Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT02368886

Recruitment Status : Completed

First Posted : February 23, 2015

Results First Posted : July 26, 2019

Last Update Posted : July 27, 2023

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Sponsor:

Collaborator:

National Cancer Institute (NCI)

Information provided by (Responsible Party):

Academic and Community Cancer Research United

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Conditions	Colon Adenocarcinoma Rectal Adenocarcinoma Stage III Colorectal Cancer AJCC v7 Stage IIIA Colorectal Cancer AJCC v7 Stage IIIB Colorectal Cancer AJCC v7 Stage IIIC Colorectal Cancer AJCC v7 Stage IV Colorectal Cancer AJCC v7 Stage IVA Colorectal Cancer AJCC v7 Stage IVB Colorectal Cancer AJCC v7
Interventions	Drug: Clobetasol Propionate Other: Pharmacological Study Other: Quality-of-Life Assessment Drug: Regorafenib
Enrollment	123

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy)	Arm A2 (Regorafenib Dose Escalation + Reactive Strategy)	Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy)	Arm B2 (Regorafenib Standard Dose + Reactive Strategy)
Arm/Group Description	In the regorafenib dose escalation ...	In the regorafenib dose escalation ...	In the regorafenib standard dose gr...	In the regorafenib standard dose gr...
Arm/Group Description	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy).
Period Title: Overall Study
Started	29	27	34	33
Completed	28	26	33	29
Not Completed	1	1	1	4
Reason Not Completed
Cancel	1	1	1	3
Ineligible	0	0	0	1

Baseline Characteristics

Arm/Group Title		Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy)	Arm A2 (Regorafenib Dose Escalation + Reactive Strategy)	Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy)	Arm B2 (Regorafenib Standard Dose + Reactive Strategy)	Total
Arm/Group Description		In the regorafenib dose escalation ...	In the regorafenib dose escalation ...	In the regorafenib standard dose gr...	In the regorafenib standard dose gr...	Total of all reporting groups
Arm/Group Description		In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy).	Total of all reporting groups
Overall Number of Baseline Participants		28	26	33	29	116
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The data for the pre-emptive and reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies (regorafenib dose escalation group (Arms A1 + A2) versus regorafenib standard dose group (Arms B1 + B2)).
Age, Continuous Median (Full Range) Unit of measure: Years
	Number Analyzed	28 participants	26 participants	33 participants	29 participants	116 participants
		65 (38 to 77)	57 (29 to 76)	61 (32 to 78)	62 (34 to 81)	61 (29 to 81)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	28 participants	26 participants	33 participants	29 participants	116 participants
	Female	9 32.1%	9 34.6%	17 51.5%	10 34.5%	45 38.8%
	Male	19 67.9%	17 65.4%	16 48.5%	19 65.5%	71 61.2%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	28 participants	26 participants	33 participants	29 participants	116 participants
	American Indian or Alaska Native	0 0.0%	1 3.8%	0 0.0%	0 0.0%	1 0.9%
	Asian	2 7.1%	1 3.8%	1 3.0%	1 3.4%	5 4.3%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 3.6%	4 15.4%	0 0.0%	4 13.8%	9 7.8%
	White	25 89.3%	19 73.1%	31 93.9%	24 82.8%	99 85.3%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	1 3.8%	1 3.0%	0 0.0%	2 1.7%
Region of Enrollment Measure Type: Count of Participants Unit of measure: Participants
United States	Number Analyzed	28 participants	26 participants	33 participants	29 participants	116 participants
United States		28 100.0%	26 100.0%	33 100.0%	29 100.0%	116 100.0%
ECOG Performance Status ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	28 participants	26 participants	33 participants	29 participants	116 participants
	0	9 32.1%	11 42.3%	15 45.5%	8 27.6%	43 37.1%
	1	19 67.9%	15 57.7%	18 54.5%	21 72.4%	73 62.9%
		[1] Measure Description: Eastern Cooperative Oncology Group PS Scale: 0)Fully active, able to carry on all pre-disease performance without restriction; 1)Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2)Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3)Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4)Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.

Outcome Measures

1.Primary Outcome


Title	Proportion of Patients in Each Arm Who Complete 2 Cycles of Protocol Treatment and Initiate Cycle 3
Description	Fisher exact test will be used to detect a difference course 3 between...
Description	Fisher exact test will be used to detect a difference course 3 between arms (starting low dose [pooled arm A1 and A2] versus [vs.] standard dose [pooled arm B1 and B2]). The proportion of patients who complete 2 courses of protocol treatment and initiate course 3 will be computed by arm with its 95% confidence interval using exact method.
Time Frame	At 8 weeks

Outcome Measure Data

Analysis Population Description

The data for the pre-emptive and reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies (regorafenib dose escalation group (Arms A1 + A2) versus regorafenib standard dose group (Arms B1 + B2)).


Arm/Group Title	Regorafenib Dose Escalation Group	Regorafenib Standard Dose Group
Arm/Group Description:	In the regorafenib dose escalation ...	In the regorafenib standard dose gr...
Arm/Group Description:	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).
Overall Number of Participants Analyzed	54	62
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: proportion of patients
	0.43 (0.29 to 0.56)	0.26 (0.15 to 0.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib Dose Escalation Group, Regorafenib Standard Dose Group
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0434
	Comments	1-sided
	Method	Fisher Exact
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95% 0.00 to 0.34
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Overall Survival (OS)
Description	OS is defined as the time from randomization to death due to any cause...
Description	OS is defined as the time from randomization to death due to any cause and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments.
Time Frame	Time from randomization to death due to any cause, assessed up to 2 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Regorafenib Dose Escalation Group	Regorafenib Standard Dose Group
Arm/Group Description:	In the regorafenib dose escalation ...	In the regorafenib standard dose gr...
Arm/Group Description:	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).
Overall Number of Participants Analyzed	54	62
Median (95% Confidence Interval) Unit of Measure: months
	9.8 (7.5 to 11.9)	6.0 (4.9 to 10.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib Dose Escalation Group, Regorafenib Standard Dose Group
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1241
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95% 0.47 to 1.10
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Progression Free Survival (PFS)
Description	PFS is defined as the time from randomization to the earlier of diseas...
Description	PFS is defined as the time from randomization to the earlier of disease progression or death due to any cause, where progressed disease (PD) is defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments.
Time Frame	Time from randomization to the earlier of disease progression or death due to any cause, where progressed disease (PD) is defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Regorafenib Dose Escalation Group	Regorafenib Standard Dose Group
Arm/Group Description:	In the regorafenib dose escalation ...	In the regorafenib standard dose gr...
Arm/Group Description:	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).
Overall Number of Participants Analyzed	54	62
Median (95% Confidence Interval) Unit of Measure: months
	2.8 (2.0 to 5.0)	2.0 (1.8 to 2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib Dose Escalation Group, Regorafenib Standard Dose Group
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3797
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95% 0.57 to 1.24
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Time to Progression (TTP)
Description	TTP is defined as the time from randomization to disease progression, ...
Description	TTP is defined as the time from randomization to disease progression, where PD is defined by RECIST 1.1 and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments.
Time Frame	Time from randomization to disease progression, where PD is defined by RECIST 1.1, assessed up to 2 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Regorafenib Dose Escalation Group	Regorafenib Standard Dose Group
Arm/Group Description:	In the regorafenib dose escalation ...	In the regorafenib standard dose gr...
Arm/Group Description:	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).
Overall Number of Participants Analyzed	54	62
Median (95% Confidence Interval) Unit of Measure: months
	2.8 (1.9 to 5.7)	2.0 (1.8 to 3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib Dose Escalation Group, Regorafenib Standard Dose Group
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4614
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95% 0.55 to 1.31
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Cumulative (Total) Dose of Regorafenib Received by Patients in the First Two Cycles
Description	Will be summarized with descriptive statistics and compared between re...
Description	Will be summarized with descriptive statistics and compared between regorafenib arms (A vs. B).
Time Frame	Up to 8 weeks

Outcome Measure Data

Analysis Population Description

The data for the pre-emptive & reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies ((Arms A1 + A2) versus (Arms B1 + B2)). There are patients off-protocol treatment during cycle 1; therefore, we do not have cycle 2 dosing information for those patients who are off-protocol treatment during cycle 1.


Arm/Group Title		Regorafenib Dose Escalation Group	Regorafenib Standard Dose Group
Arm/Group Description:		In the regorafenib dose escalation ...	In the regorafenib standard dose gr...
Arm/Group Description:		In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).
Overall Number of Participants Analyzed		54	62
Mean (Standard Deviation) Unit of Measure: mg/day
Cycle 1	Number Analyzed	54 participants	62 participants
Cycle 1		91.8 (33.4)	133.1 (34.6)
Cycle 2	Number Analyzed	41 participants	41 participants
Cycle 2		121.3 (40.0)	117.3 (48.9)

6.Secondary Outcome


Title	Dose Intensity of Regorafenib Received by Patients in the First Two Cycles as Measured by the Percentage of Planned Dose Received
Description	Dose intensity of regorafenib received by patients in the first two cy...
Description	Dose intensity of regorafenib received by patients in the first two cycles as measured by the percentage (%) of planned dose received
Time Frame	Up to 8 weeks

Outcome Measure Data

Analysis Population Description

The data for the pre-emptive & reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies ((Arms A1 + A2) versus (Arms B1 + B2)).


Arm/Group Title	Regorafenib Dose Escalation Group	Regorafenib Standard Dose Group
Arm/Group Description:	In the regorafenib dose escalation ...	In the regorafenib standard dose gr...
Arm/Group Description:	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).
Overall Number of Participants Analyzed	54	62
Median (Standard Deviation) Unit of Measure: percentage of planned dose received
	76.2 (25.3)	76.0 (21.0)

7.Secondary Outcome


Title	Proportion of Patients Overall and Within Each Arm Experiencing Grade 3 or 4 Hand and Foot Syndrome (HFS) or Fatigue
Description	Will be computed with 95% confidence intervals, and differences betwee...
Description	Will be computed with 95% confidence intervals, and differences between regorafenib dosing strategies (pooled across HFS strategies) tested using a Fisher Exact test. The incidence of grade 3 or 4 HFS will also be descriptively compared between those receiving a pre-specified preemptive vs. reactive approach for hand and foot syndrome (pooled across dosing strategies), and tested using a Fisher Exact test.
Time Frame	Up to 2 years

Outcome Measure Data Not Reported

8.Secondary Outcome


Title	Changes in Quality of Life (QOL) (According to the HFS14 Questionnaire)
Description	Patients will be descriptively compared between treatment arms and bet...
Description	Patients will be descriptively compared between treatment arms and between HFS treatment strategies (pre-emptive vs. reactive) according to self-reported outcomes given on the HFS14 questionnaire. Results from the course 1 and 2 HSF14 questionnaires will also be summarized descriptively as they relate to the pre-emptive versus reactive palmar-plantar erythrodysesthesia syndrome (PPES) strategies, with comparisons made within and between arms using the t-test or Wilcoxon rank sum test as appropriate, as well as taking time-dependence into account.
Time Frame	Baseline to up to 8 weeks

Outcome Measure Data Not Reported

9.Secondary Outcome


Title	Changes in QOL (According to the Linear Analogue Self-Assessment [LASA] Questionnaire)
Description	Changes in QOL (according to the LASA questionnaire as measured by the...
Description	Changes in QOL (according to the LASA questionnaire as measured by the overall QOL question) from baseline will be compared between the treatment arms using the Kruskal-Wallis test.
Time Frame	Baseline to 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy)	Arm A2 (Regorafenib Dose Escalation + Reactive Strategy)	Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy)	Arm B2 (Regorafenib Standard Dose + Reactive Strategy)
Arm/Group Description:	In the regorafenib dose escalation ...	In the regorafenib dose escalation ...	In the regorafenib standard dose gr...	In the regorafenib standard dose gr...
Arm/Group Description:	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).	In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy).
Overall Number of Participants Analyzed	20	11	14	16
Mean (Standard Deviation) Unit of Measure: LASA overall score change from baseline
	-0.9 (1.12)	-0.3 (1.42)	-0.7 (2.09)	-0.9 (1.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy), Arm A2 (Regorafenib Dose Escalation + Reactive Strategy), Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy), Arm B2 (Regorafenib Standard Dose + Reactive Strategy)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7319
	Comments	[Not Specified]
	Method	Kruskal-Wallis
	Comments	[Not Specified]

10.Other Pre-specified Outcome


Title	Pharmacokinetics (PK) Parameters of Regorafenib Using Liquid Chromatography Mass Spectrometry
Description	After quantitation, the average trough concentration, calculated from ...
Description	After quantitation, the average trough concentration, calculated from all available data, will be calculated. This average trough concentration will be correlated with toxicity and efficacy endpoints. Further descriptive characteristics of the pharmacokinetics will also be calculated, an example includes (but is not limited to) within-patient variability in the trough concentrations pharmacokinetic parameters will also be calculated, both overall and within courses, as a ratio of the maximum:minimum value.
Time Frame	Baseline, prior to treatment, days 7, 14, and 21 prior to treatment (course 1), and days 1 and 21 prior to treatment (course 2)

Outcome Measure Data Not Reported

Adverse Events

Time Frame	Adverse events were assessed during the active monitoring phase (weekly during Cycles 1 and 2, then every 4 weeks until progression); up to 2 years. The total study duration (accrual and follow-up) is expected to be approximately 2 years.
Adverse Event Reporting Description	Each CTCAE term is a representation of a specific event used for medical documentation & analysis & is a single MedDRA Lowest Level Term (LLT). All graded AEs are reported for non-cancel patients. Serious AE (SAE) reports may include any secondary serious or non-serious events considered related to the primary event (the reason for filing an expedited report); collectively, these events are referred to as Expedited AEs, & appear in the SAE table.

Arm/Group Title	Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy)		Arm A2 (Regorafenib Dose Escalation + Reactive Strategy)		Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy)		Arm B2 (Regorafenib Standard Dose + Reactive Strategy)
Arm/Group Description	In the regorafenib dose escalation ...		In the regorafenib dose escalation ...		In the regorafenib standard dose gr...		In the regorafenib standard dose gr...
Arm/Group Description	In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).		In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy).		In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).		In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy).
All-Cause Mortality
	Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy)		Arm A2 (Regorafenib Dose Escalation + Reactive Strategy)		Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy)		Arm B2 (Regorafenib Standard Dose + Reactive Strategy)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/28 (0.00%)		3/26 (11.54%)		3/33 (9.09%)		2/30 (6.67%)
Serious Adverse Events Serious Adverse Events
	Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy)		Arm A2 (Regorafenib Dose Escalation + Reactive Strategy)		Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy)		Arm B2 (Regorafenib Standard Dose + Reactive Strategy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/28 (14.29%)		10/26 (38.46%)		10/33 (30.30%)		10/30 (33.33%)
Blood and lymphatic system disorders
Anemia ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Cardiac disorders
Myocardial infarction ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Sinus tachycardia ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	2/28 (7.14%)	2	5/26 (19.23%)	5	3/33 (9.09%)	3	1/30 (3.33%)	1
Ascites ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Colitis ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Colonic obstruction ^† 1	1/28 (3.57%)	1	2/26 (7.69%)	2	0/33 (0.00%)	0	0/30 (0.00%)	0
Constipation ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Lower gastrointestinal hemorrhage ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Nausea ^† 1	0/28 (0.00%)	0	2/26 (7.69%)	2	0/33 (0.00%)	0	0/30 (0.00%)	0
Rectal fistula ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Rectal obstruction ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Vomiting ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
General disorders
Death NOS ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	1/33 (3.03%)	1	0/30 (0.00%)	0
Fatigue ^† 1	1/28 (3.57%)	1	1/26 (3.85%)	1	2/33 (6.06%)	3	0/30 (0.00%)	0
Pain ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Infections and infestations
Abdominal infection ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Infections and infestations - Other, specify ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Lung infection ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Sepsis ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	1/30 (3.33%)	1
Urinary tract infection ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Investigations
Alanine aminotransferase increased ^† 1	2/28 (7.14%)	2	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Alkaline phosphatase increased ^† 1	2/28 (7.14%)	2	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Aspartate aminotransferase increased ^† 1	2/28 (7.14%)	2	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Blood bilirubin increased ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
INR increased ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Investigations - Other, specify ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Platelet count decreased ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Metabolism and nutrition disorders
Anorexia ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	1/30 (3.33%)	1
Dehydration ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	2/33 (6.06%)	2	1/30 (3.33%)	1
Hyperglycemia ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Hypoalbuminemia ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Hypocalcemia ^† 1	2/28 (7.14%)	2	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Hypokalemia ^† 1	1/28 (3.57%)	1	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Hyponatremia ^† 1	2/28 (7.14%)	2	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Chest wall pain ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Generalized muscle weakness ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	1/33 (3.03%)	1	0/30 (0.00%)	0
Myalgia ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify ^† 1	0/28 (0.00%)	0	2/26 (7.69%)	2	1/33 (3.03%)	1	1/30 (3.33%)	1
Nervous system disorders
Encephalopathy ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Syncope ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Transient ischemic attacks ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Psychiatric disorders
Confusion ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Renal and urinary disorders
Urinary retention ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Dyspnea ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	1/33 (3.03%)	1	2/30 (6.67%)	2
Pleural effusion ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Respiratory failure ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	1/30 (3.33%)	1
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	2	0/33 (0.00%)	0	0/30 (0.00%)	0
Rash maculo-papular ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Vascular disorders
Thromboembolic event ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
1 Term from vocabulary, MedDRA 12 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy)		Arm A2 (Regorafenib Dose Escalation + Reactive Strategy)		Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy)		Arm B2 (Regorafenib Standard Dose + Reactive Strategy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/28 (100.00%)		24/26 (92.31%)		31/33 (93.94%)		30/30 (100.00%)
Blood and lymphatic system disorders
Anemia ^† 1	4/28 (14.29%)	5	8/26 (30.77%)	15	7/33 (21.21%)	10	6/30 (20.00%)	8
Blood and lymphatic system disorders - Other, specify ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	2/30 (6.67%)	3
Thrombotic thrombocytopenic purpura ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	5	0/33 (0.00%)	0	0/30 (0.00%)	0
Cardiac disorders
Sinus tachycardia ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	1/30 (3.33%)	1
Ear and labyrinth disorders
Tinnitus ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	2	0/30 (0.00%)	0
Endocrine disorders
Hypothyroidism ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Eye disorders
Watering eyes ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	2/28 (7.14%)	3	1/26 (3.85%)	1	3/33 (9.09%)	3	2/30 (6.67%)	2
Ascites ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	3	0/33 (0.00%)	0	0/30 (0.00%)	0
Constipation ^† 1	2/28 (7.14%)	2	1/26 (3.85%)	1	1/33 (3.03%)	1	4/30 (13.33%)	5
Diarrhea ^† 1	14/28 (50.00%)	30	10/26 (38.46%)	20	17/33 (51.52%)	37	10/30 (33.33%)	24
Dry mouth ^† 1	2/28 (7.14%)	7	1/26 (3.85%)	1	0/33 (0.00%)	0	3/30 (10.00%)	3
Dyspepsia ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Dysphagia ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Flatulence ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	5	0/30 (0.00%)	0
Gastroesophageal reflux disease ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Gastrointestinal disorders - Other, specify ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	2/30 (6.67%)	2
Mucositis oral ^† 1	1/28 (3.57%)	1	4/26 (15.38%)	5	5/33 (15.15%)	7	5/30 (16.67%)	7
Nausea ^† 1	8/28 (28.57%)	16	12/26 (46.15%)	21	16/33 (48.48%)	43	13/30 (43.33%)	17
Oral pain ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	2/33 (6.06%)	2	3/30 (10.00%)	5
Stomach pain ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Vomiting ^† 1	5/28 (17.86%)	7	7/26 (26.92%)	8	9/33 (27.27%)	12	5/30 (16.67%)	6
General disorders
Chills ^† 1	1/28 (3.57%)	2	1/26 (3.85%)	3	1/33 (3.03%)	1	2/30 (6.67%)	2
Edema limbs ^† 1	1/28 (3.57%)	1	1/26 (3.85%)	1	1/33 (3.03%)	1	0/30 (0.00%)	0
Fatigue ^† 1	25/28 (89.29%)	72	20/26 (76.92%)	53	26/33 (78.79%)	83	27/30 (90.00%)	72
Fever ^† 1	1/28 (3.57%)	2	0/26 (0.00%)	0	1/33 (3.03%)	1	3/30 (10.00%)	3
General disorders and administration site conditions - Other, specify ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	2/33 (6.06%)	3	2/30 (6.67%)	4
Non-cardiac chest pain ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Pain ^† 1	4/28 (14.29%)	4	1/26 (3.85%)	1	2/33 (6.06%)	2	1/30 (3.33%)	1
Hepatobiliary disorders
Hepatic failure ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Hepatobiliary disorders - Other, specify ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Infections and infestations
Sinusitis ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Urinary tract infection ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Investigations
Activated partial thromboplastin time prolonged ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Alanine aminotransferase increased ^† 1	2/28 (7.14%)	4	4/26 (15.38%)	4	6/33 (18.18%)	13	3/30 (10.00%)	3
Alkaline phosphatase increased ^† 1	3/28 (10.71%)	4	4/26 (15.38%)	4	7/33 (21.21%)	13	5/30 (16.67%)	6
Aspartate aminotransferase increased ^† 1	2/28 (7.14%)	3	5/26 (19.23%)	8	8/33 (24.24%)	16	8/30 (26.67%)	9
Blood bilirubin increased ^† 1	3/28 (10.71%)	5	5/26 (19.23%)	5	9/33 (27.27%)	10	9/30 (30.00%)	10
Creatinine increased ^† 1	0/28 (0.00%)	0	2/26 (7.69%)	2	1/33 (3.03%)	1	3/30 (10.00%)	4
Investigations - Other, specify ^† 1	1/28 (3.57%)	8	1/26 (3.85%)	1	2/33 (6.06%)	5	3/30 (10.00%)	4
Lymphocyte count decreased ^† 1	1/28 (3.57%)	1	4/26 (15.38%)	5	2/33 (6.06%)	3	4/30 (13.33%)	6
Platelet count decreased ^† 1	4/28 (14.29%)	4	2/26 (7.69%)	3	6/33 (18.18%)	8	2/30 (6.67%)	2
Weight loss ^† 1	2/28 (7.14%)	3	3/26 (11.54%)	9	6/33 (18.18%)	9	5/30 (16.67%)	5
White blood cell decreased ^† 1	1/28 (3.57%)	2	1/26 (3.85%)	1	3/33 (9.09%)	3	1/30 (3.33%)	1
Metabolism and nutrition disorders
Anorexia ^† 1	8/28 (28.57%)	11	6/26 (23.08%)	7	6/33 (18.18%)	10	13/30 (43.33%)	20
Dehydration ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	2/33 (6.06%)	2	2/30 (6.67%)	2
Hyperglycemia ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	2	0/33 (0.00%)	0	1/30 (3.33%)	1
Hyperkalemia ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	1/33 (3.03%)	1	1/30 (3.33%)	1
Hypermagnesemia ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Hypoalbuminemia ^† 1	3/28 (10.71%)	6	2/26 (7.69%)	2	3/33 (9.09%)	5	4/30 (13.33%)	5
Hypocalcemia ^† 1	2/28 (7.14%)	3	2/26 (7.69%)	3	0/33 (0.00%)	0	4/30 (13.33%)	4
Hypokalemia ^† 1	2/28 (7.14%)	5	0/26 (0.00%)	0	3/33 (9.09%)	4	3/30 (10.00%)	3
Hyponatremia ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	6/33 (18.18%)	8	5/30 (16.67%)	5
Hypophosphatemia ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Metabolism and nutrition disorders - Other, specify ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	2/30 (6.67%)	2
Musculoskeletal and connective tissue disorders
Arthritis ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	2	0/30 (0.00%)	0
Back pain ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	3/33 (9.09%)	4	2/30 (6.67%)	2
Bone pain ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	1/33 (3.03%)	1	0/30 (0.00%)	0
Chest wall pain ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	2	0/30 (0.00%)	0
Generalized muscle weakness ^† 1	3/28 (10.71%)	4	2/26 (7.69%)	2	1/33 (3.03%)	2	1/30 (3.33%)	1
Musculoskeletal and connective tissue disorder - Other, specify ^† 1	1/28 (3.57%)	3	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Myalgia ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	4/33 (12.12%)	5	3/30 (10.00%)	3
Myositis ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Pain in extremity ^† 1	1/28 (3.57%)	1	3/26 (11.54%)	3	2/33 (6.06%)	4	1/30 (3.33%)	2
Nervous system disorders
Cognitive disturbance ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Dizziness ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	1/30 (3.33%)	2
Dysgeusia ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	1/33 (3.03%)	3	2/30 (6.67%)	2
Encephalopathy ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Headache ^† 1	3/28 (10.71%)	3	2/26 (7.69%)	6	3/33 (9.09%)	7	0/30 (0.00%)	0
Paresthesia ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	2	0/30 (0.00%)	0
Peripheral motor neuropathy ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	1/30 (3.33%)	1
Peripheral sensory neuropathy ^† 1	5/28 (17.86%)	6	1/26 (3.85%)	1	4/33 (12.12%)	8	2/30 (6.67%)	4
Psychiatric disorders
Insomnia ^† 1	2/28 (7.14%)	2	1/26 (3.85%)	1	0/33 (0.00%)	0	1/30 (3.33%)	1
Psychiatric disorders - Other, specify ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Renal and urinary disorders
Hematuria ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Urinary frequency ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Atelectasis ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Cough ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	2/33 (6.06%)	3	0/30 (0.00%)	0
Dyspnea ^† 1	3/28 (10.71%)	5	3/26 (11.54%)	7	5/33 (15.15%)	5	4/30 (13.33%)	4
Epistaxis ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Hiccups ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Hoarseness ^† 1	4/28 (14.29%)	11	4/26 (15.38%)	8	5/33 (15.15%)	6	3/30 (10.00%)	3
Hypoxia ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	0/30 (0.00%)	0
Pleuritic pain ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Productive cough ^† 1	1/28 (3.57%)	2	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Sinus disorder ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	0/33 (0.00%)	0	0/30 (0.00%)	0
Skin and subcutaneous tissue disorders
Alopecia ^† 1	1/28 (3.57%)	1	0/26 (0.00%)	0	4/33 (12.12%)	9	2/30 (6.67%)	2
Dry skin ^† 1	1/28 (3.57%)	3	1/26 (3.85%)	1	2/33 (6.06%)	7	1/30 (3.33%)	1
Nail discoloration ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	1	0/33 (0.00%)	0	0/30 (0.00%)	0
Pain of skin ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	1/30 (3.33%)	1
Palmar-plantar erythrodysesthesia syndrome ^† 1	18/28 (64.29%)	37	17/26 (65.38%)	43	22/33 (66.67%)	61	22/30 (73.33%)	42
Pruritus ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	1/30 (3.33%)	1
Rash maculo-papular ^† 1	8/28 (28.57%)	16	2/26 (7.69%)	3	8/33 (24.24%)	12	8/30 (26.67%)	11
Skin and subcutaneous tissue disorders - Other, specify ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	1/33 (3.03%)	1	1/30 (3.33%)	1
Vascular disorders
Hot flashes ^† 1	0/28 (0.00%)	0	0/26 (0.00%)	0	0/33 (0.00%)	0	1/30 (3.33%)	1
Hypertension ^† 1	21/28 (75.00%)	46	14/26 (53.85%)	36	17/33 (51.52%)	62	19/30 (63.33%)	44
Thromboembolic event ^† 1	0/28 (0.00%)	0	1/26 (3.85%)	2	0/33 (0.00%)	0	0/30 (0.00%)	0
1 Term from vocabulary, MedDRA 12 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.

Results Point of Contact

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Name/Title:	Tanios Bekaii-Saab, M.D.
Organization:	Mayo Clinic Arizona
Phone:	507/266-0800
EMail:	Bekaii-Saab.Tanios@mayo.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bekaii-Saab TS, Ou FS, Ahn DH, Boland PM, Ciombor KK, Heying EN, Dockter TJ, Jacobs NL, Pasche BC, Cleary JM, Meyers JP, Desnoyers RJ, McCune JS, Pedersen K, Barzi A, Chiorean EG, Sloan J, Lacouture ME, Lenz HJ, Grothey A. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019 Aug;20(8):1070-1082. doi: 10.1016/S1470-2045(19)30272-4. Epub 2019 Jun 28.

Weinberg BA, Hartley ML, Salem ME. Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets-PART 2: Approaches Beyond First-Line Therapy, and Novel Biologic Agents Under Investigation. Oncology (Williston Park). 2017 Jul 15;31(7):573-80.

Layout table for additonal information

Responsible Party:	Academic and Community Cancer Research United
ClinicalTrials.gov Identifier:	NCT02368886
Other Study ID Numbers:	RU021407I NCI-2015-00011 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) RU021407I ( Other Identifier: Academic and Community Cancer Research United ) P30CA015083 ( U.S. NIH Grant/Contract )
First Submitted:	February 16, 2015
First Posted:	February 23, 2015
Results First Submitted:	June 6, 2019
Results First Posted:	July 26, 2019
Last Update Posted:	July 27, 2023

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