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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: November 10, 2014
Last verified: November 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. Period 1 is placebo and placebo-regorafenib with placebo period only before unblinding. Period 2 is placebo-regorafenib with regorafenib period only.

Participant Flow for 2 periods

Period 1:   Period 1 Without/Before Drug Switch
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
STARTED     505     255  
Participants Received Treatment     500     253  
COMPLETED     429     237  
NOT COMPLETED     76     18  
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 2:   Period 2 Switched From Pla to Reg
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
STARTED     0     4 [1]
COMPLETED     0     3  
NOT COMPLETED     0     1  
Adverse Event                 0                 1  
[1] Participants in the placebo + BSC group switched to Regorafenib treatment after unblinding.



  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). ]

Measure Type Primary
Measure Title Overall Survival
Measure 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).  
Safety Issue No  

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.
Intent to treat (ITT)

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

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  505     255  
Overall Survival  
[units: Days]
Median ( 95% Confidence Interval )
  196  
  ( 178 to 222 )  
  151  
  ( 134 to 177 )  


Statistical Analysis 1 for Overall Survival
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.005178
Hazard Ratio (HR) [4] 0.774
95% Confidence Interval ( 0.636 to 0.942 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  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).
[4] Other relevant estimation information:
  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:   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. ]

Measure Type Secondary
Measure Title Progression-free Survival (Based on Investigator’s Assessment)
Measure 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 (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.  
Safety Issue No  

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.
ITT

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

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  505     255  
Progression-free Survival (Based on Investigator’s Assessment)  
[units: Days]
Median ( 95% Confidence Interval )
  59  
  ( 57 to 65 )  
  52  
  ( 51 to 53 )  


Statistical Analysis 1 for Progression-free Survival (Based on Investigator’s Assessment)
Groups [1] All groups
Method [2] Log Rank
P Value [3] <0.000001
Hazard Ratio (HR) [4] 0.494
95% Confidence Interval ( 0.419 to 0.582 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Comparison based on pre-specified alpha level of 0.025 (1-sided).
[4] Other relevant estimation information:
  Hazard ratio (Regorafenib / Placebo)



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. ]

Measure Type Secondary
Measure Title Objective Tumor Response
Measure 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 (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.  
Safety Issue No  

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.
ITT

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

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  505     255  
Objective Tumor Response  
[units: Percentage of participants]
  1.0     0.4  


Statistical Analysis 1 for Objective Tumor Response
Groups [1] All groups
Method [2] Cochran-Mantel-Haenszel
P Value [3] 0.188432
Difference [4] -0.60
95% Confidence Interval ( -1.74 to 0.53 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Comparison based on pre-specified alpha level of 0.025 (1-sided).
[4] Other relevant estimation information:
  Difference = Placebo - Regorafenib 160 mg



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. ]

Measure Type Secondary
Measure Title Disease Control
Measure 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 (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.  
Safety Issue No  

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.
ITT

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

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  505     255  
Disease Control  
[units: Percentage of participants]
  41.0     14.9  


Statistical Analysis 1 for Disease Control
Groups [1] All groups
Method [2] Cochran-Mantel-Haenszel
P Value [3] <0.000001
Difference [4] -25.94
95% Confidence Interval ( -32.06 to -19.82 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Comparison based on pre-specified alpha level of 0.025 (1-sided).
[4] Other relevant estimation information:
  Difference = Placebo - Regorafenib 160 mg



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. ]

Measure Type Secondary
Measure Title Tumor Response
Measure 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 (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.  
Safety Issue No  

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.
ITT

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

Measured Values
    Regorafenib (Stivarga, BAY73-4506)     Placebo  
Number of Participants Analyzed  
[units: participants]
  505     255  
Tumor Response  
[units: 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  

No statistical analysis provided for Tumor Response




  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame AE was collected up to 30 days after end of study treatment (per protocol) over a period of approximately 3.7 years.
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 (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. It is for placebo period only before unblinding.
Placebo - Regorafenib After Unblinding Participants in the placebo + BSC group switched to treatment with Regorafenib after unblinding. It is for Regorafenib treatment period only

Serious Adverse Events
    Regorafenib (BAY73-4506)     Placebo     Placebo - Regorafenib After Unblinding  
Total, serious adverse events        
# participants affected / at risk     232/500 (46.40%)     103/253 (40.71%)     2/4 (50.00%)  
Blood and lymphatic system disorders        
DIC * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Edema: Limb * 1      
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)     0/4 (0.00%)  
# events     1     1     0  
Edema: Trunk/Genital * 1      
# participants affected / at risk     0/500 (0.00%)     2/253 (0.79%)     0/4 (0.00%)  
# events     0     4     0  
Edema: Viscera * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     3     0  
Hemoglobin * 1      
# participants affected / at risk     4/500 (0.80%)     2/253 (0.79%)     0/4 (0.00%)  
# events     8     2     0  
INR * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     5     0     0  
Neutrophils * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Platelets * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Thrombotic microangiopathy * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Cardiac disorders        
Cardiac arrhythmia - Other * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Cardiac ischemia/infarction * 1      
# participants affected / at risk     6/500 (1.20%)     1/253 (0.40%)     0/4 (0.00%)  
# events     6     2     0  
Hypertension * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Hypotension * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Left ventricular systolic dysfunction * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     3     0     0  
Supraventricular arrhythmia, Atrial fibrillation * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
cTnT * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Eye disorders        
Diplopia * 1      
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)     0/4 (0.00%)  
# events     1     1     0  
Ocular - Other * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Gastrointestinal disorders        
Anorexia * 1      
# participants affected / at risk     5/500 (1.00%)     2/253 (0.79%)     0/4 (0.00%)  
# events     8     2     0  
Ascites * 1      
# participants affected / at risk     1/500 (0.20%)     2/253 (0.79%)     1/4 (25.00%)  
# events     2     2     1  
Constipation * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Dehydration * 1      
# participants affected / at risk     3/500 (0.60%)     2/253 (0.79%)     0/4 (0.00%)  
# events     3     2     0  
Diarrhea * 1      
# participants affected / at risk     8/500 (1.60%)     0/253 (0.00%)     0/4 (0.00%)  
# events     9     0     0  
Distension * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Enteritis * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Fistula, GI, Abdomen NOS * 1      
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)     0/4 (0.00%)  
# events     2     1     0  
Fistula, GI, Anus * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Fistula, GI, Small bowel NOS * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
GI - Other * 1      
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)     0/4 (0.00%)  
# events     1     1     0  
Hemorrhoids * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Ileus * 1      
# participants affected / at risk     2/500 (0.40%)     3/253 (1.19%)     0/4 (0.00%)  
# events     3     3     0  
Mucositis (functional/symptomatic), Small bowel * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Necrosis, GI, Peritoneal cavity * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Obstruction, GI, Colon * 1      
# participants affected / at risk     9/500 (1.80%)     6/253 (2.37%)     0/4 (0.00%)  
# events     11     8     0  
Obstruction, GI, Ileum * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Obstruction, GI, Small bowel NOS * 1      
# participants affected / at risk     4/500 (0.80%)     7/253 (2.77%)     0/4 (0.00%)  
# events     5     9     0  
Obstruction, GI, Stomach * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Perforation, GI, Colon * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Stricture, GI, Biliary tree * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Ulcer, GI, Duodenum * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Vomiting * 1      
# participants affected / at risk     3/500 (0.60%)     0/253 (0.00%)     1/4 (25.00%)  
# events     3     0     1  
General disorders        
Constitutional symptoms - Other * 1      
# participants affected / at risk     34/500 (6.80%)     23/253 (9.09%)     0/4 (0.00%)  
# events     49     39     0  
Death not associated with CTCAE term, Disease progression NOS * 1      
# participants affected / at risk     16/500 (3.20%)     6/253 (2.37%)     1/4 (25.00%)  
# events     17     6     1  
Death not associated with CTCAE term, Multi-Organ Failure * 1      
# participants affected / at risk     4/500 (0.80%)     1/253 (0.40%)     0/4 (0.00%)  
# events     4     1     0  
Death not associated with CTCAE term, Sudden death * 1      
# participants affected / at risk     2/500 (0.40%)     2/253 (0.79%)     0/4 (0.00%)  
# events     2     2     0  
Fatigue * 1      
# participants affected / at risk     5/500 (1.00%)     5/253 (1.98%)     0/4 (0.00%)  
# events     6     5     0  
Fever * 1      
# participants affected / at risk     17/500 (3.40%)     2/253 (0.79%)     0/4 (0.00%)  
# events     21     2     0  
Pain, Abdomen NOS * 1      
# participants affected / at risk     13/500 (2.60%)     2/253 (0.79%)     0/4 (0.00%)  
# events     21     2     0  
Pain, Back * 1      
# participants affected / at risk     4/500 (0.80%)     4/253 (1.58%)     0/4 (0.00%)  
# events     6     5     0  
Pain, Buttock * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     4     0     0  
Pain, Cardiac/Heart * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Pain, Chest wall * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Pain, Chest/Thorax NOS * 1      
# participants affected / at risk     4/500 (0.80%)     1/253 (0.40%)     0/4 (0.00%)  
# events     4     1     0  
Pain, Extremity - limb * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     6     0     0  
Pain, Head/Headache * 1      
# participants affected / at risk     2/500 (0.40%)     1/253 (0.40%)     0/4 (0.00%)  
# events     2     1     0  
Pain, Joint * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Pain, Liver * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Pain, Neuralgia/Peripheral nerve * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Pain, Pain NOS * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Pain, Tumor pain * 1      
# participants affected / at risk     3/500 (0.60%)     1/253 (0.40%)     0/4 (0.00%)  
# events     3     1     0  
Syndromes - Other * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Tumor flare * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Weight loss * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Hepatobiliary disorders        
Cholecystitis * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Hepatobiliary - Other * 1      
# participants affected / at risk     2/500 (0.40%)     1/253 (0.40%)     0/4 (0.00%)  
# events     2     1     0  
Liver dysfunction * 1      
# participants affected / at risk     17/500 (3.40%)     5/253 (1.98%)     0/4 (0.00%)  
# events     28     11     0  
Immune system disorders        
Allergic reaction * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     4     0     0  
Infections and infestations        
Infection (documented clinically), Abdomen NOS * 1      
# participants affected / at risk     4/500 (0.80%)     0/253 (0.00%)     0/4 (0.00%)  
# events     4     0     0  
Infection (documented clinically), Anal/perianal * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Infection (documented clinically), Appendix * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Infection (documented clinically), Bladder (urinary) * 1      
# participants affected / at risk     2/500 (0.40%)     1/253 (0.40%)     0/4 (0.00%)  
# events     2     1     0  
Infection (documented clinically), Blood * 1      
# participants affected / at risk     3/500 (0.60%)     2/253 (0.79%)     0/4 (0.00%)  
# events     5     2     0  
Infection (documented clinically), Bronchus * 1      
# participants affected / at risk     3/500 (0.60%)     0/253 (0.00%)     0/4 (0.00%)  
# events     3     0     0  
Infection (documented clinically), Catheter-related * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Infection (documented clinically), Kidney * 1      
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)     0/4 (0.00%)  
# events     1     1     0  
Infection (documented clinically), Lung (Pneumonia) * 1      
# participants affected / at risk     9/500 (1.80%)     3/253 (1.19%)     0/4 (0.00%)  
# events     11     4     0  
Infection (documented clinically), Skin (Cellulitis) * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Infection (documented clinically), Soft tissue NOS * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Infection (documented clinically), Urinary tract NOS * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Infection (documented clinically), Wound * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Infection - Other * 1      
# participants affected / at risk     5/500 (1.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     6     2     0  
Infection with normal ANC, Blood * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Infection with normal ANC, Catheter-related * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Infection with normal ANC, Colon * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Infection with normal ANC, Gallbladder (Cholecystitis) * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Infection with normal ANC, Kidney * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Infection with normal ANC, Lung (Pneumonia) * 1      
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)     0/4 (0.00%)  
# events     1     1     0  
Infection with normal ANC, Soft tissue NOS * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Infection with unknown ANC, Kidney * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Infection with unknown ANC, Lung (Pneumonia) * 1      
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)     0/4 (0.00%)  
# events     1     1     0  
Metabolism and nutrition disorders        
AST * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Bilirubin (Hyperbilirubinemia) * 1      
# participants affected / at risk     8/500 (1.60%)     3/253 (1.19%)     0/4 (0.00%)  
# events     11     3     0  
Hypoalbuminemia * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Hypocalcemia * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Hyponatremia * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Metabolic/Lab - Other * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Musculoskeletal and connective tissue disorders        
Fracture * 1      
# participants affected / at risk     4/500 (0.80%)     2/253 (0.79%)     0/4 (0.00%)  
# events     4     3     0  
Gait/Walking * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Muscle weakness left-sided * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Muscle weakness, Extremity - lower * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Muscle weakness, Whole body/generalized * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Musculoskeletal - Other * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Myositis * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)        
Secondary malignancy (possibly related to cancer treatment) * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Nervous system disorders        
Ataxia * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
CNS ischemia * 1      
# participants affected / at risk     1/500 (0.20%)     2/253 (0.79%)     0/4 (0.00%)  
# events     2     2     0  
Cognitive disturbance * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Confusion * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Dizziness * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Encephalopathy * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Mood Alteration, Anxiety * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Neurology - Other * 1      
# participants affected / at risk     3/500 (0.60%)     2/253 (0.79%)     0/4 (0.00%)  
# events     4     2     0  
Neuropathy: Cranial, CN III Pupil, upper eyelid, extra ocular mov * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Neuropathy: motor * 1      
# participants affected / at risk     3/500 (0.60%)     0/253 (0.00%)     0/4 (0.00%)  
# events     3     0     0  
Seizure * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Somnolence * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Speech impairment * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Syncope (Fainting) * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Renal and urinary disorders        
Cystitis * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Fistula, GU, Bladder * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Obstruction, GU, Ureter * 1      
# participants affected / at risk     2/500 (0.40%)     1/253 (0.40%)     0/4 (0.00%)  
# events     2     1     0  
Renal - Other * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Renal failure * 1      
# participants affected / at risk     5/500 (1.00%)     3/253 (1.19%)     0/4 (0.00%)  
# events     6     5     0  
Urinary retention * 1      
# participants affected / at risk     0/500 (0.00%)     2/253 (0.79%)     0/4 (0.00%)  
# events     0     2     0  
Respiratory, thoracic and mediastinal disorders        
ARDS * 1      
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)     0/4 (0.00%)  
# events     1     1     0  
Cough * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Dyspnea (Shortness of breath) * 1      
# participants affected / at risk     12/500 (2.40%)     4/253 (1.58%)     0/4 (0.00%)  
# events     18     4     0  
Pleural effusion * 1      
# participants affected / at risk     1/500 (0.20%)     4/253 (1.58%)     0/4 (0.00%)  
# events     2     4     0  
Pneumonitis * 1      
# participants affected / at risk     1/500 (0.20%)     1/253 (0.40%)     0/4 (0.00%)  
# events     2     1     0  
Pneumothorax * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     3     0     0  
Pulmonary - Other * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Skin and subcutaneous tissue disorders        
Dermatology - Other * 1      
# participants affected / at risk     1/500 (0.20%)     2/253 (0.79%)     0/4 (0.00%)  
# events     2     3     0  
Erythema multiforme * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Hand-foot skin reaction * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     3     0     0  
Rash/Desquamation * 1      
# participants affected / at risk     4/500 (0.80%)     1/253 (0.40%)     0/4 (0.00%)  
# events     7     1     0  
Wound complication, non-infectious * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Vascular disorders        
Hematoma * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Hemorrhage - Other * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Hemorrhage pulmonary, Bronchus * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Hemorrhage pulmonary, Mediastinum * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Hemorrhage, GI, Abdomen NOS * 1      
# participants affected / at risk     2/500 (0.40%)     0/253 (0.00%)     0/4 (0.00%)  
# events     4     0     0  
Hemorrhage, GI, Anus * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Hemorrhage, GI, Lower GI NOS * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Hemorrhage, GI, Rectum * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Hemorrhage, GI, Stoma * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Hemorrhage, GI, Upper GI NOS * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Hemorrhage, GI, Varices (esophageal) * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Hemorrhage, GI, Varices (rectal) * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     1     0     0  
Hemorrhage, GU, Vagina * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
Thrombosis/Embolism (vascular access) * 1      
# participants affected / at risk     0/500 (0.00%)     1/253 (0.40%)     0/4 (0.00%)  
# events     0     1     0  
Thrombosis/Thrombus/Embolism * 1      
# participants affected / at risk     6/500 (1.20%)     3/253 (1.19%)     0/4 (0.00%)  
# events     6     5     0  
Vascular - Other * 1      
# participants affected / at risk     1/500 (0.20%)     0/253 (0.00%)     0/4 (0.00%)  
# events     2     0     0  
* Events were collected by non-systematic assessment
1 Term from vocabulary, NCI-CTCAE v.3.0




  Other Adverse Events


  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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