Daily Oral Regorafenib for Chemotherapy-Refractory, Metastatic and Locally Advanced Angiosarcoma

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02048722
• Collaborator: Bayer (Industry), National Cancer Institute (NCI) (NIH)
• Enrollment: 31
• Locations: 7
• Arm: 1
• Actual Duration (Months): 88
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to see whether a drug called regorafenib might be effective in treating angiosarcoma. This study is for patients who have angiosarcoma that has gotten worse after they received chemotherapy. Regorafenib is a type of drug called a kinase inhibitor. Regorafenib interferes with how some kinase proteins work. Some of these kinases in cancer cells might normally help the cancer cells grow or form new blood vessels that could feed a growing tumor. By blocking these proteins, regorafenib may help stop the growth of certain cancers.

Condition or Disease	Intervention/Treatment	Phase
Adult Angiosarcoma; Recurrent Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma	Drug: regorafenib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To define the progression-free survival (PFS) at 4 months with daily oral regorafenib (160 mg) in previously treated locally advanced/metastatic angiosarcoma patients

SECONDARY OBJECTIVES:

1. Progression-free rate at 3 and 6 months. II. Progression-free survival. III. Overall survival (up to 5 years). IV. Response rate (by Response Evaluation Criteria in Solid Tumors [RECIST] version [v] 1.1).

2. Rate and duration of tumor control (complete response [CR] + partial response [PR] + stable disease [SD]).

3. Safety/tolerability of regorafenib.

OUTLINE:

Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter, Open-Label Phase II Study of Daily Oral Regorafenib for Chemotherapy-Refractory, Metastatic and Locally Advanced Angiosarcoma
• Actual Study Start Date: Jun 13, 2014
• Actual Primary Completion Date: Oct 14, 2019
• Actual Study Completion Date: Oct 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (regorafenib) Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: regorafenib; Given PO; Other Names: BAY 73-4506 multikinase inhibitor BAY 73-4506 Stivarga

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) at 4 Months [At 4 months (of treatment)]

   The progression-free survival (PFS) at 4 months will be defined as the number of patients with progression absent at 4 months divided by the total number of evaluable study patients. This will be measured from start of treatment until time of progression or death, whichever occurs first and will be estimated using Kaplan-Meier methods and reported as a survival probability. Progression will be evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in RECIST v 1.1. Progression will be defined as: Progressive disease (PD): > 20% increase in the sum diameters of target lesions, taking as reference the smallest sum diameters while on study. The sum diameters must also demonstrate an absolute increase of 5 mm. The appearance of one or more new lesions also qualifies as PD.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) at 3 and 6 Months [Assessed at 3 months and 6 months]

   The progression-free survival (PFS) at 3 and 6 months will be defined as the number of patients with progression absent at 3 months and 6 months divided by the total number of evaluable study patients. This will be measured from start of treatment until time of progression or death, whichever occurs first and will be estimated using Kaplan-Meier methods and reported as a survival probability. Progression will be evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in RECIST v 1.1. Progression will be defined as: Progressive disease (PD): > 20% increase in the sum diameters of target lesions, taking as reference the smallest sum diameters while on study. The sum diameters must also demonstrate an absolute increase of 5 mm. The appearance of one or more new lesions also qualifies as PD.

2. Median Progression-free Survival (PFS) [The duration of time from start of treatment until time of progression, up to 5 years]

   The median progression-free rate (PFR) will be defined as the number of patients with progression absent divided by the total number of evaluable study patients. This will be measured from start of treatment until time of progression or death, whichever occurs first for up to 5 years and will be estimated using Kaplan-Meier methods. Progression will be evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in RECIST v 1.1. Progression will be defined as: Progressive disease (PD): > 20% increase in the sum diameters of target lesions, taking as reference the smallest sum diameters while on study. The sum diameters must also demonstrate an absolute increase of 5 mm. The appearance of one or more new lesions also qualifies as PD.

3. Overall Survival [From start of treatment up to 5 years]

   Overall survival will be defined as the time from start of treatment until death from any cause and will be estimated using Kaplan-Meier methods and reported as a survival probability. Patients that are alive at the time of data analysis will be censored at the date of known survival status.

4. Response Rate [At baseline and after every 2 cycles, up to 12 cycles where one cycle is 28 days]

   Imaging (such as a CT scan) will be done at baseline (within 4 weeks before the first dose) then after every 2 cycles while on treatment for tumor response evaluation. Response will be evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in RECIST v 1.1. Best response of each patient will be used and responses will be defined as the following: Complete response (CR): Disappearance of all target lesions Partial response (PR): > 30% decrease in the baseline sum diameters of target lesions

5. Rate of Tumor Control [At baseline and after every 2 cycles, up to 12 cycles where one cycle is 28 days]

   Imaging will be used at baseline then after every 2 cycles while on treatment to measure tumor size and response to treatment, the data collected from all patients on study will be used to calculate the rate and duration of tumor control. Response will be evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in RECIST v 1.1. Response and stable disease will be defined as the following: Complete response (CR): Disappearance of all target lesions Partial response (PR): > 30% decrease in the baseline sum diameters of target lesions Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study

6. Number of Grade 1, 2, 3, 4, and 5 Related Adverse Events Observed During Study Treatment (Defined by CTCAE v 4.0) [From treatment initiation though 30 days post the last treatment for a max of 12 cycles where one cycle is 28 days]

   Overall worst grade related toxicity (number of patients) was collected from the start of treatment until 30 days post the last treatment where patients were treated until progressive disease or unacceptable toxicity or patient withdrawal of treatment. All Adverse events that were determined to be at least possibly related to treatment are reported. All adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The severity of an AE is graded as follows: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Life expectancy of at least 4 months

• Histologically confirmed angiosarcoma

• Tumor deemed unresectable or metastatic

• Measurable disease per RECIST v 1.1

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

• Progressive disease under last palliative therapy with a history of prior ifosfamide, doxorubicin or taxane therapy for angiosarcoma; up to 4 prior therapies are allowed

• All acute toxic effects of any prior treatment have resolved to grade 1 or less (by National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] v 4.0) at the time of registration; NOTE: Exceptions to this criterion will include alopecia and fatigue

• Total bilirubin =< 1.5 x the upper limits of normal (ULN)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer)

• Alkaline phosphatase limit =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer)

• Lipase =< 1.5 x the ULN

• Serum creatinine =< 1.5 x the ULN

• International normalized ratio (INR)/partial thromboplastin time (PTT) < 1.5 x ULN

• Platelet count > 100000/mm^3

• Hemoglobin > 9 g/dL

• Absolute neutrophil count > 1500/mm^3

• If baseline urine protein creatinine (UPC) >= 1, a 24-hour urine protein must be assessed; patients must have a 24-hour urine protein value < grade 3 (> 3.5 g/24 hours) to be eligible

• NOTE: Blood transfusion to meet the above criteria will not be allowed; NOTE: Patients who are prophylactically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists; close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care

• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug; post-menopausal women (defined as age

= 50 years and no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test

• Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at registration until at least 3 months after the last dose of study drug; the definition of adequate contraception will be based on the judgment of the principal investigator

• Subject must be able to swallow and retain oral medication

• Subjects must be able to understand and be willing to sign the written informed consent form; a signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure

Exclusion Criteria:

• Uncontrolled hypertension (systolic pressure > 140 mmHg or diastolic pressure > 90 mmHg on repeated measurement) despite optimal medical management

• Active or clinically significant cardiac disease including:

• Congestive heart failure - New York Heart Association > class II

• Active coronary artery disease

• Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin

• Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before registration, or myocardial infarction within 6 months before registration

• Evidence or history of bleeding diathesis or coagulopathy

• Any hemorrhage or bleeding event grade 3 within 4 weeks prior to registration

• Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months of informed consent

• Subjects with any previously untreated or concurrent cancer unrelated to angiosarcoma; NOTE: Exceptions include cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor; subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before registration are allowed; all treatments must have been completed at least 3 years prior to registration

• Patients with pheochromocytoma

• Patients with severe hepatic impairment (Child-Pugh class C)

• Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection requiring treatment with antiviral therapy

• Ongoing infection > grade 2

• Evidence of significant central nervous system disease including seizure disorder requiring medication, symptomatic metastatic brain or meningeal tumors

• Presence of a non-healing wound, non-healing ulcer, or bone fracture

• Renal failure requiring hemo-or peritoneal dialysis

• Dehydration > grade 1

• Interstitial lung disease with ongoing signs and symptoms at the time of registration

• Pleural effusion or ascites that causes respiratory compromise (>= grade 2 dyspnea)

• History of organ allograft (including corneal transplant)

• Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial

• Any malabsorption condition

• Evidence of abdominal fistula, gastrointestinal (GI) perforation or intraabdominal abscess

• Women who are pregnant or breast-feeding

• Concurrent anti-cancer therapy (chemotherapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than study treatment (regorafenib)

• Prior use of regorafenib

• Prior use of sorafenib

• Use of cytotoxic chemotherapy within 21 days of registration

• Use of targeted therapy within two half-lives of registration

• Radiation directed at target lesion within 28 days of registration

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before registration

• Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) or with heparins and heparinoids; NOTE: Prophylactic anticoagulation as described below is allowed:

• Low dose warfarin (1 mg orally, once daily) with prothrombin time (PT)-international normalized ratio (INR) =< 1.5 x ULN is permitted; infrequent bleeding or elevations in PT-INR have been reported in some subjects taking warfarin while on regorafenib therapy; therefore, subjects taking concomitant warfarin should be monitored regularly for changes in PT, PT-INR or clinical bleeding episodes

• Low dose aspirin (=< 100 mg daily)

• Prophylactic doses of heparin

• Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation

• Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sarcoma Oncology Center	Santa Monica	California	United States	90403
2	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
3	Northwestern University	Chicago	Illinois	United States	60611
4	University of Iowa	Iowa City	Iowa	United States	52246
5	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota	United States	55455
6	Mayo Clinic	Rochester	Minnesota	United States	55905
7	Washington University-St. Louis	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Northwestern University
• Bayer
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mark Agulnik, M.D., Northwestern University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 19, 2019

More Information

Publications

None provided.

• Responsible Party: Northwestern University
• ClinicalTrials.gov Identifier: NCT02048722
• Other Study ID Numbers: NU 13S02; NCI-2013-02278; STU00087654; ONC-2013-129; NU 13S02; P30CA060553
• First Posted: Jan 29, 2014
• Last Update Posted: Apr 25, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Sarcoma; Hemangiosarcoma

Study Results

Participant Flow

Recruitment Details	The study was opened for enrollment March 12, 2014 with the first patient starting treatment June 13, 2014. A total of 31 patients were treated under the protocol. The study was permanently suspended to further enrollment August 5, 2019.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO
Period Title: 2 Cycles of Treatment
STARTED	31
Attempted 1st Cycle	31
Attempted 2nd Cycle	23
COMPLETED	23
NOT COMPLETED	8
Period Title: 2 Cycles of Treatment
STARTED	23
Assessed for First Response	23
Went on to Cycle 3 and Beyond	13
COMPLETED	13
NOT COMPLETED	10
Period Title: 2 Cycles of Treatment
STARTED	31
COMPLETED	4
NOT COMPLETED	27

Baseline Characteristics

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO
Overall Participants	31
Age, Customized (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.32 (14.58)
Sex: Female, Male (Count of Participants)
Female	16 51.6%
Male	15 48.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	31 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 9.7%
White	27 87.1%
More than one race	0 0%
Unknown or Not Reported	1 3.2%
Region of Enrollment (participants) [Number]
United States	31 100%
Type of disease (Count of Participants)
Metastatic	21 67.7%
Locally advanced/Unresectable	9 29%
Not reported	1 3.2%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) at 4 Months
Description	The progression-free survival (PFS) at 4 months will be defined as the number of patients with progression absent at 4 months divided by the total number of evaluable study patients. This will be measured from start of treatment until time of progression or death, whichever occurs first and will be estimated using Kaplan-Meier methods and reported as a survival probability. Progression will be evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in RECIST v 1.1. Progression will be defined as: Progressive disease (PD): > 20% increase in the sum diameters of target lesions, taking as reference the smallest sum diameters while on study. The sum diameters must also demonstrate an absolute increase of 5 mm. The appearance of one or more new lesions also qualifies as PD.
Time Frame	At 4 months (of treatment)

Outcome Measure Data

Analysis Population Description

8 Patients were not included due to the following reasons: progressive disease, patient refused further treatment (withdrawal of consent for further treatment), toxicity. This was due to data having either missing time points or "cycle 1" or "Cycle 1: follow up" missing from the dataset at the time of the analysis.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO
Measure Participants	23
Number (95% Confidence Interval) [percentage of patients alive]	52.17

2. Secondary Outcome

Title	Progression-Free Survival (PFS) at 3 and 6 Months
Description	The progression-free survival (PFS) at 3 and 6 months will be defined as the number of patients with progression absent at 3 months and 6 months divided by the total number of evaluable study patients. This will be measured from start of treatment until time of progression or death, whichever occurs first and will be estimated using Kaplan-Meier methods and reported as a survival probability. Progression will be evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in RECIST v 1.1. Progression will be defined as: Progressive disease (PD): > 20% increase in the sum diameters of target lesions, taking as reference the smallest sum diameters while on study. The sum diameters must also demonstrate an absolute increase of 5 mm. The appearance of one or more new lesions also qualifies as PD.
Time Frame	Assessed at 3 months and 6 months

Outcome Measure Data

Analysis Population Description

8 Patients were not included due to the following reasons: progressive disease, patient refused further treatment (withdrawal of consent for further treatment), toxicity. This was due to data having either missing time points or "cycle 1" or "Cycle 1: follow up" missing from the dataset at the time of the analysis.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO
Measure Participants	23
3 months	56.52
6 months	47.83

3. Secondary Outcome

Title	Median Progression-free Survival (PFS)
Description	The median progression-free rate (PFR) will be defined as the number of patients with progression absent divided by the total number of evaluable study patients. This will be measured from start of treatment until time of progression or death, whichever occurs first for up to 5 years and will be estimated using Kaplan-Meier methods. Progression will be evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in RECIST v 1.1. Progression will be defined as: Progressive disease (PD): > 20% increase in the sum diameters of target lesions, taking as reference the smallest sum diameters while on study. The sum diameters must also demonstrate an absolute increase of 5 mm. The appearance of one or more new lesions also qualifies as PD.
Time Frame	The duration of time from start of treatment until time of progression, up to 5 years

Outcome Measure Data

Analysis Population Description

8 Patients were not included due to the following reasons: progressive disease, patient refused further treatment (withdrawal of consent for further treatment), toxicity. This was due to data having either missing time points or "cycle 1" or "Cycle 1: follow up" missing from the dataset at the time of the analysis.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO
Measure Participants	23
Median (95% Confidence Interval) [months]	5.49

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival will be defined as the time from start of treatment until death from any cause and will be estimated using Kaplan-Meier methods and reported as a survival probability. Patients that are alive at the time of data analysis will be censored at the date of known survival status.
Time Frame	From start of treatment up to 5 years

Outcome Measure Data

Analysis Population Description

8 Patients were not included due to the following reasons: progressive disease, patient refused further treatment (withdrawal of consent for further treatment), toxicity. This was due to data having either missing time points or "cycle 1" or "Cycle 1: follow up" missing from the dataset at the time of the analysis.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO
Measure Participants	23
Median (95% Confidence Interval) [months]	14.06

5. Secondary Outcome

Title	Response Rate
Description	Imaging (such as a CT scan) will be done at baseline (within 4 weeks before the first dose) then after every 2 cycles while on treatment for tumor response evaluation. Response will be evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in RECIST v 1.1. Best response of each patient will be used and responses will be defined as the following: Complete response (CR): Disappearance of all target lesions Partial response (PR): > 30% decrease in the baseline sum diameters of target lesions
Time Frame	At baseline and after every 2 cycles, up to 12 cycles where one cycle is 28 days

Outcome Measure Data

Analysis Population Description

8 Patients were not included due to the following reasons: progressive disease, patient refused further treatment (withdrawal of consent for further treatment), toxicity. This was due to data having either missing time points or "cycle 1" or "Cycle 1: follow up" missing from the dataset at the time of the analysis.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO
Measure Participants	23
Complete Response	2 6.5%
Partial Response	2 6.5%

6. Secondary Outcome

Title	Rate of Tumor Control
Description	Imaging will be used at baseline then after every 2 cycles while on treatment to measure tumor size and response to treatment, the data collected from all patients on study will be used to calculate the rate and duration of tumor control. Response will be evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 Committee. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in RECIST v 1.1. Response and stable disease will be defined as the following: Complete response (CR): Disappearance of all target lesions Partial response (PR): > 30% decrease in the baseline sum diameters of target lesions Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study
Time Frame	At baseline and after every 2 cycles, up to 12 cycles where one cycle is 28 days

Outcome Measure Data

Analysis Population Description

8 Patients were not included due to the following reasons: progressive disease, patient refused further treatment (withdrawal of consent for further treatment), toxicity. This was due to data having either missing time points or "cycle 1" or "Cycle 1: follow up" missing from the dataset at the time of the analysis.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO
Measure Participants	23
Complete Response	2
Partial Response	2
Stable Disease	9

7. Secondary Outcome

Title	Number of Grade 1, 2, 3, 4, and 5 Related Adverse Events Observed During Study Treatment (Defined by CTCAE v 4.0)
Description	Overall worst grade related toxicity (number of patients) was collected from the start of treatment until 30 days post the last treatment where patients were treated until progressive disease or unacceptable toxicity or patient withdrawal of treatment. All Adverse events that were determined to be at least possibly related to treatment are reported. All adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The severity of an AE is graded as follows: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death
Time Frame	From treatment initiation though 30 days post the last treatment for a max of 12 cycles where one cycle is 28 days

Outcome Measure Data

Analysis Population Description

At the time of data pull (12/02/2019) for this outcome measure two patients remained on treatment. Any subsequent AEs determined to be related to treatment for these patients is not included here.

Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO
Measure Participants	31
Grade 1	5 16.1%
Grade 2	3 9.7%
Grade 3	3 9.7%
Grade 4	0 0%
Number of patients who didn't experience any grade	20 64.5%
Grade 1	1 3.2%
Grade 2	0 0%
Grade 3	0 0%
Grade 4	0 0%
Number of patients who didn't experience any grade	30 96.8%
Grade 1	2 6.5%
Grade 2	0 0%
Grade 3	0 0%
Grade 4	0 0%
Number of patients who didn't experience any grade	29 93.5%
Grade 1	14 45.2%
Grade 2	9 29%
Grade 3	3 9.7%
Grade 4	0 0%
Number of patients who didn't experience any grade	5 16.1%
Grade 1	11 35.5%
Grade 2	8 25.8%
Grade 3	4 12.9%
Grade 4	0 0%
Number of patients who didn't experience any grade	8 25.8%
Grade 1	1 3.2%
Grade 2	2 6.5%
Grade 3	0 0%
Grade 4	0 0%
Number of patients who didn't experience any grade	28 90.3%
Grade 1	0 0%
Grade 2	1 3.2%
Grade 3	0 0%
Grade 4	0 0%
Number of patients who didn't experience any grade	30 96.8%
Grade 1	10 32.3%
Grade 2	4 12.9%
Grade 3	5 16.1%
Grade 4	0 0%
Number of patients who didn't experience any grade	12 38.7%
Grade 1	14 45.2%
Grade 2	2 6.5%
Grade 3	3 9.7%
Grade 4	1 3.2%
Number of patients who didn't experience any grade	11 35.5%
Grade 1	7 22.6%
Grade 2	3 9.7%
Grade 3	1 3.2%
Grade 4	0 0%
Number of patients who didn't experience any grade	20 64.5%
Grade 1	1 3.2%
Grade 2	0 0%
Grade 3	0 0%
Grade 4	0 0%
Number of patients who didn't experience any grade	30 96.8%
Grade 1	11 35.5%
Grade 2	2 6.5%
Grade 3	1 3.2%
Grade 4	0 0%
Number of patients who didn't experience any grade	17 54.8%
Grade 1	3 9.7%
Grade 2	1 3.2%
Grade 3	2 6.5%
Grade 4	0 0%
Number of patients who didn't experience any grade	25 80.6%
Grade 1	0 0%
Grade 2	1 3.2%
Grade 3	0 0%
Grade 4	0 0%
Number of patients who didn't experience any grade	30 96.8%
Grade 1	9 29%
Grade 2	1 3.2%
Grade 3	1 3.2%
Grade 4	0 0%
Number of patients who didn't experience any grade	20 64.5%
Grade 1	14 45.2%
Grade 2	6 19.4%
Grade 3	1 3.2%
Grade 4	0 0%
Number of patients who didn't experience any grade	10 32.3%
Grade 1	3 9.7%
Grade 2	8 25.8%
Grade 3	4 12.9%
Grade 4	0 0%
Number of patients who didn't experience any grade	16 51.6%

Adverse Events

Time Frame	Adverse events were collected for each patient from the initiation of treatment up until 30 days post last dose of treatment for a maximum of 12 cycles for any patient (where 1 Cycle = 28 days).
Adverse Event Reporting Description	Due to data collection methods, some serious adverse event (SAEs) data maybe captured within the other adverse event data information. There are patients currently on treatment and these sections will be updated with complete information at the study completion. SAEs for any patients that were screenfails (i.e., signed consent but never started study treatment) have been removed from these results. These patients were not included in the participant flow and baseline characteristics section.
Arm/Group Title	Treatment (Regorafenib)
Arm/Group Description	Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. regorafenib: Given PO
All Cause Mortality
	Treatment (Regorafenib)
	Affected / at Risk (%)	# Events
Total	24/31 (77.4%)
Serious Adverse Events
	Treatment (Regorafenib)
	Affected / at Risk (%)	# Events
Total	15/31 (48.4%)
Gastrointestinal disorders
Intra-abdominal hemorrhage	1/31 (3.2%)	1
Nausea	1/31 (3.2%)	1
Nausea	1/31 (3.2%)	1
Lower gastrointestinal hemorrhage	1/31 (3.2%)	1
General disorders
Intractable pain	1/31 (3.2%)	1
Fever	1/31 (3.2%)	1
Neck pain	1/31 (3.2%)	1
Infections and infestations
Lung infection	1/31 (3.2%)	1
Metabolism and nutrition disorders
Hyponatremia	1/31 (3.2%)	1
Musculoskeletal and connective tissue disorders
Generalized weakness	1/31 (3.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Disease progression	2/31 (6.5%)	2
Tumor hemorrhage	1/31 (3.2%)	2
Nervous system disorders
Peripheral sensory neuropathy	1/31 (3.2%)	1
Confusion	1/31 (3.2%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/31 (3.2%)	1
Pleural Effusion	1/31 (3.2%)	1
Pleural effusion	1/31 (3.2%)	1
Dyspnea	1/31 (3.2%)	1
Skin and subcutaneous tissue disorders
Skin ulceration	1/31 (3.2%)	1
Vascular disorders
Vascular Disorder	1/31 (3.2%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Regorafenib)
	Affected / at Risk (%)	# Events
Total	31/31 (100%)
Blood and lymphatic system disorders
Anemia	14/31 (45.2%)
Leukocytosis	1/31 (3.2%)
Cardiac disorders
Cardiac disorders - Other, specify	2/31 (6.5%)
Chest pain - cardiac	1/31 (3.2%)
Myocardial infarction	1/31 (3.2%)
Sinus tachycardia	1/31 (3.2%)
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify	1/31 (3.2%)
Ear pain	1/31 (3.2%)
Tinnitus	1/31 (3.2%)
Endocrine disorders
Hypothyroidism	1/31 (3.2%)
Eye disorders
Blurred vision	1/31 (3.2%)
Eye disorders - Other, specify	1/31 (3.2%)
Gastrointestinal disorders
Abdominal pain	6/31 (19.4%)
Ascites	1/31 (3.2%)
Constipation	12/31 (38.7%)
Diarrhea	16/31 (51.6%)
Dry mouth	8/31 (25.8%)
Dysphagia	1/31 (3.2%)
Flatulence	2/31 (6.5%)
Gastrointestinal disorders - Other, specify	2/31 (6.5%)
Hemorrhoids	1/31 (3.2%)
Ileus	1/31 (3.2%)
Intra-abdominal hemorrhage	1/31 (3.2%)
Lower gastrointestinal hemorrhage	1/31 (3.2%)
Mucositis oral	11/31 (35.5%)
Nausea	16/31 (51.6%)
Oral dysesthesia	3/31 (9.7%)
Stomach pain	2/31 (6.5%)
Vomiting	11/31 (35.5%)
General disorders
Chills	2/31 (6.5%)
Edema face	2/31 (6.5%)
Edema limbs	4/31 (12.9%)
Fatigue	23/31 (74.2%)
Fever	6/31 (19.4%)
Gait disturbance	5/31 (16.1%)
General disorders and administration site conditions - Other, specify	2/31 (6.5%)
Malaise	1/31 (3.2%)
Non-cardiac chest pain	1/31 (3.2%)
Pain	8/31 (25.8%)
Infections and infestations
Gum infection	1/31 (3.2%)
Lung infection	1/31 (3.2%)
Otitis externa	1/31 (3.2%)
Otitis media	1/31 (3.2%)
Peripheral nerve infection	1/31 (3.2%)
Tooth infection	1/31 (3.2%)
Upper respiratory infection	2/31 (6.5%)
Urinary tract infection	1/31 (3.2%)
Injury, poisoning and procedural complications
Fall	1/31 (3.2%)
Fracture	3/31 (9.7%)
Hip fracture	1/31 (3.2%)
Investigations
Activated partial thromboplastin time prolonged	2/31 (6.5%)
Alanine aminotransferase increased	6/31 (19.4%)
Alkaline phosphatase increased	7/31 (22.6%)
Aspartate aminotransferase increased	7/31 (22.6%)
Blood bilirubin increased	9/31 (29%)
Cholesterol high	1/31 (3.2%)
Creatinine increased	7/31 (22.6%)
INR increased	5/31 (16.1%)
Investigations - Other, specify	2/31 (6.5%)
Lipase increased	3/31 (9.7%)
Lymphocyte count decreased	16/31 (51.6%)
Neutrophil count decreased	1/31 (3.2%)
Platelet count decreased	11/31 (35.5%)
Serum amylase increased	1/31 (3.2%)
Weight loss	6/31 (19.4%)
White blood cell decreased	1/31 (3.2%)
Metabolism and nutrition disorders
Anorexia	13/31 (41.9%)
Dehydration	1/31 (3.2%)
Hyperglycemia	6/31 (19.4%)
Hyperkalemia	4/31 (12.9%)
Hypernatremia	1/31 (3.2%)
Hypoalbuminemia	16/31 (51.6%)
Hypocalcemia	13/31 (41.9%)
Hypoglycemia	1/31 (3.2%)
Hypokalemia	8/31 (25.8%)
Hypomagnesemia	5/31 (16.1%)
Hyponatremia	10/31 (32.3%)
Hypophosphatemia	1/31 (3.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/31 (12.9%)
Back pain	7/31 (22.6%)
Chest wall pain	1/31 (3.2%)
Flank pain	1/31 (3.2%)
Generalized muscle weakness	5/31 (16.1%)
Muscle weakness lower limb	1/31 (3.2%)
Musculoskeletal and connective tissue disorder - Other, specify	2/31 (6.5%)
Myalgia	4/31 (12.9%)
Neck pain	3/31 (9.7%)
Pain in extremity	8/31 (25.8%)
Trismus	1/31 (3.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	2/31 (6.5%)
Tumor pain	2/31 (6.5%)
Nervous system disorders
Ataxia	2/31 (6.5%)
Dizziness	6/31 (19.4%)
Dysgeusia	3/31 (9.7%)
Headache	9/31 (29%)
Movements involuntary	1/31 (3.2%)
Paresthesia	2/31 (6.5%)
Peripheral sensory neuropathy	6/31 (19.4%)
Syncope	1/31 (3.2%)
Psychiatric disorders
Anxiety	2/31 (6.5%)
Confusion	3/31 (9.7%)
Insomnia	8/31 (25.8%)
Renal and urinary disorders
Acute kidney injury	1/31 (3.2%)
Urinary frequency	1/31 (3.2%)
Urinary incontinence	1/31 (3.2%)
Urinary retention	1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders
Cough	6/31 (19.4%)
Dyspnea	9/31 (29%)
Epistaxis	3/31 (9.7%)
Hoarseness	6/31 (19.4%)
Laryngeal mucositis	1/31 (3.2%)
Nasal congestion	1/31 (3.2%)
Pleural effusion	1/31 (3.2%)
Postnasal drip	1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders - Other, specify	1/31 (3.2%)
Sore throat	3/31 (9.7%)
Skin and subcutaneous tissue disorders
Alopecia	3/31 (9.7%)
Dry skin	1/31 (3.2%)
Erythema multiforme	2/31 (6.5%)
Palmar-plantar erythrodysesthesia syndrome	12/31 (38.7%)
Pruritus	1/31 (3.2%)
Rash acneiform	3/31 (9.7%)
Rash maculo-papular	7/31 (22.6%)
Skin and subcutaneous tissue disorders - Other, specify	9/31 (29%)
Skin ulceration	2/31 (6.5%)
Vascular disorders
Hypertension	17/31 (54.8%)
Hypotension	4/31 (12.9%)
Vascular disorders - Other, specify	1/31 (3.2%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE 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.