0/4 (0.00%)  0
Fatigue * 1  318/500 (63.60%)  612 115/253 (45.45%)  168 0/4 (0.00%)  0
Fever * 1  136/500 (27.20%)  189 40/253 (15.81%)  48 2/4 (50.00%)  3
Flu-like syndrome * 1  27/500 (5.40%)  30 6/253 (2.37%)  8 1/4 (25.00%)  1
Insomnia * 1  39/500 (7.80%)  43 14/253 (5.53%)  15 0/4 (0.00%)  0
Pain, Abdomen NOS * 1  121/500 (24.20%)  239 47/253 (18.58%)  53 0/4 (0.00%)  0
Pain, Back * 1  79/500 (15.80%)  114 25/253 (9.88%)  27 0/4 (0.00%)  0
Pain, Buttock * 1  4/500 (0.80%)  5 0/253 (0.00%)  0 1/4 (25.00%)  1
Pain, Chest/Thorax NOS * 1  26/500 (5.20%)  29 12/253 (4.74%)  14 0/4 (0.00%)  0
Pain, Extremity - limb * 1  51/500 (10.20%)  83 14/253 (5.53%)  19 0/4 (0.00%)  0
Pain, Head/Headache * 1  50/500 (10.00%)  65 18/253 (7.11%)  23 0/4 (0.00%)  0
Pain, Joint * 1  32/500 (6.40%)  34 13/253 (5.14%)  14 0/4 (0.00%)  0
Pain, Muscle * 1  50/500 (10.00%)  64 14/253 (5.53%)  16 0/4 (0.00%)  0
Pain, Throat/Pharynx/Larynx * 1  9/500 (1.80%)  12 1/253 (0.40%)  1 1/4 (25.00%)  1
Weight loss * 1  167/500 (33.40%)  240 30/253 (11.86%)  34 2/4 (50.00%)  7
Hepatobiliary disorders       
Hepatobiliary - Other * 1  8/500 (1.60%)  9 4/253 (1.58%)  4 1/4 (25.00%)  3
Metabolism and nutrition disorders       
ALT * 1  28/500 (5.60%)  53 7/253 (2.77%)  8 0/4 (0.00%)  0
AST * 1  37/500 (7.40%)  72 12/253 (4.74%)  13 0/4 (0.00%)  0
Alkaline phosphatase * 1  35/500 (7.00%)  49 8/253 (3.16%)  12 0/4 (0.00%)  0
Bilirubin (Hyperbilirubinemia) * 1  97/500 (19.40%)  160 22/253 (8.70%)  37 1/4 (25.00%)  3
Creatinine * 1  15/500 (3.00%)  19 7/253 (2.77%)  8 1/4 (25.00%)  2
GFR * 1  4/500 (0.80%)  9 1/253 (0.40%)  2 1/4 (25.00%)  1
Hyperuricemia * 1  12/500 (2.40%)  13 1/253 (0.40%)  1 1/4 (25.00%)  1
Hypocalcemia * 1  34/500 (6.80%)  57 1/253 (0.40%)  1 0/4 (0.00%)  0
Hypokalemia * 1  50/500 (10.00%)  84 6/253 (2.37%)  7 0/4 (0.00%)  0
Hyponatremia * 1  32/500 (6.40%)  43 6/253 (2.37%)  10 0/4 (0.00%)  0
Hypophosphatemia * 1  32/500 (6.40%)  62 2/253 (0.79%)  3 1/4 (25.00%)  2
Lipase * 1  32/500 (6.40%)  74 3/253 (1.19%)  4 0/4 (0.00%)  0
Metabolic/Lab - Other * 1  42/500 (8.40%)  69 8/253 (3.16%)  15 0/4 (0.00%)  0
Proteinuria * 1  40/500 (8.00%)  109 6/253 (2.37%)  11 0/4 (0.00%)  0
Nervous system disorders       
Dizziness * 1  28/500 (5.60%)  31 13/253 (5.14%)  13 0/4 (0.00%)  0
Neuropathy: sensory * 1  51/500 (10.20%)  68 25/253 (9.88%)  27 0/4 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Cough * 1  56/500 (11.20%)  77 28/253 (11.07%)  32 1/4 (25.00%)  1
Dyspnea (Shortness of breath) * 1  89/500 (17.80%)  110 34/253 (13.44%)  46 0/4 (0.00%)  0
Voice changes * 1  160/500 (32.00%)  211 16/253 (6.32%)  17 1/4 (25.00%)  1
Skin and subcutaneous tissue disorders       
Alopecia * 1  39/500 (7.80%)  43 4/253 (1.58%)  4 0/4 (0.00%)  0
Cheilitis * 1  4/500 (0.80%)  4 0/253 (0.00%)  0 1/4 (25.00%)  3
Dermatology - Other * 1  30/500 (6.00%)  45 7/253 (2.77%)  10 0/4 (0.00%)  0
Dry skin * 1  50/500 (10.00%)  59 10/253 (3.95%)  11 0/4 (0.00%)  0
Hand-foot skin reaction * 1  235/500 (47.00%)  720 19/253 (7.51%)  21 1/4 (25.00%)  3
Pruritus * 1  29/500 (5.80%)  39 11/253 (4.35%)  11 0/4 (0.00%)  0
Rash/Desquamation * 1  145/500 (29.00%)  211 13/253 (5.14%)  17 1/4 (25.00%)  2
Vascular disorders       
Hemorrhage pulmonary, Nose * 1  45/500 (9.00%)  55 6/253 (2.37%)  6 0/4 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, NCI-CTCAE v.3.0
At 2nd IA, pre-specified O’Brien-Fleming-type efficacy boundary was crossed. DMC concluded OS result positive and after positive risk benefit assessment, recommended unblinding of study. OS from 2nd IA are the final formal and definitive results.
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 agreed point of publication is 12-18 months after database lock at the earliest. Bayer will have 30-45 days to review publications, and may request an additional publication delay of up to 60 days to allow for filing a Patent Application (if applicable). No publication of single center data should be done prior of publication if multi-center data.
Results Point of Contact
Name/Title: Therapeutic Area Head
Organization: BAYER
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01103323     History of Changes
Other Study ID Numbers: 14387
2009-012787-14 ( EudraCT Number )
First Submitted: April 8, 2010
First Posted: April 14, 2010
Results First Submitted: October 19, 2012
Results First Posted: November 19, 2012
Last Update Posted: June 24, 2015