GRID: Study of Regorafenib as a 3rd-line or Beyond Treatment for Gastrointestinal Stromal Tumors (GIST)

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01271712
• Collaborator: (none)
• Enrollment: 199
• Locations: 57
• Arms: 2
• Actual Duration (Months): 99.3
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

A randomized, double-blind, placebo-controlled phase III study of regorafenib plus best supportive care versus placebo plus best supportive care for subjects with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite prior treatment with at least imatinib and sunitinib.

The study is composed of 3 periods: A Screening Period, a Treatment Period, and a Survival Follow up Period.

Subjects randomized to be treated with regorafenib will receive 160 mg po od for 3 weeks of every 4 week (28 day) cycle (ie, 3 weeks on/1 week off). In addition subjects will receive best supportive care which excludes any disease specific anti cancer therapy such as any kinase inhibitor, chemotherapy, radiation therapy, or surgery.

Tumor assessment will be every 4 weeks for the first 3 months, every 6 weeks for the next 3 months (through month 6), and every 8 weeks until the end of treatment, or more frequently if clinically indicated. Tumor assessments include CT or MRI and will be performed until tumor progression is seen in a central radiology review.

Subjects receiving placebo who experience disease progression may be offered active treatment.

Subjects who experience progression during regorafenib treatment may continue open label treatment.

All subjects will enter the Survival Follow-up Period upon discontinuation of randomized study treatment.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Stromal Tumors	Drug: Regorafenib (Stivarga, BAY73-4506); Drug: Placebo; Drug: Best supportive care	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 199 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Phase III Study of Regorafenib Plus Best Supportive Care Versus Placebo Plus Best Supportive Care for Subjects With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GIST) Whose Disease Has Progressed Despite Prior Treatment With at Least Imatinib and Sunitinib
• Actual Study Start Date: Jan 4, 2011
• Actual Primary Completion Date: Jan 26, 2012
• Actual Study Completion Date: Apr 15, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regorafenib (Stivarga, BAY73-4506) Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Drug: Regorafenib (Stivarga, BAY73-4506); 160 mg po once daily (od), 3 weeks on/1 week off. Route of administration: oral; Drug: Best supportive care; Best supportive care includes any method to preserve the comfort and dignity of the patients, and excludes any disease-specific anti-neoplastic therapy such as any kinase inhibitor, chemotherapy, radiation therapy, or surgical intervention.
Placebo Comparator: Placebo Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Drug: Placebo; once daily (od), 3 weeks on/1 week off. Route of administration: oral; Drug: Best supportive care; Best supportive care includes any method to preserve the comfort and dignity of the patients, and excludes any disease-specific anti-neoplastic therapy such as any kinase inhibitor, chemotherapy, radiation therapy, or surgical intervention.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [From randomization of the first subject until approximately 144 progression-free survival events had occurred (study duration approximately one year)]

   Progression-free Survival (PFS) was defined as the time from date of randomization to radiological disease progression or death due to any cause, whichever occurs first. PFS was based on central radiological assessment using modified RECIST (Response Evaluation Criteria in Solid Tumors) v.1.1. Progression is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study; or unequivocal progression of existing non-target lesions; or appearance of new lesions. Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation. Results are based on central evaluation.

Secondary Outcome Measures

1. Overall Survival [From randomization of the first subject until date of database cutoff (08 Jun 2015)]

   Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their date of last contact. Median OS was not observed at the time of PFS analysis and first analysis of OS, therefore only the proportion of death events was reported in the results posting system. This approach was maintained for the subsequent updates in the results posting system.

2. Time to Progression (TTP) [From randomization of the first subject until until date of database cutoff (26 Jan 2012); study duration approximately 1 year]

   Time to progression (TTP) was defined as the time from date of randomization to disease progression (based on central radiological assessment using modified RECIST [Response Evaluation Criteria in Solid Tumors] v.1.1). Progression is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study; or unequivocal progression of existing non-target lesions; or appearance of new lesions. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation. Results are based on central evaluation.

3. Tumor Response [From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year]

   Tumor Response of a subject was defined as the best tumor response (Complete Response [CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).], Partial Response [PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.], Stable Disease [SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.], or Progressive Disease [PD: at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study or unequivocal progression of existing non-target lesions, or appearance of new lesions.]) observed during the trial period and assessed according to RECIST v1.1 criteria. Results are based on central evaluation.

4. Objective Response Rate [From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year.]

   Objective response rate was defined as the percentage of subjects whose best response was Complete Response (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Results are based on central evaluation.

5. Disease Control Rate (DCR) [From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year]

   Disease Control Rate (DCR) was defined as the percentage of subjects whose best response was Complete Response (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).), Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.), or Stable Disease (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to RECIST v1.1 criteria. SD had to be maintained for at least 12 weeks from the first demonstration of that rating. Results are based on central evaluation.

6. Duration of Response (DOR) [From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year]

   Duration of Response was defined as the time from date of first response (Complete Response [CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).] or Partial Response [PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.]) to the date when Progressive Disease (PD: at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study or unequivocal progression of existing non-target lesions, or appearance of new lesions.) is first documented, or to the date of death, whichever occurs first, according to RECIST v1.1. Subjects still having CR or PR and have not died at the time of analysis were censored at their last date of tumor evaluation. Duration of response defined for responders only, i.e CR or PR. Results are based on central evaluation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female subjects 18 years of age.

• Subjects with histologically confirmed metastatic and/or unresectable GIST.

• At least imatinib and sunitinib as prior treatment regimens, with objective disease progression or intolerance to imatinib, as well as disease progression while on sunitinib therapy. Additionally, disease progression or intolerance to other systemic therapies, as well as investigational new agents, is allowed, except prior treatment with any other vascular endothelial growth factor receptor (VEGFR) inhibitor.

• Subjects must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion prior to study enrollment.

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

• Adequate bone marrow, liver, and renal function as assessed by laboratory parameters.

Recovery to NCI-CTCAE v4.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure-related toxicity (except alopecia and anemia).

Exclusion Criteria:

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication.

• Congestive heart failure New York Heart Association (NYHA) class 2.

• Unstable angina (angina symptoms at rest, new-onset angina, ie, within the last 3 months) or myocardial infarction (MI) within the past 6 months before start of study medication.

• Uncontrolled hypertension (systolic blood pressure 140 mmHg or diastolic pressure 90 mmHg despite optimal medical management).

Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of study drug or venous thrombotic events such as deep vein thrombosis within the 3 months before start of study drug.

• Ongoing infection grade 2 National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

Symptomatic metastatic brain or meningeal tumors.

• Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event NCI-CTCAE version 4.0 grade 3 or higher within 4 weeks prior to the start of study drug.

Non-healing wound, ulcer, or bone fracture.

• Persistent proteinuria of NCI-CTCAE version 4.0 grade 3 or higher (3.5 g/24 hrs, measured by urine protein:creatinine ratio on a random urine sample).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Scottsdale	Arizona	United States	85258
2		Evanston	Illinois	United States	60201
3		Skokie	Illinois	United States	60076
4		Boston	Massachusetts	United States	02115
5		Minneapolis	Minnesota	United States	55455
6		New York	New York	United States	10065
7		Portland	Oregon	United States	97239-2964
8		Philadelphia	Pennsylvania	United States	19111-2497
9		Seattle	Washington	United States	98109
10		Graz	Steiermark	Austria	8036
11		Innsbruck		Austria	6020
12		Wien		Austria	1090
13		Leuven		Belgium	3000
14		Edmonton	Alberta	Canada	T6G 1Z2
15		London	Ontario	Canada	N6A 4L6
16		Toronto	Ontario	Canada	M5G 1X5
17		Guangzhou	Guangdong	China	510060
18		Nanjing	Jiangsu	China	210002
19		Beijing		China	100071
20		Shanghai		China	200030
21		Helsinki		Finland	00290
22		Bordeaux Cedex		France	33076
23		Lille Cedex		France	59020
24		Lyon Cedex 08		France	69373
25		Villejuif		France	94805
26		Mannheim	Baden-Württemberg	Germany	68167
27		Tübingen	Baden-Württemberg	Germany	72076
28		Bad Saarow	Brandenburg	Germany	15526
29		Hannover	Niedersachsen	Germany	30625
30		Düsseldorf	Nordrhein-Westfalen	Germany	40479
31		Essen	Nordrhein-Westfalen	Germany	45122
32		Köln	Nordrhein-Westfalen	Germany	50924
33		Tel Aviv		Israel	64239
34		Bologna	Emilia-Romagna	Italy	40138
35		Milano	Lombardia	Italy	20133
36		Torino	Piemonte	Italy	10060
37		Palermo	Sicilia	Italy	90127
38		Nagoya	Aichi	Japan	466-8650
39		Kashiwa	Chiba	Japan	277-8577
40		Sapporo	Hokkaido	Japan	060-8648
41		Chuo-ku	Tokyo	Japan	104-0045
42		Niigata		Japan	951-8520
43		Osaka		Japan	543-0035
44		Goyang-si	Gyeonggido	Korea, Republic of	410-769
45		Busan		Korea, Republic of	49201
46		Seoul		Korea, Republic of	03080
47		Seoul		Korea, Republic of	06351
48		Seoul		Korea, Republic of	138-736
49		Leiden		Netherlands	2333 ZA
50		Nijmegen		Netherlands	6525 GA
51		Warszawa		Poland	02-781
52		Singapore		Singapore	169610
53		L'Hospitalet de Llobregat	Barcelona	Spain	08907
54		Barcelona		Spain	08035
55		Leicester	Leicestershire	United Kingdom	LE1 5WW
56		London		United Kingdom	SW3 6JJ
57		Manchester		United Kingdom	M20 4BX

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here to find results for studies related to Bayer Healthcare products.
• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01271712
• Other Study ID Numbers: 14874; 2009-017957-37
• First Posted: Jan 7, 2011
• Last Update Posted: Jan 29, 2021
• Last Verified: Jan 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bayer: Gastrointestinal stromal cancer; GIST; multikinase inhibitor
• Additional relevant MeSH terms: Gastrointestinal Stromal Tumors

Study Results

Participant Flow

Recruitment Details	A total of 240 participants with metastatic and/or unresectable GIST whose disease had progressed despite prior treatments with at least imatinib and sunitinib were screened; 199 were randomized. Patients must have shown objective disease progression or intolerance to imatinib, as well as disease progression while on sunitinib treatment.
Pre-assignment Detail	Participants were randomized in a 2:1 ratio to receive either regorafenib (133 patients) or placebo (66 patients). Randomization was stratified according 3rd vs. 4th line of therapy (at least 50% of patients were to be 3rd line), and geographical region (Asia vs.rest of world).

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)	Placebo First, Then Option of Open Label Regorafenib Treatment
Arm/Group Description	Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Double blind phase: participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks. Open Label phase: participants on placebo who switched to Regorafenib, received Regorafenib 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks.
Period Title: Double Blind Treatment
STARTED	133	66
Participants Received Treatment	132	66
COMPLETED	91	58
NOT COMPLETED	42	8
Period Title: Double Blind Treatment
STARTED	91	58
COMPLETED	0	0
NOT COMPLETED	91	58
Period Title: Double Blind Treatment
STARTED	118	52
COMPLETED	97	37
NOT COMPLETED	21	15
Period Title: Double Blind Treatment
STARTED	100	39
COMPLETED	85	33
NOT COMPLETED	15	6

Baseline Characteristics

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)	Placebo	Total
Arm/Group Description	Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Total of all reporting groups
Overall Participants	133	66	199
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	58.2 (12.5)	58.1 (13.9)	58.2 (12.9)
Sex: Female, Male (Count of Participants)
Female	48 36.1%	24 36.4%	72 36.2%
Male	85 63.9%	42 63.6%	127 63.8%
ECOG Performance Status (PS)] (Count of Participants)
PS 0	73 54.9%	37 56.1%	110 55.3%
PS 1	60 45.1%	29 43.9%	89 44.7%
PS 2	0 0%	0 0%	0 0%
Missing	0 0%	0 0%	0 0%
Prior anti-cancer drug group (Count of Participants)
3rd line	74 55.6%	39 59.1%	113 56.8%
4th line and beyond	59 44.4%	27 40.9%	86 43.2%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Progression-free Survival (PFS) was defined as the time from date of randomization to radiological disease progression or death due to any cause, whichever occurs first. PFS was based on central radiological assessment using modified RECIST (Response Evaluation Criteria in Solid Tumors) v.1.1. Progression is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study; or unequivocal progression of existing non-target lesions; or appearance of new lesions. Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation. Results are based on central evaluation.
Time Frame	From randomization of the first subject until approximately 144 progression-free survival events had occurred (study duration approximately one year)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) - defined as all randomized participants.

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)	Placebo
Arm/Group Description	Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Measure Participants	133	66
Median (95% Confidence Interval) [Days]	147	28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib (Stivarga, BAY73-4506), Placebo
	Comments	The two treatment groups were compared using a stratified log rank test with a one-sided alpha of 0.01 stratified by (3rd vs 4th-line; and geographical region). The null hypothesis that both treatment arms have the same PFS distribution was tested against the alternative hypothesis that the distribution of PFS in the regorafenib arm is different from the control arm according to a proportional hazards relation between the treatment arms.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.000001
	Comments
	Method	Log Rank
	Comments	stratified

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regorafenib (Stivarga, BAY73-4506), Placebo
	Comments	Hazard ratio and its 95% CI (Confidence Interval) was based on stratified Cox Regression Model
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.268
	Confidence Interval	(2-Sided) 95%; 0.185 to 0.388
	Parameter Dispersion	Type: Value:
	Estimation Comments	regorafenib over placebo

2. Secondary Outcome

Title	Overall Survival
Description	Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their date of last contact. Median OS was not observed at the time of PFS analysis and first analysis of OS, therefore only the proportion of death events was reported in the results posting system. This approach was maintained for the subsequent updates in the results posting system.
Time Frame	From randomization of the first subject until date of database cutoff (08 Jun 2015)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). 58 (87.9%) patients in placebo group and 91 (68.4%) patients in regorafenib had started open-label treatment with regorafenib before time of final database cutoff 08 Jun 2015

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)	Placebo
Arm/Group Description	Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Measure Participants	133	66
Number [Percentage of patients with death]	82.0	80.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib (Stivarga, BAY73-4506), Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.285777
	Comments
	Method	Log Rank
	Comments	stratified

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regorafenib (Stivarga, BAY73-4506), Placebo
	Comments	Hazard ratio and its 95% CI was based on stratified Cox Regression Model
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.909
	Confidence Interval	(2-Sided) 95%; 0.653 to 1.265
	Parameter Dispersion	Type: Value:
	Estimation Comments	regorafenib over control. 58 (87.9%) patients in placebo group and 91 (68.4%) patients in regorafenib had started open-label treatment with regorafenib before time of final database cutoff 08 Jun 2015.

3. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to progression (TTP) was defined as the time from date of randomization to disease progression (based on central radiological assessment using modified RECIST [Response Evaluation Criteria in Solid Tumors] v.1.1). Progression is defined as at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study; or unequivocal progression of existing non-target lesions; or appearance of new lesions. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation. Results are based on central evaluation.
Time Frame	From randomization of the first subject until until date of database cutoff (26 Jan 2012); study duration approximately 1 year

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS)

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)	Placebo
Arm/Group Description	Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Measure Participants	133	66
Median (95% Confidence Interval) [Days]	165	28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib (Stivarga, BAY73-4506), Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.000001
	Comments
	Method	Log Rank
	Comments	stratified

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regorafenib (Stivarga, BAY73-4506), Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.248
	Confidence Interval	(2-Sided) 95%; 0.170 to 0.364
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Tumor Response
Description	Tumor Response of a subject was defined as the best tumor response (Complete Response [CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).], Partial Response [PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.], Stable Disease [SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.], or Progressive Disease [PD: at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study or unequivocal progression of existing non-target lesions, or appearance of new lesions.]) observed during the trial period and assessed according to RECIST v1.1 criteria. Results are based on central evaluation.
Time Frame	From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS)

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)	Placebo
Arm/Group Description	Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Measure Participants	133	66
Complete Response (CR)	0 0%	0 0%
Partial Response (PR)	4.5 3.4%	1.5 2.3%
Stable Disease (SD)	71.4 53.7%	33.3 50.5%
Progressive Disease (PD)	21.1 15.9%	63.6 96.4%
Not Assessable	3.0 2.3%	1.5 2.3%

5. Secondary Outcome

Title	Objective Response Rate
Description	Objective response rate was defined as the percentage of subjects whose best response was Complete Response (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Results are based on central evaluation.
Time Frame	From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year.

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS)

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)	Placebo
Arm/Group Description	Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Measure Participants	133	66
Number (95% Confidence Interval) [Percentage of Participants]	4.5 3.4%	1.5 2.3%

6. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	Disease Control Rate (DCR) was defined as the percentage of subjects whose best response was Complete Response (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).), Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.), or Stable Disease (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to RECIST v1.1 criteria. SD had to be maintained for at least 12 weeks from the first demonstration of that rating. Results are based on central evaluation.
Time Frame	From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS)

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)	Placebo
Arm/Group Description	Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Measure Participants	133	66
Number (95% Confidence Interval) [Percentage of Participants]	52.6 39.5%	9.1 13.8%

7. Secondary Outcome

Title	Duration of Response (DOR)
Description	Duration of Response was defined as the time from date of first response (Complete Response [CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).] or Partial Response [PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.]) to the date when Progressive Disease (PD: at least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study or unequivocal progression of existing non-target lesions, or appearance of new lesions.) is first documented, or to the date of death, whichever occurs first, according to RECIST v1.1. Subjects still having CR or PR and have not died at the time of analysis were censored at their last date of tumor evaluation. Duration of response defined for responders only, i.e CR or PR. Results are based on central evaluation.
Time Frame	From randomization of the first subject until date of database cutoff (26 Jan 2012); study duration approximately 1 year

Outcome Measure Data

Analysis Population Description

Full Analysis Set with response participants

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)	Placebo
Arm/Group Description	Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks	Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
Measure Participants	6	1
Median (95% Confidence Interval) [Days]	99	30

Adverse Events

Time Frame	From first administration of treatment till 30 days after last dose of treatment.
Adverse Event Reporting Description	At primary completion (cutoff 26JAN2012) blinded patients who received either regorafenib or placebo were reported in "Regorafenib (DoubleBlindOnly)" and "Placebo (DoubleBlindOnly)" respectively; patients who received regorafenib after unblinding were reported in "Placebo, OpenLabelOnly(Switch to Regorafenib)". This safety update (cutoff 15APR2019) was reported in "Treated with Regorafenib at any time" and "Treated with Regorafenib for>1 year".
Arm/Group Title	Regorafenib (Double Blind Only)		Placebo (Double Blind Only)		Placebo, Open Label Only (Switch to Regorafenib)		Treated With Regorafenib at Any Time		Treated With Regorafenib for > 1 Year
Arm/Group Description	Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks		Participants received matching Placebo tablets per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks		Participants switched to Open-label Regorafenib treatment from Placebo. Participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks		Treated with Regorafenib at any time: At any time, participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks		Treated with Regorafenib for > 1 year: For more than a year, participants received Regorafenib (Stivarga) 160 mg (4 x 40 mg tablets) per os once daily, 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks
All Cause Mortality
	Regorafenib (Double Blind Only)		Placebo (Double Blind Only)		Placebo, Open Label Only (Switch to Regorafenib)		Treated With Regorafenib at Any Time		Treated With Regorafenib for > 1 Year
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/41 (97.6%)		7/8 (87.5%)		47/58 (81%)		155/190 (81.6%)		48/75 (64%)
Serious Adverse Events
	Regorafenib (Double Blind Only)		Placebo (Double Blind Only)		Placebo, Open Label Only (Switch to Regorafenib)		Treated With Regorafenib at Any Time		Treated With Regorafenib for > 1 Year
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/41 (56.1%)		8/8 (100%)		31/58 (53.4%)		103/190 (54.2%)		39/75 (52%)
Blood and lymphatic system disorders
Anemia	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	2	2/190 (1.1%)	3	0/75 (0%)	0
Cardiac disorders
Acute coronary syndrome	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	7/190 (3.7%)	7	6/75 (8%)	6
Atrial fibrillation	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	1/190 (0.5%)	1	1/75 (1.3%)	1
Cardiac arrest	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Chest pain - cardiac	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	2	1/75 (1.3%)	2
Conduction disorder	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Heart failure	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Cardiac disorders - Other	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Congenital, familial and genetic disorders
Congenital, familial and genetic disorders - Other	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Ear and labyrinth disorders
Vertigo	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Eye disorders
Eye disorders - Other	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	1/190 (0.5%)	1	1/75 (1.3%)	1
Gastrointestinal disorders
Abdominal pain	5/41 (12.2%)	5	0/8 (0%)	0	2/58 (3.4%)	2	9/190 (4.7%)	10	1/75 (1.3%)	1
Anal fistula	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Ascites	3/41 (7.3%)	4	0/8 (0%)	0	0/58 (0%)	0	3/190 (1.6%)	4	0/75 (0%)	0
Colonic fistula	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Colonic obstruction	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	2	1/190 (0.5%)	2	0/75 (0%)	0
Colonic perforation	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	2	2/190 (1.1%)	4	1/75 (1.3%)	2
Constipation	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	2/190 (1.1%)	2	2/75 (2.7%)	2
Diarrhea	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	3/190 (1.6%)	4	2/75 (2.7%)	3
Gastric hemorrhage	1/41 (2.4%)	1	0/8 (0%)	0	1/58 (1.7%)	1	2/190 (1.1%)	2	0/75 (0%)	0
Intra-abdominal hemorrhage	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	3/190 (1.6%)	3	0/75 (0%)	0
Ileus	1/41 (2.4%)	1	0/8 (0%)	0	1/58 (1.7%)	1	2/190 (1.1%)	2	0/75 (0%)	0
Lower gastrointestinal hemorrhage	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Nausea	0/41 (0%)	0	1/8 (12.5%)	1	1/58 (1.7%)	1	2/190 (1.1%)	2	1/75 (1.3%)	1
Obstruction gastric	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Gastrointestinal disorders - Other	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Peritoneal necrosis	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Retroperitoneal hemorrhage	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Small intestinal obstruction	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	2	1/75 (1.3%)	2
Upper gastrointestinal hemorrhage	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Vomiting	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	2/190 (1.1%)	2	1/75 (1.3%)	1
General disorders
Death NOS	1/41 (2.4%)	1	2/8 (25%)	2	1/58 (1.7%)	1	3/190 (1.6%)	3	2/75 (2.7%)	2
Edema limbs	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	2	1/190 (0.5%)	2	0/75 (0%)	0
Fatigue	2/41 (4.9%)	4	1/8 (12.5%)	2	2/58 (3.4%)	2	5/190 (2.6%)	7	2/75 (2.7%)	2
Fever	1/41 (2.4%)	1	0/8 (0%)	0	2/58 (3.4%)	2	5/190 (2.6%)	5	2/75 (2.7%)	2
Malaise	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Multi-organ failure	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	2/190 (1.1%)	2	0/75 (0%)	0
Non-cardiac chest pain	0/41 (0%)	0	1/8 (12.5%)	1	0/58 (0%)	0	0/190 (0%)	0	0/75 (0%)	0
General disorders and administration site conditions - Other	1/41 (2.4%)	1	1/8 (12.5%)	1	2/58 (3.4%)	3	5/190 (2.6%)	6	3/75 (4%)	3
Pain	1/41 (2.4%)	1	0/8 (0%)	0	2/58 (3.4%)	3	3/190 (1.6%)	4	1/75 (1.3%)	1
Hepatobiliary disorders
Bile duct stenosis	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	2/190 (1.1%)	2	1/75 (1.3%)	1
Cholecystitis	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	2/190 (1.1%)	2	2/75 (2.7%)	2
Hepatic failure	1/41 (2.4%)	2	0/8 (0%)	0	1/58 (1.7%)	1	3/190 (1.6%)	4	0/75 (0%)	0
Hepatic hemorrhage	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	2/190 (1.1%)	3	1/75 (1.3%)	1
Hepatobiliary disorders - Other	0/41 (0%)	0	1/8 (12.5%)	1	1/58 (1.7%)	1	2/190 (1.1%)	2	1/75 (1.3%)	1
Portal vein thrombosis	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	1/190 (0.5%)	1	0/75 (0%)	0
Infections and infestations
Abdominal infection	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	2/190 (1.1%)	2	0/75 (0%)	0
Appendicitis	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Bronchial infection	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	2/190 (1.1%)	3	1/75 (1.3%)	2
Catheter related infection	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	2	1/190 (0.5%)	2	0/75 (0%)	0
Enterocolitis infectious	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	3	2/190 (1.1%)	3	1/75 (1.3%)	2
Lung infection	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	2/190 (1.1%)	2	1/75 (1.3%)	1
Infections and infestations - Other	1/41 (2.4%)	1	0/8 (0%)	0	4/58 (6.9%)	4	8/190 (4.2%)	9	3/75 (4%)	4
Sepsis	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	2	3/190 (1.6%)	3	1/75 (1.3%)	1
Upper respiratory infection	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	3/190 (1.6%)	3	3/75 (4%)	3
Urinary tract infection	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Wound infection	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Injury, poisoning and procedural complications
Fracture	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	2	4/190 (2.1%)	5	3/75 (4%)	4
Hip fracture	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	1/190 (0.5%)	1	1/75 (1.3%)	1
Investigations
Alanine aminotransferase increased	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	2	3/190 (1.6%)	6	1/75 (1.3%)	3
Aspartate aminotransferase increased	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	1/190 (0.5%)	1	0/75 (0%)	0
Blood bilirubin increased	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	2	3/190 (1.6%)	3	1/75 (1.3%)	1
Creatinine increased	1/41 (2.4%)	2	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	2	0/75 (0%)	0
INR increased	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Neutrophil count decreased	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	1/190 (0.5%)	1	0/75 (0%)	0
Investigations - Other	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	2/190 (1.1%)	2	0/75 (0%)	0
Platelet count decreased	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	2	1/190 (0.5%)	2	0/75 (0%)	0
Metabolism and nutrition disorders
Acidosis	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Anorexia	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Dehydration	0/41 (0%)	0	1/8 (12.5%)	1	0/58 (0%)	0	3/190 (1.6%)	3	3/75 (4%)	3
Hyperglycemia	0/41 (0%)	0	1/8 (12.5%)	1	0/58 (0%)	0	0/190 (0%)	0	0/75 (0%)	0
Hyperkalemia	1/41 (2.4%)	3	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	3	0/75 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	2	2/190 (1.1%)	2	1/75 (1.3%)	1
Generalized muscle weakness	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Musculoskeletal and connective tissue disorder - Other	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	1/190 (0.5%)	1	1/75 (1.3%)	1
Muscle weakness right-sided	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	1/41 (2.4%)	1	0/8 (0%)	0	3/58 (5.2%)	3	6/190 (3.2%)	6	3/75 (4%)	3
Tumor pain	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	4	3/190 (1.6%)	5	1/75 (1.3%)	1
Nervous system disorders
Amnesia	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Hypoglossal nerve disorder	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Intracranial hemorrhage	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Nervous system disorders - Other	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	2	2/190 (1.1%)	2	0/75 (0%)	0
Paresthesia	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Reversible posterior leukoencephalopathy syndrome	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Somnolence	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Stroke	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	2/190 (1.1%)	2	2/75 (2.7%)	2
Transient ischemic attacks	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	2/190 (1.1%)	2	2/75 (2.7%)	2
Psychiatric disorders
Confusion	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	1/190 (0.5%)	1	1/75 (1.3%)	1
Mania	0/41 (0%)	0	1/8 (12.5%)	4	0/58 (0%)	0	0/190 (0%)	0	0/75 (0%)	0
Psychiatric disorders - Other	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Renal and urinary disorders
Acute kidney injury	2/41 (4.9%)	2	0/8 (0%)	0	1/58 (1.7%)	2	4/190 (2.1%)	5	1/75 (1.3%)	1
Renal and urinary disorders - Other	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	3/190 (1.6%)	4	1/75 (1.3%)	2
Renal colic	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Urinary retention	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	2/190 (1.1%)	2	1/75 (1.3%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Dyspnea	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	2/190 (1.1%)	2	0/75 (0%)	0
Pleural effusion	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Pneumonitis	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Respiratory failure	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	1/190 (0.5%)	1	1/75 (1.3%)	1
Surgical and medical procedures
Surgical and medical procedures - Other	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	4/190 (2.1%)	4	2/75 (2.7%)	2
Vascular disorders
Hypertension	1/41 (2.4%)	1	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Vascular disorders - Other	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	0/75 (0%)	0
Peripheral ischemia	0/41 (0%)	0	0/8 (0%)	0	0/58 (0%)	0	1/190 (0.5%)	1	1/75 (1.3%)	1
Thromboembolic event	1/41 (2.4%)	1	0/8 (0%)	0	1/58 (1.7%)	2	4/190 (2.1%)	5	0/75 (0%)	0
Other (Not Including Serious) Adverse Events
	Regorafenib (Double Blind Only)		Placebo (Double Blind Only)		Placebo, Open Label Only (Switch to Regorafenib)		Treated With Regorafenib at Any Time		Treated With Regorafenib for > 1 Year
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/41 (97.6%)		7/8 (87.5%)		58/58 (100%)		189/190 (99.5%)		75/75 (100%)
Blood and lymphatic system disorders
Anemia	4/41 (9.8%)	7	0/8 (0%)	0	11/58 (19%)	25	35/190 (18.4%)	77	17/75 (22.7%)	35
Blood and lymphatic system disorders - Other	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	9	6/190 (3.2%)	17	4/75 (5.3%)	9
Ear and labyrinth disorders
Hearing impaired	1/41 (2.4%)	1	0/8 (0%)	0	1/58 (1.7%)	1	7/190 (3.7%)	7	5/75 (6.7%)	5
Ear and labyrinth disorders - Other	0/41 (0%)	0	0/8 (0%)	0	4/58 (6.9%)	4	7/190 (3.7%)	7	4/75 (5.3%)	4
Endocrine disorders
Hypothyroidism	4/41 (9.8%)	4	0/8 (0%)	0	6/58 (10.3%)	6	39/190 (20.5%)	50	25/75 (33.3%)	32
Eye disorders
Blurred vision	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	2	7/190 (3.7%)	7	7/75 (9.3%)	7
Eye disorders - Other	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	6/190 (3.2%)	6	4/75 (5.3%)	4
Gastrointestinal disorders
Abdominal pain	14/41 (34.1%)	18	0/8 (0%)	0	16/58 (27.6%)	23	62/190 (32.6%)	122	26/75 (34.7%)	60
Ascites	2/41 (4.9%)	2	1/8 (12.5%)	1	2/58 (3.4%)	2	6/190 (3.2%)	8	1/75 (1.3%)	3
Bloating	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	7/190 (3.7%)	10	6/75 (8%)	9
Constipation	10/41 (24.4%)	14	5/8 (62.5%)	6	16/58 (27.6%)	30	63/190 (33.2%)	101	28/75 (37.3%)	52
Diarrhea	15/41 (36.6%)	20	1/8 (12.5%)	1	24/58 (41.4%)	67	96/190 (50.5%)	353	53/75 (70.7%)	281
Dyspepsia	4/41 (9.8%)	4	1/8 (12.5%)	2	6/58 (10.3%)	9	19/190 (10%)	39	11/75 (14.7%)	30
Dry mouth	5/41 (12.2%)	5	0/8 (0%)	0	5/58 (8.6%)	6	15/190 (7.9%)	16	5/75 (6.7%)	6
Flatulence	4/41 (9.8%)	4	0/8 (0%)	0	3/58 (5.2%)	3	10/190 (5.3%)	11	5/75 (6.7%)	6
Mucositis oral	14/41 (34.1%)	18	2/8 (25%)	3	21/58 (36.2%)	48	81/190 (42.6%)	174	38/75 (50.7%)	111
Nausea	9/41 (22%)	12	3/8 (37.5%)	4	18/58 (31%)	33	61/190 (32.1%)	110	32/75 (42.7%)	66
Gastrointestinal disorders - Other	4/41 (9.8%)	4	0/8 (0%)	0	4/58 (6.9%)	7	17/190 (8.9%)	21	11/75 (14.7%)	15
Stomach pain	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	2	7/190 (3.7%)	7	5/75 (6.7%)	5
Vomiting	10/41 (24.4%)	11	3/8 (37.5%)	5	12/58 (20.7%)	24	48/190 (25.3%)	85	21/75 (28%)	54
General disorders
Chills	1/41 (2.4%)	1	0/8 (0%)	0	4/58 (6.9%)	4	11/190 (5.8%)	19	8/75 (10.7%)	16
Edema limbs	3/41 (7.3%)	4	3/8 (37.5%)	3	11/58 (19%)	20	33/190 (17.4%)	72	17/75 (22.7%)	53
Fatigue	18/41 (43.9%)	32	3/8 (37.5%)	4	32/58 (55.2%)	83	104/190 (54.7%)	251	46/75 (61.3%)	137
Fever	10/41 (24.4%)	17	1/8 (12.5%)	1	18/58 (31%)	24	52/190 (27.4%)	83	25/75 (33.3%)	46
Flu like symptoms	1/41 (2.4%)	1	0/8 (0%)	0	3/58 (5.2%)	3	18/190 (9.5%)	22	14/75 (18.7%)	17
Localized edema	2/41 (4.9%)	2	1/8 (12.5%)	1	3/58 (5.2%)	5	8/190 (4.2%)	10	5/75 (6.7%)	7
Non-cardiac chest pain	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	7/190 (3.7%)	8	6/75 (8%)	7
General disorders and administration site conditions - Other	1/41 (2.4%)	1	0/8 (0%)	0	4/58 (6.9%)	5	10/190 (5.3%)	11	5/75 (6.7%)	6
Pain	5/41 (12.2%)	8	1/8 (12.5%)	1	19/58 (32.8%)	46	55/190 (28.9%)	115	29/75 (38.7%)	73
Immune system disorders
Allergic reaction	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	4/190 (2.1%)	4	4/75 (5.3%)	4
Infections and infestations
Bronchial infection	0/41 (0%)	0	0/8 (0%)	0	4/58 (6.9%)	4	11/190 (5.8%)	12	9/75 (12%)	10
Infections and infestations - Other	2/41 (4.9%)	3	0/8 (0%)	0	5/58 (8.6%)	7	21/190 (11.1%)	39	13/75 (17.3%)	26
Rash pustular	2/41 (4.9%)	2	0/8 (0%)	0	2/58 (3.4%)	17	13/190 (6.8%)	49	10/75 (13.3%)	42
Sinusitis	1/41 (2.4%)	1	0/8 (0%)	0	1/58 (1.7%)	1	6/190 (3.2%)	6	5/75 (6.7%)	5
Skin infection	0/41 (0%)	0	0/8 (0%)	0	3/58 (5.2%)	4	6/190 (3.2%)	7	4/75 (5.3%)	4
Tooth infection	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	6/190 (3.2%)	6	5/75 (6.7%)	5
Upper respiratory infection	0/41 (0%)	0	0/8 (0%)	0	9/58 (15.5%)	12	26/190 (13.7%)	41	21/75 (28%)	36
Urinary tract infection	2/41 (4.9%)	3	0/8 (0%)	0	2/58 (3.4%)	4	12/190 (6.3%)	17	6/75 (8%)	9
Investigations
Alanine aminotransferase increased	4/41 (9.8%)	9	1/8 (12.5%)	2	6/58 (10.3%)	15	20/190 (10.5%)	41	4/75 (5.3%)	10
Alkaline phosphatase increased	1/41 (2.4%)	1	1/8 (12.5%)	1	3/58 (5.2%)	6	11/190 (5.8%)	21	3/75 (4%)	4
Aspartate aminotransferase increased	4/41 (9.8%)	9	2/8 (25%)	2	8/58 (13.8%)	15	23/190 (12.1%)	58	6/75 (8%)	24
Blood bilirubin increased	4/41 (9.8%)	6	1/8 (12.5%)	3	9/58 (15.5%)	15	22/190 (11.6%)	52	7/75 (9.3%)	27
GGT increased	0/41 (0%)	0	1/8 (12.5%)	2	2/58 (3.4%)	2	4/190 (2.1%)	4	1/75 (1.3%)	1
Lipase increased	1/41 (2.4%)	1	0/8 (0%)	0	3/58 (5.2%)	11	6/190 (3.2%)	19	3/75 (4%)	14
Neutrophil count decreased	0/41 (0%)	0	0/8 (0%)	0	6/58 (10.3%)	8	13/190 (6.8%)	25	6/75 (8%)	12
Investigations - Other	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	14	14/190 (7.4%)	49	10/75 (13.3%)	28
Platelet count decreased	1/41 (2.4%)	5	0/8 (0%)	0	6/58 (10.3%)	25	15/190 (7.9%)	46	10/75 (13.3%)	34
White blood cell decreased	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	2	6/190 (3.2%)	17	4/75 (5.3%)	15
Weight gain	0/41 (0%)	0	1/8 (12.5%)	1	2/58 (3.4%)	3	3/190 (1.6%)	4	2/75 (2.7%)	3
Weight loss	4/41 (9.8%)	5	2/8 (25%)	2	11/58 (19%)	20	40/190 (21.1%)	72	22/75 (29.3%)	44
Metabolism and nutrition disorders
Anorexia	15/41 (36.6%)	21	3/8 (37.5%)	5	20/58 (34.5%)	42	77/190 (40.5%)	134	32/75 (42.7%)	72
Dehydration	0/41 (0%)	0	1/8 (12.5%)	1	5/58 (8.6%)	5	6/190 (3.2%)	8	4/75 (5.3%)	6
Hypoalbuminemia	2/41 (4.9%)	2	0/8 (0%)	0	3/58 (5.2%)	3	9/190 (4.7%)	10	2/75 (2.7%)	2
Hypocalcemia	1/41 (2.4%)	2	0/8 (0%)	0	3/58 (5.2%)	8	9/190 (4.7%)	15	4/75 (5.3%)	4
Hypokalemia	0/41 (0%)	0	0/8 (0%)	0	12/58 (20.7%)	18	20/190 (10.5%)	31	13/75 (17.3%)	22
Hyponatremia	0/41 (0%)	0	2/8 (25%)	2	3/58 (5.2%)	4	8/190 (4.2%)	11	2/75 (2.7%)	2
Hypophosphatemia	1/41 (2.4%)	1	0/8 (0%)	0	1/58 (1.7%)	1	10/190 (5.3%)	13	5/75 (6.7%)	7
Hypercalcemia	0/41 (0%)	0	1/8 (12.5%)	1	3/58 (5.2%)	3	4/190 (2.1%)	4	4/75 (5.3%)	4
Hyperglycemia	1/41 (2.4%)	3	0/8 (0%)	0	5/58 (8.6%)	5	13/190 (6.8%)	18	9/75 (12%)	10
Hyperuricemia	1/41 (2.4%)	1	1/8 (12.5%)	1	2/58 (3.4%)	2	7/190 (3.7%)	7	2/75 (2.7%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/41 (2.4%)	1	0/8 (0%)	0	4/58 (6.9%)	7	14/190 (7.4%)	20	8/75 (10.7%)	14
Back pain	2/41 (4.9%)	2	1/8 (12.5%)	1	4/58 (6.9%)	6	21/190 (11.1%)	29	14/75 (18.7%)	20
Bone pain	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	3	5/190 (2.6%)	9	5/75 (6.7%)	9
Flank pain	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	5/190 (2.6%)	5	4/75 (5.3%)	4
Generalized muscle weakness	1/41 (2.4%)	1	1/8 (12.5%)	1	4/58 (6.9%)	7	6/190 (3.2%)	14	3/75 (4%)	11
Myalgia	5/41 (12.2%)	5	3/8 (37.5%)	3	10/58 (17.2%)	17	34/190 (17.9%)	76	17/75 (22.7%)	49
Neck pain	0/41 (0%)	0	1/8 (12.5%)	1	0/58 (0%)	0	2/190 (1.1%)	2	1/75 (1.3%)	1
Musculoskeletal and connective tissue disorder - Other	1/41 (2.4%)	1	0/8 (0%)	0	4/58 (6.9%)	5	14/190 (7.4%)	17	10/75 (13.3%)	12
Pain in extremity	5/41 (12.2%)	5	1/8 (12.5%)	2	7/58 (12.1%)	15	28/190 (14.7%)	51	17/75 (22.7%)	37
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/41 (2.4%)	2	1/8 (12.5%)	1	3/58 (5.2%)	4	7/190 (3.7%)	9	2/75 (2.7%)	2
Nervous system disorders
Dizziness	0/41 (0%)	0	1/8 (12.5%)	1	1/58 (1.7%)	1	6/190 (3.2%)	16	6/75 (8%)	16
Dysgeusia	2/41 (4.9%)	2	0/8 (0%)	0	4/58 (6.9%)	4	17/190 (8.9%)	19	9/75 (12%)	11
Headache	4/41 (9.8%)	4	0/8 (0%)	0	11/58 (19%)	21	37/190 (19.5%)	72	23/75 (30.7%)	55
Paresthesia	0/41 (0%)	0	0/8 (0%)	0	3/58 (5.2%)	5	11/190 (5.8%)	19	9/75 (12%)	13
Peripheral sensory neuropathy	5/41 (12.2%)	7	0/8 (0%)	0	4/58 (6.9%)	8	16/190 (8.4%)	22	6/75 (8%)	7
Somnolence	0/41 (0%)	0	1/8 (12.5%)	1	0/58 (0%)	0	0/190 (0%)	0	0/75 (0%)	0
Psychiatric disorders
Anxiety	4/41 (9.8%)	4	0/8 (0%)	0	3/58 (5.2%)	4	9/190 (4.7%)	10	4/75 (5.3%)	5
Confusion	0/41 (0%)	0	1/8 (12.5%)	1	1/58 (1.7%)	1	2/190 (1.1%)	2	0/75 (0%)	0
Depression	2/41 (4.9%)	2	0/8 (0%)	0	2/58 (3.4%)	2	10/190 (5.3%)	11	4/75 (5.3%)	5
Insomnia	3/41 (7.3%)	3	1/8 (12.5%)	1	3/58 (5.2%)	4	21/190 (11.1%)	22	14/75 (18.7%)	15
Renal and urinary disorders
Hematuria	1/41 (2.4%)	1	0/8 (0%)	0	3/58 (5.2%)	3	7/190 (3.7%)	9	3/75 (4%)	3
Renal and urinary disorders - Other	3/41 (7.3%)	3	0/8 (0%)	0	0/58 (0%)	0	10/190 (5.3%)	12	4/75 (5.3%)	5
Proteinuria	0/41 (0%)	0	0/8 (0%)	0	6/58 (10.3%)	11	23/190 (12.1%)	58	9/75 (12%)	21
Urinary frequency	0/41 (0%)	0	0/8 (0%)	0	2/58 (3.4%)	2	7/190 (3.7%)	8	4/75 (5.3%)	5
Respiratory, thoracic and mediastinal disorders
Cough	1/41 (2.4%)	1	1/8 (12.5%)	1	11/58 (19%)	18	27/190 (14.2%)	44	15/75 (20%)	32
Dyspnea	4/41 (9.8%)	6	0/8 (0%)	0	7/58 (12.1%)	9	22/190 (11.6%)	32	11/75 (14.7%)	16
Epistaxis	0/41 (0%)	0	0/8 (0%)	0	4/58 (6.9%)	6	10/190 (5.3%)	15	7/75 (9.3%)	10
Hiccups	0/41 (0%)	0	1/8 (12.5%)	1	0/58 (0%)	0	0/190 (0%)	0	0/75 (0%)	0
Hoarseness	8/41 (19.5%)	8	0/8 (0%)	0	9/58 (15.5%)	11	42/190 (22.1%)	71	17/75 (22.7%)	36
Pneumonitis	0/41 (0%)	0	0/8 (0%)	0	3/58 (5.2%)	3	5/190 (2.6%)	5	4/75 (5.3%)	4
Voice alteration	2/41 (4.9%)	2	1/8 (12.5%)	1	11/58 (19%)	12	28/190 (14.7%)	32	14/75 (18.7%)	17
Skin and subcutaneous tissue disorders
Alopecia	7/41 (17.1%)	9	0/8 (0%)	0	21/58 (36.2%)	26	62/190 (32.6%)	84	33/75 (44%)	49
Dry skin	2/41 (4.9%)	3	0/8 (0%)	0	2/58 (3.4%)	3	13/190 (6.8%)	15	7/75 (9.3%)	8
Erythema multiforme	1/41 (2.4%)	1	0/8 (0%)	0	1/58 (1.7%)	3	10/190 (5.3%)	17	7/75 (9.3%)	12
Erythroderma	0/41 (0%)	0	0/8 (0%)	0	4/58 (6.9%)	5	9/190 (4.7%)	11	6/75 (8%)	6
Hyperhidrosis	0/41 (0%)	0	1/8 (12.5%)	2	2/58 (3.4%)	2	6/190 (3.2%)	11	4/75 (5.3%)	9
Skin and subcutaneous tissue disorders - Other	3/41 (7.3%)	3	0/8 (0%)	0	7/58 (12.1%)	10	27/190 (14.2%)	41	17/75 (22.7%)	28
Pain of skin	0/41 (0%)	0	0/8 (0%)	0	1/58 (1.7%)	1	9/190 (4.7%)	39	6/75 (8%)	36
Palmar-plantar erythrodysesthesia syndrome	17/41 (41.5%)	37	1/8 (12.5%)	1	39/58 (67.2%)	151	126/190 (66.3%)	666	58/75 (77.3%)	455
Pruritus	4/41 (9.8%)	4	1/8 (12.5%)	2	7/58 (12.1%)	8	20/190 (10.5%)	27	10/75 (13.3%)	15
Rash acneiform	2/41 (4.9%)	2	0/8 (0%)	0	3/58 (5.2%)	3	12/190 (6.3%)	12	7/75 (9.3%)	7
Rash maculo-papular	6/41 (14.6%)	7	0/8 (0%)	0	8/58 (13.8%)	10	32/190 (16.8%)	71	16/75 (21.3%)	26
Vascular disorders
Hypotension	1/41 (2.4%)	1	0/8 (0%)	0	1/58 (1.7%)	1	7/190 (3.7%)	8	4/75 (5.3%)	5
Hypertension	18/41 (43.9%)	32	3/8 (37.5%)	3	37/58 (63.8%)	97	124/190 (65.3%)	697	62/75 (82.7%)	552
Thromboembolic event	0/41 (0%)	0	2/8 (25%)	2	1/58 (1.7%)	1	6/190 (3.2%)	7	5/75 (6.7%)	5

Limitations/Caveats

Overall survival results are confounded by the fact that 85% of the participants initially randomized to placebo switched to open-label regorafenib.

More Information

Certain Agreements

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

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.