Clinical trial NCT02048722
Conditions: Adult Angiosarcoma Recurrent Adult Soft Tissue Sarcoma Stage III Adult Soft Tissue Sarcoma Stage IV Adult Soft Tissue Sarcoma
Sponsor: Northwestern University
Start date: 2014-06-13; Completion date: 2021-10-12
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Detailed description:
PRIMARY OBJECTIVES:

I. 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:

I. 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).

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

VI. 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.

Arms: arm 1: Patients receive regorafenib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: regorafenib
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
April 3, 2019,
1
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NU 13S02
Multicenter, Open-Label Phase II Study of Daily Oral Regorafenib for 
Chemotherapy-Refractory, Metastatic and Locally Advanced Angiosarcoma
Principal Investigator:
Mark Agulnik, MD 
Northwestern University
Division of Hematology/Oncology 
676 N. St. Claire, Suite 850
Chicago, IL 60611
Phone: (312) 695-1222
Fax: (312) 695-6189
Email: m-agulnik@northwestern.edu
Sub-Investigators/Participating Sites in the Midwest Sarcoma Trials Partnership (MSTP)
Scott Okuno, MD 
Mayo Clinic
200 1st St. SW
Rochester, MN 55905
Phone: (507) 284-4849
okuno.scott@mayo.edu
Steven Attia, DO 
Mayo Clinic
4500 San Pablo Road S 
Jacksonville, FL 32225
Phone: (904) 953-2558
attia.steven@mayo.edu
Sant P. Chawla, MD 
Sarcoma Oncology Research 
Center
2811 Wilshire Blvd, Suite 414 
Santa Monica, CA 90403 
Phone: 310-552-9999
santchawla@sarcomaoncology.com
Mohammed Milhem, MD
Brian Van Tine, MD, PhD
University of Iowa
Washington University
200 Hawkins Dr. GH C32
660 S. Euclid Ave, Box 8056
Iowa City, IA 52246
St. Louis, MO 63110
Phone: (319) 356-2324
Phone: (314) 747-8475
mohammed-milhem@uiowa.edu
bvantine@dom.wustl.edu
Biostatistician:
Alfred Rademaker, PhD 
rademaker@northwestern.edu
Study Drug:
Regorafenib
IND Number:
120139 EXEMPT
IND Holder Name:
Mark Agulnik, MD
Funding Source:
Bayer HealthCare
Version Date:
April 3, 2019,
Northwestern University
Robert H. Lurie Comprehensive Cancer Center 
Clinical Research Office
676 N. St. Clair Street, Suite 1200 
Chicago, IL 60611
IRB #: STU00087654-CR0004 Approved by NU IRB for use on or after 8/19/2019 through 8/18/2020.


SYNOPSIS
Title
Multicenter, Open-Label Phase II Study of Daily Oral Regorafenib for 
Chemotherapy-Refractory, Metastatic and Locally Advanced 
Angiosarcoma
Short Title
Regorafenib for Advanced Angiosarcoma
Phase/Design
Phase II, open-label
Study Center(s)
Lead Site:
Northwestern University – Robert H. Lurie Comprehensive Cancer 
Center
Participating Sites:
Mayo Clinic (Rochester, MN) 
Mayo Clinic (Jacksonville, FL) 
Washington University 
University of Iowa
Sarcoma Oncology Research Center
Study Objective(s)
Primary:
Progression-free survival at 4 months
Secondary:
Progression-free rate at 3 and 6 months 
Progression-free survival Overall 
survival (up to 5 years) Response
rate (by RECIST v 1.1)
Rate and duration of tumor control (CR+PR+SD) 
Safety and tolerability
Sample Size
1st stage: N = 12
2nd stage: N = 19
Diagnosis & Main Inclusion 
Criteria
•
Histologically-confirmed, metastatic or locally advanced, 
unresectable angiosarcoma with measurable disease
•
Progressive disease with prior ifosfamide, doxorubicin or taxane 
therapy
•
No prior sorafenib
Treatment Plan
Patients will be treated with regorafenib 160 mg PO daily for the first 3 
weeks of each cycle (1 cycle = 4 weeks) until disease progression.
Response evaluation will be every 2 cycles (approximately 2 months) 
using RECIST v 1.1.
Plan for statistical analysis
Optimal two-stage Simon design. First stage includes 12 patients. If > 3 
patients have PFS > 4 months, and additional 19 will be enrolled for a 
total of 31 patients.
Version Date:April 3, 2019
2
Northwestern University
Bayer  Healthcare  Study  Number: ONC-2013-129
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Version Date: April3,2019
3
I
SCHEMA
Scre€ning 
Consent 
Enrollment
I !
!
!
L-·
 
.
Study/Toxicity Visit (q2weeks)
---+)1
Study/Toxicity Visit & Disease Assessment (q8weeks)
!
!
!
!
I
Rego<afenib
160 mg po daily 
(day 1-21)
Regorafenib
Until PO,
160 mg po daily
withdrawal,
(day85-105)
roxieiry
•••
Cycle 1 (day 1-28)
Cycle 2 (day 29-56)
Cycle 3 (day 57-84)
Cycle 4 (day 85-112)
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TABLE OF CONTENTS
Synopsis......................................................................................................................................2
Schema........................................................................................................................................3
Table of Contents........................................................................................................................4
List of Abbreviations..................................................................................................................5
1.0  Introduction .........................................................................................................................6
2.0  Study Objectives..................................................................................................................9
3.0  Selection of Subjects ...........................................................................................................9
4.0  Treatment Plan....................................................................................................................12
5.0  Study Procedures ...............................................................................................................23
6.0  Endpoint Assessment.........................................................................................................25
7.0  Adverse Events and Safety Monitoring.............................................................................28
8.0  Drug Information...............................................................................................................33
9.0  Statistical Methods and Determination of Sample Size ....................................................34
10.0Study Management ............................................................................................................35
Appendices                                                                                                                   
References ................................................................................................................................40
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LIST OF ABBREVIATIONS
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BUN
Blood Urea Nitrogen
CR
Complete Response
CTCAE
Common Terminology Criteria for Adverse Events
ECOG
Eastern Cooperative Oncology Group
ERK
Extracellular Signal-regulated Kinases
FDA
Food and Drug Administration
FGFR
Fibroblast Growth Factor Receptor
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HFSR
Hand-foot-skin reaction
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
MAPK
Mitogen Activated Protein Kinase
PD
Progressive Disease
PDGFR-β
Platelet Derived Growth Factor Receptor-beta
PFS
Progression-free survival
PO
per oris, oral
PR
Partial Response
PS
Performance Status
PT/INR
Prothrombin time/ International Normalized Ratio
QD
quaque die, once daily
RAF
Rapidly Accelerated Fibrosarcoma
RAS
Rat sarcoma
RECIST
Response Evaluation Criteria for Solid Tumors
SAE
Serious Adverse Event
SD
Stable Disease
TK
Tyrosine Kinase
TTP
Time to Progression
VEGF
Vascular Endothelial Growth Factor
VEGFR
Vascular Endothelial Growth Factor Receptor
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INTRODUCTION
Angiosarcoma is an aggressive soft tissue sarcoma of endothelial differentiation. 
Angiosarcoma has a particularly poor prognosis with 5 year overall survival rates of 
approximately 30-40%. Deaths are almost universally attributable to distant metastatic 
disease. Median overall survival of metastatic angiosarcoma is less than one year (1). In 
addition to clinically aggressive behavior, survival is limited by a paucity of efficacious 
systemic therapies. The identification of novel, active agents is urgently needed to improve 
the duration and quality of life for angiosarcoma patients.
1.1
BACKGROUND
Treatment of locally advanced and metastatic angiosarcoma is inadequate. Three 
phase II trials have been conducted in this setting. The first, ANGIOTAX, examined 
weekly paclitaxel in 30 patients with metastatic or unresectable angiosarcoma 
between April 2005 and October 2006 (1). Progression-free survival at 4 months was 
45%. Response rate was less than 20% and median overall survival was 8 months. 
Despite these sobering results, retrospective analysis has demonstrated that weekly 
paclitaxel is slightly more active than single agent doxorubicin – the mainstay of 
metastatic soft tissue sarcoma therapy (2). A small retrospective series of 25 locally 
advanced or metastatic angiosarcoma patients treated between January 2008 and 
November 2010 suggests single agent gemcitabine may also have modest activity in 
this disease (3).
The inability of traditional cytotoxins to durably control angiosarcoma coupled with the 
observation this malignancy displays endothelial differentiation prompted interest in 
targeted anti-vascular therapies. Consequently, the two additional phase II trials in 
this setting have examined agents that antagonize the VEGF-VEGFR signaling axis. 
Agulnik and colleagues reported their phase II experience with bevacizumab in 
unresectable and metastatic angiosarcoma (4). Between August 2005 and April 2011, 
23 angiosarcoma patients were treated with single agent bevacizumab. The median 
progression-free and overall survival were 3 months and 1 year, respectively.
Responses were rare with only 2 (9%) experiencing a partial response. The French 
Sarcoma Group reported the third phase II trial in angiosarcoma examining the multi- 
targeted tyrosine kinase inhibitor, sorafenib, in 41 patients treated between June 2008 
and June 2009 (5). Although progression-free and overall survival rates were 
disappointing, a 40% tumor control rate and 23% response rate were observed in 
patients previously treated with cytotoxic chemotherapy.
Taken together, these data suggest both (A) conventional cytotoxic therapy is 
inadequate in angiosarcoma and (B) the most promising approach observed in phase 
II trials is multi-targeted tyrosine kinase inhibition after failure of conventional cytotoxic 
therapy. As discussed in detail below, regorafenib is a highly promising agent in 
angiosarcoma. Similar to bevacizumab and sorafenib, regorafenib antagonizes the 
endothelial VEGF-VEGFR axis. However, in contrast to these agents (and other 
tested VEGFR antagonists such as sunitinib), regorafenib also displays potent activity 
against the endothelial Tie2 tyrosine kinase receptor – a newly identified therapeutic 
target in human angiosarcomas. Consequently, we have hypothesized that 
regorafenib will display clinically meaningful activity in patients with refractory, locally 
advanced and metastatic angiosarcoma.
1.2
RATIONALE FOR THE STUDY
The greater activity of sorafenib in advanced angiosarcoma compared to 
bevacizumab and sunitinib prompted the hypothesis that this enhanced activity
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derived from a broader range of kinase inhibition. In particular, the greater activity of 
sorafenib was hypothesized to result from inhibition of the Tie2 kinase receptor.
Sorafenib displays modest activity against Tie2 in cell-based assays (IC50 330 nM).
To determine if Tie2 receptor kinase antagonism may be a viable therapeutic strategy 
in advanced angiosarcoma, expression of Tie2 signaling components (Tie1, Tie2, 
Ang1 and Ang2) was assessed in 51 human angiosarcomas. Strikingly, moderate to 
strong expression of both the Tie2 receptor and its agonist ligand, Ang1, was 
observed in > 80% of human samples (6). To extend these observations, the effects 
of VEGFR and Tie2 antagonism on angiosarcoma growth were assessed in vitro and 
in mouse xenograft models (7). As hypothesized, a highly selective Tie2 receptor 
tyrosine kinase inhibitor inhibited tumor cell proliferation in vitro and tumor growth in 
vivo. Moreover, the Tie2 antagonist displayed synergistic antiproliferative activity 
when combined with a VEGFR antagonist in a model of aggressive, high-grade 
angiosarcoma. More recently, stable and selective knock-down of the Tie2 receptor 
has been shown to reduce angiosarcoma cell proliferation in vitro and potently inhibit 
tumor growth in vivo (Kozak, unpublished results). These data strongly suggest 
concurrent, potent inhibition of VEGFR and Tie2 represents an attractive therapeutic 
strategy in angiosarcoma.
Regorafenib displays potent VEGFR inhibition with IC50s generally half that observed 
with sorafenib. Moreover, regorafenib displays approximately 10-fold greater potency 
against the Tie2 receptor (as assessed in cellular kinase activity assays) compared to 
sorafenib (8,9). Beyond these favorable characteristics, regorafenib also possesses 
far greater activity than sorafenib (and other related TKIs) against additional potential 
targets in angiosarcoma including PDGFRs, RAF, KIT and FGFR (9). Taken together, 
these data raise the possibility that regorafenib will have considerable activity in the 
treatment of angiosarcoma.IC50
The proposed single-arm phase II trial will assess progression-free survival at 4 
months as the primary efficacy endpoint. If this trial meets efficacy criteria, it would be 
prudent for subsequent phase III or other large-scale confirmatory trials to employ an 
interim analysis to provide a double-check on the efficacy results.
1.3
REGORAFENIB
Regorafenib is a small molecule inhibitor of multiple membrane-bound and 
intracellular kinases involved in normal cellular functions and in pathologic processes 
such as oncogenesis, tumor angiogenesis, and maintenance of the tumor 
microenvironment (9,10). In in vitro biochemical or cellular assays, regorafenib or its 
major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, 
VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, 
Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Ab1 at
concentrations of regorafenib that have been achieved clinically. In in vivo models, 
regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition 
of tumor growth as well as anti-metastatic activity in several mouse xenograft models 
including some for human colorectal carcinoma. Regorafenib activity corresponds to 
long-lasting anti-angiogenic activity as measured by dynamic contrast enhanced 
(DCE) – magnetic resonance imaging (MRI).
1.3.1
Preclinical experience
In vivo, regorafenib exhibited anti-angiogenic and anti-proliferative effects in 
human colon and breast xenografts as demonstrated by a reduction in 
microvessel area, reduced Ki-67 staining, and reduced pERK1/2 staining in 
tissue sections from tumor xenografts, and dose-dependent inhibition of
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growth in multiple xenograft models (breast, colon, renal, NSCLC, melanoma, 
pancreatic, thyroid, ovarian). (9) Immunohistochemical ex-vivo studies with a 
phospho –specific monoclonal anti-ERK 1 / 2 antibody demonstrated inhibition 
of the MAPK pathway five days after treatment with regorafenib in 2 of 3
tumor models examined (MDA-MB 231 and BxPC-3), but not in NSCLC 
(H460).
In addition, all tested human tumor xenografts (MDA-MB-231, H460, BxPC-3 
and Colo-205) demonstrated a significant reduction in new blood vessels by 
histomorphometry as detected in tumor samples using a murine CD31 
antibody. (9) These data suggest that regorafenib can target the tumor cell 
MAPK pathway (tumor cell survival) and tumor vasculature in some but not all 
tumors.
1.3.2
Clinical experience
Two phase III global randomized studies have evaluated the efficacy of 
regorafenib. The CORRECT (Patients with metastatic colorectal cancer 
treated with regorafenib or placebo after failure of standard therapy) trial is an 
international, multicenter, randomized, double-blind, placebo-controlled study 
that enrolled 760 patients with mCRC whose disease has progressed after 
approved standard therapies (11). Metastatic colorectal cancer patients were 
randomized to regorafenib plus best supportive care (BSC) or placebo plus 
BSC. Treatment cycles consisted of 160 mg of regorafenib (or matching 
placebo) once daily for three weeks on / one week off plus BSC. The primary 
endpoint of this trial was overall survival. Secondary endpoints included 
progression-free survival, objective tumor response rate and disease control 
rate. The safety and tolerability of the two treatment groups were also 
compared.
At a preplanned second interim analysis, there was a statistically significant 
survival benefit for regorafenib. The estimated hazard ratio for overall survival 
was 0.773 (95% confidence interval [CI], 0.635 to 0.941; 1-sided p = .0051). 
Patients treated with regorafenib had a median overall survival of 6.4 months, 
compared with 5.0 months for placebo — a 29% increase in survival. In 
addition to improved overall survival, progression-free survival was superior; 
median progression-free survival was 1.9 months (95% CI, 1.88 to 2.17) for
regorafenib and 1.7 months (95% CI, 1.68 to 1.74) for placebo. The estimated
hazard ratio for progression-free survival was 0.493 (95% CI, 0.418 to 0.581; 
1-sided p< .000001). There was a substantial difference in disease control 
rate in the regorafenib and placebo groups (44% vs. 15%; p<.000001).
Regorafenib demonstrated comparable efficacy benefits across patient 
subgroups analyzed including age, number of mets, number of lines of prior 
therapy, and kras status.
The most frequent grade 3+ adverse events in the regorafenib group were 
hand–foot skin reaction (17%), fatigue (15%), diarrhea (8%), 
hyperbilirubinemia (8%), and hypertension (7%). The efficacy and safety from 
the CORRECT study supported FDA approval in September 2012.
The efficacy and safety of regorafenib were examined in the Phase III GRID 
trial in patients with gastrointestinal stromal tumors (GISTs) who had 
exhausted all other treatment options (12). The study involved 199 patients 
with metastatic and/or unresectable GIST that had become resistant to 
imatinib and sunitinib. Patients were randomized 2:1 to regorafenib (160 mg
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orally once daily on a 3 weeks on/1 week off cycle) or placebo, plus best 
supportive care.
The results showed that treatment with regorafenib led to a statistically 
significant 3.9-month improvement in progression-free survival
(PFS), compared with placebo (4.8 months vs. 0.9 months; hazard ratio [HR]
= 0.27; p <.0001). Overall survival was statistically similar between groups as 
expected due to a trial design that allowed crossover to regorafenib for 
disease progression. The median survival period without tumor growth 
among patients on regorafenib was 4.8 months while for the control group on 
placebo it was less than a month. The overall disease control rate combining 
partial responses with durable stable disease for at least 12 weeks was 53% 
with regorafenib compared with 9% in the control group. The most common 
grade ≥3 adverse events associated with regorafenib were hand-foot skin 
reaction (56.1%), hypertension (48.5%), and diarrhea (40.9%). GRID study 
data recently prompted FDA approval of regorafenib for treatment of 
previously treated patients with locally advanced, unresectable or metastatic 
GIST.
STUDY OBJECTIVES
2.1
PRIMARY OBJECTIVE
The primary study objective is to define the progression-free survival (PFS) at 4 
months with daily oral regorafenib (160 mg) in previously treated locally 
advanced/metastatic angiosarcoma patients.
2.2
SECONDARY OBJECTIVES
2.2.1
Progression-free rate at 3 and 6 months
2.2.2
Progression-free survival
2.2.3
Overall survival (up to 5 years)
2.2.4
Response rate (by RECIST v 1.1)
2.2.5
Rate and duration of tumor control (CR+PR+SD)
2.2.6
Safety/tolerability of regorafenib
SELECTION OF SUBJECTS
The target population for this phase II study is patients with locally advanced or metastatic 
angiosarcoma who have progressed after prior ifosfamide, doxorubicin or taxane therapy. 
This will be a multi-center trial with Northwestern University serving as the lead site. Potential 
patients may be referred to the Principal Investigator, Dr. Mark Agulnik, at (312) 695-0990, or 
the local investigator at each participating site.
Eligibility will be evaluated by the study teams according to the following criteria. Eligibility 
waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. All 
registrations will be centralized through the Clinical Research Office at Northwestern 
University. Please refer to Section 11 and the Appendices for complete instructions regarding 
registration procedures.
3.1
INCLUSION CRITERIA
3.1.1
Age ≥ 18 years.
3.1.2
Life expectancy of at least 4 months
3.1.3
Histologically confirmed angiosarcoma
3.1.4
Tumor deemed unresectable or metastatic
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3.1.5
Measurable disease per RECIST v 1.1
3.1.6
ECOG PS 0 or 1
3.1.7
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.If patient refuses or if IV chemotherapy is 
contraindicated, patients will be eligible if they fail one systemic therapy. 
Note: It will be up to the treating investigator to define what constitutes a 
“therapy” in each case, and final decisions on how prior therapy should be 
counted will be at the discretion of the Principal Investigator.
3.1.8
All acute toxic effects of any prior treatment have resolved to Grade 1 or less 
(by NCI-CTCAE v 4.0) at the time of registration. NOTE: Exceptions to this 
criterion will include alopecia and fatigue.
3.1.9
Patients must meet the following laboratory requirements to be considered 
eligible:
3.1.9.1
Total bilirubin ≤ 1.5 x the upper limits of normal (ULN)
3.1.9.2
ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver 
involvement of their cancer)
3.1.9.3
Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for 
subjects with liver involvement of their cancer)
3.1.9.4
Lipase ≤ 1.5 x the ULN
3.1.9.5
Serum creatinine ≤ 1.5 x the ULN
3.1.9.6
PT/INR ≤ 1.5 x ULN
3.1.9.7
Platelet count ≥ 100000 /mm3
3.1.9.8
Hemoglobin ≥ 9 g/dL
3.1.9.9
Absolute neutrophil count > 1500/mm3
3.1.9.10
If baseline 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: Subjects may not have had a transfusion within 7 days of screening 
assessment.
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 PT/INR is 
stable based on a measurement that is pre-dose as defined by the local 
standard of care.
3.1.10 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.
3.1.11 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.
3.1.12 Subject must be able to swallow and retain oral medication.
3.1.13 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.
3.2
EXCLUSION CRITERIA
3.2.1
Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic 
pressure > 90 mm Hg on repeated measurement) despite optimal medical 
management.
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3.2.2
Active or clinically significant cardiac disease including:
3.2.2.1 Congestive heart failure – New York Heart Association > Class II
3.2.2.2 Active coronary artery disease
3.2.2.3 Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers or digoxin
3.2.2.4 Unstable angina (anginal symptoms at rest), new-onset angina within 
3 months before registration, or myocardial infarction within 6 months 
before registration
3.2.3
Evidence or history of bleeding diathesis or coagulopathy.
3.2.4
Any hemorrhage or bleeding event ≥ Grade 3 within 4 weeks prior to 
registration.
3.2.5
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. 
Note: Subjects with recent DVT who have been treated with therapeutic 
anticoagulating agents for at least 6 weeks prior to study treatment are eligible
3.2.6
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.
3.2.7
Patients with pheochromocytoma.
3.2.8
Patients with severe hepatic impairment (Child-Pugh Class C)
3.2.9
Known history of human immunodeficiency virus (HIV) infection or current 
chronic or active hepatitis B or C infection requiring treatment with antiviral 
therapy.
3.2.10 Ongoing infection > Grade 2.
3.2.11 Evidence of significant central nervous system disease including seizure 
disorder requiring medication, symptomatic metastatic brain or meningeal 
tumors.
3.2.12 Presence of a non-healing wound, non-healing ulcer, or bone fracture.
3.2.13 Renal failure requiring hemo-or peritoneal dialysis.
3.2.14 Dehydration > Grade 1.
3.2.15 Interstitial lung disease with ongoing signs and symptoms at the time of 
registration.
3.2.16 Pleural effusion or ascites that causes respiratory compromise (≥ Grade 2 
dyspnea).
3.2.17 History of organ allograft (including corneal transplant).
3.2.18 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.
3.2.19 Any malabsorption condition.
3.2.20 Evidence of abdominal fistula, GI perforation or intraabdominal abscess.
3.2.21 Women who are pregnant or breast-feeding.
3.2.22 Concurrent anti-cancer therapy (chemotherapy, surgery, immunotherapy, 
biologic therapy, or tumor embolization) other than study treatment 
(regorafenib).
3.2.23 Prior use of regorafenib.
3.2.24 Prior use of sorafenib.
3.2.25 Use of cytotoxic chemotherapy within 21 days of registration.
3.2.26 Use of targeted therapy within two half-lives of registration.
3.2.27 Radiation directed at target lesion within 28 days of registration.
3.2.28 Major surgical procedure, open biopsy, or significant traumatic injury within 28 
days before registration.
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3.2.29 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 PT-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.
3.2.30 Any condition which, in the investigator’s opinion, makes the subject 
unsuitable for trial participation.
3.2.31 Substance abuse, medical, psychological or social conditions that may 
interfere with the subject’s participation in the study or evaluation of the study 
results.
3.2.32 Unable or unwilling to discontinue use of strong inducers and inhibitors of 
CYP450 listed in Appendix for at least 14 days prior to the first dose of study 
treatment and for the duration of the study (Appendix A). CYP3A4 substrates 
can be administered, but investigators will need to be aware of possible 
increased or decreased effectiveness of the non-study drug and this should 
be recorded in concomitant medications. BCRP and PgP inducers and 
inhibitors should be used with caution if another alternative drug is not able to 
be used (Appendix A and B)
Note: As this list is constantly evolving, if a medication is incorrectly 
documented as prohibited in this protocol, documentation from the site 
pharmacist to the contrary will be acceptable for the purposes of registration.
TREATMENT PLAN
4.1
OVERVIEW
The eligible study population will consist of adult patients with histologically confirmed, 
measurable, unresectable or metastatic angiosarcoma who have progressive disease 
after prior treatment with ifosfamide, doxorubicin or a taxane. Patients will be treated 
with daily oral regorafenib (160 mg) for 3 weeks on followed by 1 week off (1 cycle = 4 
weeks). Patients will continue treatment until disease progression or withdrawal due 
to unacceptable toxicity. Once off-treatment, patients will be followed for overall 
survival up to 5 years. An optimal two-stage Simon design will be employed. The first 
stage will include 12 patients. If > 3 patients achieve a PFS > 4 months, an additional 
19 patients will be enrolled for a total of 31 patients.
4.2
TREATMENT ADMINISTRATION
Regorafenib will be administered orally at a dose of 160 mg regorafenib for 3 weeks 
on followed by 1 week off. One cycle is 4 weeks (28 days). Patients will be instructed 
to take 4 40mg regorafenib tables every morning with approximately 8 fluid ounces 
(240 mL) of water after a low-fat (< 30% fat) breakfast. Patients will be given 
examples of low fat breakfasts, such as:
•
Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon 
of jelly and 8 ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g 
of fat).
•
One cup of cereal (i.e. Special K), 8 ounces (240 mL) of skim milk, one piece of 
toast with jam (no butter or marmalade), apple juice, and one cup of coffee or tea 
(2 g fat, 17 g protein, 93 g of carbohydrate, 520 calories).
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4.3
DOSE MODIFICATION & MANAGEMENT OF TOXICITY
4.3.1
Dose Reductions/Re-escalations
The starting dose of regorafenib is 160 mg once daily. Study medication will 
be administered on a schedule of 3 weeks on followed by 1week off (1 cycle = 
4 weeks). Doses will be delayed or reduced for clinically significant 
hematologic and non-hematologic toxicities that are related to protocol 
therapy according to the guidelines shown in Table 1 below. Dose 
modifications will follow predefined dose levels. Dose adjustments for 
hematologic toxicity are based on the blood counts obtained in preparation for 
the day of treatment.
NOTE: In some cases, dose re-escalation may be permitted at the discretion 
of the treating investigator. Please refer to the tables below for details 
regarding when this is acceptable and under what conditions.
Table 1: Pre-defined dose modification levels
Dose Level
Dose
# of Regorafenib Tablets
Dose level 0 1
160 mg PO qd
4 40mg tablets
Dose level - 1
120 mg PO qd
3 40-mg tablets
Dose level - 2
80 mg PO qd
2 40-mg tablets
1 Standard starting dose
If a subject experiences more than one toxicity, dose reduction should be 
according to the toxicity with the highest grade unless that toxicity is 
unequivocally deemed not to be causally related to study treatment. In such 
cases, the investigator may dose reduce according to the toxicity deemed 
most causally related to study treatment.
Table 2 below outlines dose adjustments for toxicities related to study drug 
except hand-foot skin reaction, hypertension and liver function test 
abnormalities.
Table 2: Dose Modifications for Toxicities*
Toxicity Grade
a
Dose
Interruption
Dose
Modification b
Dose for
Subsequent Cycles
Grade 0-2
None – Treat 
on time
No change
No change
Grade 3
Delay until ≤
Grade 2c
Reduce by 1 
dose level
If toxicity remains < 
Grade 2, dose re- 
escalation can be 
considered at the 
discretion of the 
treating investigator. 
If dose is re- 
escalated and toxicity 
(≥ Grade 3) recurs,
institute permanent 
dose reduction.
Grade 4
Delay until ≤
Grade 2c
Reduce by 1 
dose level. 
Permanent
discontinuation
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can be 
considered at 
treating
investigator’s 
discretion.
a. According to the National Cancer Institute – Common Terminology 
Criteria for Adverse Events, version 4.0 (NCI CTCAE v 4.0)
b. Excludes alopecia, non-refractory nausea/vomiting, non-refractory 
hypersensitivity and nonclinical and asymptomatic laboratory 
abnormalities.
c. If no recovery after a 4 week delay*, treatment should be permanently 
discontinued unless subject is deriving clinical benefit.
* Dose modifications are for toxicities except hand-foot-skin reaction, 
hypertension, and ALT/AST/bilirubin abnormalities. Refer to the tables 
below for management of these.
In addition to these recommended dose modifications, subjects who develop 
diarrhea, mucositis, anorexia or other events predisposing to fluid loss or 
inadequate fluid intake should be carefully monitored and rehydrated as 
clinically necessary. This is in order to minimize the risk of postural 
hypotension and renal failure.
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4.3.2
Management and Dose Modifications for HFSR 
Table 3: Grading for Hand-Foot-Skin Reaction
Grade 1
Grade 2
Grade 3
CTCAE v 4.0: Palmar- 
plantar
erythrodysesthesia 
syndrome a
Minimal skin changes or dermatitis 
(e.g., erythema, edema, or 
hyperkeratosis) without pain
Skin changes (e.g., peeling, 
blisters bleeding, edema, or 
hyperkeratosis) with pain
Severe skin changes (e.g., 
peeling, blisters, bleeding,
edema, or hyperkeratosis) with 
pain
Further description / examples 
of skin changes
Numbness, dysesthesia / 
paresthesia tingling, painless
swelling, or erythema of the hands 
and/or feet
Painful erythema and swelling 
of the hands and/or feet
Moist desquamation, ulceration, 
blistering, or severe pain of the 
hands and/or feet
Effect on activities
Does not disrupt normal activities
Limiting instrumental activities 
of daily life (e.g., preparing 
meals, shopping for groceries
or clothes, using the telephone, 
managing money)
Limiting self-care activities of 
daily life (e.g., bathing, dressing 
and undressing, feeding self,
using the toilet, taking 
medications) and not bedridden
a. Palmer-planter erythrodysesthesia syndrome is a disorder characterized by redness, marked discomfort, swelling, and tingling in the 
palms of hands or the soles of the feet.


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Table 4: Recommended Dose Modification for Hand-Foot-Skin Reactiona
CTCAE v 4.0 Grade
Occurrence
Suggested Dose Modification
Grade 1
Any
Maintain dose level and immediately institute supportive measures for
symptomatic relief
1st occurrence
No improvement within
Tolerable Grade 2: No change
In-tolerable Grade 2: Decrease dose by one dose level and immediately 
institute supportive measures. If no improvement, interrupt therapy for a 
minimum of 7 days, until toxicity resolves to Grade 0-1 b, c
7 days or 2nd 
occurrence
Interrupt therapy until toxicity resolves to Grade 0-1.c
When resuming treatment, treat at reduced dose level b
3rd occurrence
Interrupt therapy until toxicity resolves to Grade 0-1. c
When resuming treatment, decrease dose by one dose level. b, d
Grade 2
4th occurrence
Discontinue therapy
1st occurrence
Institute supportive measures immediately. Interrupt therapy for a minimum 
of 7 days until toxicity resolves to Grade 0-1. c When resuming treatment,
decrease dose by one dose level. b, d
2nd occurrence
Institute supportive measures immediately. Interrupt therapy for a minimum
of 7 days until toxicity resolves to Grade 0-1. c When resuming treatment, 
decrease dose by one additional dose level b, d
Grade 3
3rd occurrence
Discontinue treatment permanently.
a. More conservative management is allowed if judged medically appropriate by the investigator.
b. If toxicity returns to Grade 0-1 after dose reduction, dose re-escalation is permitted at the discretion of the investigator if subject has 
completed one cycle at reduced dose without recurrence of event.
c. If there is no recovery after a 4-week delay, treatment with regorafenib will be discontinued permanently.
d. Subjects requiring > 2 dose reductions should go off protocol therapy.
4.3.2.1 Supportive care guidelines for HFSR
At first occurrence of HFSR, independent of grade, prompt institution of supportive measures such as topical 
emollients, low potency steroids, or urea-containing creams should be administered.
Recommended prevention/management strategies for skin toxicities consistent with HFSR are summarized 
below:


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Control of calluses
Before initiating treatment with regorafenib:
•
Check condition of hands and feet.
•
Suggest a manicure/pedicure, when indicated.
•
Recommend pumice stone use for callus or
‘rough spot’ removal.
During regorafenib treatment:
•
Avoid pressure points.
•
Avoid items that rub, pinch or create friction.
Use of creams
•
Non-urea based creams may be applied liberally.
•
Keratolytic creams (e.g. urea-based creams, salicylic acid 6%) may be used sparingly 
and only to affected (hyperkeratotic) areas.
•
Alpha hydroxyl acids (AHA) based creams may be applied liberally 2 times a day. 
Approximately
5% to 8% provides gentle chemical exfoliation.
•
Topical analgesics (e.g. lidocaine 2%) are to be considered for pain control.
•
Topical corticosteroids like clobetasol 0.05% 
should be considered for subjects with Grade 2 or 
3 HFSR. Avoid systemic steroids.
Tender areas should be protected as follows:
•
Use socks/gloves to cover moisturizing creams
•
Wear well-padded footwear
•
Use insole cushions or inserts (e.g. silicon, gel)
•
Foot soaks with tepid water and Epson salts
4.3.3
Management and Dose Modifications for Hypertension
Hypertension is a known AE associated with regorafenib treatment. Subjects will have their blood pressure 
measured at least weekly at the study site during the first 6 weeks of treatment. If additional blood pressure 
measurements are done outside the study site, and the blood pressure is >
140 mm Hg systolic or > 90 mm Hg diastolic, then the subject will be instructed to contact study personnel. The 
management of hypertension,
including the choice of antihypertensive medication, will be performed
according to local institutional standards and to the usual practice of the investigator. Every effort should be made to 
control blood pressure by medical means other than study drug dose modification. If necessary, Table 5 outlines


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suggested dose reductions.
Table 5: Recommended Dose Modifications for Hypertension
CTCAE v4.0 Grade
Antihypertensive Therapy
Regorafenib Dosing
Grade 1:
Prehypertension (systolic BP 
120 - 139 mmHg or diastolic BP 
80 - 89 mmHg)
None
• Continue regorafenib
• Consider increasing blood pressure (BP) monitoring
Grade 2:
Systolic BP 140 - 159 mmHg 
or diastolic BP 90 - 99 mmHg
OR
Symptomatic increase by > 20 
mmHg (diastolic) if previously 
within normal limits
• Treat with the aim to achieve diastolic BP
≤ 90 mm Hg:
• If BP previously within normal limits, start 
anti-hypertensive monotherapy
• If patient already on anti-hypertensive 
medication, titrate up the dose.
• Continue regorafenib
• If symptomatic, hold regorafenib until symptoms 
resolve AND diastolic BP ≤ 90 mm Hga. When 
regorafenib is restarted, continue at the same dose 
level.
Grade 3:
Systolic BP ≥ 160 mmHg or 
diastolic BP ≥ 100 mmHg
OR
More than one drug or more 
intensive therapy than previously 
used indicated
Treat with the aim to achieve diastolic BP ≤
90 mm Hg:
Start anti-hypertensive medication
AND/OR
Increase current anti-hypertensive 
medication
AND/OR
Add additional anti-hypertensive 
medications.
• Hold regorafenib until diastolic BP ≤ 90 mm Hg, and 
if symptomatic, until symptoms resolve.a
• When regorafenib is restarted, continue at the same 
dose level.
• If BP is not controlled with the addition of new or 
more intensive therapy, reduce by 1 dose level.b
• If Grade 3 hypertension recurs despite dose 
reduction and antihypertensive therapy, reduce 
another dose level.c
Grade 4:
Life-threatening consequences 
(eg, malignant hypertension, 
transient or permanent
neurologic deficit, hypertensive 
crisis)
Per institutional guidelines
Discontinue therapy
a. Patients requiring a delay of > 4 weeks should go off protocol therapy
b. If BP remains controlled for at least one cycle, dose re-escalation permitted per investigator’s discretion.
c. Patients requiring >2 dose reductions should go off protocol therapy.


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4.3.4
Liver Function Abnormalities
For patients with observed worsening of serum liver tests considered related to regorafenib (i.e. where no alternative 
cause is evident, such as post-hepatic cholestasis or disease progression), the dose modification and monitoring 
advice in Table 6 should be followed.
Regorafenib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s 
syndrome.
Table 6: Dose Modifications/Delays for Liver Function Abnormalities
Observed
Elevations
1st Occurrence
Restart
Re-occurrence
AST and/or ALT
≤ 5 X ULN (< G3)
Continue dosing, with weekly monitoring of liver
function until transaminases return to <3 X ULN (≤ 
G1) or baseline.
ALT and/or AST
>5 X ULN (≥ G3)
Interrupt dosing, with weekly monitoring until 
transaminases return to < 3 X ULN or baseline.
If the potential benefit for reinitiating 
regorafenib is considered to outweigh the 
risk of hepatotoxicity: Reduce one dose
level and measure serum liver tests weekly 
for at least 4 weeks.
Discontinue
ALT and/or AST
> 20 X ULN (≥ G4)
Discontinue
ALT and/or AST
> 3 X ULN (≥ G2)
with concurrent 
bilirubin > 2 X ULN
Discontinue treatment and measure serum liver 
tests weekly until resolution.
Exception: patients with Gilbert’s syndrome who 
develop elevated transaminases should be 
managed as per the recommendations outlined 
above for ALT/AST elevations.
ALT, AST, and bilirubin must be monitored prior to initiation of regorafenib treatment. During the first 2 cycles (2 months) of treatment, ALT, 
AST and bilirubin will be monitored at least every 2 weeks.


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4.3.5
Prevention/Management Strategies for Diarrhea
Diarrhea can be a common side effect of regorafenib. The 
preventive/management strategies for diarrhea should be consistent with local 
institutional standards (e.g., anti-diarrheals and optimized hydration status).
Anti-diarrhea medications may be introduced if symptoms occur. Previous 
trials have shown that the diarrhea could be managed with loperamide. The 
recommended dose of loperamide is 4 mg at first onset, followed by 2 mg 
every 2 to 4 hours until diarrhea-free for 12 hours.
4.4
PRIOR AND CONCOMITANT THERAPY
All medication that is considered necessary for the subject’s welfare, and which is not 
expected to interfere with the evaluation of the study treatment, may be given at the 
discretion of the investigator. All medications (including contrast media) taken within 2 
weeks prior to the start of the study and during the study must be recorded in the 
subject’s source documentation and in the appropriate eCRF (including start/stop 
dates, dose frequency, route of administration, and indication).
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of 
regorafenib decreased the mean exposure of regorafenib, increased the mean 
exposure of the active metabolite M-5, and resulted in no change in the mean 
exposure of the active metabolite M-2. Avoid concomitant use of regorafenib with 
strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, 
and St. John’s Wort)
Co administration of a strongCYP3A4 inhibitor (ketoconazole) with a single 160mg 
dose of regorafenib increased the mean exposure of regorafenib and decreased the 
mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of 
regorafenib with strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit 
juice, itraconazole, ketoconazole, nefazadone, posaconazole, telithromycin, and 
voriconazole).
4.4.1
Permitted Concomitant Therapies
•
Standard therapies for concurrent medical conditions.
•
Supportive care for any underlying illness.
•
Palliative radiation therapy is allowed if the target lesion(s) are not 
included within the radiation field and no more than 30% of total bone 
marrow is irradiated to a total of 20 Gy (EQD2). Protocol treatment 
should be held 7 days before, during and 7 days after palliative radiation, 
or at the discretion of the site radiation oncologist. Palliative radiation 
cannot include target lesions.
•
Palliative surgery: Protocol treatment should be held 7 days before and 
until the wound is healed. If treatment is not resumed within 3 weeks, the 
case will be reviewed by QAM and PI to determine whether or not subject 
can restart treatment. Palliative surgery cannot include surgery on target 
lesions.
•
Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic 
growth factors may be used in the management of acute toxicity, such as 
febrile neutropenia, when clinically indicated or at the investigator’s 
discretion. However, they may not be substituted for a required dose 
reduction. Subjects are permitted to take chronic erythropoietin.
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•
Treatment with nonconventional therapies (such as acupuncture), and 
vitamin/mineral supplements are permitted provided that they do not 
interfere with the study endpoints, in the opinion of the investigator.
•
Bisphosphonates
•
Subjects who are prophylactically treated with an agent such as warfarin 
or heparin will be allowed to participate. Close monitoring (day 1 of each 
cycle) is mandatory. NOTE: Therapeutic doses of anti-coagulants are not 
permitted.
4.4.2
Concomitant Therapies Not Permitted:
•
Other investigational treatment during study treatment.
•
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.
•
Concurrent systemic antitumor therapy, including cytotoxic therapy, signal 
transduction inhibitors, immunotherapy, and hormonal therapy.
•
Bone marrow transplant or stem cell rescue.
•
Subjects taking narrow therapeutic index medications should be monitored 
proactively (e.g. phenytoin, quinidine, carbamazepine, Phenobarbital, 
cyclosporin, and digoxin). NOTE: Warfarin is metabolized by the 
cytochrome enzyme CYP2C9 and it’s levels may be especially affected by 
regorafenib; therefore, only prophylactic doses of warfarin are permitted.
•
Use of drugs that induce CYP3A4 including (but not limited to):
o
Glucocorticoids (cortisone, hydrocortisone, prednisone, 
methylprednisone, dexamethasone)
o
Anticonvulsants (phenytoin, carbarnazepine, phenobarbital, 
oxcarbazepine)
o
HIV antivirals (efavirenz, nevirapine)
o
Antibiotics (rifampin, rifabutin, rifapentine)
o
St. John’s Wort
o
Modafinil
o
Pioglitazone
4.8
STUDY DURATION AND WITHDRAWAL CRITERIA
Patients will continue treatment until disease progression or development of 
unacceptable toxicity. In addition, patients may be discontinued from treatment and/or 
withdrawn from the study for other reasons, as outlined below. Any subject removed 
from the trial will remain under medical supervision until discharge or transfer is 
medically acceptable. In all cases, the reason for withdrawal must be recorded in the 
appropriate eCRF and in the subject's medical records. Patients will be followed once 
off-treatment for up to 5 years for overall survival endpoints.
4.8.1
Mandatory Withdrawal Criteria
Subjects must be withdrawn from the trial (treatment and procedures) for 
the following reasons:
•
Subject withdraws consent from study treatment and study procedures. A 
subject must be removed from the trial at his/her own request or at the 
request of his/her legally acceptable representative. At any time during 
the trial and without giving reasons, a subject may decline to participate 
further. The subject will not suffer any disadvantage as a result.
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•
Pregnancy. Pregnancy will be reported within the same timelines as an 
SAE, although a pregnancy per se is not considered an SAE. NOTE: 
subjects who have been withdrawn from treatment with study drug 
because of pregnancy should not undergo CT scans [with contrast]/MRI 
or bone scans while pregnant.
•
The investigator concludes that continuation of the trial would be harmful 
to the subject's well-being.
•
Subject is lost to follow-up.
•
Death occurs.
4.8.2
Possible Withdrawal Criteria
Subjects may be withdrawn from the study for any of the following reasons:
•
The subject is non-compliant with study drug, trial procedures, or both; 
including the use of anti-cancer therapy not prescribed by the study 
protocol. Subject compliance with the treatment and protocol includes 
willingness to comply with all aspects of the protocol, and to have blood 
collected for all safety evaluations. At the discretion of the investigator, a 
subject may be discontinued from the trial for non-compliance with follow- 
up visits or study drug.
•
Severe allergic reaction to regorafenib (such as exfoliative erythroderma 
or Grade 3 or 4 hypersensitivity reaction).
•
The development of a second cancer.
•
Development of an intercurrent illness or situation which would, in the 
judgment of the investigator, significantly affect assessments of clinical 
status and trial endpoints.
•
Deterioration of ECOG performance status to 4.
•
Use of illicit drugs or other substances that may, in the opinion of the 
investigator, have a reasonable chance of contributing to toxicity or 
otherwise skewing trial result.
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STUDY PROCEDURES
Table 7: Study Visit Parameters
Baseline 
(-28days)
On Treatment
Off Treatment
Follow-Up i
Screening j
Cycle 1l, n
Cycle 2 g,l,n
Cycle 3+
g,l,n
End of study 
treatment
Week
0
1
2
3
4
5
6
7
8
9+
Regorafenib 160 mg e
On
Off
On
Off
Continue e
Informed consent
X
Medical history h
X
Physical examination
X
X
X
X
X
Vital signs a
X
X
X
X
X
X
X
X
X
X
X
CBC/Diff
X
X
X
X
X
PT/INR b
X
X b
X b
X b
X b
Clinical chemistry c
X
X
X
X
X
X c
X
Pregnancy test f
X
Urine Protein/Creatinine 
Ratio (UPC)
X
ECOG PS
X
X
X
X
X
Disease Measurements d
X d
X d
Xd
Study medication 
dispensing & pill diary 
collection
X
X
X
Tolerability/AE reporting
X
X
X
X
X
X
X
X
Adverse Event Self- 
Report Survey (AESRS)
Xk
X
X
Concomitant medications
X
X
X
X
X
Phone callm, i
Xm
Xm
Xm
Xi


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a-
Vital signs to include height (height is recorded at screen visit only), weight, blood pressure, pulse, temperature. Blood pressure should be monitored 
weekly for the first six weeks of study treatment. A patient blood pressure log will be maintained to aid in monitoring (See Appendices). Patients 
will record blood pressure at home during the weeks they are not coming to the clinic for exams.
b-
PT/INR should be closely monitored on day 1 of each cycle.
c-
Electrolytes, calcium, magnesium, BUN, serum creatinine, total bilirubin, AST, ALT, alk phos, albumin, amylase, lipase. Should be done every 2 weeks 
during Cycles 1 and 2; if no abnormalities are seen, may be done on day 1 only of subsequent cycles. Mid-cycle labs may be performed at a local laboratory 
if needed to accommodate patient travel logistics..
d Imaging should be done as clinically indicated (i.e. CT, MRI and visual measurements), which satisfy RECIST v 1.1 to evaluate disease (such as in 
extremity, head and neck). Imaging studies will be done at baseline (within 4 weeks (28 days) before the first dose) and repeated after every 2 cycles of 
treatment (prior to each odd cycle) for tumor response evaluation.
ePatients will receive regorafenib daily x 3 weeks followed by 1 week off (1 cycle = 4 weeks).
f-
Women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration.
g-
Assessments including physical examination, vital signs, ECOG PS, clinical chemistry, CBC/Diff and PT/INR should immediately precede initiation of the 
next cycle of therapy. Clinically indicated scans should be performed during the off week immediately preceding initiation of odd numbered cycles.
h-
Medical history findings (i.e. previous diagnoses, diseases or surgeries) will be collected, including those not pertaining to the study indication, beginning 
before registration, that are considered relevant to the study.
i-
Once off treatment, patients will be followed approximately every 6 months by phone for survival endpoints. Follow-up will continue up to 5 years.
j-
Screening assessments must be completed within 15 days prior to registration, unless otherwise specified. Screening assessments may be used for C1D1 
assessments if completed ≤ 15 days before study drug initiation.
k-
Adverse Event Self-Report Survey (AESRS) should be disseminated to each patient on day 1 of cycle 1, but no data is collected.
l-
Unless otherwise noted, on-therapy windows for testing will be as follows: imaging scans should be completed within +/- 1 week of the target time point, 
and labs and physical examination within +/- 3 days of the target time point .
m-
Subjects will be instructed to follow-up weekly with the study team IF they are experiencing any side effects.
n-
Day 1 of each cycle should be every 28 days. In the event that this day falls on a holiday or other such event, study team should use +/- 3 day window to 
complete pre-treatment procedures, and dispense protocol agents to patients with instructions to commence treatment on day 1. Any missed doses will not 
be made up and should be skipped to maintain a 28-day cycle.


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ENDPOINT ASSESSMENT
6.1
DEFINITIONS AND RESPONSE CRITERIA
Response and 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.
Note: Lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used because it 
does not provide additional meaning or accuracy.
6.1.1
Measurable and non-measurable disease
Measurable tumor lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 10 
mm on CT (with less than 5 mm slice thickness) or ≥ 10 mm by caliper 
measurement during clinical examination. For superficial lesions measured by 
caliper, documentation by color photography including a ruler in the field of 
view is strongly recommended. MRI may be used in clinically appropriate 
circumstances to measure tumor lesions. Measurable lymph nodes are 
defined as those that can be accurately measured as > 15 mm in short axis 
when assessed by CT.
Lesions failing to reach size criteria above and those that are not reproducibly 
measurable including leptomeningeal disease, effusions/ascites, inflammatory 
breast disease, diffuse lymphangitic disease and blastic bone lesions are 
defined as non-measurable. Previously irradiated lesions will also be 
considered non-measurable except if unequivocal progression is documented 
and radiation was greater than 28 days prior to study entry.
6.1.2
Target and non-target lesions
All measurable lesions up to a maximum of two lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the diameter for all target lesions 
(long axis for tumor lesions and short axis for lymph nodes, if included) will be 
calculated and reported as the baseline sum diameters. The baseline sum 
diameters will be used as reference by which to characterize the objective 
tumor response.
All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline. Non-target lesions include 
measurable lesions that exceed the maximum numbers per organ or total of 
all involved organs as well as non-measurable lesions. Measurements of 
these lesions are not required but the presence or absence of each should be 
noted.
6.1.3
Guidelines for evaluation of response
Target lesion measurements should be obtained at baseline (within 4 weeks 
from initiation of regorafenib). Repeat measurements will be performed using 
the same technique as that used at baseline. For each measurement, a sum
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of diameters will be calculated and non-target lesions will be followed as 
“present”, “absent” or in rare cases “unequivocal progression.”
6.1.3.1 Target lesion responses
Target lesions will be evaluated as follows:
6.1.3.1.1
Complete response (CR): Disappearance of all 
target lesions
6.1.3.1.2
Partial response (PR): > 30% decrease in the 
baseline sum diameters of target lesions
6.1.3.1.3
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
6.1.3.1.4
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.
6.1.3.2 Non-target lesions responses:
Non-target lesions will be evaluated as follows:
6.1.3.2.1
Complete response (CR): Disappearance of all non- 
target lesions with all lymph nodes < 10 mm in short 
axis.
6.1.3.2.2
Non-CR/Non-PD: Persistence of one or more non- 
target lesions
6.1.3.2.3
Progressive disease (PD): Unequivocal progression 
of non-target lesions (meriting discontinuation of 
regorafenib). The appearance of one or more new 
lesions also qualifies as PD.
6.1.4
Evaluation of best overall response
The best overall response is the best response recorded from the start of the 
treatment until the end of treatment taking into account requirements for 
confirmation. Please refer to Table 8 below.
Table 7: Evaluation of Best Overall Response
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
Inevaluable
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
Patients with a global deterioration of health status requiring discontinuation of 
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should be classified as having “symptomatic deterioration.” Every effort 
should be made to document the objective progression, even after 
discontinuation of treatment.
6.1.5
Confirmatory Measurement/Duration of Response
6.1.5.1 Confirmation
To be assigned a status of confirmed PR or CR, changes in tumor 
measurements must be confirmed by repeat assessment no less than 
4 weeks after the criteria for response are first met. In the case of SD, 
follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval of 8 weeks.
6.1.5.2 Duration of overall response/stable disease
The duration of overall response is measured from the time that 
measurement criteria are met for CR or PR (whichever is recorded 
first) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease 
the smallest measurements recorded since treatment started).
The duration of overall CR is measured from the time that 
measurement criteria are first met for CR until the date that recurrent 
disease is objectively documented.
Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest 
measurements recorded since treatment started.
6.2
PRIMARY ENDPOINT ASSESSMENT
The primary endpoint of the study will be progression-free survival (PFS) at 4 months, 
defined as the absence of progression at 4 months. Patients must complete at least 2 
cycles of study treatment to be considered evaluable for this endpoint.
6.3
SECONDARY ENDPOINT ASSESSMENT
The progression-free rate (PFR) at 3 and 6 months will be defined as the number of 
patients with progression absent at these timepoints divided by the total number of 
study patients. Median PFS (defined as the duration of time from start of treatment 
until time of progression or death, whichever occurs first) will be estimated as a 
secondary endpoint. Overall survival will be defined as the time from start of treatment 
until death by any cause. Response rate (by RECIST v 1.1) will be calculated using 
the definitions above. The rate and duration of tumor control will be defined as the 
number of CR+PR+SD responses. Patients must complete at least 2 cycles of study 
treatment to be considered evaluable for efficacy endpoints.
To evaluate the safety and tolerability of regorafenib, all subjects who receive at least 
one dose of study treatment will be considered evaluable for the safety analysis.
Safety variables will include the following: AEs, laboratory changes (complete blood 
counts, electrolytes, chemistry, and coagulation), changes in vital signs (blood 
pressure, heart rate, respiratory rate, and temperature) and results of clinically 
indicated studies outside study guidance, such as ECG or chest x-ray images, as 
produced at the investigator’s discretion. All AEs whether considered drug-related or 
not, will be reported with a diagnosis, start/stop dates, action taken, whether treatment
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was discontinued, any corrective measures taken, outcome, and other possible 
causes. For all events, the relationship to treatment and the intensity of the event will 
be determined by the investigator. All observations pertinent to the safety of the study 
treatment will be recorded and included in the final report. This trial will use the NCI 
CTCAE v 4.0 criteria for assessment of toxicity and SAE reporting with regard to 
toxicity grade.
ADVERSE EVENTS AND SAFETY MONITORING
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of 
the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer to 
Appendices for additional information). The level of risk attributed to this study requires High 
Intensity Monitoring, as outlined in the DSMP. In addition, the study will abide by all safety 
reporting regulations, as set forth in the Code of Federal Regulations and as required by the 
NCI AdEERS Reporting Guidelines.
Investigators should refer to the Safety Information section of the current IB for regorafenib, 
including the DCSI (development core safety information), for the expected side effects of 
regorafenib. As with any agent, there is always the potential for unexpected AEs, including 
hypersensitivity reactions. The IB will be updated if any new relevant safety data are 
obtained.
7.1
ADVERSE EVENT MONITORING
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of subjects enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Subjects must be 
carefully monitored for AEs. This monitoring also includes clinical laboratory tests. 
Adverse events should be assessed in terms of their seriousness, intensity, and 
relationship to the study drug, or other chemotherapy/treatment. Adverse events are 
reported in a routine manner at scheduled times during a trial. Additionally, certain 
adverse events must be reported in an expedited manner to allow for optimal 
monitoring of patient safety and care.
All patients experiencing an adverse event, regardless of its relationship to study 
drug, will be monitored until:
•
the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline;
•
any abnormal laboratory values have returned to baseline;
•
there is a satisfactory explanation other than the study drug for the changes 
observed; or
•
death occurs.
Therapeutic monitoring should be performed following dose modification of 
regorafenib in a manner consistent with the local clinical standard of care. In general, 
subjects should be closely monitored for side effects of all concomitant medications 
regardless of the path of drug elimination.
7.2
DEFINITIONS & DESCRIPTIONS
7.2.1
Adverse event (AE)
An adverse event (AE) is any untoward medical occurrence in a patient 
receiving study treatment and which does not necessarily have a causal
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relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an experimental intervention, 
whether or not related to the intervention.
7.2.2
Severity of AEs
All adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE v. 4 is available 
at http://ctep.cancer.gov/reporting/ctc.html.
If no CTCAE grading is available, the severity of an AE is graded as follows:
7.2.2.1 Mild (grade 1): the event causes discomfort without disruption of 
normal daily activities.
7.2.2.2 Moderate (grade 2): the event causes discomfort that affects normal 
daily activities.
7.2.2.3 Severe (grade 3): the event makes the patient unable to perform 
normal daily activities or significantly affects his/her clinical status.
7.2.2.4 Life-threatening (grade 4): the patient was at risk of death at the time 
of the event.
7.2.2.5 Fatal (grade 5): the event caused death.
7.2.3
Serious adverse events (SAEs)
All SAEs, regardless of attribution, occurring during the study or within 30 
days of the last administration of study drug must be reported upon discovery 
or occurrence. Additional expedited or routine reporting may be required, 
depending on the nature of the SAE (as outlined in 7.3 below). A “serious” 
adverse event is defined in regulatory terminology as any untoward medical 
occurrence that:
7.2.3.1 Results in death.
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself.
7.2.3.2 Is life-threatening.
The patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe.
7.2.3.3 Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24hours.
7.2.3.4 Results in persistent or significant disability or incapacity.
7.2.3.5 Is a congenital anomaly/birth defect.
7.2.3.6 Is an important medical event.
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.
Examples: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
7.2.4
Medical History vs. Adverse Event
7.2.4.1 A surgical procedure that was planned prior to the start of the study 
by any physician treating the subject should not be recorded as AE
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(however, the condition for which the surgery is required may be an 
AE if worsens compared to baseline).
7.2.4.2 Conditions that started before registration and for which no symptoms 
or treatment are present until after registration are recorded as 
medical history (e.g. seasonal allergy without acute complaints).
7.2.4.3 Conditions that started before registration and for which symptoms or 
treatment are present after registration, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis).
7.2.4.4 Conditions that started or deteriorated after registration will be 
documented as adverse events.
7.2.5
Exceptions to the Definition of SAE
Certain hospitalizations or prolongation of hospitalizations should not be 
considered SAEs, including those that meeting the following criteria:
7.2.5.1 An admission resulting in a hospital stay of less than 12 hours.
7.2.5.2 An admission that is pre-planned (i.e. elective or scheduled surgery 
arranged prior to the start of the study).
7.2.5.3
An admission that is not associated with an AE (i.e. social 
hospitalization for purposes of respite care).
7.2.6
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO)
A UPIRSO includes events that meet ALL of the following criteria:
7.3.3.1.1
Are unanticipated in terms of nature, severity, or 
frequency;
7.3.3.1.2
Place the research subject or others at a different or 
greater risk of harm; AND
7.3.3.1.3
Are deemed to be related or possibly related to 
participation in the study.
7.3
ADVERSE EVENT REPORTING
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the 
appropriate eCRF according to the time intervals noted in the Schedule of 
Events. Routine AEs will be reviewed by the Data Monitoring Committee 
(DMC) according to the study’s phase and risk level, as outlined in the DSMP.
7.3.2
Steps to determine if expedited reporting is required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) 
must also be reported accordingly.
7.3.2.1 Identify the type of adverse event using the NCI CTCAE v 4.0.
7.3.2.2 Grade the adverse event using the NCI CTCAE v 4.0.
7.3.2.3 Determine whether the adverse event is related to the protocol 
therapy.
Attribution categories are as follows:
7.3.2.3.1
Definite: AE is clearly related to the study treatment.
7.3.2.3.2
Probable: AE is likely related to the study treatment.
7.3.2.3.3
Possible: AE may be related to the study treatment.
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7.3.2.3.4
Unrelated: AE is clearly NOT related to the study 
treatment.
7.3.2.4 Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:
7.3.2.4.1
the current protocol;
7.3.2.4.2
the drug package insert;
7.3.2.4.3
the current Investigator’s Brochure.
7.3.3
Documentation of AEs
Each event should be described in detail along with start and stop dates, 
severity, relationship to regorafenib, action taken and outcome.
Any action on study treatment to resolve the AE is to be documented on the 
appropriate eCRF using the categories listed below:
•
Drug withdrawn
•
Drug interrupted
•
Dose reduced
•
Dose not changed
•
Dose increased
•
Not applicable
•
Unknown
In addition, the outcome of the AE is to be documented as follows:
•
Recovered/resolved
•
Recovering/resolving
•
Recovered/resolved with sequelae
•
Not recovered/not resolved
•
Fatal
•
Unknown
7.3.4
Expedited Reporting of SAEs
Completion of the Medwatch form is the preferred method of reporting. This 
form can be found at: http://www.fda.gov/medwatch/.
7.3.4.1 Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event. Completion of the NU CRO SAE Form, 
provided as a separate document, is required.
The completed form should assess whether or not the event qualifies 
as a UPIRSO. The report should also include:
•
Protocol description and number(s)
•
The patient’s identification number
•
A description of the event, severity, treatment, and outcome (if 
known)
•
Supportive laboratory results and diagnostics
•
The hospital discharge summary (if available/applicable)
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All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
7.3.4.2 Reporting to the IRB
The following information pertains to the responsibilities of the lead 
site (Northwestern University). Additional participating sites should 
follow their local IRB guidelines for reporting to their local IRBs.
•
Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly 
reported to the NU IRB within 24 hours of notification.
•
Any death of an NU subject that is actively on study treatment 
(regardless of whether or not the event is possibly related to 
study treatment)
•
Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to the 
NU IRB within 5 working days of notification.
•
All other deaths of NU subjects not previously reported, other 
non-NU subject deaths that were unanticipated and unrelated, 
and any other SAEs that were not previously reported as 
UPIRSOs will be reported to the NU IRB at the time of annual 
continuing review.
7.3.4.3 Reporting to the FDA
This applies to studies conducted under an IND or IDE, as set forth in 
the Code of Federal Regulations, Section 312.32
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life- 
threatening.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were 
not initially deemed reportable, but are later determined to meet the 
criteria for reporting (i.e. by the DMC).
All other SAEs will be reported on an annual basis as part of the 
annual FDA report.
7.3.4.4 Reporting to Bayer HealthCare
Investigators should report SAEs to Bayer using one of the following 
methods:
•
Email: DrugSafety.GPV.US@bayer.com
•
Fax: (973) 709-2185
•
Mail:
Global Pharmacovigilance - USA
Bayer HealthCare Pharmaceuticals Inc.
P.O. Box 1000
Montville, NJ 07045-1000
•
FedEx or UPS:
Global Pharmacovigilance – USA
340 Changebridge Road
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Pine Brook, NJ 07058
•
Phone call to the Clinical Communications Department:
1-888-765-3203-2937
7.3.5
Pregnancies
The investigator must report to Bayer any pregnancy occurring in a study 
subject, or in his partner, during the subject’s participation in this study. The 
report should be submitted within the same timelines as an SAE, although a 
pregnancy per se is not considered an SAE. For a study subject, the outcome 
of the pregnancy should be followed up carefully, and any abnormal outcome 
of the mother or the child should be reported. For the pregnancy of a study 
subject’s partner, all efforts should be made to obtain similar information on 
course and outcome, subject to the partner’s consent. For all reports, the 
forms provided are to be used.
DRUG INFORMATION
8.1
SUPPLY AND STORAGE GUIDELINES
Regorafenib tablets will be packaged in high density polyethylene bottles with a white 
child resistant closure and induction seal. Each bottle includes 30 tablets and a 3- 
gram desiccant. The bottles will have a label affixed containing study identification, 
product identification, and quantity of tablets. Once the drug has been received it 
must be kept in a secure, dry location. Study drug must be stored in its original bottle 
at a temperature not above 25°C (77°F).
The study drug must be exclusively used for the investigation specified in this protocol 
and it will only be accessible to authorized staff.
8.2
DOSAGE AND ADMINISTRATION
The starting dose for all subjects on this study will be 160 mg daily (4 40 mg tablets). 
Regorafenib is administered orally. Please refer to Section 4 for further details 
regarding administration and dose modifications.
8.3
DRUG LOGISTICS AND ACCOUNTABILITY
All study drugs will be stored at the investigational site in accordance with Good 
Clinical Practice (GCP) and Good Manufacturing Practices (GMP) requirements and 
the instructions given by the clinical supplies department of the Institution and will be 
inaccessible to unauthorized personnel. Study drug for all sites will be shipped to the 
lead site (Northwestern University); the lead site will then be responsible for shipping 
drug to each of the participating sites. For questions about drug ordering or to request 
drug, please contact the following individual at Bayer Heatlhcare:
Joy Wang, MA
Bayer Healthcare - U.S. Medical Affairs
Investigator Sponsored Studies & Medical Education 
6 West Belt Parkway
Wayne, NJ 07470
Office: 973.487.5333
Email: joy.wang1@bayer.com
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8.3.1
Accountability
An adequate record of receipt, distribution, and return of all study drugs must 
be kept at each site. Patients will maintain a pill diary (see Appendices).
8.3.2
Destruction and Return
At the end of the study, unused supplies of regorafenib should be destroyed 
according to local institutional policies. A certificate of destruction should be 
sent to Bayer that outlines how much drug was destroyed. This may be sent 
via:
E-mail: Karen.marini@bayer.com
OR
Fax:
973-709-2193
OR
Mail:
[VP of Medical Affairs named in contract] 
Bayer HealthCare Pharmaceuticals
6 West Belt
Wayne, NJ  07470
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
9.1
PRIMARY OUTCOME OF INTEREST
The primary endpoint will be progression-free survival at 4 months. Standard of care 
therapy currently provides a median PFS of about 3 months with a SD of 
approximately 2.5 months.
9.2
SECONDARY OUTCOMES OF INTEREST
Secondary endpoints of interest will include progression free rates at 3 and 6 months, 
median PFS, overall survival, response rates, duration of responses, rates of stable 
disease, safety and tolerability. Standard of care therapy currently provides a median 
overall survival of about 9 months with a SD of approximately 4 months.
9.3
TRIAL DESIGN AND DETERMINATION OF SAMPLE SIZE
A two-stage optimal Simon design will be employed to test the null hypothesis that the 
probability of progression-free survival of 4 months or greater (P) is < 0.22 versus the 
alternative that the probability > 0.45. To test this hypothesis with adequate power, a 
first stage involving 12 patients will be completed. If > 3 patients achieve progression- 
free survival of 4 months, the trial will be continued for a total of 31 patients. If > 11 
out of 31 patients achieve progression-free survival of 4 months, the trial will reject the 
hypothesis that P < 0.22 and conclude that P > 0.45,
To determine sample size, the following parameters were employed: P0 = 0.22, P1 = 
0.45, α = 0.05 and β = 0.20. Computations originally performed using software PASS 
(www.ncss.com).
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Bayer Healthcare Study Number: ONC-2013-129
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Version Date: April 3rd, 2019
Definitions:
N1 – sample size in the first stage
R1 – drug rejection number in the first stage 
PET – probability of early termination of study 
N – combined sample size of both stages
R – combined drug rejection number after both stages
Avg N – average sample size if this design is repeated many times
α – probability of rejecting that P < P0 when this is true 
β – probability of rejecting that P > P1 when this is true 
P0 – response proportion P of a poor drug
P1 – response proportion P of a good drug
9.4
PLANNED ANALYSES
Survival data will be analyzed using parametric (exponential) and non-parametric 
(Kaplan-Meier) methods. Exact methods for providing confidence intervals for 
proportions “surviving” landmarks will be used as needed. Statistical software will be 
SAS (and others as merited) and analysis will be conducted under the supervision of 
Alfred Rademaker, PhD, in the Biostatistical Core Facility at Northwestern University.
Descriptive statistics (mean, standard deviation, mean change from baseline, etc.) will 
be presented for laboratory values. Detailed examination of AEs by NCI CTCAE 
grade and frequency tabulation will be presented. Missing data for partial dates on 
AEs or concomitant medications may be imputed.
STUDY MANAGEMENT
10.1
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the consent 
form and protocol.
In obtaining and documenting informed consent, the investigator should comply with 
the applicable regulatory requirement(s), and should adhere to Good Clinical Practice 
(GCP) and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the 
FDA Regulations and local or state regulations. Once this essential information has 
been provided to the patient and the investigator is assured that the patient 
understands the implications of participating in the study, the patient will be asked to 
give consent to participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should 
be signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
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Robert H. Lurie Comprehensive Cancer Center 
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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Version Date: April 3rd, 2019
10.2
AMENDMENTS
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. Modifications to the study protocol will not be implemented by the 
investigator without discussion and agreement by Bayer. All amendments will be 
subject to the review and approval of the appropriate local, institutional, and 
governmental regulatory bodies. Amendments will be distributed by the lead 
institution (Northwestern) to all affiliate sites upon approval by the Northwestern 
University IRB.
10.3
REQUIRED DOCUMENTATION FOR MULTI-SITE STUDIES
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office at Northwestern University:
10.3.1 Signed and completed Letter of Invitation to participate in the study.
10.3.2 Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission.
10.3.3 A copy of the official IRB approval letter for the protocol and informed 
consent.
NOTE: Informed consent form should be submitted to the Clinical Research 
Office for review/approval prior to submission to the local IRB.
10.3.4 CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study at the site.
10.3.5 Form FDA 1572 appropriately filled out and signed with appropriate 
documentation.
Additional activities may be required prior to site activation (i.e. contract execution, 
study-specific training). Full requirements will be outlined in a memo upon receipt of 
the signed Letter of Invitation.
10.4
SUBJECT REGISTRATION PROCEDURES
Patients may not begin protocol treatment prior to registration. All patient registrations 
will be registered centrally through the Clinical Research Office at Northwestern 
University before enrollment to study. Please contact the assigned Quality Assurance 
Monitor (QAM) or email the QA Department (croqualityassurance@northwestern.edu) 
for questions regarding patient registration.
Prior to registration, eligibility criteria must be confirmed by the assigned QAM. The 
study coordinator will screen all subjects for potential registration via the web-based 
application NOTIS (Northwestern Oncology Trial Information System), which is 
available at: https://notis.nubic.northwestern.edu. Please note that a username and 
password is required to use this program, and will be provided during site activation 
prior to training on the NOTIS system.
Registering a Patient to a Phase II Study
For potential patients this study, study teams are asked to inform the QAM of the 
date and time that the patient will need to be registered 
(croqualityassurance@northwestern.edu).
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive a subject identification number:
• Eligibility eCRF (complete in NOTIS)
• Eligibility checklist (signed and dated by the treating physician – upload in NOTIS)
• Signed and dated informed consent document (upload in NOTIS)
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Robert H. Lurie Comprehensive Cancer Center 
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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• Pathology Report (upload in NOTIS)
The QAM will review the registration, register the patient, assign a subject 
identification number, and send a confirmation of registration to study personnel. 
Registration will then be complete and the patient may begin study treatment.
10.5
DATA SUBMISSION
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate 
document). Generally, for all phase II patients, data are due at the end of every cycle 
within 10 days.
10.6
DATA MANAGEMENT AND MONITORING/AUDITING
This study will be conducted in compliance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University (please refer to NOTIS for additional information). The level of risk 
attributed to this study requires High Intensity Monitoring, as outlined in the DSMP. 
The assigned QAM, with oversight from the Data Monitoring Committee, will monitor 
this study in accordance with the study phase and risk level. Please refer NOTIS for 
additional data submission instructions.
10.7
ADHERENCE TO THE PROTOCOL
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.
10.7.1 Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.
For any such emergency modification implemented, an IRB modification form 
must be completed within five (5) business days of making the change.
10.7.2 Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved protocol 
that:
10.6.2.1
Is generally noted or recognized after it occurs.
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Robert H. Lurie Comprehensive Cancer Center 
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Lead Site Study Number: NU 13S02 
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10.6.2.2
Has no substantive effect on the risks to research participants
10.6.2.3
Has no substantive effect on the scientific integrity of the 
research plan or the value of the data collected.
10.6.2.4
Did not result from willful or knowing misconduct on the part 
Of the investigator(s).
A protocol deviation may be considered an instance of Reportable New 
Information (RNI)if the variance:
10.6.2.5
Has harmed or increased the risk of harm to one or more 
research participants.
10.6.2.6
Has damaged the scientific integrity of the data collected for 
the study.
10.6.2.7
Results from willful or knowing misconduct on the part of the 
investigator(s).
10.6.2.8
Demonstrates serious or continuing noncompliance with 
federal regulations, State laws, or University policies.
10.8
OBLIGATIONS OF INVESTIGATORS
The Principal Investigator is responsible for the conduct of the clinical trial at the site 
in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration 
of Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators 
and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study 
completion.
The Principal Investigator at each institution or site (local PI) will be responsible for 
assuring that all the required data will be collected, entered onto the appropriate 
eCRFs, and submitted within the study-specific timeframes. Periodically, monitoring 
visits may be conducted and the Principal Investigator will provide access to his/her 
original records to permit verification of proper entry of data. The study may also be 
subject to routine audits by the Audit Committee, as outlined in the DSMP.
10.9
PREMATURE TERMINATION OF THE STUDY
The study may be halted prematurely for any of the following reasons:
•
If risk-benefit ratio becomes unacceptable owing to, for example:
o
Safety findings from this study (e.g. SAEs)
o
Results of any interim analysis
o
Results of parallel clinical studies
o
Results of parallel animal studies (on e.g. toxicity, teratogenicity, 
carcinogenicity or reproduction toxicity).
•
If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame.
For any of the above closures, the following applies:
•
Closures should occur only after consultation between involved parties (including 
approval from the Data Monitoring Committee at Northwestern University).
•
All affected institutions and their IRBs, competent authority (ies), study center, 
and the head of study center must be informed as applicable according to local 
law.
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Robert H. Lurie Comprehensive Cancer Center 
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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Version Date: April 3rd, 2019
•
In case of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner.
10.10
PUBLICATION POLICY
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with 
the policies and processes set forth in the Lurie Cancer Center DSMP. For trials that 
require high intensity monitoring, the assigned QAM will prepare a preliminary data 
summary (to be approved by the DMC) no later than 3 months after the study reaches 
its primary completion date (the date that the final subject is examined or receives an 
intervention for the purposes of final data collection for the primary endpoint). If the 
investigator’s wish to obtain DMC-approved data prior to this point (or prior to the 
point dictated by study design), the PI must send a written request for data to the 
QAM which includes justification. If the request is approved, data will be provided no 
later than 4 weeks after this request approval. The data will be presented to the DMC 
at their next available meeting, and a final, DMC-approved dataset will be released 
along with any DMC decisions regarding publication. The investigators are expected 
to use only DMC-approved data in future publications. The investigators should 
submit a copy of the manuscript to the biostatistician to confirm that the DMC- 
approved data are used appropriately. Once the biostatistician gives final approval, 
the manuscript may be submitted to Bayer Healthcare(funding source).
Bayer recognizes the right of the investigator to publish results upon completion of the 
study. However, the investigator must send a draft manuscript of the publication or 
abstract to Bayer at least 30 days in advance of submission in order to obtain 
approval prior to submission of the final version for publication or congress 
presentation. This will be reviewed promptly and approval will not be withheld 
unreasonably. In case of a difference of opinion between Bayer and the 
investigator(s), the contents of the publication will be discussed in order to find a 
solution which satisfies both parties. All relevant aspects regarding data reporting and 
publication will be part of the contract between Bayer and the investigator/institution. 
The Principal Investigator should also ensure that the information regarding the study 
be publicly available on the internet at www.clinicaltrials.gov.
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Robert H. Lurie Comprehensive Cancer Center 
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REFERENCES
1) Young RJ, Brown NJ, Reed MW, Hughes D, Woll PJ. Angiosarcoma. Lancet Oncol. 2010 
Oct;11:983-991.
2) Italiano A, Cioffi A, Penel N, Levra MG, Delcambre C, Kalbacher E, Chereau C, Bertucci 
F, Isambert N, Blay J-Y, Bui B, Antonescu C, D’Adamo DR, Maki RG, Keohan ML. 
Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas. 
Cancer. 2012 July;118:3330-3336.
3) Stacchiotti S, Palassini E, Sanfilippo R, Vincenzi B, Arena MG, Bochicchio AM, DeRosa 
P, Nuzzo A, Turano S, Morosi C, DeiTos AP, Pilotti S, Casali PG. Gemcitabine in advanced 
angiosarcoma: a retrospective case series analysis from the Italian Rare Cancer Network. 
Ann Oncol. 2012 Feb;23:501-508.
4) Agulnik M, Yarber JL, Okuno SH, von Mehren M, Jovanovic BD, Brockstein BE, Evens 
AM, Benjamin RS. An open-label, multicenter, phase II study of bevacizumab for the 
treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013 
Jan;24:257-263.
5) Ray-Coquard I, Italiano A, Bompas E, Le Cesne A, Robin YM, Chevreau C, Bay JO, 
Bousquet G, Piperno-Neumann S, Isambert N, Lemaitre L, Fournier C, Gauthier E, Collard 
O, Cupissol D, Clisant S, Blay JY, Penel N; French Sarcoma Group (GSF/GETO). Sorafenib 
for patients with advanced angiosarcoma: a phase II trial from the French Sarcoma Group 
(GSF/GETO). Oncologist. 2012 Feb;17:260-266.
6) Buehler D, Rush P, Hasenstein JR, Rice SR, Hafez GR, Longley BJ, Kozak KR. Expression 
of angiopoietin-TIE system components in angiosarcoma. Modern Pathol. Epub ahead of 
print Apr 5, 2013.
7) Hasenstein JR, Kasmerchak K, Buehler D, Hafez GR, Cleary K, Moody JS, Kozak KR. 
Efficacy of Tie2 receptor antagonism in angiosarcoma. Neoplasia. 2012 Feb;14:131-140.
8) Burkholder TP, Clayton JR, Rempala ME, Henry JR, Knobeloch JM, Mendel D, McLean 
JA, Hao Y, Barda DA, Considine EL, Uhlik MT, Chen Y, Ma L, Bloem LJ, Akunda JK, 
McCann DJ, Sanchez-Felix M, Clawson DK, Lahn MM, Starling JJ. Discovery of 
LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of 
activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem 
duplication mutant human tumor xenograft model. Invest New Drugs. 2012 Jun;30:936-949.
9) Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, Thierauch KH, Zopf D. 
Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and 
oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 
2011 Jul;129:245-255.
10) Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both 
pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 
2003 May;111(9):1287-95.
11) Grothey A et al. Regorafenib monotherapy for previously treated metastatic colorectal 
cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 
trial. Lancet 2013 Jan;381:303-312.
IRB #: STU00087654-CR0004 Approved by NU IRB for use on or after 8/19/2019 through 8/18/2020.


Robert H. Lurie Comprehensive Cancer Center 
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
41
Version Date: April 3rd, 2019
12) Demetri G et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal 
tumors after failure of imatinib and sunitinib (GRID): an international, multicentre, 
randomised, placebo-controlled, phase 3 trial. Lancet 2013 Jan;381:295-302.
13) Guidance for Industry – Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics. U.S. Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER).
14) Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, 
Verweij J. New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009 Jan;45:228-247.
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Lead Site Study Number: NU 13S02 
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APPENDIX I – DATA COLLECTION & SUBMISSION GUIDELINES
Study-specific instructions regarding the entry and submission of data using eCRFs through 
NOTIS will be provided at the time of training prior to study activation. In addition, 
instructional videos on data entry using NOTIS and eCRFs are available on the CRO’s 
website at: https://www.cancertrials.northwestern.edu/working-with-the-cro. The Internal 
and Affiliate Data Compliance Policies of the Lurie Cancer Center’s DMC regarding will be 
strictly enforced.
Please refer to stand-alone document in NOTIS 
‘NU13S02 Data submission guidelines’ for more details.
APPENDIX II – PILL DIARY
Pill diary available as stand-alone document in NOTIS
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Robert H. Lurie Comprehensive Cancer Center 
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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APPENDIX III – BLOOD PRESSURE LOG
Protocol Number 
Institution   
Subject Initials 
 
Subject ID#  
Date of 
assessment
Time of 
assessment
Systolic/Diastolic 
(mmHg)
Comments
Wk1:
Wk2:
Wk3:
Wk4:
Wk5:
Wk6:
Blood pressure should be recorded weekly during the first six weeks of treatment.
CRA Initials Date of Completion
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Robert H. Lurie Comprehensive Cancer Center 
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Lead Site Study Number: NU 13S02 
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APPENDIX IV – DATA SAFETY MONITORING PLAN
This trial will be conducted and monitored in accordance with the Data Safety Monitoring 
Plan (DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University. A copy of the plan can be obtained from the following link:
https://www.cancertrials.northwestern.edu/cpsrms/cpsrms-p-ps
Data is expected to be submitted according to requirements described in appendix I. The 
QAM will review and assess each submitted eCRF for completeness, protocol 
adherence/compliance, toxicities, potential subject safety issues, and disease outcome and 
response. The QAM will routinely query study teams regarding any issues or for outstanding 
data. The QAM will present SAEs, protocol deviations, data summaries, and any other issues 
that may impact patient safety or data integrity to the DMC on a semi-monthly basis.
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Robert H. Lurie Comprehensive Cancer Center 
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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APPENDIX V - ADVERSE EVENTS SELF-REPORT SURVEY
Available as stand-alone document in NOTIS
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Robert H. Lurie Comprehensive Cancer Center 
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APPENDIX VI – PROTOCOL HISTORY OF CHANGES
Initial Version approved by Scientific Review Committee – May 10, 2013
Amendment 1 (pre-IRB submission) – October 10, 2013
Approved by SRC – October 22, 2013
Section(s) Affected
Prior Version
Amendment 1 
Changes
Rationale
Throughout
n/a
Adds the Bayer 
Healthcare study
number to the header 
(ONC-2013-129)
Administrative
Synopsis, 2.1 (Primary
Objective), 6.2 (Primary 
Endpoint Assessment),
9.1 (Primary Outcome of 
Interest)
Primary objective was 
progression-free 
survival (PFS).
Changed primary 
objective to PFS at 4 
months.
This was changed at 
the recommendation of 
the company providing 
regorafenib (Bayer 
Healthcare). PFS at 4 
months is the only 
endpoint that the study 
is designed to assess 
with a pre-identified risk 
of error, which makes it 
the logical basis for
conclusion of efficacy in 
this trial.
Synopsis, 2.2 
(Secondary Objectives),
6.3 (Secondary Endpoint 
Assessment), 9.2 
(Secondary Outcomes of 
Interest)
n/a
Adds overall PFS and 
progression-free rate 
(PFR) at 3 and 6 
months secondary 
objectives.
PFR has been 
established as an 
endpoint for soft tissue 
sarcoma by the Soft 
Tissue and Bone 
Sarcoma Group of the 
European Organization 
for Research and 
Treatment of Cancer 
(EORTCSTBSG) to
account for low PR 
rates in this disease. 
This was changed at
the recommendation of 
Bayer Healthcare.
1.2 (Rationale)
n/a
Adds a statement that 
future phase III or other 
large-scale 
confirmatory trials 
should employ an 
interim analysis as an 
efficacy double-check if
this trial meets efficacy 
criteria.
Added at the 
recommendation of 
Bayer Healthcare.
3.1 (Inclusion Criteria)
n/a
Adds that “Patients who 
are prophylactically 
treated with an agent 
such as warfarin or
heparin will be allowed 
to participate provided
Added at the 
recommendation of 
Bayer Healthcare.
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that no prior evidence 
of underlying 
abnormality in 
coagulation parameters 
exists.” Gives 
recommendations for
how to monitor this.
3.1 (Inclusion Criteria)
No limit on the number 
of prior therapies for 
eligibility.
Allows up to 4 prior 
therapies for eligibility; 
clarifies that 
progressive disease
must have been under 
last palliative therapy.
Added at the 
recommendation of 
Bayer Healthcare.
Table 4 (Recommended 
Dose Modification for
Hand-Foot-Skin 
Reaction)
n/a
Removes footnote “e”.
Administrative – did not 
pertain to any part of 
the table.
Table 6 (Dose 
Modifications/Delays for 
Liver Function 
Abnormalities), Table 7 
(Study Visit Parameters)
Stated that ALT, AST 
and bilirubin will be 
monitored at least 
weekly during the first 
2 cycles of treatment.
Changes this to require 
monitoring prior to 
initiation of regorafenib 
treatment, and then 
every 2 weeks during 
the first 2 cycles; adds 
that 2 cycles = 2 
months. Updates visit
parameters 
accordingly.
Clarification and 
change requested by 
Bayer Healthcare.
4.3.5
(Prevention/Management 
Strategies for Diarrhea)
Stated that the same 
dose modification 
algorithm used for 
skin toxicities should 
be used for diarrhea.
Revises this to state 
only that diarrhea 
prevention and 
management should be
consistent with local 
institutional practices.
Update requested by 
Bayer Healthcare.
4.4 (Prior and 
Concomitant Therapy)
General background 
given on the 
interactions of 
CYP3A4 inducers and 
inhibitors on 
regorafenib.
Adds detailed 
background information 
on the effects of co- 
administration of strong 
CYP3A4 inducers (such 
as rifampin) and strong 
CYP3A4 inhibitors (such 
as ketoconazole) on 
exposure of regorafenib 
and its metabolites.
Update requested by 
Bayer Healthcare.
4.4 (Prior and 
Concomitant Therapy)
Mentioned that 
“caution should be 
taken when 
considering or 
administering a 
concomitant 
medication that is 
metabolized by the
cytochrome enzymes 
CYP2C8, CYP2B6
Removes this 
statement.
Per Bayer Healthcare, 
only strong CYP3A4 
inducers and inhibitors 
are prohibited.
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and CYP2C9. Such 
concomitant 
medication should be 
avoided, if possible.”
4.4.1 (Permitted 
Concomitant Therapies),
4.4.2 (Concomitant 
Therapies Not Permitted)
Stated that 
therapeutic anti- 
coagulation with 
agents such as 
warfarin or heparin
are allowed.
Revises this to indicate 
that only prophylactic 
treatment with such 
agents is permitted.
Changed to be 
consistent with eligibility 
criteria (3.2.29).
4,8.1 (Mandatory 
Withdrawal Criteria)
“Pregnancy” and 
“investigator 
conclusion that 
continuation of the 
trial would be harmful” 
listed as possible 
withdrawal criteria.
Changes “pregnancy” 
and “investigator 
conclusion that 
continuation of the trial 
would be harmful” to 
events requiring 
mandatory withdrawal. 
Clarifies that pregnancy 
itself is not an SAE, but 
that it should be
reported along the 
timelines as an SAE.
Added at the 
recommendation of 
Bayer Healthcare.
Table 7 (Study Visit 
Parameters)
Footnote “b” 
mentioned therapeutic
doses of anti- 
coagulants.
Removes reference to 
this.
Therapeutic doses of 
anticoagulants are not 
permitted.
Table 7 (Study Visit 
Parameters)
AE/tolerability 
reporting required on 
day 1 of each cycle.
Changed to require AE 
reporting weekly over 
the phone during cycle
1 (and then day 1 of 
each cycle thereafter).
Added at the 
recommendation of 
Bayer Healthcare.
Table 7 (Study Visit 
Parameters)
n/a
Adds “& pill diary 
collection” to be done 
at the time of
dispensation of study 
medication.
Administrative
8.1 (Supply and Storage 
Guidelines), 8.2 (Dose 
and Administration)
n/a
Removes language 
about the contents of 
regorafenib tablets.
Removed at the 
request of Bayer 
Healthcare.
10.4 (Subject 
Registration Procedures)
Contained some 
outdated language 
and instructions.
Updates the language 
and instructions 
pertaining to
registration of study 
patients.
Administrative update
Appendix I
Contained some 
outdated language 
and generic 
instructions.
Updates the language 
to provide study- 
specific instructions 
and timelines for
submission of study 
data via eCRFs.
Administrative update
Appendix IV
n/a
Adds more study- 
specific detail regarding
how the study will be 
monitored.
Administrative
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Appendix VI
n/a
Adds a Protocol History 
of Changes to 
summarize changes by 
amendment.
Administrative
Amendment 2 – September 19, 2014
Approved by SRC – November 5, 2014
Section(s) Affected
Prior Version
Amendment 2 
Changes
Rationale
List of Abbreviations,
3.1.9.6, and 2nd NOTE in 
2.1.9
PTT
PT/INR replaces PTT.
Revised for accuracy.
5.0 (Study parameters 
table)
Rows entitled “CT 
C/A/P” and “Other 
scans”
Combined to form one 
row entitled “Disease 
Measurements”
Clarification of disease 
measurement 
procedures
5.0 (Study parameters 
table)
Footnote “d” relating 
to “CT C/A/P” and 
footnote “e” relating to 
“Other scans”
Footnotes “d” and “e” 
combined into footnote 
“d” now relating to 
“Disease 
Measurements”.
Footnote “d” revised to 
add “MRI and visual 
measurements” as 
options for other 
imaging studies that 
are clinically indicated. 
All remaining footnotes
re-lettered to reflect 
change.
Clarification of disease 
measurement 
procedures
5.0 (Study parameters 
table)
Footnote “j” reading 
“Screening 
assessments must be 
completed within 2 
weeks prior to 
registration, unless 
otherwise specified.”
Revised to add 
“Screening 
assessments may be 
used for C1D1 
assessments if 
completed ≤ 2 weeks
before study drug 
initiation.”
Revised so that patients 
do not repeat screening 
assessments 
unnecessarily.
5.0 (Study parameters 
table)
n/a
Footnote
“k”
added, 
“Adverse
Event Self- 
Report Survey (AESRS) 
should be disseminated 
to each patient on day 1 
of cycle 1, but no data is 
collected.”
Clarification
5.0 (Study parameters 
table)
n/a
Footnote 
“l” 
added. 
“Unless
otherwise
noted,
on-therapy 
windows for testing will 
be as follows: imaging 
scans 
should 
be 
completed within +/- 1 
week of the target time
point, and labs and
Revised to add 
windows for on therapy 
testing.
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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Version Date: April 3rd, 2019
physical
examination
within +/- 3 days of the 
target time point.”
Amendment 3 – May 18, 2015
Approved by SRC – May 20, 2015
Section(s) Affected
Prior Version
Amendment 3 
Changes
Rationale
Cover Page
IND #: TBD
Added IND exemption
120139 EXEMPT.
New information
3.1 (Inclusion Criteria)
n/a
Adds
how 
prior 
therapies are counted is 
at the discretion of the 
treating physician and
principal investigator.
Clarification
5.0 (Study parameters 
table)
Urinalysis
Changes urinalysis to 
urine protein/creatinine 
ratio (UPC) as this is
what is required for 
eligibility in section 3.1.
Clarification
Amendment 4 – February28, 2017
Section(s) Affected
Prior Version
Amendment 4 
Changes
Rationale
Protocol title page and 
Study summary
Mayo Clinic 
(Scottsdale), 
University of 
Wisconsin and
Minnesota included 
as affiliate sites
Removed Mayo Clinic 
(Scottsdale), University 
of Wisconsin and 
Minnesota as affiliate 
sites.
Added University of 
Iowa to the summary 
section
They are no longer 
affiliate sites for this 
study
Correction of error
Section 3.1.9 
Inclusion criteria
List of laboratory 
requirements to be 
considered for 
eligibility with a note 
that blood transfusion 
will not be allowed in 
order to meet criteria
Note modified to state 
that “subjects may not 
have had a transfusion 
within 7 days of 
screening assessment” 
for these laboratory 
tests.
For clarity and 
flexibility
Section 3.2.5 
Exclusion criteria
Statement of 
exclusionary criteria 
for patients with 
thrombotic, embolic, 
venous or arterial 
events.
Note added to state an 
exception,
that “ Subjects with 
recent DVT who have 
been treated with 
therapeutic 
anticoagulating agents 
for at least 6 weeks 
prior to study treatment
are eligible”
For clarity and 
flexibility
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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Section 3.2.32
New exclusion criteria 
added
N/A
Criteria explaining the 
exclusion of patients 
that are unable or 
unwilling to discontinue 
use of strong inducers
and inhibitors of 
CYP450
For added clarity, 
flexibility and safety
Section 4.4.1 
Permitted Concomitant 
Therapies
Details about possible 
palliative radiation 
therapy during study 
treatment.
Added language:
“Protocol treatment 
should be held 7 days 
before, during and 7 
days after palliative 
radiation, or at the 
discretion of the site 
radiation oncologist. 
Palliative radiation 
cannot include target 
lesions.”
“Palliative surgery: 
Protocol treatment 
should be held 7 days 
before and until the 
wound is healed. If 
treatment is not 
resumed within 3 
weeks, the case will be 
reviewed by QAM and 
PI to determine whether 
or not subject can 
restart treatment.
Palliative surgery 
cannot include surgery 
on target lesions.”
For added clarity, 
flexibility and safety
Section 5.0
study procedures table
Previous list of 
footnotes
Numbering of footnotes 
corrected and some 
new footnotes added:
Footnote k: “Unless 
otherwise noted, on- 
therapy windows for 
testing will be as 
follows: imaging scans 
should be completed 
within +/- 1 week of the 
target time point, and
labs and physical 
examination within +/- 3
For added clarity, 
flexibility and safety
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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days of the target time 
point “.
Footnote L: “Subjects 
will 
be 
instructed 
to 
follow-up weekly with 
the study team IF they 
are 
experiencing 
any 
side effects.”
Footnote m:
“Day 1 of each cycle 
should be every 28 
days. In the event that 
this day falls on a 
holiday or other such 
event, study team 
should use +/- 3 day 
window to complete 
pre-treatment 
procedures, and 
dispense protocol 
agents to patients with 
instructions to 
commence treatment 
on day 1. Any missed 
doses will not be made 
up and should be 
skipped to maintain a 
28-day cycle.”
In addition,
Footnote f regarding 
assessments :CT C/A/P 
has been modified to 
read “ clinically 
indicated scans”
Footnote C regarding 
CT scans: has been 
modified to state: 
“Imaging should be 
done as clinically 
indicated (i.e. CT, MRI 
and visual 
measurements), which 
satisfy RECIST v 1.1 to 
evaluate disease (such 
as in extremity, head
and neck). Imaging 
studies will be done at
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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Version Date: April 3rd, 2019
baseline (within 4 
weeks before the first 
dose) and repeated 
after every 2 cycles of 
treatment (prior to each 
odd cycle) for tumour 
response evaluation.”
Section 7.3.4 
Expedited Reporting of 
SAEs
Previous NU protocol 
template language
Updated to current NU 
protocol template 
language
To align with current 
NUIIT protocol 
template and IRB 
requirements.
Section 10.4 
Subject registration 
procedures
Previous NU protocol 
template language
Updated to current NU 
protocol template 
language
To align with current 
NUIIT protocol
template and IRB 
requirements.
Section 10.5 
Data submission 
guidelines
(new section added)
N/A
Language added from 
current NU protocol 
template directing 
users to refer to the 
‘stand-alone’ document 
in NOTIS that contains 
the data submission 
guidelines.
(Previously, an 
outdated version of 
these guidelines were 
included in the 
Appendix. These have
been removed in this 
amendment)
To align with current 
NUIIT protocol 
template and IRB 
requirements
Section 10.6
Data management and 
monitoring/auditing
Reference to data 
Safety Monitoring 
plan in the Appendix.
Updated to refer to 
Data Safety Monitoring 
plan in NOTIS.
To align with current 
NUIIT protocol 
template and IRB 
requirements
Section 10.7.2
Other protocol deviations
Sub-section Promptly 
Reportable Non- 
Compliance(PRNC)
Term replaced with 
Reportable New 
Information(RNI)
To align with current 
NUIIT protocol 
template and IRB
requirements
Section 10.10 
Publication policy
Previous language 
stating conditions 
mandated by Bayer
Healthcare
Added language from 
current NU protocol 
template
To align with current 
NUIIT protocol 
template and IRB 
requirements
Appendix II
Entire pill dairy 
included in this 
appendix
Pill dairy removed. 
Language inserted 
asking users to refer to
NOTIS for pill dairy
For convenience and 
to align with
current NUIIT
protocol template
Appendix III
Blood pressure log
Previous template
Updated with more 
details.
For convenience and 
clarity
Adverse Event Self- 
Report Survey(AESRS)
Entire survey was 
inserted in the 
appendix
Survey removed. 
Language inserted 
stating that the survey
is available as a stand-
For convenience and 
to align with
current NUIIT 
protocol template
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Robert H. Lurie Comprehensive Cancer Center 
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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Version Date: April 3rd, 2019
alone document in
NOTIS.
Amendment 5-March 6th  , 2018
Section(s) Affected
Prior Version
Changes
Rationale
Title page 
and Synopsis
Study information along 
with affiliate site PI 
information
Added new affiliate site 
with PI information:
Sant P. Chawla, MD
Sarcoma Oncology 
Research Center, CA
On-boarding of new 
affiliate site
Section 5.0
Baseline did not have a 
definite window stated
Added a -28 day 
baseline window.
For convenience and 
consistency
Section 5.0 footnote c
The language pertaining 
to imaging was clubbed 
together with chemistry 
laboratory tests, due to 
a formatting error
The imaging language 
has now been shifted 
back to footnote d and all 
other footnotes 
readjusted to its previous 
accurate and 
corresponding positions 
in the table.
Correction of error.
Section 5.0 footnote j
The Screening 
assessments had a 2 
week window
The screening 
assessment window has 
been changed to 15 days
For convenience
Section 5.0
Follow-up footnotes 
were not clearly marked
Follow-up footnotes:
(i) and (m) clearly 
allocated in the table
For increased clarity
Section 11
Data Submission
Data submission 
guidelines for Phase II 
study
Inserted a window of 10 
days for Phase II data , as 
per CTO policy
To align with NU CTO 
policy
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Lead Site Study Number: NU 13S02 
Bayer Healthcare Study Number: ONC-2013-129
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Amendment 6 dated 4.3.19
Section(s) Affected
Prior Version
Changes in Amend 6
Rationale
Section 3.1.7 
Inclusion criteria
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
Added language to state:
“If patient refuses or if IV 
chemotherapy is 
contraindicated, patients 
will be eligible if they fail 
one systemic therapy.”
For flexibility and clarity
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