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

This study is ongoing, but not recruiting participants.

Sponsor:

Information provided by:

Bayer

ClinicalTrials.gov Identifier:

NCT01103323

First received: April 8, 2010

Last updated: April 12, 2013

Last verified: April 2013

History of Changes

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
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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. ]

Show Outcome Measure 2

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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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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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

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Other Adverse Events

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Time Frame	No text entered.
Additional Description	No text entered.

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

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

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