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

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

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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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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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. ]

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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 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. ]

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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 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. ]

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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. ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The agreed point of publication is 12-18 months after database lock at the earliest. Bayer will have 30-45 days to review publications, and may request an additional publication delay of up to 60 days to allow for filing a Patent Application (if applicable). No publication of single center data should be done prior of publication if multi-center data.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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.

Results Point of Contact:

Name/Title: Therapeutic Area Head
Organization: BAYER
e-mail: clinical-trials-contact@bayerhealthcare.com

No publications provided by Bayer

Publications automatically indexed to this study:

Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.

Mross K, Frost A, Steinbild S, Hedbom S, Büchert M, Fasol U, Unger C, Krätzschmar J, Heinig R, Boix O, Christensen O. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012 May 1;18(9):2658-67. Epub 2012 Mar 15.

Responsible Party:	Therapeutic Area Head, Bayer HealthCare Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:	NCT01103323 History of Changes
Other Study ID Numbers:	14387, 2009-012787-14
Study First Received:	April 8, 2010
Results First Received:	October 19, 2012
Last Updated:	April 12, 2013
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Italy: National Institute of Health United Kingdom: Medicines and Healthcare Products Regulatory Agency Czech Republic: State Institute for Drug Control Hungary: National Institute of Pharmacy Australia: Department of Health and Ageing Therapeutic Goods Administration China: Food and Drug Administration Japan: Pharmaceuticals and Medical Devices Agency Brazil: National Health Surveillance Agency Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica Switzerland: Swissmedic Canada: Health Canada Spain: Spanish Agency of Medicines Portugal: National Pharmacy and Medicines Institute Turkey: Ministry of Health Israel: Ministry of Health Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) Belgium: Federal Agency for Medicinal Products and Health Products United States: Food and Drug Administration