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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01103323
First received: April 8, 2010
Last updated: April 29, 2014
Last verified: April 2014
Results First Received: October 19, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Metastatic Colorectal Cancer
Interventions: Drug: Regorafenib (Stivarga, BAY73-4506)
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Participant Flow:   Overall Study
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
STARTED     505     255  
Participants Received Treatment     500     253  
COMPLETED     386     232  
NOT COMPLETED     119     23  
Adverse Event                 42                 7  
Withdrawal by Subject                 16                 5  
Protocol Violation                 2                 0  
Physician Decision                 2                 0  
ongoing with treatment                 52                 9  
did not receive study treatment                 5                 2  



  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 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Total Total of all reporting groups

Baseline Measures
    Regorafenib (Stivarga, BAY73-4506)     Placebo     Total  
Number of Participants  
[units: participants]
  505     255     760  
Age [1]
[units: Years]
Mean ( Full Range )
  60.7  
  ( 22 to 82 )  
  60.1  
  ( 25 to 85 )  
  60.5  
  ( 22 to 85 )  
Gender  
[units: Participants]
     
Female     194     102     296  
Male     311     153     464  
Eastern Cooperative Oncology Group (ECOG) performance status (PS) before treatment [2]
[units: Participants]
     
0     265     146     411  
1     240     109     349  
KRAS mutation [3]
[units: Participants]
     
No     205     94     299  
Yes     273     157     430  
Unknown     27     4     31  
[1] The age of the patient in years at enrollment in the study.
[2] 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
[3] KRAS - Kirsten rat sarcoma viral oncogene homolog (protein), member of the RAS family of GTPases (guanosine triphosphate hydrolases)



  Outcome Measures
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1.  Primary:   Overall Survival   [ 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). ]

2.  Secondary:   Progression-free Survival (Based on Investigator’s Assessment)   [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

3.  Secondary:   Objective Tumor Response   [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

4.  Secondary:   Disease Control   [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

5.  Secondary:   Tumor Response   [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]


  Serious Adverse Events
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Time Frame No text entered.
Additional 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)

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Serious Adverse Events
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Total, serious adverse events      
# participants affected / at risk     220/500 (44.00%)     101/253 (39.92%)  
Blood and lymphatic system disorders      
DIC * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Edema: Limb * 1    
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)  
# events     1     1  
Edema: Trunk/Genital * 1    
# participants affected / at risk     0/500 (0.00%)     2/253 (0.79%)  
# events     0     4  
Edema: Viscera * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     3  
Hemoglobin * 1    
# participants affected / at risk     4/500 (0.80%)     2/253 (0.79%)  
# events     8     2  
INR * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     5     0  
Neutrophils * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Platelets * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Thrombotic Microangiopathy * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Cardiac disorders      
Cardiac Arrhythmia - Other * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Cardiac General - Other * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Cardiac Ischemia/Infarction * 1    
# participants affected / at risk     6/500 (1.20%)     1/253 (0.40%)  
# events     6     2  
Hypertension * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Hypotension * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Supraventricular Arrhythmia, Atrial Fibrillation * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
cTnT * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Eye disorders      
Diplopia * 1    
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)  
# events     1     1  
Ocular - Other * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Gastrointestinal disorders      
Anorexia * 1    
# participants affected / at risk     4/500 (0.80%)     2/253 (0.79%)  
# events     6     2  
Ascites * 1    
# participants affected / at risk     1/500 (0.20%)     2/253 (0.79%)  
# events     2     2  
Constipation * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Dehydration * 1    
# participants affected / at risk     3/500 (0.60%)     2/253 (0.79%)  
# events     3     2  
Diarrhea * 1    
# participants affected / at risk     8/500 (1.60%)     0/253 (0.00%)  
# events     9     0  
Distension * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Enteritis * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Fistula, GI, Abdomen NOS * 1    
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)  
# events     2     1  
Fistula, GI, Anus * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Fistula, GI, Small Bowel NOS * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
GI - Other * 1    
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)  
# events     1     1  
Hemorrhoids * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Ileus * 1    
# participants affected / at risk     2/500 (0.40%)     3/253 (1.19%)  
# events     3     3  
Mucositis (Functional/Symptomatic), Small Bowel * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Necrosis, GI, Peritoneal Cavity * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Obstruction, GI, Colon * 1    
# participants affected / at risk     9/500 (1.80%)     6/253 (2.37%)  
# events     11     8  
Obstruction, GI, Ileum * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Obstruction, GI, Small Bowel NOS * 1    
# participants affected / at risk     3/500 (0.60%)     7/253 (2.77%)  
# events     4     9  
Obstruction, GI, Stomach * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Perforation, GI, Colon * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Stricture, GI, Biliary Tree * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Ulcer, GI, Duodenum * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Vomiting * 1    
# participants affected / at risk     3/500 (0.60%)     0/253 (0.00%)  
# events     3     0  
General disorders      
Constitutional Symptoms - Other * 1    
# participants affected / at risk     32/500 (6.40%)     23/253 (9.09%)  
# events     47     39  
Death Not Associated With CTCAE Term, Disease Progression NOS * 1    
# participants affected / at risk     15/500 (3.00%)     6/253 (2.37%)  
# events     16     6  
Death Not Associated With CTCAE Term, Multi-Organ Failure * 1    
# participants affected / at risk     4/500 (0.80%)     1/253 (0.40%)  
# events     4     1  
Death Not Associated With CTCAE Term, Sudden Death * 1    
# participants affected / at risk     2/500 (0.40%)     2/253 (0.79%)  
# events     2     2  
Fatigue * 1    
# participants affected / at risk     4/500 (0.80%)     5/253 (1.98%)  
# events     5     5  
Fever * 1    
# participants affected / at risk     16/500 (3.20%)     2/253 (0.79%)  
# events     20     2  
Pain, Abdomen NOS * 1    
# participants affected / at risk     13/500 (2.60%)     2/253 (0.79%)  
# events     21     2  
Pain, Back * 1    
# participants affected / at risk     3/500 (0.60%)     4/253 (1.58%)  
# events     5     5  
Pain, Buttock * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     4     0  
Pain, Cardiac/Heart * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Pain, Chest/Thorax NOS * 1    
# participants affected / at risk     3/500 (0.60%)     1/253 (0.40%)  
# events     3     1  
Pain, Extremity - Limb * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     6     0  
Pain, Head/Headache * 1    
# participants affected / at risk     2/500 (0.40%)     1/253 (0.40%)  
# events     2     1  
Pain, Joint * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Pain, Liver * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Pain, Neuralgia/Peripheral Nerve * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Pain, Pain NOS * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Pain, Tumor Pain * 1    
# participants affected / at risk     2/500 (0.40%)     1/253 (0.40%)  
# events     2     1  
Syndromes - Other * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Tumor Flare * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Weight Loss * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Hepatobiliary disorders      
Cholecystitis * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Hepatobiliary - Other * 1    
# participants affected / at risk     2/500 (0.40%)     1/253 (0.40%)  
# events     2     1  
Liver Dysfunction * 1    
# participants affected / at risk     17/500 (3.40%)     4/253 (1.58%)  
# events     28     9  
Immune system disorders      
Allergic Reaction * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     4     0  
Infections and infestations      
Infection (Documented Clinically), Abdomen NOS * 1    
# participants affected / at risk     4/500 (0.80%)     0/253 (0.00%)  
# events     4     0  
Infection (Documented Clinically), Anal/Perianal * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Infection (Documented Clinically), Appendix * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Infection (Documented Clinically), Bladder (Urinary) * 1    
# participants affected / at risk     2/500 (0.40%)     1/253 (0.40%)  
# events     2     1  
Infection (Documented Clinically), Blood * 1    
# participants affected / at risk     2/500 (0.40%)     2/253 (0.79%)  
# events     4     2  
Infection (Documented Clinically), Bronchus * 1    
# participants affected / at risk     3/500 (0.60%)     0/253 (0.00%)  
# events     3     0  
Infection (Documented Clinically), Catheter-Related * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Infection (Documented Clinically), Kidney * 1    
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)  
# events     1     1  
Infection (Documented Clinically), Lung (Pneumonia) * 1    
# participants affected / at risk     9/500 (1.80%)     3/253 (1.19%)  
# events     11     4  
Infection (Documented Clinically), Skin (Cellulitis) * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Infection (Documented Clinically), Soft Tissue NOS * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Infection (Documented Clinically), Urinary Tract NOS * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Infection (Documented Clinically), Wound * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Infection - Other * 1    
# participants affected / at risk     5/500 (1.00%)     1/253 (0.40%)  
# events     6     2  
Infection With Normal ANC, Blood * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Infection With Normal ANC, Catheter-Related * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Infection With Normal ANC, Gallbladder (Cholecystitis) * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Infection With Normal ANC, Kidney * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Infection With Normal ANC, Lung (Pneumonia) * 1    
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)  
# events     1     1  
Infection With Normal ANC, Soft Tissue NOS * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Infection With Unknown ANC, Kidney * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Infection With Unknown ANC, Lung (Pneumonia) * 1    
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)  
# events     1     1  
Metabolism and nutrition disorders      
AST * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Bilirubin (Hyperbilirubinemia) * 1    
# participants affected / at risk     8/500 (1.60%)     4/253 (1.58%)  
# events     11     4  
Hypoalbuminemia * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Hypocalcemia * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Hyponatremia * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Metabolic/Lab - Other * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Musculoskeletal and connective tissue disorders      
Fracture * 1    
# participants affected / at risk     3/500 (0.60%)     2/253 (0.79%)  
# events     3     3  
Gait/Walking * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Muscle Weakness Left-Sided * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Muscle Weakness, Extremity - Lower * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Muscle Weakness, Whole Body/Generalized * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Musculoskeletal - Other * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Myositis * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Nervous system disorders      
Ataxia * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
CNS Ischemia * 1    
# participants affected / at risk     1/500 (0.20%)     2/253 (0.79%)  
# events     2     2  
Cognitive Disturbance * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Confusion * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Dizziness * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Encephalopathy * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Neurology - Other * 1    
# participants affected / at risk     2/500 (0.40%)     3/253 (1.19%)  
# events     3     3  
Neuropathy: Cranial, CN III Pupil, upper Eyelid, extra Ocular Mov * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Neuropathy: Motor * 1    
# participants affected / at risk     3/500 (0.60%)     0/253 (0.00%)  
# events     3     0  
Seizure * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Somnolence * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Speech Impairment * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Syncope (Fainting) * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Renal and urinary disorders      
Cystitis * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Fistula, GU, Bladder * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Obstruction, GU, Ureter * 1    
# participants affected / at risk     2/500 (0.40%)     1/253 (0.40%)  
# events     2     1  
Renal - Other * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Renal Failure * 1    
# participants affected / at risk     5/500 (1.00%)     3/253 (1.19%)  
# events     6     5  
Urinary Retention * 1    
# participants affected / at risk     0/500 (0.00%)     2/253 (0.79%)  
# events     0     2  
Respiratory, thoracic and mediastinal disorders      
ARDS * 1    
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)  
# events     1     1  
Cough * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Dyspnea (Shortness Of Breath) * 1    
# participants affected / at risk     12/500 (2.40%)     4/253 (1.58%)  
# events     18     4  
Pleural Effusion * 1    
# participants affected / at risk     1/500 (0.20%)     3/253 (1.19%)  
# events     2     3  
Pneumonitis * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Pneumothorax * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     3     0  
Pulmonary - Other * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Skin and subcutaneous tissue disorders      
Dermatology - Other * 1    
# participants affected / at risk     0/500 (0.00%)     2/253 (0.79%)  
# events     0     3  
Erythema Multiforme * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Hand-Foot Skin Reaction * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     3     0  
Rash/Desquamation * 1    
# participants affected / at risk     4/500 (0.80%)     1/253 (0.40%)  
# events     7     1  
Wound Complication, Non-Infectious * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Vascular disorders      
Hematoma * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Hemorrhage - Other * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     2     0  
Hemorrhage Pulmonary, Bronchus * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Hemorrhage, GI, Abdomen NOS * 1    
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)  
# events     4     0  
Hemorrhage, GI, Anus * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Hemorrhage, GI, Lower GI NOS * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Hemorrhage, GI, Rectum * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Hemorrhage, GI, Stoma * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Hemorrhage, GI, Varices (Esophageal) * 1    
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)  
# events     0     1  
Hemorrhage, GI, Varices (Rectal) * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     1     0  
Hemorrhage, GU, Vagina * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
Thrombosis/Embolism (Vascular Access) * 1    
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)  
# events     1     1  
Thrombosis/Thrombus/Embolism * 1    
# participants affected / at risk     4/500 (0.80%)     3/253 (1.19%)  
# events     4     5  
Vascular - Other * 1    
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)  
# events     2     0  
* Events were collected by non-systematic assessment
1 Term from vocabulary, NCI-CTCAE v.3.0




  Other Adverse Events
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Time Frame No text entered.
Additional 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)

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

Reporting Groups
  Description
Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Other Adverse Events
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Total, other (not including serious) adverse events      
# participants affected / at risk     489/500     228/253  
Blood and lymphatic system disorders      
Edema: Limb * 1    
# participants affected / at risk     46/500 (9.20%)     16/253 (6.32%)  
# events     53     19  
Hemoglobin * 1    
# participants affected / at risk     70/500 (14.00%)     28/253 (11.07%)  
# events     127     45  
Platelets * 1    
# participants affected / at risk     77/500 (15.40%)     6/253 (2.37%)  
# events     125     9  
Cardiac disorders      
Hypertension * 1    
# participants affected / at risk     152/500 (30.40%)     20/253 (7.91%)  
# events     207     22  
Gastrointestinal disorders      
Anorexia * 1    
# participants affected / at risk     234/500 (46.80%)     72/253 (28.46%)  
# events     352     95  
Constipation * 1    
# participants affected / at risk     119/500 (23.80%)     48/253 (18.97%)  
# events     146     58  
Diarrhea * 1    
# participants affected / at risk     214/500 (42.80%)     44/253 (17.39%)  
# events     436     57  
Mucositis (Functional/Symptomatic), Oral Cavity * 1    
# participants affected / at risk     144/500 (28.80%)     12/253 (4.74%)  
# events     257     12  
Nausea * 1    
# participants affected / at risk     112/500 (22.40%)     55/253 (21.74%)  
# events     149     67  
Taste Alteration * 1    
# participants affected / at risk     37/500 (7.40%)     6/253 (2.37%)  
# events     40     6  
Vomiting * 1    
# participants affected / at risk     80/500 (16.00%)     41/253 (16.21%)  
# events     112     50  
General disorders      
Constitutional Symptoms - Other * 1    
# participants affected / at risk     29/500 (5.80%)     17/253 (6.72%)  
# events     36     19  
Fatigue * 1    
# participants affected / at risk     316/500 (63.20%)     116/253 (45.85%)  
# events     584     168  
Fever * 1    
# participants affected / at risk     133/500 (26.60%)     39/253 (15.42%)  
# events     183     47  
Flu-Like Syndrome * 1    
# participants affected / at risk     25/500 (5.00%)     6/253 (2.37%)  
# events     28     8  
Insomnia * 1    
# participants affected / at risk     39/500 (7.80%)     14/253 (5.53%)  
# events     43     15  
Pain, Abdomen NOS * 1    
# participants affected / at risk     118/500 (23.60%)     47/253 (18.58%)  
# events     194     53  
Pain, Back * 1    
# participants affected / at risk     74/500 (14.80%)     24/253 (9.49%)  
# events     107     26  
Pain, Extremity - Limb * 1    
# participants affected / at risk     47/500 (9.40%)     14/253 (5.53%)  
# events     77     19  
Pain, Head/Headache * 1    
# participants affected / at risk     50/500 (10.00%)     18/253 (7.11%)  
# events     63     23  
Pain, Joint * 1    
# participants affected / at risk     31/500 (6.20%)     13/253 (5.14%)  
# events     32     14  
Pain, Muscle * 1    
# participants affected / at risk     49/500 (9.80%)     14/253 (5.53%)  
# events     63     16  
Weight Loss * 1    
# participants affected / at risk     162/500 (32.40%)     28/253 (11.07%)  
# events     220     32  
Metabolism and nutrition disorders      
ALT * 1    
# participants affected / at risk     27/500 (5.40%)     5/253 (1.98%)  
# events     49     5  
AST * 1    
# participants affected / at risk     35/500 (7.00%)     9/253 (3.56%)  
# events     67     9  
Alkaline Phosphatase * 1    
# participants affected / at risk     32/500 (6.40%)     8/253 (3.16%)  
# events     44     12  
Bilirubin (Hyperbilirubinemia) * 1    
# participants affected / at risk     95/500 (19.00%)     22/253 (8.70%)  
# events     156     37  
Hypocalcemia * 1    
# participants affected / at risk     33/500 (6.60%)     1/253 (0.40%)  
# events     51     1  
Hypokalemia * 1    
# participants affected / at risk     46/500 (9.20%)     5/253 (1.98%)  
# events     58     6  
Hyponatremia * 1    
# participants affected / at risk     29/500 (5.80%)     6/253 (2.37%)  
# events     40     10  
Hypophosphatemia * 1    
# participants affected / at risk     32/500 (6.40%)     2/253 (0.79%)  
# events     55     3  
Lipase * 1    
# participants affected / at risk     31/500 (6.20%)     3/253 (1.19%)  
# events     70     4  
Metabolic/Lab - Other * 1    
# participants affected / at risk     37/500 (7.40%)     8/253 (3.16%)  
# events     60     14  
Proteinuria * 1    
# participants affected / at risk     40/500 (8.00%)     6/253 (2.37%)  
# events     89     11  
Nervous system disorders      
Dizziness * 1    
# participants affected / at risk     26/500 (5.20%)     13/253 (5.14%)  
# events     29     13  
Neuropathy: Sensory * 1    
# participants affected / at risk     50/500 (10.00%)     25/253 (9.88%)  
# events     66     27  
Respiratory, thoracic and mediastinal disorders      
Cough * 1    
# participants affected / at risk     55/500 (11.00%)     28/253 (11.07%)  
# events     76     32  
Dyspnea (Shortness Of Breath) * 1    
# participants affected / at risk     85/500 (17.00%)     33/253 (13.04%)  
# events     103     45  
Voice Changes * 1    
# participants affected / at risk     160/500 (32.00%)     16/253 (6.32%)  
# events     205     17  
Skin and subcutaneous tissue disorders      
Alopecia * 1    
# participants affected / at risk     39/500 (7.80%)     4/253 (1.58%)  
# events     43     4  
Dermatology - Other * 1    
# participants affected / at risk     29/500 (5.80%)     6/253 (2.37%)  
# events     43     8  
Dry Skin * 1    
# participants affected / at risk     50/500 (10.00%)     10/253 (3.95%)  
# events     59     11  
Hand-Foot Skin Reaction * 1    
# participants affected / at risk     234/500 (46.80%)     19/253 (7.51%)  
# events     685     21  
Pruritus * 1    
# participants affected / at risk     27/500 (5.40%)     11/253 (4.35%)  
# events     36     11  
Rash/Desquamation * 1    
# participants affected / at risk     142/500 (28.40%)     13/253 (5.14%)  
# events     207     17  
Vascular disorders      
Hemorrhage Pulmonary, Nose * 1    
# participants affected / at risk     45/500 (9.00%)     6/253 (2.37%)  
# events     54     6  
* Events were collected by non-systematic assessment
1 Term from vocabulary, NCI-CTCAE v.3.0



  Limitations and Caveats
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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
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.


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