Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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). ]
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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. ]

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


  Other Adverse Events
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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)

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

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

Other Adverse Events
    Regorafenib (BAY73-4506)     Placebo     Placebo - Regorafenib After Unblinding  
Total, other (not including serious) adverse events        
# participants affected / at risk     489/500     229/253     4/4  
Blood and lymphatic system disorders        
Edema: Limb * 1      
# participants affected / at risk     49/500 (9.80%)     16/253 (6.32%)     0/4 (0.00%)  
# events     57     19     0  
Hemoglobin * 1      
# participants affected / at risk     76/500 (15.20%)     29/253 (11.46%)     0/4 (0.00%)  
# events     142     46     0  
Platelets * 1      
# participants affected / at risk     79/500 (15.80%)     6/253 (2.37%)     1/4 (25.00%)  
# events     136     9     2  
Cardiac disorders        
Hypertension * 1      
# participants affected / at risk     155/500 (31.00%)     21/253 (8.30%)     1/4 (25.00%)  
# events     213     23     1  
Endocrine disorders        
Hypothyroidism * 1      
# participants affected / at risk     27/500 (5.40%)     1/253 (0.40%)     1/4 (25.00%)  
# events     29     1     1  
Eye disorders        
Ocular - Other * 1      
# participants affected / at risk     5/500 (1.00%)     0/253 (0.00%)     1/4 (25.00%)  
# events     5     0     1  
Gastrointestinal disorders        
Anorexia * 1      
# participants affected / at risk     239/500 (47.80%)     73/253 (28.85%)     0/4 (0.00%)  
# events     388     96     0  
Ascites * 1      
# participants affected / at risk     23/500 (4.60%)     6/253 (2.37%)     1/4 (25.00%)  
# events     24     8     1  
Constipation * 1      
# participants affected / at risk     119/500 (23.80%)     48/253 (18.97%)     0/4 (0.00%)  
# events     147     58     0  
Diarrhea * 1      
# participants affected / at risk     218/500 (43.60%)     44/253 (17.39%)     2/4 (50.00%)  
# events     514     57     2  
Fistula, GI, Colon/Cecum/Appendix * 1      
# participants affected / at risk     0/500 (0.00%)     0/253 (0.00%)     1/4 (25.00%)  
# events     0     0     1  
Mucositis (functional/symptomatic), Oral cavity * 1      
# participants affected / at risk     145/500 (29.00%)     12/253 (4.74%)     0/4 (0.00%)  
# events     267     12     0  
Nausea * 1      
# participants affected / at risk     115/500 (23.00%)     55/253 (21.74%)     1/4 (25.00%)  
# events     162     67     1  
Taste alteration * 1      
# participants affected / at risk     39/500 (7.80%)     6/253 (2.37%)     0/4 (0.00%)  
# events     44     6     0  
Vomiting * 1      
# participants affected / at risk     85/500 (17.00%)     41/253 (16.21%)     1/4 (25.00%)  
# events     144     50     3  
General disorders        
Constitutional symptoms - Other * 1      
# participants affected / at risk     30/500 (6.00%)     17/253 (6.72%)     0/4 (0.00%)  
# events     33     19     0  
Fatigue * 1      
# participants affected / at risk     318/500 (63.60%)     115/253 (45.45%)     0/4 (0.00%)  
# events     612     168     0  
Fever * 1      
# participants affected / at risk     136/500 (27.20%)     40/253 (15.81%)     2/4 (50.00%)  
# events     189     48     3  
Flu-like syndrome * 1      
# participants affected / at risk     27/500 (5.40%)     6/253 (2.37%)     1/4 (25.00%)  
# events     30     8     1  
Insomnia * 1      
# participants affected / at risk     39/500 (7.80%)     14/253 (5.53%)     0/4 (0.00%)  
# events     43     15     0  
Pain, Abdomen NOS * 1      
# participants affected / at risk     121/500 (24.20%)     47/253 (18.58%)     0/4 (0.00%)  
# events     239     53     0  
Pain, Back * 1      
# participants affected / at risk     79/500 (15.80%)     25/253 (9.88%)     0/4 (0.00%)  
# events     114     27     0  
Pain, Buttock * 1      
# participants affected / at risk     4/500 (0.80%)     0/253 (0.00%)     1/4 (25.00%)  
# events     5     0     1  
Pain, Chest/Thorax NOS * 1      
# participants affected / at risk     26/500 (5.20%)     12/253 (4.74%)     0/4 (0.00%)  
# events     29     14     0  
Pain, Extremity - limb * 1      
# participants affected / at risk     51/500 (10.20%)     14/253 (5.53%)     0/4 (0.00%)  
# events     83     19     0  
Pain, Head/Headache * 1      
# participants affected / at risk     50/500 (10.00%)     18/253 (7.11%)     0/4 (0.00%)  
# events     65     23     0  
Pain, Joint * 1      
# participants affected / at risk     32/500 (6.40%)     13/253 (5.14%)     0/4 (0.00%)  
# events     34     14     0  
Pain, Muscle * 1      
# participants affected / at risk     50/500 (10.00%)     14/253 (5.53%)     0/4 (0.00%)  
# events     64     16     0  
Pain, Throat/Pharynx/Larynx * 1      
# participants affected / at risk     9/500 (1.80%)     1/253 (0.40%)     1/4 (25.00%)  
# events     12     1     1  
Weight loss * 1      
# participants affected / at risk     167/500 (33.40%)     30/253 (11.86%)     2/4 (50.00%)  
# events     240     34     7  
Hepatobiliary disorders        
Hepatobiliary - Other * 1      
# participants affected / at risk     8/500 (1.60%)     4/253 (1.58%)     1/4 (25.00%)  
# events     9     4     3  
Metabolism and nutrition disorders        
ALT * 1      
# participants affected / at risk     28/500 (5.60%)     7/253 (2.77%)     0/4 (0.00%)  
# events     53     8     0  
AST * 1      
# participants affected / at risk     37/500 (7.40%)     12/253 (4.74%)     0/4 (0.00%)  
# events     72     13     0  
Alkaline phosphatase * 1      
# participants affected / at risk     35/500 (7.00%)     8/253 (3.16%)     0/4 (0.00%)  
# events     49     12     0  
Bilirubin (Hyperbilirubinemia) * 1      
# participants affected / at risk     97/500 (19.40%)     22/253 (8.70%)     1/4 (25.00%)  
# events     160     37     3  
Creatinine * 1      
# participants affected / at risk     15/500 (3.00%)     7/253 (2.77%)     1/4 (25.00%)  
# events     19     8     2  
GFR * 1      
# participants affected / at risk     4/500 (0.80%)     1/253 (0.40%)     1/4 (25.00%)  
# events     9     2     1  
Hyperuricemia * 1      
# participants affected / at risk     12/500 (2.40%)     1/253 (0.40%)     1/4 (25.00%)  
# events     13     1     1  
Hypocalcemia * 1      
# participants affected / at risk     34/500 (6.80%)     1/253 (0.40%)     0/4 (0.00%)  
# events     57     1     0  
Hypokalemia * 1      
# participants affected / at risk     50/500 (10.00%)     6/253 (2.37%)     0/4 (0.00%)  
# events     84     7     0  
Hyponatremia * 1      
# participants affected / at risk     32/500 (6.40%)     6/253 (2.37%)     0/4 (0.00%)  
# events     43     10     0  
Hypophosphatemia * 1      
# participants affected / at risk     32/500 (6.40%)     2/253 (0.79%)     1/4 (25.00%)  
# events     62     3     2  
Lipase * 1      
# participants affected / at risk     32/500 (6.40%)     3/253 (1.19%)     0/4 (0.00%)  
# events     74     4     0  
Metabolic/Lab - Other * 1      
# participants affected / at risk     42/500 (8.40%)     8/253 (3.16%)     0/4 (0.00%)  
# events     69     15     0  
Proteinuria * 1      
# participants affected / at risk     40/500 (8.00%)     6/253 (2.37%)     0/4 (0.00%)  
# events     109     11     0  
Nervous system disorders        
Dizziness * 1      
# participants affected / at risk     28/500 (5.60%)     13/253 (5.14%)     0/4 (0.00%)  
# events     31     13     0  
Neuropathy: sensory * 1      
# participants affected / at risk     51/500 (10.20%)     25/253 (9.88%)     0/4 (0.00%)  
# events     68     27     0  
Respiratory, thoracic and mediastinal disorders        
Cough * 1      
# participants affected / at risk     56/500 (11.20%)     28/253 (11.07%)     1/4 (25.00%)  
# events     77     32     1  
Dyspnea (Shortness of breath) * 1      
# participants affected / at risk     89/500 (17.80%)     34/253 (13.44%)     0/4 (0.00%)  
# events     110     46     0  
Voice changes * 1      
# participants affected / at risk     160/500 (32.00%)     16/253 (6.32%)     1/4 (25.00%)  
# events     211     17     1  
Skin and subcutaneous tissue disorders        
Alopecia * 1      
# participants affected / at risk     39/500 (7.80%)     4/253 (1.58%)     0/4 (0.00%)  
# events     43     4     0  
Cheilitis * 1      
# participants affected / at risk     4/500 (0.80%)     0/253 (0.00%)     1/4 (25.00%)  
# events     4     0     3  
Dermatology - Other * 1      
# participants affected / at risk     30/500 (6.00%)     7/253 (2.77%)     0/4 (0.00%)  
# events     45     10     0  
Dry skin * 1      
# participants affected / at risk     50/500 (10.00%)     10/253 (3.95%)     0/4 (0.00%)  
# events     59     11     0  
Hand-foot skin reaction * 1      
# participants affected / at risk     235/500 (47.00%)     19/253 (7.51%)     1/4 (25.00%)  
# events     720     21     3  
Pruritus * 1      
# participants affected / at risk     29/500 (5.80%)     11/253 (4.35%)     0/4 (0.00%)  
# events     39     11     0  
Rash/Desquamation * 1      
# participants affected / at risk     145/500 (29.00%)     13/253 (5.14%)     1/4 (25.00%)  
# events     211     17     2  
Vascular disorders        
Hemorrhage pulmonary, Nose * 1      
# participants affected / at risk     45/500 (9.00%)     6/253 (2.37%)     0/4 (0.00%)  
# events     55     6     0  
* 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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