Conditions: Metastatic Colorectal Cancer
Keywords: Colorectal cancer metastatic colorectal cancer colorectal adenocarcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
The purpose of the study is to measure high grade (3-5) toxicity of regorafenib and to monitor the impact of treatment with regorafenib on the quality of life in older adults with metastatic colorectal cancer.

Detailed description:
Subjects will be asked to participate in the study because they are aged 70 or older and require treatment for colorectal cancer that has spread to other parts of the body and has not gotten better with other treatment. Subjects will undergo some initial tests to ensure that they meet all criteria necessary to participate in the study. Once the subject has completed initial testing and meets eligibility criteria, the subject will begin treatment with 120 mg of regorafenib (3 tablets) each day for 21 days (3 weeks) in a 28 day cycle (4 weeks). After the first cycle, the doctor will discuss the possibility of increasing the dose to 160 mg (4 tablets) each day for 21 days (3 weeks) in a 28 day cycle (4 weeks) based on the subjects health status. During the study, assessments will be performed to monitor the subjects tolerance and response to the treatment. Regorafenib will continue as long as the subject is tolerating the treatment and the subjects colorectal cancer is either responding to treatment or remains stable.

Arms:
arm 1: 120 mg qd, 3 weeks on/1 week off (each cycle is 28 days)

Three 40 mg tablets should be taken in the morning with approximately 8 fluid ounces (240 mL) of water after a low-fat (\< 30% fat) breakfast.

Interventions: intervention 1: Regorafenib
Intervention descriptions: intervention 1: Regorafenib 120 mg (3 tablets) each day for 21 days of a 28 day cycle with the possibility of an increase in the dose to 160 mg (4 tablets).

Protocol document:
Prot_SAP_000.pdf: 
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NCT02466009
Regorafenib in Adults ≥ 65 Years with Metastatic Colorectal Cancer: A 
Phase II Study
Test drug:
Regorafenib
Study purpose:
Toxicity in Geriatric Population
Clinical study phase:
II
Version no.:
2.7
Date:
20APR2018
Amendment no.:
7
Date:
12Jun2019
Institution Study no.:
UGIC-14072
Principal Investigator:
Aram Hezel, MD (Medical Oncology)
University of Rochester Medical Center
601 Elmwood Avenue, Box 704
Rochester, NY 14642
Phone: (585) 275-9484
Aram_Hezel@urmc.rochester.edu
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Co-Principal Investigator:       Supriya G. Mohile, MD, MS (Medical Oncology)
University of Rochester Medical Center
601 Elmwood Avenue, Box 704
Rochester, NY 14642
Phone: (585) 276-3947
Supriya_Mohile@urmc.rochester.edu
Co-Investigators:
Joleen M. Hubbard, MD (Medical Oncology)
Mayo Clinic, Rochester
200 First St SW
Rochester, MN 55901
Phone: (507) 284-8318
Hubbard.Joleen@mayo.edu
Efrat Dotan, MD (Medical Oncology)
Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia, PA 19111
Phone: (215) 728-2500
Efrat.Dotan@fccc.edu
Comprehensive Geriatric Assessment Contact: 
Terri Lloyd
University of Rochester Medical Center
601 Elmwood Avenue, Box 704
Rochester, NY 14642
Phone: (585) 276-5652
Terri1_lloyd@urmc.rochester.edu
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Data Manager:  Matt Poquadeck 
                          University of Rochester Medical Center
                          601 Elmwood Avenue, Box 704
                          Rochester, NY 14642
                          Phone: (585)   273-2590
Statistician:  Charles E. Heckler, Ph.D., M.S.
                     University of Rochester Medical Center
                     265 Crittenden Blvd, Box 658
                     Rochester, NY 14642
                     Phone: (585) 273-1141
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for the guidance of 
the clinical investigation.  Reproduction or disclosure of this document - whether in part or in full - to 
parties not associated with the clinical investigation, or its use for any other purpose, without the prior 
written consent of the Principal Investigator is not permitted.
Throughout this document, symbols indicating proprietary names ( , TM) are not displayed.  Hence, the appearance of 
product names without these symbols does not imply that these names are not protected.
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Synopsis
Title
Regorafenib in Adults ≥ 65 Years with Metastatic Colorectal Cancer:  A 
Phase II Study
Clinical study phase
Phase II
Primary study objective
To assess grade 3-5 toxicity rates of regorafenib in older adults with 
implementation of focused education and support initiatives
Indication
Refractory metastatic colorectal cancer (mCRC)
Diagnosis and main criteria for 
inclusion
1. Histologically or cytologically confirmed colorectal carcinoma
2. Evidence of measurable (by RECIST criteria) metastatic disease
3. Age 65 years or over
4. Progression of disease on previous therapy, deemed not a   
  candidate for further standard therapy by treating oncologist, or patient
  declines other options  
5. ECOG PS 0-1
Study design
Single-arm, open label Phase II study
Type of control
Historical 
Number of subjects
60
Plan for statistical analysis
Adverse events will be grouped by system organ class and graded 
using NCI CTCAE version 4.0.  Descriptive statistics for grade 3/4 
toxicity rates and all-grade skin (HFS) toxicity will be assessed.  
Relative dose intensity for regorafenib will be calculated.
Based on expected grade 3-4 toxicity rates of 40-50%, a sample size of 
60 patients will give approximately 10% margin of error with 95% 
confidence interval.
Secondary outcomes for efficacy will be response rate (RR), 
progression-free survival (PFS) and overall survival (OS).  Kaplan-
Meier curves will be used to estimate median PFS and OS.
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Table of Contents
   Page
Title page………………………………………………………………………………………1
Synopsis……………………………………………………………………………………......4
Table of Contents………………………………………………………………………………5
List of abbreviations…………………………………………………………………………...7
1. Introduction………………………………………………………………………………..9
Background……………………………………………………………………………9
Rationale of the study………………………………………………………………....9
Regorafenib…………………………………………………………………………..10
Preclinical…………………………………………………………………………….10
Clinical experience…………………………………………………………………...10
Comprehensive Geriatric Assessment………………………………………………..11
2. Study objectives…………………………………………………………………………..14
3. Investigator[s] and other study participants………………………………………………14
4. Study design………………………………………………………………………………15
5. Study population / Eligibility / Re-Screening……………………………………………15
Inclusion criteria……………………………………………………………………...15
Exclusion criteria……………………………………………………………………..16
Excluded therapies and medications, previous and concomitant…………………….18
6. Withdrawal of subjects from study……………………………………………………….18
Withdrawal…………………………………………………………………………...18
Screen failures/withdrawals………………………………………………………….19
Replacement………………………………………………………………………….19
7. Treatment[s]………………………………………………………………………………19
Treatments to be administered……………………………………………………….19
Treatment assignment………………………………………………………………..19
Regorafenib………………………………………………………………….19
Study treatment……………………………………………………………...20
Dose modification levels…………………………………………………….20
8. Prevention/management strategies for diarrhea, hand-foot skin reactions, hypertension, 
and liver function test abnormalities……………………………………………………...22
Diarrhea……………………………………………………………………………....22
Hand-foot skin reactions……………………………………………………………..22
Hypertension…………………………………………………………………………24
Liver function abnormalities…………………………………………………………26
9. University of Rochester [UR] site administration………………………………………..27
Distribution of study documents to enrolling sites…………………………………..27
Study monitoring and auditing………………………………………………………28
Essential study documentation………………………………………………………28
Drug logistics and accountability……………………………………………………29
Accountability………………………………………………………………29
Destruction and return………………………………………………………29
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Subject information and consent…………………………………………………….30
Registration and data handling……………………………………………………....31
10. Treatment compliance…………………………………………………………………....31
Prior and concomitant therapy……………………………………………………….31
Follow-up Period……………………………………………………………………..33
Timing of Assessments……………………………………………………………....34
Medical History……………………………………………………………………...37
Efficacy……………………………………………………………………………...37
11. Safety…………………………………………………………………………………….37
Adverse Events……………………………………………………………………...37
Definitions…………………………………………………………………………..38
Classifications for adverse event assessment……………………………………….39
Seriousness…………………………………………………………………39
Intensity…………………………………………………………………….39
Causal relationship…………………………………………………………40
Action taken with study treatment………………………………………….40
Other specific treatment(s) of adverse events……………………………...41
Outcome……………………………………………………………………41
Assessments and documentation of adverse events………………………………...41
Reporting of serious adverse events………………………………………………..41
Expected adverse events……………………………………………………………43
Adverse events of special safety interest…………………………………………...43
Pregnancies…………………………………………………………………………43
Further safety……………………………………………………………………….44
Appropriateness of procedures/measurements……………………………………..44
Safety analysis……………………………………………………………………...44
12. Statistical methods and determination of sample size…………………………………..44
Statistical and analytical plans……………………………………………………...44
Determination of sample size……………………………………………………….45
13. Premature termination of the study……………………………………………………...45
14. Ethical and legal aspects…………………………………………………………………46
15. Publication policy……………………………………………………………………….46
16. Confidentiality…………………………………………………………………………..47
17. Reference list…………………………………………………………………………….48
18. Appendices………………………………………………………………………………51
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List of abbreviations
ADL
Activities of Daily Living 
ALT
Alanine aminotransferase
Ang
Angiopoietin
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BID
bis in die, twice daily
B-Raf
B isoform of Rapidly Accelerated Fibrosarcoma protein
BUN
Blood Urea Nitrogen
c-KIT
Stem Cell Factor Receptor Tyrosine Kinase
CR
Complete Response
C-RAF
C isoform of Rapidly Accelerated Fibrosarcoma protein
CTCAE
Common Terminology Criteria for Adverse Events
DCE
Dynamic Contrast Enhanced
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor
ERK
Extracellular Signal-regulated Kinases
FDA
Food and Drug Administration
FGFR
Fibroblast Growth Factor Receptor
FLT3
FMS-like Tyrosine Kinase 3
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HCC
Hepatocellular Carcinoma
HFSR
Hand-foot-skin reaction
IB
Investigator’s Brochure
IC
50
Half Maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IR
Immediate Release
IRB
Institutional Review Board
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MAPK
Mitogen Activated Protein Kinase
MEK
MAP Kinase / ERK Kinase 1
NM
Nano molar
NYHA
New York Heart Association
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
PTT
Partial thromboplastin time
QD
quaque die, once daily
RAF
Rapidly Accelerated Fibrosarcoma
RAS
Rat sarcoma
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria for Solid Tumors
RET
Rearranged during transfection
RTK
Receptor Tyrosine Kinase
SAE
Serious Adverse Event
SD
Stable Disease
SUSARs
Suspected Unexpected Serious Adverse Reactions
TIE2
Tyrosine kinase with Immunoglobulin and Epidermal Growth Factor 
(EGF) homology domain 2
TK
Tyrosine Kinase
TTP
Time to Progression
VEGF
Vascular Endothelial Growth Factor
VEGFR
Vascular Endothelial Growth Factor Receptor
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1. Introduction
Background
More than half of all patients diagnosed with colorectal cancer are above the age of 65.  Yet, 
only about 20% of patients in this age group were enrolled in the clinical trials on which our 
treatment decisions are based.  Furthermore, it is well-established that adverse events and 
diminished quality of life are more likely to accompany treatment in this age group.  This lack of 
data leads to variations in treatment patterns among older adults making them less likely to 
receive standard therapies.  It is therefore important to design trials specifically for older patients 
which incorporate tools to measure health status factors that can be used to identify patients most 
likely to benefit from treatment.
Rationale of the study
Limited evidence exists to guide risks and benefits of the multi-kinase inhibitor, regorafenib, in 
the older adult.  Participants in the Phase III CORRECT trial that led to approval of regorafenib 
in previously treated mCRC had a median age of 61.  The small number of older patients (38 
subjects ≥ 75 years of a total n=503) in this study had a disproportionately higher risk of any ≥ 
grade 3 toxicities (66% for ≥ 75 years vs. 52% for < 65 years).  More safety information is 
needed – especially since many older patients are not candidates for combination cytotoxic 
chemotherapy and may be candidates for the use of regorafenib earlier in the course of the 
disease than their younger counterparts.
The management of older colon cancer patients must be tailored to the patient’s overall 
functional status, risk of toxicities and comorbidities.  Advanced age alone should not preclude 
patients from receiving standard anti-cancer therapy and the patient’s physiologic age should 
guide treatment decisions.  Tools such as the Comprehensive Geriatric Assessment (CGA) which 
is incorporated in this study need to be developed to aid the oncologist and patient in the shared 
decision process of treatment planning.
A special focus of this study will be to provide intensive education and support for preventing 
and managing skin toxicity (hand-foot syndrome) along with other common toxicities.  This will 
be done according to standard guidelines developed by the sponsor.  It is known that the elderly 
are particularly vulnerable to toxicities and we feel it is important that close and regular 
monitoring is provided for all participants in the study.  Our hope is that this study will serve as a 
model for use of regorafenib in the geriatric patient population.
This study is timely because the use of combination cytotoxic chemotherapy (FOLFOX or 
FOLFIRI) versus monotherapy remains an issue of active debate in the management of older 
patients with metastatic colon cancer.  The FOCUS2 trial, the largest randomized clinical trial in 
older patients with metastatic colon cancer, was recently published.  The study randomized older 
patients with untreated metastatic colon cancer to capecitabine/5-FU with or without oxaliplatin 
with an initial empiric 20% dose reduction.  The addition of oxaliplatin resulted in improved 
response rates and a trend towards improvement in PFS but no improvement in OS.  The rate of 
grade 3 or higher toxicity was not increased with the addition of oxaliplatin at this lower dose.  
For now, the benefit of combination chemotherapy for adults ≥ 65 years of age is questionable 
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and considered on an individual patient basis.  Additional treatment options, such as regorafenib, 
would be helpful and need to be evaluated carefully in this patient population.
Regorafenib 
Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic activity as 
measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI). 
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.  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.
Preclinical
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 growth in multiple xenograft models (breast, colon, renal, NSCLC, melanoma, 
pancreatic, thyroid, ovarian).  Immunohistochemical ex-vivo studies with a phospho –specific 
monoclonocal 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.  These data suggest that regorafenib can target the 
tumor cell MAPK pathway (tumor cell survival) and tumor vasculature in some but not all 
tumors.
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 had progressed 
after approved standard therapies. 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 
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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 (versus placebo) group were hand–
foot skin reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and 
hypertension (7%).  The efficacy and safety results from the CORRECT study supported FDA 
approval in September 2012.
The regorafenib treatment arm in the CORRECT study included 309 patients < 65 years (307 
evaluable for safety), 155 patients 65-74 years and 38 patients ≥ 75 years.  The OS hazard ratio 
was 0.72 (95% CI 0.56-0.91) in patients <65 years and 0.86 (95% CI 0.61-1.19) in patients ≥ 65 
years.  The rate of grade ≥ 3 adverse events was 52% for patients <65 years, 57% for patients 65-
74 years and 66% for patients ≥ 75 years.  Dose modification was necessary for 76% of patients 
< 65 years, 73% for patients 65-74 years and 84% for patients ≥ 75 years.  This underscores the 
importance of close monitoring and good supportive care for older patients on regorafenib.
Comprehensive Geriatric Assessment
All participants will undergo an abbreviated cancer-specific comprehensive geriatric assessment 
(CGA) at baseline, at 4 weeks , and then every 3 months while on study (+/- 7 days). Common 
assessment instruments in oncology (e.g. Karnofsky performance status) do not address critical 
geriatric domains that predict morbidity and mortality in the older patient (e.g., functional status, 
comorbidity and social support).  A prospective study of 500 older adults with cancer 
demonstrated that traditional oncology functional assessment tools could not identify older adults 
at risk for chemotherapy toxicity.  However, a predictive model that includes geriatric 
assessment questions could identify such individuals.  
This validated cancer-specific CGA includes a compilation of reliable and validated tools to 
assess geriatric domains such as comorbidity, functional status, physical performance, cognitive 
ability, psychological state, nutrition, medication review and social support.  The CGA can 
detect unsuspected conditions that may affect cancer treatment in more than 50% of older 
patients.  Repetto et al. demonstrated that CGA added information to standard oncology 
performance measures such as Karnofsky performance score which is a one-item measure of 
function that was validated in younger patients.  CGA has great potential to identify areas of 
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vulnerability and interventions that could help improve outcomes (e.g. reducing therapy-related 
toxicity) in older cancer patients.  The initial study of this tool illustrated feasibility as 
demonstrated by a short mean time to completion of 27 minutes.  Furthermore, 90% of patients 
were satisfied with the questionnaire length, and 78% were able to complete the self-
administered portion on their own.  
The abbreviated cancer-specific CGA was also found to be feasible for use by the Cancer and 
Aging Leukemia Group-B (CALGB 360401).  Previous clinical studies, including the FOCUS2 
trial, have demonstrated that factors within a CGA can better assess toxicities and aid with 
management decision.  Based on these data, therefore, our study will incorporate CGA to assess 
the relative safety profile of regorafenib in the elderly population.  The specific instruments used 
in our study have been slightly modified from the CGA data published by Hurria et al but 
address identical geriatric domains of interest.  This CGA format is currently used in the 
SOCARE (Specialized Oncology Care and Research in the Elderly) multi-disciplinary clinic 
based at the University of Rochester Medical Center that is run by Dr. Supriya Mohile.  Staff at 
all sub-sites will be trained to conduct the CGA in a similar and replicable manner.  This training 
will be overseen by Dr. Mohile and her experienced staff.
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COMPREHENSIVE GERIATRIC ASSESSMENT
ADL: Activity of daily living 
GDS:  Geriatric Depression scale
MNA: Mini nutritional assessment
IADL: Instrumental activity of daily living
SPPB: Short physical performance battery 
BOMC: Blessed orientation-memory-concentration
BMI: Body mass index 
FACT-C: Functional Assessment of Cancer Therapy-Colon
VES: Vulnerable elderly survey 
FACT-F:  Functional Assessment of Cancer Therapy-Fatigue
MDASI: MD Anderson Symptom Inventory
DOMAIN
TOOL 
SCORE SIGNIFYING 
IMPAIRMENT
Background 
Information
Demographics:
Education
Marital status
Living Arrangements
Health status
Employment status
Driving status
Age
Zip code
Gender
Ethnicity
Race
Insurance/health care
Income
Social Services
Physical function 
ADL
IADL
Fall history
Any ADL or IADL 
impairment
Any history of fall
Objective physical      
performance 
SPPB 
 ≤ 9
Comorbidity
Average number of 
comorbid conditions
>5
Nutrition
BMI
MNA
<21
≤ 11
Social support
OARS Medical Social 
Support
Any deficit noted
Polypharmacy
Number of total 
medications
≥5 medications
Psychological
GDS
> 5
Cognition
BOMC
Mini Cog
>10
abnormal
Screening
VES-13
≥3
Quality of Life
FACT-C
FACT-F
MDASI
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2. Study objectives
Primary Objective
To measure grade 3-5 toxicity of regorafenib in older adults with mCRC with 
implementation of focused education and support initiatives
Secondary Objectives
To evaluate efficacy of regorafenib in older adults with mCRC (RR, PFS, DCR and OS)
To explore association between baseline CGA findings and risk of toxicities
To explore the association of toxicities with CGA domain changes over time
To assess patient-reported QOL on regorafenib over time
3. Investigator[s] and other study participants
Co-Principal Investigator: Aram Hezel, MD (Medical Oncology)
University of Rochester Medical Center
601 Elmwood Avenue, Box 704
Rochester, NY 14642
Co-Principal Investigator:  Supriya G. Mohile, MD, MS (Medical Oncology)
                                                University of Rochester Medical Center
                                                601 Elmwood Avenue, Box 704
                                                Rochester, NY 14642
Co-Investigators:                 Joleen M. Hubbard, MD (Medical Oncology)
                                               Mayo Clinic, Rochester
                                               200 First St SW
                                               Rochester, MN 55901
                                               Efrat Dotan, MD (Medical Oncology)
                                                Fox Chase Cancer Center
                                                333 Cottman Avenue
                                                Philadelphia, PA 1911
                                               
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4. Study Design
Given 54% grade 3/4 toxicity and required dose modification among 76% of patients in the 
regorafenib arm (randomized phase III CORRECT trial), we will initiate treatment at a reduced 
dose of 120mg in this geriatric study population on a similar 3 weeks on/1 week off schedule.  
Dose escalation to 160mg will be recommended after the first cycle (4 weeks) at the discretion of 
the treating physician.  There is good precedent for starting at reduced doses in similar trials – 
the FOCUS2 study team utilized 80% starting chemotherapy doses in their study among the 
elderly with metastatic CRC and dose escalated if tolerated.
Participants will undergo a comprehensive geriatric assessment (CGA) at baseline, at 4 weeks 
and then every 3 months (+/- 7 days) while on study to assess for any deterioration in geriatric 
domains (functional status, comorbidities, nutrition, psychological state, social support and 
cognitive ability).  All sites have personnel experienced in performing geriatric assessments and 
the University of Rochester as the lead site will conduct training to ensure that all sites will 
conduct the assessments in the same way.  
All patients will receive intensive one-on-one education about prevention/management of skin 
toxicity, diarrhea, fatigue and other toxicities at initiation and follow-up visits (see section 7 & 8 
for review of treatment strategies).  Starter packs with moisturizing cream (10% urea content), 
socks and patient-friendly ‘Tips for Skin Care’ will be distributed.  On-treatment visits will occur 
weekly for first two cycles and every 4 weeks after that.  Alternate weekly visits may be 
substituted with a home nursing visit for BP check and symptom evaluation if it is not feasible 
for patient to attend clinic visits weekly.  Pill adherence diaries will be provided to patients and 
pill counts will be performed at the end of every cycle. 
Restaging CT/MRI scans will be completed every 12 weeks (+/- 7 days) (or sooner if treating 
oncologists suspects progression of disease based on clinical symptoms).  Radiographic disease 
progression is defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (see 
Appendix A).  Subjects will have a Safety Follow-up visit within 30 days after their last dose of 
study drug or prior to the initiation of another antineoplastic therapy, whichever occurs first.  
After treatment discontinuation, survival status will be assessed periodically (see Table of 
Assessments).
5. Study Population / Eligibility/Re-Screening
Re-screening may be allowed. Subjects who are re-screened must be consented as if they were a 
new patient. If a patient re-screens, they will be assigned a new subject ID when entered into Red 
Cap.
Inclusion Criteria
Histologically or cytologically confirmed colorectal adenocarcinoma
Evidence of measurable (by RECIST criteria) metastatic disease
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Age 65 years or over
Progression of disease on standard therapy or deemed not a candidate for further 
chemotherapy by treating oncologist or patient declines other options.
ECOG PS 0-1
Life expectancy of at least 3 months.
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.
Adequate bone marrow, kidney and liver function as assessed by the following laboratory 
requirements:
o Total bilirubin ≤ 1.5 x the upper limits of normal (ULN).
o Alanine aminotransferase (ALT) and aspartate amino- transferase (AST) ≤ 2.5 x 
ULN (≤ 5 x ULN for subjects with liver involvement of their cancer).
o Alkaline  phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver 
involvement of their cancer).
o   Creatinine ≤ 1.5 x the ULN.
o International normalized ratio (INR)/ Partial thromboplastin time (PTT) ≤ 1.5 x 
ULN. 
Platelet count ≥ 100000 /mm3, hemoglobin (Hb) 
≥ 9 g/dL, absolute neutrophil 
count (ANC) ≥ 1500/mm3.  Blood transfusion to meet the inclusion criteria will not 
be allowed.
Subjects (men) of childbearing potential must agree to use adequate contraception 
beginning at the signing of the ICF 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 or a designated associate.
Subject must be able to swallow and retain oral medication.
Exclusion Criteria
 Previous treatment with regorafenib.
Systemic therapy for metastatic CRC within 28 days of initiating study treatment.
Previous assignment to treatment during this study.  Subjects permanently withdrawn 
from study participation will not be allowed to re-enter study. 
Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm 
Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal medical management.
Active or clinically significant cardiac disease including:
o Congestive heart failure – New York Heart Association (NYHA) > Class II.
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o Active coronary artery disease.
o Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers, 
calcium channel blockers or digoxin.
o Unstable angina (anginal symptoms at rest), new-onset angina within 3 months 
before randomization, or myocardial infarction within 6 months before 
randomization.
Evidence or history of bleeding diathesis or coagulopathy.
Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start 
of study medication. 
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.
History of other active malignancy within past 2 years (excluding non-melanoma skin 
cancer).
Patients with phaeochromocytoma.
Known history of human immunodeficiency virus (HIV) infection or current chronic or 
active hepatitis B or C infection requiring treatment with antiviral therapy.
Ongoing infection > Grade 2 NCI-CTCAE v4.0.
Symptomatic metastatic brain or meningeal tumors.
Presence of a non-healing wound, non-healing ulcer, or bone fracture.
Major surgical procedure or significant traumatic injury within 28 days before start of 
study medication.
Renal failure requiring hemo- or peritoneal dialysis.
Dehydration Grade >1 NCI-CTCAE v4.0.
Patients with seizure disorder requiring medication.
Persistent proteinuria  Grade 3 NCI-CTCAE v4.0 (> 3.5 g/24 hrs, measured by urine 
protein: creatinine ratio on a random urine sample).
Interstitial lung disease with ongoing signs and symptoms at the time of informed 
consent. 
Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version 
4.0 Grade 2 dyspnea).
  History of organ allograft (including corneal transplant).
  Known or suspected allergy or hypersensitivity to the study drug.
  Any malabsorption condition.
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  Any condition which, in the investigator’s opinion, makes the subject unsuitable for trial 
participation.
  Substance abuse, medical, psychological or social conditions that may interfere with the 
subject’s participation in the study or evaluation of the study results.
Excluded Therapies and Medications, Previous and Concomitant
Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) other than study treatment 
(regorafenib) being used for colon cancer.
Prior use of regorafenib.
Concurrent use of another investigational drug or device therapy (i.e., outside of study 
treatment) during, or within 28 days before start of study medication.
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
before start of study medication.
Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) or with heparins 
and heparinoids.
6.Withdrawal of Subjects from Study
Withdrawal
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.
If, in the investigator
's opinion, continuation of the trial would be harmful to the subject
's 
well-being.
Subject is lost to follow-up.
Death.
Subjects may be withdrawn from the study for 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.
Severe allergic reaction to regorafenib (such as exfoliative erythroderma or Grade 3 or 4 
hypersensitivity reaction).
The development of a second cancer. 
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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.
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject
's medical 
records.
Details for the premature termination of the study as a whole (or components thereof 
[e.g. centers, dose levels]) are provided in Section 13. Premature Termination of the Study).
Screen Failures/Withdrawals
A subject who discontinues study participation prematurely for any reason is defined as a 
“withdrawal” if the subject has already been assigned to treatment or administered at least one 
dose of study drug.
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “withdrawal” (see above) is regarded as a “screen 
failure”.
Replacement
No withdrawn subjects will be replaced. 
7. Treatment[s]
Treatments to be administered
All patients will receive regorafenib 120mg daily for 3 weeks on and 1 week off with cycle 1.  
Dose escalation to 160mg will be permitted after the first cycle at the discretion of the treating 
physician.  Subjects will continue study treatment until disease progression or other reasons for 
removal from treatment (section6).
Treatment assignment
Regorafenib
Regorafenib tablets will be packaged in high density polyethylene bottles with a white child 
resistant closure and induction seal.  Each bottle includes 28 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.
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Study Treatment
The initial screening period is 14 days from the date of consent. Once approved, by the 
coordinating site, an additional 14 day period is granted for scheduling, in which subjects must 
start treatment.
Regorafenib will be administered as monotherapy during the study.  120 mg qd (starting dose) 
will be administered for 3 weeks on /1 week off.  One cycle is 28 days. Study treatment must be 
initiated within 14 days of registration.
Three 40-mg regorafenib tablets (starting dose) should be taken once a day with approximately 8 
fluid ounces (240 mL) of water after a low-fat (<30% fat) meal.   Some examples of low fat 
meals are:
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.
Dose Modification Levels
The starting dose of regorafenib is 120 mg once daily.  Study medication will be administered on 
a 3 weeks on/1week off schedule [3 weeks out of every 4].
Dose escalation to 160mg is recommended after the first cycle (4 weeks) at the discretion of the 
treating physician.  
Doses will be held or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to protocol therapy according to the guidelines shown in the Dose 
Delays/Dose Modifications tables that follow.  Doses held for toxicity will not be made up but 
will be counted as missed doses.  Dose modifications will follow predefined dose levels. Sites 
may also follow their institutional practice for dose modifications.  Missed doses are to be 
omitted rather than made up.  Dose adjustments for hematologic toxicity are based on the blood 
counts obtained in preparation for the day of treatment.
The modifications of regorafenib will follow the following predefined dose levels:
Dose level +1
160mg po qd
Four 40-mg tablets of regorafenib
Dose level 0 (starting 
dose)
120 mg po qd
Three 40-mg tablets of regorafenib
Dose level - 1
80 mg po qd 
Two 40-mg tablets of regorafenib
Dose level - 2
40 mg po qd 
One 40-mg tablets of regorafenib
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If a subject experiences more than one toxicity, dose reduction should be according to the 
toxicity with the highest grade. 
In the case of two or more toxicities of the same grade, the investigator may dose reduce 
according to that deemed most causally related to study treatment.
If a dose reduction has been performed, intra-subject dose re-escalation can be considered (up to 
the maximal 160 mg daily dose) at the discretion of the treating physician provided that the 
toxicity(ies) has resolved to baseline.
The following tables outline dose adjustments for toxicities related to study drug other than 
diarrhea, hand-foot skin reaction, hypertension and liver function test abnormalities. More 
information on dose reductions for diarrhea, hand-foot skin reaction, hypertension, and liver 
function test abnormalities follows Table 7-1.
Table 7-1:  Recommended dose modification for toxicities except diarrhea, hand-foot-skin 
reaction, hypertension and ALT/ST/bilirubin
NCI-CTCAE v4.0a
Dose Interruption
Dose 
Modificationb
Dose for 
Subsequent Cycles
Grade 0-1
Treat on time
No change
No change
Grade 2c
Treat on time
No change
No change
Grade 3
Hold until ≤ Grade 2
c
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
Hold until ≤ Grade 2
c
Reduce by 1 dose 
level.
Permanent 
discontinuation
can be considered at
treating investigator’s
discretion.
a. NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events,
    version 4.0
b. Excludes alopecia, non-refractory nausea/vomiting, non-refractory hypersensitivity, and non-
clinically significant and asymptomatic laboratory abnormalities.
c. If subject is experiencing multiple grade 2 toxicities, treatment can be interrupted at discretion 
of treating oncologist until toxicities are ≤ grade 1 and then resumed at reduced dose (by 1 
level)
d. If no recovery after a 4 week delay, treatment should be permanently discontinued unless 
subject is deriving clinical benefit.
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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 in order to minimize the risk of postural 
hypotension and renal failure.
8.Prevention/Management Strategies for Diarrhea, Hand-Foot Skin 
Reaction, Hypertension, and Liver Function Test Abnormalities
Diarrhea
Diarrhea can be a common side effect of regorafenib.  The preventive/management strategies for 
diarrhea should be consistent with local standards (e.g., anti-diarrheals and optimized hydration 
status).
Anti-diarrhea medications may be introduced if symptoms occur.  Previous trials have shown 
that diarrhea can 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.
Hand-Foot Skin Reaction
Table 8-1: Grading for Hand-Foot-Skin-Reaction
Grade 1
Grade 2
Grade 3
NCI-CTCAE v4.0 
Palmar-plantar 
erythrodysesthesia 
syndromea
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 8-2 Recommended dose modification for hand-foot-skin reactiona
Grade of event 
(NCI-CTCAE v4.0)
Occurrence
Suggested Dose Modification
Grade 1
Any
Maintain dose level and reinforce supportive measures 
for symptomatic relief
1st occurrence
Interrupt therapy until toxicity resolves to Grade 0-1.
b, c 
When resuming treatment, treat at reduced dose level.
2nd occurrence
Interrupt therapy until toxicity resolves to Grade 0-1.
b, c
When resuming treatment, treat at reduced dose level.
Grade 2
3rd occurrence
Discontinue therapy
1st occurrence
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
Grade 3
2nd 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.
e. The maximum daily dose is 160 mg.
At first occurrence of HFSR, independent of grade, prompt reinforcement 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:
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.
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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
Hypertension
Hypertension is a known AE associated with regorafenib treatment.  Subject will have their 
blood pressure measured weekly during the first 8 weeks of treatment (either in the office or with 
nursing services).  
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 (NCI CTCAE v4.0), then the subject must 
contact study personnel.  
The management of hypertension, including the choice of antihypertensive medication, will be 
performed according to local 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 8-4 outlines suggested dose reductions.
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Table 8-3:  Management of Treatment-Emergent Hypertension
Grade 
(CTCAE v4.0)
Antihypertensive Therapy
Regorafenib Dosing
1
Prehypertension (systolic 
BP
120 - 139 mmHg or 
diastolic
BP 80 - 89 mmHg)
None
Continue regorafenib
Consider increasing blood pressure 
(BP) monitoring
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.
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
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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Liver Function Abnormalities
For patients with observed worsening of  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 8-5 should be followed.
Regorafenib is a UGT1A1 inhibitor.  Mild, indirect (unconjugated) hyperbilirubinemia may
occur in patients with Gilbert’s syndrome.
Table 8-4: Dose Modification/interruption for alanine aminotransferase and/or aspartate 
aminotransferase increases related to study drug
Increases in 
ASL/ALT (per NCI-
CTCAE v 4.0)
1st Occurrence
Restart
Recurrence
AST and/or ALT < 5 
X ULN (<Grade 3)
Continue dosing, with 
weekly monitoring of 
liver function until 
transaminases return 
to < 3 X ULN (< 
Grade 1) or baseline.
ALT and/or AST > 5 
X ULN (> Grade 3)
Interrupt dosing, with 
weekly monitoring 
until transaminases 
return to < 3 X ULN 
or baseline.
If the potential 
benefit of reinitiating 
regorafenib is 
considered to 
outweigh the risk of 
hepatotoxicity: 
reduce 1 dose level 
and measure   
transaminases weekly 
for at least 4 weeks.
Discontinue
ALT and/or AST > 
20 X ULN (> Grade 
4)
Discontinue
ALT and/or AST > 3 
X ULN (> Grade 2) 
with concurrent 
bilirubin > 2 X ULN
Discontinue treatment 
and measure   
transaminases weekly 
until resolution. 
Exception: subjects 
with Gilbert
's 
syndrome who 
develop elevated 
transaminases should 
be managed as per the 
recommendations 
outlined above for 
ALT/AST elevations.
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9.  University of Rochester [UR] Site Administration
The Wilmot Cancer Institute, Clinical Trials Office at the University of Rochester will serve as 
the Coordinating Center for this multi-site study. The lead PI of the Coordinating Center is 
affiliated with the UR and is also the UR enrolling site PI. Both the lead PI and Coordinating 
Center will assume responsibility for the overall conduct and management of the study, including 
the following responsibilities:
Ensure all approval of protocol documents, including model consent forms are 
distributed to enrolling sites and approved by enrolling site IRBs prior to 
implementation.
Maintain a regulatory file for the Coordinating Center and for each enrolling site.
Monitor subject enrollment and participation.
Ensure informed consent is obtained from each subject and consent is in 
compliance with federal, state and local regulations, as well as the study protocol.
Ensure compliance with the study protocol (including timely reporting of all 
research events) and data validity and integrity.
Convey study-related information to enrolling sites, sponsors and study-specific 
committees, as needed.
Respond to enrolling site protocol inquires and questions.
Provide enrolling site staff continued training on the conduct of the study, as 
necessary.
Ensure all enrolling sites are notified when enrollment is complete, and all study-
related activities are complete.
Verify each enrolling site closed the study with their IRB.
Ensure the data set and any stored samples are appropriately de-identified or 
coded and managed per the study protocol.
Distribution of Study Documents to Enrolling Sites and Obtaining Enrolling Site 
IRB Approval
Protocol documents (submitted both at the time of initial approval and via amendment) should be 
submitted and approved by the Coordinating Center’s IRB prior to distribution to enrolling sites. 
Once enrolling sites receive the study documents, they then must submit applications to their 
respective IRB for approval prior to initiation of the study at their site. 
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Any changes to protocol documents requested by the enrolling site and/or their IRB should be 
reviewed and approved by the Coordinating Center prior to re-submission to the enrolling site’s 
IRB. Any substantive changes to study documents by the enrolling site should be appropriately 
justified. Every effort should be made to avoid changing the protocol for individual enrolling 
sites; however, in certain circumstances it may be appropriate for sites to include site-specific 
addendums in order to comply with their institution’s policies and procedures. Editorial changes 
to the consent form are also generally permissible as long as they do not change the content or 
intent of the document. 
Once the study and/or amendment has been approved by the enrolling site IRB, a copy of the 
approval notification and all related approved study documents must be provided to the 
Coordinating Center prior to initiation of the study at the enrolling site.
Study Monitoring & Auditing
All aspects of the study will be monitored closely by the site PI’s, the Coordinating Center and 
the Sponsor.  Monitoring will be conducted according to GCP and standard operating procedures 
for compliance with applicable government regulations. As a participating site, the Investigator 
grants permission to the Coordinating Center and/or appropriate regulatory authorities to conduct 
routine remote monitoring and/or on-site monitoring of all appropriate study documentation if 
requested. 
Inspections by regulatory health authority representatives i.e. FDA and IEC(s)/IRB(s) can occur 
at any time during or after completion of the study.  The investigator should notify the 
Coordinating Center immediately of any such inspection. 
Documentation of monitoring will be maintained by the Coordinating Center.
Essential Study Documentation
The Coordinating Center will be responsible for maintaining essential documentation for the 
Coordinating Center as well as for the enrolling sites. These essential documents permit the 
conduct of the study and demonstrate compliance with the protocol and regulatory requirements. 
Copies of all regulatory documents from each enrolling site should be scanned and emailed to:  
Cynthia_Doane@urmc.rochester.edu. The regulatory team at the Coordinating Center will track 
and monitor these documents.
Examples of these documents include but are not limited to:
Dated IRB approval notifications for site protocols, informed consent forms, recruitment 
materials, and case report forms (including initial approvals, amendments and progress 
reports); include all approved versions;
Signed clinical trial agreements between all involved parties;
Signed and dated CVs;
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Investigational product label samples, handling instructions, shipping records and 
accountability records;
All versions of the Investigator’s Brochure, if applicable;
Monitoring reports; and
Reportable research events.
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice.
Drug logistics and accountability
The drug will be shipped directly to the Investigational Pharmacy at the Coordinating Center, 
which will in turn dispense the medication to the other enrolling sites.
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.
Accountability
The investigator at each site or a responsible party designated by the investigator must maintain a 
careful record of the inventory and disposition of the agent, including dates and lot numbers of 
all study drug received.  All study drug supplies issued to, used by, and returned by each patient 
must be recorded using the NCI Drug Accountability Record or another comparable drug 
accountability form. (See the CTEP website at http://ctep.cancer.gov/protocolDevelopment for 
the “Policy and Guidelines for Accountability and Storage of Investigational Agents” or to 
obtain a copy of the drug accountability form.)
Destruction and Return
At the end of the study, unused supplies of Regorafenib, opened or unopened should be 
destroyed according to institutional policies in accordance with the requirements outlined in the 
study contract ONLY after study drug accountability has been completed and with approval of 
the study PI. Destruction will be documented in the Drug Accountability Record Form. The 
certificate of destruction should be sent to the Coordinating Center.  
A completed “Unused Study Drug Disposition Form Destruction or Return Confirmation” 
should be sent to the Coordinating Center.  The Coordinating Center will ensure all forms from 
sites are sent to Bayer at the following address:  
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Bayer:
E-mail: Karen.marini@bayer.com
  OR
Mail: (VP of Medical Affairs named in contract) at
Bayer HealthCare Pharmaceuticals
100 Bayer Boulevard
Whippany, NJ 07981
UR Coordinating Center Pharmacy Contact:
Noel Forrett, Pharm D
University of Rochester
Cancer Center Pharmacy, Room 1.0773
601 Elmwood Avenue
Rochester, NY 14642
Phone: 585-275-6357
Fax: 585-292-1701
Email: Noel_Forrett@urmc.rochester.edu
Subject information and consent
Patients must be informed of the investigational nature of this study and must sign and give 
written informed consent in accordance with institutional and federal guidelines. Voluntary 
written informed consent must be obtained before registration or performance of any study-
related procedure not part of normal medical care.
Each subject will have ample time and opportunity to ask questions and will be informed about 
the right to withdraw from the study at any time without any disadvantage and without having to 
provide reasons for this decision.
Only if the subject voluntarily agrees to sign the informed consent form and has done so, may 
he/she enter the study.  Additionally, the investigator and other information provider (if any) will 
personally sign and date the form.  The subject will receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed consent 
was obtained prior to these procedures.
The informed consent form and any other written information provided to subjects will be 
revised whenever important new information becomes available that may be relevant to the 
subject’s consent, or there is an amendment to the protocol that necessitates a change to the 
content of the subject information and / or the written informed consent form.  
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The Coordinating Center will first approve consent form/amendment changes through their IRB 
and once approved, will distribute to enrolling sites. Once these changes have been approved by 
the enrolling site IRB, a copy of the approval notification and all related approved study 
documents must be provided to the Coordinating Center prior to use. The investigator will 
inform the subject of changes in a timely manner and will ask the subject to confirm his/her 
participation in the study by signing the revised informed consent form.  
Registration and Data handling
All patients will be registered through the Coordinating site, Clinical Trials Office, which is 
located at the:
James P. Wilmot Cancer Institute
University of Rochester Medical Center
Rochester, NY 14642
Each site will receive access to the study-specific, REDCap database at the University of 
Rochester. 
It is the expectation that all data has source documentation available at the enrolling sites.  Site 
personnel will be responsible for entering their patient data regularly into this database.  
At the time of registration, the signed informed consent form and documents that support 
eligibility should be emailed in pdf format to the data manager, Matt Poquadeck, at the 
Coordinating Center: matt_poquadeck@urmc.rochester.edu. 
The signed consent form and supporting documents can also be faxed to the Coordinating Center 
at (585) 442-0137. Please inform the data manager by email that the eligibility forms have been 
faxed.
Any question regarding eligibility or that may arise during the conduct of the study should be 
addressed to:
Name: 
Aram Hezel, MD
Email: 
Aram_Hezel@urmc.rochester.edu
Phone:   (585) 275-9484
10.Treatment compliance
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 principal investigator, a subject may be discontinued from the trial for non-compliance 
with follow-up visits or study drug.
Prior and concomitant therapy
All medication that is considered necessary for the subject’s welfare may be given at the 
discretion of the investigator.  All medications (including contrast media) taken within 2 weeks 
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prior to the start of the study and during the study must be recorded in the subject’s source 
documentation and in the CRF (including start/stop dates, dose frequency, route of 
administration, and indication).  Specific caution should be taken when considering or 
administering a concomitant medication that is metabolized by the cytochrome enzymes 
CYP2C8, CYP2B6 and CYP2C9.  Such concomitant medication should be avoided, if possible.
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).
Permitted concomitant therapy includes:
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 10% of the bone marrow is irradiated.
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.
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
The following are not permitted:
Other investigational treatment during or within 28 days before starting study treatment
Systemic antitumor therapy, including cytotoxic therapy, signal transduction inhibitors, 
immunotherapy, and hormonal therapy for colorectal cancer
Bone marrow transplant or stem cell rescue
Subjects taking narrow therapeutic index medications should be monitored proactively 
(e.g. phenytoin, quinidine, carbamazepine, Phenobarbital, cycloosporin, and digoxin).  
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Liver function tests should be obtained before initiation of regorafenib and monitored at 
least every 2 weeks during first 2 months of treatment.  Thereafter liver function should 
be monitored monthly or more frequently as clinically indicated
Follow-up Period
Follow-up Prior to Progression
Patients who come off treatment for reasons other than progression of disease will have 
physical exams performed at least every 3 months or earlier as clinically indicated until 
the follow-up period is terminated (see Reasons for Follow-up Termination).  Frequency 
of radiographic studies will be at the discretion of the treating physicians.
After disease progression, follow-up assessments will occur every 6 months and will 
include subsequent anti-neoplastic therapy and survival status of the patient until the 
follow-up period is terminated (see Reasons for Follow-up Termination).  Physical 
exams, and all other assessments, are at the discretion of the treating physicians.
Reasons for Follow-up Termination
Patients will remain in the follow-up period until any of the reasons below are satisfied:
Completion of the study
Patient death
Patient withdraws consent from the follow-up period
Patient is lost-to follow-up
Termination of Follow-up
Patients whose follow-up period terminates should have the final date of contact recorded in the 
End of Study CRF in REDCap.
For patients in follow-up at completion of the study, please use the study termination date
Patients found to be deceased in the follow-up period should have their date of death 
recorded in the End of Study CRF.
For patients who withdraw consent from follow-up, use the date the patient withdrew 
consent.  Notify the Coordinating Center’s data manager of the patient withdrawal of 
consent from follow-up, along with supporting documentation, should this occur.
For patients who meet the criteria to be lost-to follow-up, enter the last date of known 
contact with the patient, along with comments in the CRF indicating the patient is lost-to 
follow-up.
Lost-to Follow-up
All efforts should be made to assess the survival status of each patient until the follow-up period 
is terminated.  A patient will be considered lost-to follow-up when 1) the patient is due for a 
follow-up contact as per the Table of Assessments, and 2) at least 2 attempts to contact the 
patient have occurred since the follow-up was due.  Documentation of these 2 attempts should be 
sent to the Coordinating Center’s data manager (see Registration and Data Handling).
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Timing of assessments
See Table of Assessments
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Cycle 1
Cycle 2
Cycle 3
Cycle 4
PRE
W
W
W
W
W
W
W
W
W
W
W
W
W
W
W
Wb
     Study Day 
a
STUDYk
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
FU Prior to 
Progressionc
Safety FU
30 days 
after last 
treatment 
dose 
FU After 
Progressiond
REQUIRED STUDIES
PHYSICAL
History and Physical 
Exame
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and 
Performance Statuse
X
X
X
X
X
X
X
X
X
X
X
X
Blood Pressuree
X
X
X
X
X
X
X
X
X
X
X
X
Disease Assessment
X
X
X
X
X
Toxicity 
Evaluation/Supporte
X
X
X
X
X
X
X
X
X
X
X
Comprehensive 
Geriatric Assessmentf
X
X
X
Pill count
X
X
X
X
LABORATORYL
CBC/Differential 
X
X
X
X
X
X
X
XJ
X
Comprehensive 
Metabolic Panelg
X
X
X
X
X
X
X
XJ
X
- Phosphorus
X
X
X
X
X
X
X
XJ
X
INR
X
aPTT
X
SCANS
CT/MRI of Chesth
X
X
X
CT/MRI of Abdomen 
and Pelvish
X
X
X
TREATMENT
Regorafenibi
X
X
X
X
X
X
X
X
X
X
X
X
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a Except for week 1 visit, there is a window of +/- 5 days for subsequent follow up visits. 
b Patients with stable disease and on protocol treatment beyond cycle 4 will be followed every 4 weeks until disease progression.
c Patients off protocol treatment secondary to reasons other than progression will have physical exams performed at least every 3 months or earlier as clinically indicated until closure 
of the study.  Frequency of radiographic studies will be determined by the treating physicians.
d After disease progression subsequent anti-neoplastic therapy and survival status will be assessed every 6 months for the remainder of the study or until death.
e Alternate weekly visits may be substituted with a home visit or phone call for BP check and symptom evaluation if it is not feasible for patients to attend clinic visits weekly.  
f Comprehensive geriatric assessment (CGA) will be performed at baseline, at 4 weeks, and then every 12 weeks during the study protocol  (+/- 7 days). The baseline CGA can be 
performed at the week 1 visit prior to dispensing Regorafenib. These questionnaires can be completed at the study visit or given to the patient to take home, complete, and send back, 
or mailed to the patient to be completed prior to the next visit. 
g CMP to include Sodium (Na), Potassium (K), Chloride (Cl), Bicarbonate (HCO3), Blood Urea Nitrogen (BUN), Creatinine (Cr), Glucose, Calcium (Ca), Magnesium (Mg), Total Protein, 
Albumin, Alkaline Phosphatase, Total Bilirubin, Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST).
h Pre-study imaging must have been completed within 30 days prior to registration.  Restaging imaging will be performed every 12 weeks (+/- 7 days) when patients are on protocol 
treatment until disease progression and is defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
i
 Treatment will be given 3 weeks on/1 week off and will continue until disease progression or other reason for discontinuation of protocol treatment. 
J Lab work is required every 4 weeks after cycle 4 as long as patient remains on study
k Initial screening period is 14 days from the date of consent.  Once approved, by the coordinating site, an additional 14 day period is granted for scheduling, in which subjects must 
start treatment 
L Pre study labs can be used for week 1.
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Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria listed 
below will be collected:
Not pertaining to the study indication.
Started before signing of the informed consent.
Considered relevant to the study.
Detailed instructions on the differentiation between (i) medical history and (ii) adverse events 
can be found in Section 11 (Definitions).
Efficacy
Efficacy variables to be measured include response rate (RR), progression-free survival (PFS), 
disease control rate (DCR) and overall survival (OS).
Response rate (RR) is defined as the percentage of subjects with a partial response (PR) or 
complete response (CR) as defined by RECIST criteria (see Appendix A).  PFS will be measured 
from the date of randomization until disease progression or death from any cause.  DCR will be 
the rate of CR, PR and stable disease (SD) combined together.  OS will be measured from the 
date of randomization until death from any cause.
11. Safety
All subjects who receive at least one dose of study treatment will be valid for the safety analysis. 
All observations pertinent to the safety of the study treatment will be recorded and included in 
the final report.
Safety variables include the following: AEs, laboratory changes (complete blood counts, 
electrolytes, chemistry, and coagulation) and changes in vital signs (blood pressure, heart rate, 
respiratory rate, and temperature).
All AEs whether considered drug-related or not, will be reported in with a diagnosis, start/stop 
dates, action taken, whether treatment 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.
This trial will use the NCI-CTCAE v4.0 criteria for assessment of toxicity and SAE reporting 
with regard to toxicity grade.
Adverse events
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.
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Therapeutic monitoring should be performed following dose selection or 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.
All concomitant medications must be recorded in the subject’s source documentation.
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.
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
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 (however, the condition for which the surgery is required 
may be an AE if worsens compared to baseline).
Conditions that started before signing of informed consent and for which no symptoms or 
treatment are present until signing of informed consent are recorded as medical history 
(e.g. seasonal allergy without acute complaints).
Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis).
Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a. Results in death.
b. Is life-threatening.
The term ‘life-threatening’ in the definition refers to an event in which the patient was at 
risk of death at the time of the event, it does not refer to an event which hypothetically 
might have caused death if it were more severe.
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c. Requires inpatient hospitalization or prolongation of existing hospitalization.
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at 
least one of the following exceptions is met:
- The admission results in a hospital stay of less than 12 hours.
- The admission is pre-planned. 
(i.e. elective or scheduled surgery arranged prior to the start of the study)
- The admission is not associated with an AE.
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity.
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e. Is a congenital anomaly / birth defect.
f. Is another medically important serious event as judged by the investigator.
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories detailed 
below.
Seriousness
For each AE, the seriousness must be determined according to the criteria given in Section 11 
(Definitions).
Intensity
The intensity of the AE is classified according to the CTCAEv4.0.  Grade refers to the severity 
(intensity) of the AE:
CTCAEv4 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention is not indicated.
CTCAEv4 Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; 
limiting to age-appropriate instrumental activities of daily living (ADL; instrumental 
ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc).
CTCAEv4 Grade 3: Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization is indicated; disabling; limiting to self 
care ADL (self care ADL refers to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden).
CTCAEv4 Grade 4: life-threatening consequences; urgent intervention is indicated.
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CTCAEv4 Grade 5: death due to an AE.
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment is a 
clinical decision based on all available information.
The assessment is based on the question whether there was a “reasonable causal relationship” to 
the study treatment in question.
Possible answers are “yes” or “no”.
An assessment of “no” would include:
1. The existence of a clear alternative explanation, e.g. mechanical bleeding at surgical site.
or
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no indication 
that the drug caused disorientation that may have caused the event; cancer developing a 
few days after the first drug administration.
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is associated 
with the use of the study treatment.
Factors to be considered in assessing the relationship of the AE to study treatment include:
- The temporal sequence from drug administration:  The event should occur after the drug is 
given.  The length of time from drug exposure to event should be evaluated in the clinical 
context of the event.
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction (re-
challenge):
- Subject’s response after de-challenge or subjects response after re-challenge should be 
considered in the view of the usual clinical course of the event in question.
- Underlying, concomitant, intercurrent diseases:  
Each event should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the subject may have.
- Concomitant medication or treatment: 
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them may be suspected to cause the event in question.
- The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of the 
study treatment, coupled with the individual subject’s pharmacodynamics should be 
considered.
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories listed 
below.
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־Drug withdrawn
־Drug interrupted
־Dose reduced
־Dose not changed
־Not applicable
Other specific treatment(s) of adverse events
־None
־Remedial drug therapy
Outcome
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
Assessments and documentation of adverse events
Adverse events and grade will be recorded at each follow-up visit. Serious adverse events will be 
collected and reported from the time patient signs informed consent until the End of Treatment 
safety follow-up visit.  Non-serious adverse events will be collected from the time of first study 
drug dosing until the End of Treatment safety follow-up visit.
Reporting of serious adverse events
The definition of serious adverse events (SAEs) is given in Section 11(Definitions).
Each serious adverse event must be followed up until resolution or stabilization, by submission 
of updated reports to the designated person. An isolated laboratory abnormality that is assigned 
grade 4, according to CTC definition, is not reportable as an SAE; unless the investigator 
assesses that the event meets standard ICH criteria for an SAE.  CTC grade 4 baseline laboratory 
abnormalities that are part of the disease profile should not be reported as an SAE, specifically 
when they are allowed or not excluded by the protocol inclusion/exclusion criteria.  
When required, and according to local law and regulations, serious adverse events must be 
reported to the Ethics Committee and Regulatory Authorities. 
All serious adverse events should be reported to the Coordinating Center within 24 hours.  The 
Coordinating Center will then inform the DSMC and Bayer and will report to the RSRB using 
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the “reportable event” form in the ROSS system. In the event of such an event, the investigator 
should refer to the Pharmacovigilance section of the contract for reporting procedures.
Non-reportable research events across all sites (including UR site) will be submitted in summary 
at the time of the Coordinating Center’s Continuing Review.
The Investigator may report serious adverse drug reactions (SADRs) using either:
An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html  
OR
A MedWatch form available at http://www.fda.gov/medwatch/ 
All reports shall be sent electronically to: 
UR Coordinating Center
Electronic Mailbox: 
 Matt_Poquadeck@urmc.rochester.edu 
Facsimile:  
(585) 442-0137 
Address -- Mail only:
 Matt Poquadeck
University of Rochester 
Wilmot Cancer Institute
Clinical Trials Office
601 Elmwood Ave, Box 704
Rochester, NY 14642 
The Coordinating Center will ensure that all reports are then passed on to Bayer. All reports shall 
be sent electronically to:
Bayer
Electronic Mailbox:  
DrugSafety.GPV.US@bayer.com 
Facsimile: 
(973) 709-2185 
Address -- Mail only:
Global Pharmacovigilance - USA 
Bayer HealthCare Pharmaceuticals Inc.
                     
P.O. Box 915 
                     
Whippany, NJ 07981-0915 
Address – 
FDX or UPS only:  
100 Bayer Boulevard, Whippany, NJ 07981 
Reports for all Bayer products can also be phoned in via our Clinical Communications 
Dept: 
Phone: 
1-888-842-2937
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Expected adverse events
Overview listings of frequent adverse events are shown in the most current version of the 
investigator’s brochure (IB) / summary of product characteristics.
If relevant new safety information is identified, the information will be integrated into an update 
of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the Coordinating Center and Bayer according to 
the applicable reference document and according to all local regulations.
Adverse events of special safety interest
As with any new chemical entity, there is always potential for unexpected adverse events, 
including hypersensitivity reactions.
Based on data studies with regorafenib and from current knowledge of the pharmacological 
properties of other small molecule tyrosine kinase inhibitors in this drug class, as soon as there is 
reasonable suspicion of any of the following AEs, the investigator should immediately notify the 
Coordinating Center as outlined in Section 11 (Reporting of Serious Adverse Events). 
Reportable adverse events include:
Acute renal failure (NCI-CTCAE version 4.0 ≥ grade 3) or severe proteinuria (NCI-
CTCAE version 4.0 ≥ grade 3)
Interstitial lung disease
Acute cardiac failure
Clinically significant bleeding (NCI-CTCAE version 4.0 ≥ grade 3)
Stevens-Johnson Syndrome and erythema multiforme
Hepatic failure
Reversible posterior leukoencephalopathy syndrome
Gastrointestinal perforation or fistula
Pregnancies
The investigator must report to the Coordinating Center any pregnancy occurring in a study 
subject’s 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 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.
The MedWatch form should be used to submit this information and is available at 
http://www.fda.gov/medwatch/ 
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Further safety
Progressive disease
If progressive disease leads to signs and symptoms that meet the criteria for an SAE 
(i.e., hospitalization, disability, death, or important medical event), the signs and symptoms 
should be reported as an SAE and not the underlying progressive disease.
Death
If any subject dies during the trial or within 30 days of the end-of-treatment visit, the investigator 
will inform the Coordinating Center and will record the cause of death in detail (using the SAE 
Form) within 24 hours.
Appropriateness of procedures / measurements
The assessments described in the previous sections are widely used and generally recognized as 
reliable, accurate, and relevant for determining the safety and efficacy of therapies in this 
disease.
Safety Analyses
The Data Safety Monitoring Committee (DSMC) at the James P. Wilmot Cancer of the 
University of Rochester will review and monitor toxicity and accrual data from this trial.  The 
committee is composed of clinical specialists with experience in oncology who have no direct 
relationship with the study.  Information that raises any questions about participant safety will be 
addressed with the investigators and study team.
The DSMC will provide oversight of study progress and safety by review of accrual and adverse 
event data at semi-annual meetings or more frequently if concerns arise.  Any adverse effects 
requiring expedited review per protocol will be submitted to the chair of this committee for 
determination as to whether further action is required.  This committee will meet after 6 patients 
have been enrolled and received at least one cycle of therapy.  If >3 of these first 6 patients have 
delays in treatment administration due to toxicity, accrual will be held pending review and 
discussion with the investigators.
The study team will record and monitor adverse event rates utilizing the University of Rochester 
Cancer Center Clinical Trial database.  If the study has two or more of the same SAEs reported 
in a month or more than six of the same SAEs in six months, the DSMC will review a summary 
of SAEs, discuss events with study investigators and conduct a detailed review.  The DSMC will 
determine if further action is required.  A copy of the DSMC reports will always be sent to all 
participating sites for review and submission to their local IRB.
12. Statistical Methods and Determination of Sample Size
Statistical and analytical plans
The primary end-point is grade 3-5 toxicity incidence rates.  Adverse events will be grouped by 
system organ class and graded using NCI CTCAE version 4.0.  Descriptive statistics (counts and 
percentages) for grade 3 and 4 toxicity rates and all-grade skin toxicity will be assessed and 
evaluated in relation to CGA domains.
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Relative dose intensity (dose reductions, dose delays, or inability to tolerate treatment) for 
regorafenib will be calculated.  Specific toxicities associated with dose reductions, delays and/or 
early discontinuation of treatment course will be identified.
Efficacy outcomes will be response rate (RR), disease control rate (DCR), progression-free 
survival (PFS) and overall survival (OS).  Best response will be classified per RECIST criteria 
into complete response (CR), partial response (PR), stable disease (SD) and progressive disease 
(PD).  Disease control will be the combination of CR + PR + SD.  Kaplan-Meier survival curves 
will be used to estimate median PFS and OS.  All statistical tests will be conducted using SAS 
version 9.2 (SAS Institute Inc).
Analysis of CGA results will be descriptive and will describe mean, median and standard 
deviations of scores at baseline and at follow up time points.  CGA deficits will be captured at 
baseline and follow up time points.  Each domain will be evaluated individually and scores will 
be compared between baseline and follow up time points.  Overall CGA deficits will be 
examined and proportion of patients who decline in more than 1 domain will be determined for 
each time point.
Determination of sample size
Based on data from the CORRECT trial, an anticipated grade 3-4 toxicity rate of 40-50% is 
expected for our study.  This is slightly lower than the observed grade 3-4 toxicity rate seen 
among patients > 65 years in the CORRECT trial.  However, we hypothesize that starting at a 
lower dose and instituting extensive supportive care will lower the observed toxicity rate in our 
patient population.  Using a sample size of 60 subjects with an expected toxicity rate of 45%, we 
will have a 90% CI of [0.341, 0.564] and an approximate 12% margin of error.  Our plan is to 
accrue 3-4 patients per month among the four participating sites.
13. Premature Termination of the Study
If risk-benefit ratio becomes unacceptable owing to, for example,
o Safety findings from this study (e.g. SAEs)
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.
The investigator has the right to close his/her center at any time.
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For any of the above closures, the following applies:
Closures should occur only after consultation between involved parties (Coordinating 
Center and enrolling site).
All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; head 
of study center) must be informed as applicable according to local law.
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.
Details for individual subject
's withdrawal can be found in  Section 6.
14. Ethical and Legal Aspects
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the investigator abide by Good Clinical Practice (GCP) 
guidelines and under the guiding principles detailed in the Declaration of Helsinki.  The study 
will also be carried out in keeping with applicable local law(s) and regulation(s).
Investigator Requirements:
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol.
Modifications to the study protocol will not be implemented by the investigator without 
discussion and agreement by the Coordinating Center.  However, the investigator may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to 
the trial subjects without prior IEC/IRB/Coordinating Center approval/favorable opinion.  As 
soon as possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical institution.  
Any deviations from the protocol must be explained and documented by the investigator and 
reported to the Coordinating Center by faxing: 585-442-0137.
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 Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all applicable 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion.
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and properly documented.
15. Publication policy
The Coordinating Center 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 the Coordinating Center (who will then forward this to Bayer) at least 
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thirty 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 the Coordinating 
Center (including 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 the Coordinating Center and the 
investigator/institution.
The Principal Investigator should ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov.
16. Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual.
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17. Reference list
Bandeen-Roche, K., et al., Phenotype of frailty: characterization in the women
's health and aging 
studies. J Gerontol A Biol Sci Med Sci, 2006. 61(3): p. 262-6.
Bergers, G., et al., Benefits of targeting both pericytes and endothelial cells in the tumor 
vasculature with kinase inhibitors. J Clin Invest. 2003 May;111(9):1287-95.
Bylow, K., et al., Obese frailty, physical performance deficits, and falls in older men with 
biochemical recurrence of prostate cancer on androgen deprivation therapy: a case-control study. 
Urology, 2011. 77(4): p. 934-40.
Charlson, M.E., et al., A new method of classifying prognostic comorbidity in longitudinal 
studies: development and validation. J Chronic Dis, 1987. 40(5): p. 373-83.
Dotan E, Browner I, Hurria A., et al.  Challenges in the management of older patients with colon 
cancer.  J Natl Compr Canc Netw, 2012.  10(2): p. 213-225.
Ferrara, N., VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002 Oct; 2 
(10):795-803.
Fillenbaum, G., et al., Sensitivity and specificity of standardized screens of cognitive impairment 
and dementia among elderly black and white community residents. J Clin Epidemiol, 1990. 
43(7): p. 651-60.
Fillenbaum, G.G. and M.A. Smyer, The development, validity, and reliability of the OARS 
multidimensional functional assessment questionnaire. J Gerontol, 1981. 36(4): p. 428-34.
Fried, L.P., et al., Untangling the concepts of disability, frailty, and comorbidity: implications for 
improved targeting and care. J Gerontol A Biol Sci Med Sci, 2004. 59(3): p. 255-63.
Frost, A., et al., Phase I study of  an inhibitor of oncogenic and angiogenic kinases in patients 
with advanced solid tumors: final results of a dose-escalation study. J Clin Oncol (meeting 
abstracts) 2008;26:2558.
George, L.K. and G.G. Fillenbaum, OARS methodology. A decade of experience in geriatric 
assessment. J Am Geriatr Soc, 1985. 33(9): p. 607-15.
Grothey, A., et al.,  Regorafenib monotherapy for previously treated metastatic colorectal cancer 
(CORRECT): an international, multicenter, randomized, placebo-controlled, phase 3 trial.  
Lancet 2012
Guralnik, J.M., et al., Lower-extremity function in persons over the age of 70 years as a predictor 
of subsequent disability. N Engl J Med, 1995. 332(9): p. 556-61
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Guralnik, J.M., et al., A short physical performance battery assessing lower extremity function: 
association with self-reported disability and prediction of mortality and nursing home admission. 
J Gerontol, 1994. 49(2): p. M85-94.
Hays, R.D., C.D. Sherbourne, and R.M. Mazel, The RAND 36-Item Health Survey 1.0. Health 
Econ, 1993. 2(3): p. 217-27.
Hurria, A., H.J. Cohen, and M. Extermann, Geriatric Oncology Research in the Cooperative 
Groups: A Report of a SIOG Special Meeting. J Geriatr Oncol, 2010. 1(1): p. 40-44.
Hurria, A., et al., Implementing a geriatric assessment in cooperative group clinical cancer trials: 
CALGB 360401. J Clin Oncol, 2011. 29(10): p. 1290-6.
Hurria, A., et al., Developing a cancer-specific geriatric assessment: a feasibility study. Cancer, 
2005. 104(9): p. 1998-2005.
Juurlink, D.N., et al., Drug-drug interactions among elderly patients hospitalized for drug 
toxicity. JAMA, 2003. 289(13): p. 1652-8.
Katz, S., et al., Studies of Illness in the Aged. The Index of Adl: A Standardized Measure of 
Biological and Psychosocial Function. JAMA, 1963. 185: p. 914-9.
Kawas, C., et al., Reliability of the Blessed Telephone Information-Memory-Concentration Test. 
J Geriatr Psychiatry Neurol, 1995. 8(4): p. 238-42.
Klepin, H., S. Mohile, and A. Hurria, Geriatric assessment in older patients with breast cancer. J 
Natl Compr Canc Netw, 2009. 7(2): p. 226-36.
Lawton, M.P., Scales to measure competence in everyday activities. Psychopharmacol Bull, 
1988. 24(4): p. 609-14.
Mohile, S.G., et al., A pilot study of the vulnerable elders survey-13 compared with the 
comprehensive geriatric assessment for identifying disability in older patients with prostate 
cancer who receive androgen ablation. Cancer, 2007. 109(4): p. 802-10.
Nasreddine, Z.S., et al., The Montreal Cognitive Assessment, MoCA: a brief screening tool for 
mild cognitive impairment. J Am Geriatr Soc, 2005. 53(4): p. 695-9.
Pal, S.K., V. Katheria, and A. Hurria, Evaluating the older patient with cancer: understanding 
frailty and the geriatric assessment. CA Cancer J Clin, 2010. 60(2): p. 120-32.
Pfeiffer, E., A short portable mental status questionnaire for the assesssment of organic brain 
deficit in elderly patients. J Am Geriatr Soc, 1975. 23(10): p. 433-41.
Podsiadlo, D. and S. Richardson, The timed "Up & Go": a test of basic functional mobility for 
frail elderly persons. J Am Geriatr Soc, 1991. 39(2): p. 142-8.
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Rao, A.V., et al., Geriatric evaluation and management units in the care of the frail elderly cancer 
patient. J Gerontol A Biol Sci Med Sci, 2005. 60(6): p. 798-803.
Repetto, L., et al., Comprehensive geriatric assessment adds information to Eastern Cooperative 
Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric 
Oncology Study. J Clin Oncol, 2002. 20(2): p. 494-502.
Rodin, M.B. and S.G. Mohile, A practical approach to geriatric assessment in oncology. J Clin 
Oncol, 2007. 25(14): p. 1936-44.
Seymour, M.T., et al., Chemotherapy options in elderly and frail patients with metastatic 
colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial. The Lancet, 2011. 
377(9779): p. 1749-1759.
Stewart, A.L. and C.J. Kamberg, in Measuring functioning and well-being:  The Medical 
Outcomes Study approach., A.L. Stewart and J.E. Ware, Jr., Editors. 1992, Duke University 
Press: Durham, North Carolina. p. 86-101.
Van Cutsem E., Sobrero A., Siena S., et al., Regorafenib in progressive metastatic colorectal 
cancer (mCRC): Analysis of age subgroups in the phase III CORRECT trial.  ASCO 2013 
Meeting (Abstract 3636).
Ware, J.E., Jr. and C.D. Sherbourne, The MOS 36-item short-form health survey (SF-36). I. 
Conceptual framework and item selection. Med Care, 1992. 30(6): p. 473-83.
Wilhelm, S.M., et al.,  Regorafenib : A new oral multikinase inhibitor of angiogenic, stromal, 
and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 
2010 Dec 17.
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18. Appendices
Appendix A – RECIST 1.1 Criteria
RECIST 1.1
Measurable 
Disease: Tumor 
Lesions
Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded with a 
minimum size of):
-      10mm by CT /MRI scan (scan slice thickness no greater than 5mm)
 -       10mm caliper measurement by clinical exam (lesions which cannot 
be accurately measured with calipers should be recorded as non-
measurable)
-       20mm by chest X-ray
Measurable 
Disease: Malignant 
Lymph Node
Sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions)
Measure SHORT axis:
-      Target lesion if short axis > 1.5cm
-      Non-target if short axis 1.0 to <1.5cm or pathological 
-      Normal lymph node if short axis < 1.0cm
Add ACTUAL short axis measurement to sum of longest diameters of 
non-nodal lesions.
Target Lesions
All measurable lesions:
-       Up to 5 target lesions max in total
-       Up to 2 target lesions max per organ
Non-Target 
Lesions
All other lesions (site of disease). Measurements are not required and 
these lesions should be followed as:
  -      Present
-      Absent
-      Unequivocal progression
New Lesions
The appearance of new malignant lesions denotes disease 
progression.
Methods for 
Evaluation of 
Measurable 
Disease
All measurements should be taken and recorded in metric notation, using 
a ruler, calipers, or digital measurement tool. All baseline evaluations 
should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be 
used to characterize each identified and reported lesion at baseline and 
during follow-up. Imaging-based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam.
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Appendix B: Investigators Brochure
Will be provided upon request
Appendix C: Comprehensive Geriatric Assessment Tools
CGA Team 
Assessment 12Apr2017.pdf
CGA Pati
ent 
Assessment 12Apr2017.pdf
Appendix D: Handout on ‘Tips for Skin Care’ for patients
STIVARGA® for 
Patients _ Managing Hand Foot Skin Reaction.pdf
Appendix E: Handout on ‘Planning Low-Fat Meals’ for patients
STIVARGA - Helping 
You Plan Your Low-Fat Meals IRB approved.pdf
Appendix F: Subject Diary
Regorafenib Subject 
Diary IRB Approved.pdf
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UGIC-14072 
RSRB 55031
version 14Jun2019
NCT02466009
Consent Form
A Phase II Study of Regorafenib in Adults ≥ 65 Years with Metastatic Colorectal Cancer
Principal Investigators: Aram Hezel, M.D. and Supriya G. Mohile, M.D.
This consent form describes the research study, what you may expect if you decide to take 
part and important information to help you make your decision.  Please read this form 
carefully.
The study staff will explain this study to you. Please ask questions about anything that is not 
clear before you agree to participate.  You may take the consent form home to think about 
and discuss with family or friends.
Being in this study is voluntary – it is your choice.
If you join this study, you can change your mind and stop at any time.
If you choose not to take part, your routine medical care will not be changed in any way.
There are risks from participating and you should understand what these mean to you.
Introduction:
You are being asked to take part in this study because you are aged 65 or older and require 
treatment for colorectal cancer that has spread to other parts of the body (metastatic) and has 
not gotten better with other treatment.
This study is being conducted at the University of Rochester’s James P. Wilmot Cancer Institute, 
Mayo Clinic (Mayo Clinic refers to Mayo Clinic in  Rochester, Minnesota) and Fox Chase Cancer 
Center.  At the University of Rochester, this study is being conducted by Dr. Aram Hezel and Dr. 
Supriya Mohile.
Purpose of Study:
The purpose of this study is to monitor the impact of a drug called regorafenib on quality of life 
and other issues relevant to the elderly.  The study will also assess how well this drug controls 
cancer growth and extends life in patients aged 65 or older.
The standard treatment for metastatic colorectal cancer usually includes chemotherapy which 
can have side effects that are more difficult to tolerate for older patients with cancer.  
RSRB Approval Date: 6/13/2019
Expiration Date: 1/21/2020
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Regorafenib (a non-chemotherapy option) was recently approved by the FDA for treatment of 
patients with your type of cancer that has grown on all standard chemotherapy agents.
This study is being done among elderly patients, whose cancer has grown on all chemotherapy 
agents or who are not able to tolerate chemotherapy, to measure the safety of regorafenib in 
the elderly population and to assess how well the drug controls cancer growth.  Each subject 
will start at a slightly lower dose of regorafenib and this will then be increased to the full dose 
after 28 days depending on how the drug is tolerated by that individual.  This study will use 
supportive care measures and close monitoring to help subjects tolerate regorafenib better.
Description of Study Procedures
If you decide to take part in this study, you will be asked to undergo some initial tests to ensure 
that you meet all the criteria necessary to take part in the study.  Once you have completed 
your initial testing and meet the eligibility criteria, you will begin treatment.
Initially, you will be asked to take 120mg of regorafenib (3 tablets) each day for 21 days (3 
weeks) in a 28-day cycle.  After the first cycle, your study doctor will discuss the possibility of 
increasing the dose to 160mg (4 tablets) based on your health status.  Treatment will continue 
as long as you are tolerating treatment and your colorectal cancer is either responding to 
treatment or remains stable.
During the study, you will have the following assessments:
You will be asked about your medical history and current medications you are taking.
You will have physical exams (including vital signs, blood pressure, weight, temperature)
You will also undergo a Comprehensive Geriatric Assessment (CGA) before you begin 
the study, at 4 weeks and then every 3 months +/- 7 days while on study. These are 
being done to assess health areas specific to older cancer patients, taking into account 
demographic information, health conditions, quality of life, ability to perform basic daily 
activities, memory, physical performance (walking, leg strength, and balance), mood and 
social support.  Several tests as well as questionnaires will be used to assess for any 
deterioration in these areas. 
These questionnaires can be completed at the study visit or given to you to take home, 
complete, and send back or mailed to you to be completed prior to the next visit. 
You will have routine blood work to look at your blood counts, liver and kidney function 
and your electrolytes. Approximately 6ml will be taken.
You will have routine tumor scans to monitor the status of your cancer, usually a 
computed tomography (CT) scan or magnetic resonance imaging (MRI) scan.
Number of Subjects
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Approximately 60 subjects from 3 study centers will take part in this research.  Locally, about 20 
subjects will participate.
Duration of the Study
Your participation in the study is expected to last between 6 and 12 months from the time you 
start treatment.
Risks of Participation
Regorafenib is a standard treatment for metastatic colorectal cancer.  However, older patients 
may not tolerate the side effects of regorafenib.  Everyone taking part in the study will be 
watched and supported carefully for any side effects.  
Risks of Regorafenib
Drugs used for anti-cancer therapy are usually linked with undesirable side-effects.  In the 
following section, side effects which have been so far detected in regorafenib studies with 
patients are described.  You may experience none or some of these side-effects and they may 
be mild, moderate or severe and in some case, they may be life-threatening in nature or result 
in death.  Many of the side effects disappear after study treatment is stopped.  If you have any 
discomfort or experience any side effects, you must report these to your study doctor and/or 
study nurse.  Your study doctor may then prescribe other medications to ease them or even 
interrupt or discontinue your use of regorafenib.
As of 31 March 2012, approximately 1200 patients have already received regorafenib in various 
studies.  The following is a list of side effects that occurred for which there is a possibility that 
they were caused by regorafenib.
The most common side-effects (occurring in more than 1/10 of patients) of regorafenib include:
Diarrhea
Hair loss (alopecia)
Headache
High blood pressure (hypertension) – symptoms may include headache, dizziness, 
palpitations, blurred vision, ringing in the ears and nose bleeds
Inflammation of lining of digestive tract (mucosal inflammation)
Loss of appetite (anorexia)
Feeling sick (nausea)
Pain (e.g. in joints, muscles, abdomen, chest)
Reduced numbers of red blood cells (hemoglobin decreased/anemia) ) – symptoms may 
include feeling tired and weak, shortness of breath, increased heart rate, dizziness or 
lightheadedness, headache, chest pain, and pale skin.
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Expiration Date: 1/21/2020
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Skin changes including rash, painful reddening of the skin of hands and feet with or 
without blistering, redness, dryness and numbness/tingling (Rash, Palmar-plantar 
erythrodysaesthesia syndrome, Hand-foot skin reaction).
Tiredness (Fatigue, Asthenia)
Voice changes or hoarseness (Dysphonia)
Vomiting
Infection (CRP increased)
Reduced numbers of cells that help the blood to clot (Thrombocytopenia)
Bleeding, generally mild or moderate in severity, but which may be life-threatening or 
fatal (especially if it affects the lung, digestive tract or brain) (Hemorrhage/Hematoma, 
at any body site)
Inflammation of the lining of the mouth which may cause mouth pain and sores 
(Stomatitis)
Jaundice (a condition in which your skin and white part of your eyes turn a yellow color) 
(Hyperbilirubinemia)
Fever (Pyrexia)
Loss of weight
Less common side effects (occurring in 1/100 to 1/10 of patients) include:
Reduced number of white blood cells (Leukopenia), which may make it hard for you to 
fight infections.
Reduced function of thyroid gland (Hypothyroidism), which may cause symptoms 
including tiredness, depression, weight gain, cold intolerance, dry coarse hair, difficulty 
having bowel movements, dry skin, muscle cramps, high cholesterol, trouble with 
concentrating and swelling of the legs.
Reduced levels of minerals in the blood including calcium, potassium, phosphorus and 
magnesium: 
o Symptoms of a low calcium level may include numbness and tingling in the hands 
and feet, muscle cramps, twitches and spasms, fatigue, confusion, disorientation 
and seizures
o Symptoms of low potassium may include muscle weakness, cramping, leg 
discomfort, an irregular heart beat and confusion
Increased levels of uric acid in the blood (Hyperuricemia)
Shaky hands (Tremor)
Changes in taste (Taste disorders)
Dry mouth
Heartburn and bringing up acid into the mouth (Gastroesophageal reflux)
Inflammation of lining of stomach and bowel which may cause stomach pain and 
diarrhea (Gastroenteritis)
 Abnormal liver enzymes – symptoms may include feeling overly tired or weak, you may 
bruise or bleed more easily, abdominal pain, or yellowing of the skin or eyes
Dry skin
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Muscle tightness and joint stiffness (Musculoskeletal stiffness)
Increased losses of protein through urine which may be a sign that the kidneys are not 
functioning well (Proteinuria)
Increased blood levels of pancreas enzymes called amylase and lipase (Amylase, Lipase 
increased)
Reduced ability to form blood clots which may increase the tendency for bruising and 
bleeding (Abnormal International Normalized Ratio)
Peeling rash (Exfoliative rash)
Uncommon side effects (occurring in 1/1000 to 1/100 of patients) include:
Impaired blood supply to heart muscle which may cause life-threatening heart attack 
(Angina pectoris, Myocardial injury, Ischemia, Infarction)
Severe blood pressure increase (Hypertensive crisis)
Perforation (hole) in the digestive tract which may be fatal (Gastrointestinal perforation)
Abnormal connection between the bowel and other organs which may need to be 
treated with an operation (Gastrointestinal fistula)
Severe inflammation of the liver which may result in fatal liver failure (Severe liver 
injury)
Nail disorder
Multiple skin eruptions (Erythema multiforme)
Rare side effects (occurring in fewer than 1/1000 patients) include:
Low grade skin tumors (Keratoacanthoma, Squamous cell carcinoma of the skin)
Reversible (temporary) swelling in the rear part of the brain leading to headache, 
altered consciousness, fits(seizures) and visual symptoms (Reversible posterior 
leukoencephalopathy syndrome, RPLS)
Serious reactions of the skin and/or mucous membranes which may include painful 
blisters and fever, including extensive detachment of the skin (Stevens-Johnson 
syndrome and toxic epidermal necrolysis)
Special advice on side effects to watch out for:
Severe liver inflammation is an uncommon but serious side effect which may result in fatal liver 
failure.  If recognized early, it may be prevented from getting worse.  There are several 
symptoms that may indicate something is wrong with the liver.  They include jaundice (a 
yellowish pigmentation of skin and whites of the eyes), dark colored brown urine, excessive 
tiredness and unusual sleepiness, loss of appetite, confusion and disorientation.  Your liver 
function will be regularly checked with blood tests, but if you notice these symptoms during 
your participation in this study, you should contact your study doctor immediately, so that a 
blood test can be done to check your liver function.  The blood test will help your study doctor 
decide if it is safe for you to continue treatment, or if the drug should be temporarily or 
permanently stopped to prevent damage to your liver.
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In addition to the listed side effects listed above, your study doctor may have updated 
information on side effects that occur with less frequency which he/she may discuss with you.  
You must understand that there may be side effects (including allergies) that are not yet known 
and you may have other side effects that have not been reported before.  Therefore, you must 
notify your study doctor or one of the members of the study staff of any new symptoms that 
you may have, even if you are unsure whether they are due to the drug.
General considerations regarding other risks
As part of this study, you will have regular CT or MRI scans to monitor the status of your cancer 
and these scans are associated with some risks.
You will be exposed to radiation from CT scans.  The amount of radiation you receive from 
these diagnostic tests is considered minimal. The dye injected in your vein during the CT scan 
may cause pain, burning sensation, hot flushes, and a severe allergic reaction, particularly in 
those with prior allergies to iodine.  CT contrast solution can cause kidney damage, especially if 
you are diabetic, dehydrated or elderly.
The MRI scan uses a powerful magnetic field to generate images of the body.  The magnet 
could move objects within your body that contain metal such as implants, clips or pacemakers.  
Certain magnetic imaging devices, such as 3T MRI machines, can demagnetize cochlear 
implants.  If you have any of these items you should not participate in this study.
As explained above, blood samples will be taken during your clinic visits.  The risk of blood 
drawing includes discomfort at the site of the blood draw with bruising, bleeding, infection and 
rarely, fainting and nerve damage.
Before taking part in the study, it will be necessary to stop taking some herbal drugs, any 
treatments used to treat cancer (whether they are marketed or experimental treatments) and 
some drugs that are used to stimulate the immune system.  You will not be allowed to use 
these treatments during this study or within 30 days before the first dose of regorafenib.
Tell your study doctor if you are taking or have recently taken any other medicines, including 
medicines obtained without a prescription or even over-the-counter medicines, such as 
vitamins or dietary supplements.  Some medicines may affect the way regorafenib works or 
regorafenib may affect how other medicines work and cause serious side effects.  Especially tell 
your study doctor if you are taking anything on this list:
- Some medicines to treat fungal infections (e.g. ketoconazole, itraconazole, 
posaconazole and voriconazole)
- Some medicines to treat bacterial infections (e.g. rifampicin, clarithromycin, 
telithromycin)
- Medicines typically used to treat epilepsy (seizures) (e.g. phenytoin, carbamazepine or 
phenobarbital)
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- Methotrexate – a medicine typically used to treat cancer
- Digoxin – a medicine typically used to treat heart failure
- Warfarin or phenprocoumon – medicines typically used to thin your blood
- St. John’s wort – a herbal treatment for depression (medicine obtained without a 
prescription)
You should not eat grapefruit, drink grapefruit juice or beverages containing grapefruit while 
taking regorafenib.  This can affect the way regorafenib works.
You should always check with your study doctor before you start using any additional 
treatments during the study.
Fertility Risks
It is likely that regorafenib may have a potentially harmful effect on an unborn child.  If you are 
a sexually active and possibly fertile man, you will be asked to use a medically approved 
method of birth control (contraception) during the treatment period and for at least 8 weeks 
after you finish taking your regorafenib.  Check with your study doctor about what kind of birth 
control methods to use and for how long to use them.
If you plan to father a child during the study or within 8 weeks of the end of the study, you 
cannot take part in this study.  If you think that your partner may be pregnant at any time while 
on this study, you must inform your study doctor immediately.  You will be asked to take part in 
monitoring the outcome of the pregnancy and the study doctor will remain in contact with you 
to determine the conclusion of your pregnancy.  
Benefits of Participation
You might not benefit from being in this research study.  The potential benefit to you from 
being in this study might be that your cancer would be controlled.
New Study Findings
If we discover anything that might make you change your mind about continuing in the study, 
we will let you know.
Alternatives to Participation
Your other choices may include:
Getting treatment or care without being in a research study
Taking part in another research study
Getting no treatment
If you decide that you don’t want any more treatment, one of your options is called ‘comfort 
care.’  Comfort care includes pain medications and other support.  It aims to maintain your 
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Expiration Date: 1/21/2020
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comfort and dignity rather than cure disease.  Usually this care can be provided at home.  If you 
think you might prefer comfort care, please discuss this with your family, friends and your 
doctor.
Talk to your study doctor about your choices before you decide to take part in this study.
Sponsor Support
The University of Rochester is receiving payment from Bayer, the company supplying the study 
drug regorafenib, for conducting this research study.
Costs
You and/or your health insurance company will be billed for parts of the study that are 
standard care for your disease.  Standard of care tests, procedures and medications are those 
that you would undergo or receive as part of treatment for your condition whether you were 
participating in a research study or not.  Your health insurance company may or may not pay for 
these charges.  You will be responsible for all of the costs linked with this study that are related 
to standard care and are not covered by other payers (HMO, health insurance company etc.) 
such as co-pays, deductibles and other out-of-pocket expenses that you would normally be 
required to pay for the treatment of your cancer.
The study drug regorafenib will be provided by the study sponsors at no cost to you.  
Procedures that are done only for the study, such as the Comprehensive Geriatric Assessments 
will be paid for by the study and will not be billed to you or your insurance company.
You might have unexpected expenses from being in this study.  Ask your study doctor to discuss 
the costs that will or will not be covered by the sponsor.  This discussion should include who 
will pay the costs of treating possible side effects.
Payments
You will not be paid for participating in this study.
Circumstances for Removal from Study
There are some cases where you could be removed from the study without your consent.  You 
may be withdrawn from the study if your disease becomes worse or if your study doctor feels 
that staying in the study is harmful to your health.  You may be withdrawn from the study if you 
do not keep appointments for study visits, if you experience a treatment delay, or if you cannot 
complete study activities.  
You also may decide that you no longer wish to participate in this research study.  If you decide 
you would like to stop being in this study, we ask that that you notify your study doctor or study 
coordinator of your decision to stop participation.  You will be asked to complete one additional 
end-of-study visit for safety follow-up.
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Expiration Date: 1/21/2020
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Study Completion
To ensure your safety after you have stopped the study drug, you will be asked to return 
approximately 30 days after your last dose to complete an end-of-study visit which will include 
physical exam, review of medical history and current medications, and end-of-study blood work 
(approximately 6ml will be taken).
If you come off treatment due to progression of your cancer, information about any other 
cancer therapies you may receive and how they work for you will be monitored until the study 
closes.
If you come off treatment early for any other reason other than the progression of your cancer, 
information about your health status and cancer will be collected until the study closes.
Compensation for Injury
If you are directly injured by the drug(s) being studied, or by medical procedures needed 
because of this study, and you receive medical care for the injury, you may need to pay for that 
care.  You will be reimbursed for reasonable and necessary medical costs for such care, but you 
might not be reimbursed for care covered and paid for by a third party like your health 
insurance provider, or costs such as required co-payments or deductibles related to that 
coverage.  No other funds have been set aside to pay for such things as lost wages or expenses 
due to a current underlying illness or condition.
If your research injury is paid for by the University or Sponsor, we will collect your name, date 
of birth, gender, and Medicare Health Insurance Claim Number or Social Security Number to 
determine your Medicare status. This information will be used only in accordance with the law. 
If you are a Medicare beneficiary, information about the study you are in, and any payments 
made related to your injury, will be reported to the Centers for Medicare & Medicaid Services 
(CMS), in accordance with CMS requirements.  This information will not be used for any other 
purpose.
Confidentiality of Records and Authorization to Use and Disclose Information for Research 
Purposes
The University of Rochester makes every effort to keep the information collected from you 
private.  In order to do so, we will limit access of research information collected on this study to 
include only trained research personnel assigned to this study.  Sometimes, however, 
researchers need to share information that may identify you with people that work for the 
University, regulators or the study sponsor.
If you have never received a copy of the University of Rochester Medical Center (URMC) and
Affiliates Notice of Privacy Practices, please ask the investigators for one.
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Expiration Date: 1/21/2020
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What information may be used and given to others?
The study doctor will get your personal and medical information.  For example:
Research records
Records about phone calls made as part of this research
Records about your study visits
Past and present medical records related to this study
Results of medical tests
Who may use and give out information about you?
The study doctor and study staff
URMC and Affiliates
Your information may be given to:
The University of Rochester, including the Institutional Review Board that oversees the 
research.
Other University of Rochester physicians involved in your clinical care.
The Sponsor of this study (Bayer) and the people or groups it hires to help perform this 
research. 
Federal  and  State  agencies  
(such  as  
the  U.S.  Food  and  Drug  Administration  
(FDA),  
the 
Department of Health and Human Services, the National Institutes of Health and other 
United States agencies) or government agencies 
in other countries that oversee or review 
research. They may also need to inspect study records at some point during the study or 
even after it has been completed.  In the event that this should occur, every effort will be 
made to keep identifying information about you private.
A group that oversees the data (study information) and safety of this research.
Why will this information be used and/or given to others?
To do the research
To study the results
To see if the research was done right
If the results of this study are made public, information that identifies you will not be used.
What if I decide not to give permission to use and give out my health information?
Then you will not be able to be in this research study.
May I review or copy my information?
Yes, but only after the research is over.
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Expiration Date: 1/21/2020
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How long will this permission be valid?
This permission will last indefinitely.
May I cancel my permission to use and disclose information?
Yes.  You may cancel your permission to use and disclose your health information at any time.  
You do this by sending written notice to the study doctor.  Upon receiving the written notice, 
the study team will no longer use or disclose your health information and you will not be able 
to stay in this study.  Information that has already been gathered may need to be used and 
given to others for the validity of the study.
May I withdraw from the study?
Yes.  If you withdraw your permission to be in the study, no new health information identifying 
you will be gathered after that date.  Information that has already been gathered may still be 
used and given to others.
Is my health information protected after it has been given to others?
No.  There is a risk that your information will be given to others without your permission.
Results of Research testing and documenting study participation:
Results of research testing and information about your participation in this study will be 
included in your electronic health record.  The study team may be notified if you receive 
other health care services at URMC and Affiliates.  
Individuals who have a reason to access your electronic health record in the University 
of Rochester Medical Center and its Affiliates (Strong Memorial Hospital, Highland 
Hospital, URMC primary care and specialist physician offices, etc.) will have access to the 
results of testing performed as part of this research study and will know that you 
participated in this research study.
More Information
A description of this clinical trial will be available on the internet at 
http://www.ClinicalTrials.gov as required by U.S. Law.  This web site will not include 
information that can identify you.  At most, the web site will include a summary of the results.  
You can search this web site at any time.
Contact Persons
For more information concerning this research or if you feel that your participation has resulted 
in any research related injury, emotional or physical discomfort, please contact:
Dr. Aram Hezel at 585-275-5863 (24 hours)
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Expiration Date: 1/21/2020
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Please contact the University of Rochester Research Subjects Review Board at 265 Crittenden 
Blvd., CU 420628, Rochester, NY 14642, Telephone (585) 276-0005 or (877) 449-4441 for the 
following reasons:
- You wish to talk to someone other than the research staff about your rights as a 
research subject;
- To voice concerns about the research;
- To provide input concerning the research process;
- In the event the study staff could not be reached
Voluntary Participation
Participation 
in this study 
is voluntary. 
 You are free not to participate or to withdraw at any time, 
for whatever reason, without risking loss of present or future care you would otherwise expect 
to receive.  In the event that you do withdraw from this study, the information you have already 
provided will be kept in a confidential manner.
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Expiration Date: 1/21/2020
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Signature/Dates
After reading and discussing the information in this consent form you should understand:
- Why this study is being done;
- What will happen during the study;
- Any possible risks and benefits to you;
- Other options you may have instead of being in the study;
- How your personal information will be protected;
- What to do if you have problems or questions about this study.
Subject Consent
I have read (or have had read to me) the contents of this consent form and have been encouraged 
to ask questions.  I have received answers to my questions.  I agree to participate in this study.  I 
will receive a signed copy of this form for my records and future reference.
Study Subject: _________________________________ Print Name
Study Subject: _________________________________ Signature
_______________ Date
Person Obtaining Consent
I have read this form to the subject and/or the subject has read this form.  I will provide the 
subject  with  a  signed  copy  of  this  consent  form  for  their  records  and  future  reference.  
  An 
explanation  of  the  research  was  given  and  questions  from  the  subject  were  solicited  and 
answered  to  the  subject’s  satisfaction.    In  my  judgment,  the  subject  has  demonstrated 
comprehension  of  the  
information.  
  I  have  given  the  subject  adequate  opportunity  to  read 
consent before signing.
_______________________________________________ Print Name and Title
_______________________________________________ Signature
_________________ Date
RSRB Approval Date: 6/13/2019
Expiration Date: 1/21/2020
Complion Document ID: 1248253