Clinical trial NCT02080260
Conditions: Pancreatic Cancer
Sponsor: Wake Forest University Health Sciences
Start date: 2014-06-06; Completion date: 2017-06-28
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study tests regorafenib as a single agent in the treatment of metastatic pancreatic cancer patients who have progressed after prior chemotherapy with gemcitabine. The prognosis for these patients is particularly grim, no other standard treatment options exist, and novel approaches are desperately needed.

Detailed description:
This is a single arm, single stage Phase II study designed to evaluate progression free survival (PFS) in patients with metastatic pancreatic cancer who have failed at least one prior line of therapy and treatment with gemcitabine. This study is open at the Levine Cancer Institute (LCI). A total of 32 patients will be enrolled over a two years. Following informed consent and eligibility check, all patients will start oral regorafenib therapy (120 mg daily for 3 weeks on / 1 week off; 28 day cycle) with a built-in dose escalation to 160mg after the first cycle as tolerated, and will continue therapy until progression or patient withdrawal. Patients will undergo radiological staging after the first two cycles of regorafenib therapy. Patients with progressive disease will be removed from the study. Patients who have at least stable disease will continue regorafenib therapy, at the Investigator's discretion, and will be radiologically restaged bimonthly.

Arms: arm 1: Oral Regorafenib
Interventions: intervention 1: regorafenib
Intervention descriptions: intervention 1: Single agent drug therapy with regorafenib

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Number:  LCI-GI-PAN-REG-001 
Version 7: February 19, 2016 
  
i 
 
Protocol #:  LCI-GI-PAN-REG-001 
TITLE:  A Pilot Study Testing Single-Agent Regorafenib in Advanced Previously-Treated 
Adenocarcinoma of the Pancreas 
LAY TITLE:  A Study of Regorafenib in Advanced Pancreatic Cancer Patients 
Funding Company:  Bayer HealthCare 
Coordinating Center: 
Levine Cancer Institute – Research and Academic Headquarters 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
Sponsor-Investigator: 
J. Stuart Salmon, MD 
101 W. T. Harris Blvd., Suite 1214 
Charlotte, NC 28262 
Telephone:  (704) 863-6169 
Email:  Stuart.Salmon@carolinashealthcare.org 
 
Co-Sponsor-Investigator: 
Edward S. Kim, MD  
1021 Morehead Medical Drive  
Charlotte, NC 28204  
Telephone: (980) 442-3100  
Email:  Edward.Kim@carolinashealthcare.org 
 
Central Radiologist: 
Charlotte Radiology 
1000 Blythe Boulevard, Suite 4 
Charlotte, NC 28203 
Richard Redvanly, MD 
Email:  Richard.Redvanly@carolinashealthcare.org  
 
 
 
 
 
 
 
 
 
 
 
  Study Pathologist: 
Carolinas Pathology Group 
1000 Blythe Boulevard 
Charlotte, NC 28203 
William Ahrens, MD 
Email:  William.Ahrens@carolinashealthcare.org  
 


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Roper Pathologist: 
Coastal Pathology Laboratory 
1128 Lango Avenue 
Charleston, SC 29407 
George F. Worsham, MD 
Email: George.Worsham@rsfh.com 
 
Statistician: 
James Symanowski, PhD 
1100 South Tryon Street, Suite 220 
Charlotte, NC 28203 
Telephone:  (980) 442-2348 
Email:  James.Symanowski@carolinashealthcare.org 
 
CHS Tissue Procurement & Translational Research: 
Carol Farhangfar, PhD 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Telephone: (980) 442-3227 
Email: Carol.Farhangfar@carolinashealthcare.org 
 
MUC1 Studies: 
Pinku Mukherjee, PhD 
University of North Carolina at Charlotte 
9201 University City Blvd 
Charlotte, NC 28223 
Telephone: (704) 687-5459 
Email: pmukherj@uncc.edu  
 
Investigator-Initiated Research Coordinator: 
Melanie Bamberg, MHA, CCRP 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Telephone:  (980) 442-2366 
Email:  Melanie.Bamberg@carolinashealthcare.org  
 
 
 
 
 
 


Protocol Number:  LCI-GI-PAN-REG-001 
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The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
 
 
 
 
 
 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
Sponsor-Investigator is not permitted. 


Protocol Number:  LCI-GI-PAN-REG-001 
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Commercial agents:  Bayer Regorafenib           Original Phase 2 /Version 5 /January 14, 2015 
PROTOCOL SUMMARY 
A. Study Title 
A Pilot Study Testing Single-Agent Regorafenib in Advanced Previously-
Treated Adenocarcinoma of the Pancreas 
B. Indication 
Advanced, second-line pancreatic cancer 
C. Clinical Phase 
II 
D. Summary of 
Rationale 
Patients who have failed the current standard of care therapy, gemcitabine, 
have a dismal expected survival of less than 2.5 months and novel approaches 
are desperately needed. This study tests regorafenib as a single agent in 
advanced, previously treated pancreatic cancer.  Regorafenib is an oral multi-
targeted kinase inhibitor that blocks pathways involved in the growth and 
spread of pancreatic cancer, and preclinical data suggests activity in this 
disease.  Evidence of clinical benefit in this population has the potential to 
lead to subsequent development of the drug in combination with more 
standard chemotherapy treatments earlier in the disease course.   
E. Study 
     Objectives 
The primary study objective is to assess the potential benefit of regorafenib in 
the treatment of advanced, previously-treated pancreatic cancer.  The primary 
objective is to evaluate the 16-week Progression Free Survival (PFS) rate 
relative to historical controls.  Secondary objectives include critical 
examination of Response Rate (RR), Disease Control Rate (DCR), Overall 
Survival (OS), and toxicity.  Tissue and blood samples will be collected for 
analysis of the MUC1 antigen, and future exploratory biomarker analyses. 
F. Sample 
32 subjects 
G. Inclusion/ 
    Exclusion 
-Histologically or cytologically-proven metastatic adenocarcinoma of the 
exocrine pancreas.   
-Life expectancy of at least 8 weeks. 
-ECOG Performance Status 0 – 2. 
-Subjects must have previously undergone at least one documented line of 
chemotherapy for advanced disease and have had prior treatment with 
gemcitabine either as part of adjuvant therapy or for advanced disease.  
H. Dosage, Route, 
and Dose 
Regimen 
Subjects will take 120 mg oral regorafenib (tablets) once daily (with a low-fat 
breakfast) for cycle 1. If well tolerated, the daily dose will be escalated to 160 
mg daily.  Dose reductions will follow protocol guidelines regardless of 
whether subject is dose escalated or not. Each cycle is 28 days, with daily 
dosing for 21 days, followed by a 7 day break.  
I. Statistical 
Analysis 
The frequency and proportion of subjects alive and progression free after 16 
weeks will be calculated, along with a 95% Clopper-Pearson confidence 
interval.  A one-sided test of proportions, with α = 0.10, will be carried out, 
testing the null hypothesis that the 16-week progression free survival 
probability is less than 15%. 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LIST OF ABBREVIATIONS 
 
Regorafenib dose escalation as tolerated to 160mg 
daily for 21 days of each 28 day cycle 
RESTAGING  
every 8 weeks              
Contrasted CT Imaging, 
Central Review  
Progression 
Response/ 
Stable 
Continue Regorafenib until 
progression 
➢ Recurrent/Metastatic Pancreatic Adenocarcinoma 
➢ Prior chemotherapy treatment for advanced disease 
➢ Prior treatment with gemcitabine 
➢ CT scan staging, CA 19-9  
Regorafenib 120mg daily for the first 21 days of 
the first 28 day cycle 
• 
Endpoints 
• 
Primary Endpoint:  PFS (in terms of 16-week progression free survival rate) 
• 
Secondary Endpoints:  RR, DCR, OS, toxicity 
• 
Exploratory Endpoints: Biomarkers in tissue and blood  
• 
Statistical Plan 
• 
This will be a single arm, single stage design 
o 
32 subjects will be enrolled and the final analysis will be conducted on the 
population of subjects who begin regorafenib treatment  
Off Treatment 


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ABBREVIATIONS 
 
ADL 
Activities of Daily Living  
ADR 
Adverse Drug Reaction 
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 
BSR 
Biospecimen Repository 
BUN 
Blood Urea Nitrogen 
c-KIT 
Stem Cell Factor Receptor Tyrosine Kinase 
CHS 
Carolinas Healthcare System 
CR 
Complete Response 
C-RAF 
C isoform of Rapidly Accelerated Fibrosarcoma protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DCE 
Dynamic Contrast Enhanced 
DC-MRI 
Dynamic Contrast-Magnetic Resonance Imaging 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
EIA 
Enzyme Immunoassay 
ERK 
Extracellular Signal-regulated Kinases 
FDA 
Food and Drug Administration 


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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 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IR 
Immediate Release 
IRB 
Institutional Review Board 
LTF 
Lost to follow-up 
MAPK 
Mitogen Activated Protein Kinase 
MEK 
MAP Kinase / ERK Kinase 1 
MUC1 
Mucin1 
NM 
Nano molar 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PD 
Progressive Disease 
PDGFR-β 
Platelet Derived Growth Factor Receptor-beta 
PFS 
Progression free survival 
PO 
Per Oris, oral 
PR 
Partial Response 


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PS 
Performance Status 
PTT 
Partial thromboplastin time 
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 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
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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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY .......................................................................................................... iv 
SCHEMA ....................................................................................................................................... v 
LIST OF ABBREVIATIONS ..................................................................................................... v 
1. OBJECTIVES ........................................................................................................................... 1 
1.1. 
Primary Objective ............................................................................................................ 1 
1.2. 
Secondary Objectives ....................................................................................................... 1 
1.3. 
Exploratory Objectives ..................................................................................................... 1 
2. BACKGROUND ....................................................................................................................... 1 
2.1. 
Study Disease and Treatment History .............................................................................. 1 
2.2. 
Experience with Regorafenib ........................................................................................... 2 
3. SUBJECT SELECTION .......................................................................................................... 6 
3.1. 
Eligibility Criteria ............................................................................................................ 6 
3.2. 
Exclusion Criteria ............................................................................................................. 7 
3.3. 
Registration ...................................................................................................................... 9 
3.4. 
Subject Withdrawal .......................................................................................................... 9 
3.5. 
Screen Failures ............................................................................................................... 10 
3.6. 
Replacement ................................................................................................................... 11 
4. INVESTIGATIONAL PLAN AND STUDY PROCEDURES ........................................... 11 
4.1. 
Milestone Date Definitions ............................................................................................ 11 
4.2. 
Overall Investigational Plan ........................................................................................... 11 
4.3. 
Study Procedures ............................................................................................................ 11 
5. STUDY CALENDAR (see footnotes on next page) ............................................................. 18 
6. TREATMENT PLAN ............................................................................................................ 20 
6.1. 
Drug Administration ...................................................................................................... 20 
6.2. 
Treatment Compliance ................................................................................................... 22 
6.3. 
Duration of Therapy ....................................................................................................... 23 
6.4. 
Drug Accountability ....................................................................................................... 23 


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6.5. 
Destruction ..................................................................................................................... 23 
7. TREATMENT-RELATED ADVERSE EVENTS .............................................................. 24 
7.1. 
Adverse Events Related to Regorafenib......................................................................... 24 
7.2. 
Prevention and Management of Adverse Events ........................................................... 24 
7.3. 
Adverse Event Grading .................................................................................................. 31 
7.4. 
Adverse Event Attribution ............................................................................................. 32 
7.5. 
Adverse Event Action and Outcome .............................................................................. 33 
8. DATA AND SAFETY MONITORING PLAN .................................................................... 33 
8.1. 
Safety Monitoring .......................................................................................................... 33 
8.2. 
Data Quality Assurance .................................................................................................. 34 
8.3. 
Communication Between Investigational Sites.............................................................. 34 
9. SAFETY DATA COLLECTION, RECORDING AND REPORTING ............................ 35 
9.1. 
Unanticipated Problem Definition ................................................................................. 35 
9.2. 
Adverse Event (AE) Definition ...................................................................................... 35 
9.3 
Adverse Drug Reaction (ADR) Definition……………………………………………..37 
9.4. 
“Serious Adverse Event (SAE)” Definition ................................................................... 37 
9.5. 
Serious Adverse Reaction (SADR) Definition............................................................... 39 
9.6. 
“Unexpected” Definition ................................................................................................ 40 
9.7. 
SAE Reporting Requirements ........................................................................................ 40 
9.8. 
Deviation Reporting to the IRB ..................................................................................... 41 
9.9. 
Deviation Reporting to the Funding Company .............................................................. 41 
10. 
MEASUREMENT OF EFFECT .................................................................................... 42 
10.1. Anti-tumor Effect ........................................................................................................... 42 
10.2. Response Criteria ........................................................................................................... 44 
Response will be evaluated using RECIST 1.1 Criteria............................................................ 44 
11. 
STATISTICAL CONSIDERATIONS ........................................................................... 46 
11.1. Sample Size .................................................................................................................... 46 
11.2. Endpoint Definitions ...................................................................................................... 46 
11.3. Analysis Populations ...................................................................................................... 47 
11.4. Analysis Methods ........................................................................................................... 48 
11.5. Interim Analyses ............................................................................................................ 49 


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12. 
STUDY COMPLETION AND TERMINATION ......................................................... 49 
12.1. Completion ..................................................................................................................... 49 
12.2. Termination .................................................................................................................... 50 
13. 
RETENTION OF RECORDS ........................................................................................ 50 
14. 
ETHICAL AND LEGAL ISSUES .................................................................................. 50 
14.1. Ethical and Legal Conduct of the Study......................................................................... 50 
14.2. Confidentiality ................................................................................................................ 51 
15. 
PUBLICATION POLICY ............................................................................................... 52 
REFERENCES…………………………………………………………………………………52 
APPENDICES………………………………………………………………………………….55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
OBJECTIVES 
 
1.1. Primary Objective 
 
The primary study objective is to assess the potential benefit of regorafenib in the 
treatment of advanced previously-treated pancreatic cancer.  The primary endpoint is 
progression free survival (PFS) calculated for each subject and the primary objective 
is to evaluate the 16-week progression free survival rate relative to a historical 
control. 
 
1.2. Secondary Objectives 
 
Secondary objectives include critical examination of Response Rate (RR), Disease 
Control Rate (DCR, defined as CR+PR+SD), Overall Survival (OS), and toxicity.  
 
1.3. Exploratory Objectives 
 
Tissue and blood samples will be collected for MUC1 antigen analyses and future 
exploratory biomarker analyses. 
 
2. 
BACKGROUND 
 
2.1. Study Disease and Treatment History 
 
Approximately 40,000 people will develop pancreatic cancer in the United States this 
year, the great majority of whom will die of their disease.  Only 15-25% of patients 
have surgically resectable disease at the time of diagnosis, and most of those that are 
resected will recur after surgery.  For these reasons, cancer of the pancreas is the 
fourth-leading cause of cancer death in the United States. 
 
Progress in the treatment of advanced pancreatic cancer has been very slow, and 
novel approaches remain desperately needed.  Between the 1950’s and the 1990’s, 5-
fluorouricil was the standard treatment.  However, even with leucovorin-modulated 5-
FU, response rates were only 5-10%, with median survivals of approximately 5 
months.  In 1997, a randomized trial comparing 5-FU with the nucleoside analogue 
gemcitabine suggested a small but clinically and statistically significant benefit for 
the newer agent.1  Gemcitabine demonstrated an improvement in the primary 
endpoint “clinical benefit response,” defined as a composite measure of pain, 
performance status, and weight (24% for gemcitabine vs. 5% for 5-FU), as well as 
improvements in median OS (5.65 months vs. 4.41 months), and 1-year survival 


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(18% vs. 2%).  This study has solidified gemcitabine as a standard therapy for the 
initial treatment of advanced pancreatic cancer. 
 
Attempts to improve upon the rather modest benefit of single-agent gemcitabine have 
met with mixed success.  Phase III studies have combined gemcitabine with 5-FU2, 
cisplatin3, irinotecan4, pemetrexed5, capecitabine6, oxaliplatin7, exatecan8, 
cetuximab9, and bevacizumab10 without a survival benefit over gemcitabine alone.  A 
randomized phase III study demonstrated a clinically small but statistically significant 
survival benefit with the addition of the epidermal growth-factor receptor (EGFR) 
tyrosine kinase inhibitor erlotinib to standard gemcitabine therapy (median OS=6.37 
months vs. 5.91 months, HR=0.82, 95% CI:   0.69-0.99).11  More recently, the 
addition of nab-paclitaxel to gemcitabine demonstrated an improvement in survival 
compared to gemcitabine alone (median OS 8.5 months vs. 6.7 months, HR=0.72, 
95% CI: 0.617-0.835, p=0.000015), which establishes this combination as an 
appropriate first-line standard treatment option in patients with advanced pancreatic 
cancer.12  
 
The only non-gemcitabine based regimen to improve outcomes is the multi-agent 
combination of FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and infusional 
fluorouracil).  A 342 patient randomized study demonstrated a clinically and 
statistically significant improvement in OS (overall survival) for FOLFIRINOX 
compared to single-agent gemcitabine (11.1 months vs. 6.8 months, HR 0.57, 95% 
CI: 0.45-0.73, p<0.0001)13, which makes it an appropriate front-line choice for 
healthier patients who can tolerate this relatively toxic regimen.   
 
Unfortunately, the prognosis for patients who have had failure of previous 
gemcitabine-based therapy is dismal with a median expected survival of less than 2.5 
months.  The randomized phase III CONKO-003 study tested second-line salvage 
therapy with oxaliplatin, folinic acid, and 5-fluorouricil compared to best-supportive 
care, but was stopped early after only 46 patients had been accrued.14 Although this 
study suggested the possibility of clinical benefit with oxaliplatin-fluoropyrimidine 
based therapy, the very small sample size precludes any definitive conclusions.  
Currently, no standard second-line treatment options exist for advanced pancreatic 
cancer.  Thus, we wish to examine regorafenib in this setting. 
 
2.2. Experience with Regorafenib 
 
2.2.1. Pre-clinical 
 
In vivo, regorafenib exhibited anti-angiogenic and anti-proliferative effects in  


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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 monoclonal anti-ERK 1/ 2 antibody demonstrated 
inhibition of the MAPK pathway five days after treatment with regorafenib in 
2 of 3 tumor models examined (MDA-MB 231 and BxPC-3), but not in 
NSCLC (H460). 
 
In addition, all tested human tumor xenografts (MDA-MB-231, H460, BxPC-
3 and Colo-205) demonstrated a significant reduction in new blood vessels by 
histomorphometry as detected in tumor samples using a murine CD31 
antibody.  These data suggest that regorafenib can target the tumor cell 
MAPK pathway (tumor cell survival) and tumor vasculature in some but not 
all tumors. 
 
2.2.2. Clinical 
 
Two phase III global randomized studies have evaluated the efficacy of 
regorafenib. The CORRECT (Patients with metastatic colorectal cancer 
treated with regorafenib or placebo after failure of standard therapy) trial is an 
international, multicenter, randomized, double-blind, placebo-controlled study 
that enrolled 760 patients with mCRC whose disease has progressed after 
approved standard therapies. Metastatic colorectal cancer patients were 
randomized to regorafenib plus best supportive care (BSC) or placebo plus 
BSC. Treatment cycles consisted of 160 mg of regorafenib (or matching 
placebo) once daily for three weeks on / one week off plus BSC. The primary 
endpoint of this trial was overall survival. Secondary endpoints included 
progression-free survival, objective tumor response rate and disease control 
rate. The safety and tolerability of the two treatment groups were also 
compared.15 
 
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 


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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 metastases, number of lines of 
prior therapy, and K-Ras status.15 
 
The most frequent grade 3+ adverse events in the regorafenib group were 
hand–foot skin reaction (17%), fatigue (15%), diarrhea (8%), 
hyperbilirubinemia (8%), and hypertension (7%).15  The efficacy and safety 
from the CORRECT study supported FDA approval in September 2012. 
 
The efficacy and safety of regorafenib was also examined in the Phase III 
GRID trial in patients with gastrointestinal stromal tumors (GISTs) who had 
exhausted all other treatment options. The study involved 199 patients with 
metastatic and/or unresectable GIST that had become resistant to imatinib and 
sunitinib. Patients were randomized 2:1 to regorafenib (160 mg orally once 
daily on a 3 weeks on/1 week off cycle) or placebo, plus best supportive 
care.16 
 
The results showed that treatment with regorafenib led to a statistically 
significant 3.9-month improvement in progression-free survival 
(PFS), compared with placebo (4.8 months vs. 0.9 months; hazard ratio [HR] 
= 0.27; p<.0001). Overall survival was statistically similar between groups as 
expected due to a trial design that allowed crossover to regorafenib for disease 
progression (85% for placebo and 31% regorafenib randomized patients).  The 
overall disease control rate combining partial responses with durable stable 
disease for at least 12 weeks was 53% with regorafenib compared with 9% in 
the control group.  The most common grade ≥3 adverse events associated with 
regorafenib were hand-foot skin reaction (56.1%), hypertension (48.5%), and 
diarrhea (40.9%).16  The efficacy and safety of the GRID study data supported 
FDA approval February 2013. 
 
2.3. Study Rationale 
 
 
Regorafenib is a potent oral inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, 
TIE-2, FGFR-1, KIT, and the RAF protein kinases.  Preclinical studies have 
demonstrated broad-spectrum antitumor activity in xenograft models, with responses 
that correlated both with inhibition of the Ras/Raf/MEK/ERK pathway and reductions 


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in vascular permeability as measured by DC-MRI.17  Phase I trials have shown that 
the drug is well tolerated at doses of 160 mg daily on a 3-weeks-on/1-week-off 
schedule, or 100 mg daily on a continuous schedule, with adverse effects typical of 
other multikinase inhibitors.  Phase III studies include the CORRECT trial, which 
demonstrated an improvement in overall survival from 5.0 months to 6.4 months 
compared to placebo in patients with refractory metastatic colorectal cancer.15  The 
GRID study tested regorafenib in patients with metastatic gastrointestinal stromal 
tumors who had failed previous therapy with imatinib and sunitinib, revealing an 
improvement in PFS from 0.9 months to 4.8 months compared to placebo.16  The 
results of these two studies have led to FDA-approval in patients with advanced, 
previously-treated colorectal cancer and GIST. 
 
Regorafenib has several potential mechanisms of benefit in the treatment of 
pancreatic cancer.  Approximately 90% of all pancreatic cancers exhibit 
constitutively-active mutations in codon 12 of the K-Ras gene.18   Raf-kinase 
inhibition with regorafenib may act as a down-stream target against mutated K-Ras.  
Pancreatic cancer is characterized by a dense desmoplastic tumor stroma which is 
involved in the processes of tumor formation, progression, invasion, and metastasis.19  
The tumor microenvironment is thought to be a dynamic compartment mediated by 
the interaction of pancreatic stellate cells and tumor cells through a variety of 
autocrine and paracrine growth factors, including TGFβ, PDGF, and FGF.  As an 
inhibitor of PDGFR and FGFR, it is possible that regorafenib may be able to disrupt 
some of these pathogenic pathways.   Although specific antiangiogenic inhibition of 
the VEGF pathway with axitinib20 and bevacizumab10 has been disappointing in 
patients with pancreatic cancer, regorafenib has a broader antiangiogenic profile, with 
kinase inhibition of potential escape pathways PDGFR, FGFR, and TIE-2.  
Regorafenib has demonstrated activity in pancreatic xenograft models, and one 
patient with pancreatic cancer had prolonged stable disease to treatment with 
regorafenib (>21 months) in the published phase I experience.21 
 
This study tests regorafenib as a single agent in the treatment of locally advanced and 
metastatic pancreatic cancer patients who have previously failed prior chemotherapy.  
The prognosis for these patients is particularly grim, no other standard treatment 
options exist, and novel approaches are desperately needed.  Treatment with single-
agent regorafenib could be a platform to examine the biology of the disease through 
exploratory blood and tissue biomarker analyses.  Furthermore, if there is evidence of 
clinical benefit in this population, this study has the potential to lead to subsequent 
development of the drug in combination with more standard chemotherapy treatments 
earlier in the disease course.   
 
 


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2.3.1. TAB 004 Studies 
 
In a collaborative study with the Hepatobiliary and Pancreas Surgery Department  
at Carolinas Medical Center, a novel antibody (TAB 004) based enzyme  
immunoassay (EIA) has been shown to detect circulating MUC1 in a stage- 
dependent manner in patients with pancreatic cancer.23 Furthermore, circulating  
levels of MUC1 correlated with its tissue expression. This study presents a unique 
opportunity to use the TAB 004 EIA and evaluate it as an indicator of  
regorafenib treatment efficacy. Protocol type TAB 004 EIA kits (manufactured at  
a GMP certified facility) will be provided by CanDiag, Inc. 
 
3. 
SUBJECT SELECTION 
 
3.1. Eligibility Criteria 
 
a. Histologically or cytologically-proven adenocarcinoma of the exocrine pancreas 
with locally advanced or metastatic disease.   
b. The site of the primary tumor must have confirmed endosonographically, 
surgically, or radiographically to have been within the pancreas. 
c. Patients must have had progression on at least one prior line of chemotherapy for 
locally-advanced or metastatic pancreatic cancer. 
d. Patients must have had tumor progression on or within 3 months of treatment with 
a gemcitabine regimen for advanced pancreatic cancer, or within 12 months of 
treatment with gemcitabine as part of adjuvant therapy. 
e. All patients must have measurable disease on axial imaging (RECIST 1.1). 
f. Age ≥ 18 years. 
g. Life expectancy of at least 8 weeks at time of eligibility. 
h. ECOG Performance Status 0 – 2.  Enrollment of patients with PS=2 will be 
capped at 7 patients. 
i. 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. 
j. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 
Grade 1 or less at the time of registration .  Exceptions to this include alopecia. 
k. Adequate bone marrow, renal, and liver function as assessed by the following 
laboratory requirements: 
• Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) 
• Alanine aminotransferase (ALT) and aspartate amino-transferease (AST)  
≤ 2.5 x ULN (≤ 5 x ULN for subjects with malignant liver involvement or 
presence of a biliary stent) 


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7 
 
• Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with 
liver involvement of their cancer) 
• Lipase ≤ 1.5 x the ULN 
• Amylase ≤ 1.5 x the ULN 
• Serum creatinine  ≤ 1.5 x the ULN 
• International normalized ratio (INR)/ Partial thromboplastin time (PTT) 
≤1.5 x ULN. Subjects who are prophylactically treated with an agent such 
as warfarin or heparin will be allowed to participate provided that no prior 
evidence of underlying abnormality in coagulation parameters exists. 
Close monitoring of at least weekly evaluations will be performed until 
INR/PTT is stable based on a measurement that is pre-dose as defined by 
the local standard of care. (See Section 4.2.7) 
• Platelet count >100000 /mm3, hemoglobin (Hb) >9 g/dL, absolute 
neutrophil count (ANC) ≥ 1500/mm3.  Blood transfusion within 72 hours 
to meet the inclusion criteria will not be allowed. 
l. Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2 according to the Modified 
Diet in Renal Disease (MDRD) abbreviated formula. 
m. Women of childbearing potential must have a negative urine pregnancy test 
performed within 7 days prior to the start of study drug.  Post-menopausal women 
(defined as no menses for at least 1 year) and surgically sterilized women are not 
required to undergo a pregnancy test.   
n. Patients (men and women) 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 Investigator.  
o. Patient must be able to swallow and retain oral medication. 
 
3.2. Exclusion Criteria 
 
a. Previously received treatment during this study.  Subjects permanently withdrawn 
from study participation will not be allowed to re-enter study. 
b. Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure 
> 90 mm Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal 
medical management. 
c. 
Active or clinically significant cardiac disease including: 
i.Congestive heart failure – New York Heart Association (NYHA) > Class 
 
2. 
ii.Active coronary artery disease. 
iii. 
Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers or digoxin. 


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iv. 
Unstable angina (anginal symptoms at rest), new-onset angina within 3 
months before registration, or myocardial infarction within 6 months 
before registration. 
d. Cerebrovascular arterial event (such as transient ischemic attack or 
cerebrovascular accident) within 6 months of registration. 
e. Evidence or history of bleeding diathesis or coagulopathy. 
f. Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior 
to start of study medication.  
g. Patients with new venous thrombotic or embolic events, such as deep vein 
thrombosis or pulmonary embolism within 3 months of start of study medication.  
Older events are permitted if the patient is on stable treatment doses of 
anticoagulation. 
h. Patients with any previously untreated or concurrent cancer that is distinct in 
primary site or histology except cervical cancer in-situ, treated ductal carcinoma 
in situ of the breast, curatively treated nonmelanoma skin carcinoma, noninvasive 
aerodigestive neoplasms, or superficial bladder tumor.  Subjects surviving a 
cancer that was curatively treated and without evidence of disease for more than 3 
years before registration are allowed. All cancer treatments must be completed at 
least 3 years prior to registration. 
i. Patients with pheochromocytoma. 
j. Known history of human immunodeficiency virus (HIV) infection or current 
chronic or active hepatitis B or C infection requiring treatment with antiviral 
therapy. 
k. Ongoing infection ≥ Grade 2 NCI-CTCAE v4.0. 
l. Symptomatic metastatic brain or meningeal tumors. 
m. Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
n. Renal failure requiring hemo-or peritoneal dialysis. 
o. Dehydration Grade >1 NCI-CTCAE v4.0. 
p. Patients with seizure disorder requiring medication. 
q. Persistent proteinuria  Grade 3 NCI-CTCAE v4.0 (>3.5 g/24 hrs, measured by 
urine protein: creatinine ratio on a random urine sample). A urine protein test is 
not required to confirm eligibility unless patient has recent history of proteinuria. 
r. Interstitial lung disease with on-going signs and symptoms at the time of informed 
consent.  
s. Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE 
version 4.0 Grade 2 dyspnea). 
t. History of organ allograft. Previous corneal transplant 3 months or more before 
registration is permitted. 
u. Known or suspected allergy or hypersensitivity to the study drugs. 
v. Any severe, uncontrolled malabsorption condition. 


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w. Women who are pregnant or breast-feeding. 
x. Any condition which, in the Investigator’s opinion, makes the subject unsuitable 
for trial participation. 
y. Substance abuse, medical, psychological or social conditions that may interfere 
with the subject’s participation in the study or evaluation of the study results. 
z. Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) other than study 
treatment (regorafenib). 
aa. Prior use of regorafenib. 
bb. Concurrent use of another investigational drug or device therapy (i.e., outside of 
study treatment) during, or within 4 weeks of trial entry (signing of the informed 
consent form). 
cc. Major surgical procedure, open biopsy, or significant traumatic injury within 28 
days before start of study medication. 
dd. Prior radiation therapy or hepatic arterial regional therapy is permitted if more 
than 4 weeks have passed since completion of the treatment and measurable 
disease outside of the treated area is present or if progression since treatment has 
occurred. 
ee. Use of St. John’s wort (Hypericum perforatum). 
 
3.3. Registration 
 
Subjects will be registered and assigned a Study ID number. The Study ID number 
will begin with “LCI” and include a two digit number identifying the enrolling 
investigational site, followed by a two digit number sequentially assigned to the 
subject. (e.g. “LCI0101” will be the Study ID number assigned to the first subject at 
the coordinating center.) A Protocol Registration Form will be completed for each 
subject.  
 
3.4. Subject 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. 


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• Pregnancy.  Pregnancy will be reported as an SAE.  (Note: Subjects who have 
been withdrawn from treatment with study drug because of pregnancy should 
not undergo CT scans [with contrast]/MRI or bone scans while pregnant.) 
• 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 after three consecutive months of attempted 
contact. 
• 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.  
• 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. 
 
• Any other (non-disease related) reason, at the Investigator’s discretion. 
 
Any subject removed from the trial will remain under medical supervision until 
discharge or transfer is medically acceptable. 
 
In all cases, the reason for withdrawal must be recorded in the 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, treatment arms, dose steps]) are provided in Section 12.2. 
 
3.5. Screen Failures 
 
A subject who, for any reason (e.g. failure to satisfy the selection criteria or 
withdraws consent), terminates the study before receiving first dose of study drug is 
regarded a “screen failure”.   
 


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All screen failures will be tracked in the CTMS (clinical trial management system). 
 
3.6. Replacement 
 
Subjects who withdraw consent after receiving first dose of study drug will not be 
replaced.  Screen failures may be replaced. 
 
4. 
INVESTIGATIONAL PLAN AND STUDY PROCEDURES 
 
4.1. Milestone Date Definitions 
 
Eligibility date: the date when the last procedure occurred that confirmed subject 
eligibility. 
Enrollment date: the date of initiation of regorafenib treatment. 
Treatment discontinuation date: the date the Investigator decides to discontinue the 
subject from regorafenib treatment. 
 
4.2. Overall Investigational Plan 
 
This is a single arm, single stage Phase II study designed to evaluate progression free 
survival in patients with locally-advanced or metastatic pancreatic cancer who have 
failed at least one prior line of therapy.  This study will initially open at LCI.  
Additional investigational site(s) beyond the coordinating site will be added following 
activation. A total of 32 subjects will be enrolled to this study over a two year accrual 
period.  Following informed consent and eligibility check, all patients will start oral 
regorafenib therapy and will continue therapy until progression or patient withdrawal.  
Treatment must start within 7 days of the eligibility date.  Subjects will undergo 
radiological staging after the first two cycles of regorafenib therapy.  Subjects with 
progressive disease as assessed by RECIST 1.1 will be removed from the study. 
Subjects who have at least stable disease will continue regorafenib therapy, at the 
Investigator’s discretion, and will be radiologically restaged bimonthly.  The overall 
duration of the study is expected to be no longer than 24 months.   
 
Data from this study will be collected on electronic case report forms (eCRFs).   
 
4.3. Study Procedures 
 
4.3.1. Informed Consent  


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Written informed consent will be obtained from each subject prior to 
undergoing protocol-specific evaluations or procedures and prior to receiving 
treatment.   In addition, all subjects will provide authorization for the release 
of their medical records for research purposes. 
 
4.3.2. Demographics and Medical/Treatment History 
 
Demographics and medical/treatment history will be collected during the 
screening visit. Medical and treatment history (oncological and relevant non-
oncological) will be collected and recorded in the eCRF.  Cancer history will 
be obtained and the following information (including but not limited to) will 
be reported in the eCRF: 
 
• Date of first histological/cytological diagnosis 
• Primary tumor site 
• Tumor histology and characteristics 
• Prior cancer therapy 
 
All medical history findings that occurred prior to the patient signing 
informed consent will be documented. 
 
4.3.3. Pregnancy Test 
 
A urine pregnancy test will be performed at screening and as clinically 
indicated for women of childbearing potential.  Women who are pregnant 
and/or breast-feeding are ineligible for study participation. Women will be 
counseled regarding risk of teratogenicity and need to use contraception 
through the course of the study.  Men will also be counseled on the need to 
use contraception for all sexual encounters. 
 
4.3.4. Office Visit 
 
Physical exam and documented evaluation by body system, height (screening 
only), and weight will be documented during screening, repeated at Week 0 (if 
not within 7 days of study treatment) and at each treatment visit.  Vital signs 
will be recorded and should include temperature, pulse rate, respiratory rate, 
blood pressure and oxygen saturation (screening and treatment).  ECOG 
performance status will be assessed during the screening and treatment visits.  
Blood pressure will be monitored weekly for the first 6 weeks of treatment 


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and then every two weeks, or as clinically indicated.  Office visits will occur 
according to the Study Calendar in Section 5. 
 
4.3.5. Adverse Event Assessment 
 
All adverse events and serious adverse events will be monitored and 
documented (regardless of grade or attribution) and reported to applicable 
agencies on an ongoing basis beginning at screening.  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. 
 
4.3.6. Concomitant Medications 
 
All medication that is considered necessary for the subject’s welfare, and 
which is not expected to interfere with the evaluation of the study treatment, 
may be given at the discretion of the Investigator.  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 the drug, 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 strong CYP3A4 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 therapies include: 
• Standard therapies for concurrent medical conditions. 
• Supportive care for any underlying illness. 


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• 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. 
• Subjects who are therapeutically treated with an agent such as warfarin or 
heparin will be allowed to participate provided that their medication dose 
and INR/PTT are stable.  Close monitoring (within 7 days of the 
enrollment date and as clinically indicated) is mandatory.  If either of 
these values are above the therapeutic range, the doses should be 
modified and the assessments should be repeated weekly until they are 
stable. 
• Subjects taking narrow therapeutic index medications should be 
monitored proactively (e.g. warfarin, phenytoin, quinidine, 
carbamazepine, Phenobarbital, cyclosporin, and digoxin).  Warfarin is 
metabolized by the cytochrome enzyme CYP2C9 and its levels may be 
especially affected by regorafenib. 
The following are not permitted: 
• Other investigational treatment during or within 30 days before starting 
study treatment. 
• Systemic antitumor therapy, including cytotoxic therapy, signal 
transduction inhibitors, immunotherapy, and hormonal therapy. 
• Bone marrow transplant or stem cell rescue. 
• Use of St. John’s wort (Hypericum perforatum).  Use of other herbal 
remedies is discouraged, and is permitted only with the specific assent of 
the Investigator.  All herbal and vitamin supplement use must be 
carefully documented. 
 
4.3.7. Laboratory Tests 
 
The blood-based clinical laboratory tests will include a complete blood count 
with differential and platelets, a basic metabolic panel (including sodium, 
potassium, chloride, bicarbonate, BUN, creatinine, glucose, and calcium.), and 


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liver function tests (Albumin, Alkaline phosphatase, ALT (SGPT), AST 
(SGOT), Direct Bilirubin, Total Bilirubin, and Total Protein) which will be 
performed at screening and then again prior to the first dose of regorafenib if 
the enrollment date is not within 7 days of eligibility confirmation. After 
enrollment, a complete blood count with differential and platelets and a 
comprehensive metabolic panel (including sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, glucose, calcium, albumin, alkaline phosphatase, 
ALT (SGPT), AST (SGOT), total bilirubin, and total protein) will be 
performed every 2 weeks according to the Study Calendar.  LDH and CA 19-9 
will be collected at Week 0 and then every 4 weeks according to the Study 
Calendar.  Amylase, lipase, coagulation panel (INR, PT, PTT), and pregnancy 
test (in appropriate subjects) will be collected at screening.   
 
4.3.8. Radiology and Tumor Measurements 
 
A CT (computed tomography) scan with oral and intravenous contrast of the 
chest, abdomen and pelvis will be performed within 28 days prior to the first 
dose of regorafenib (screening scan).  After enrollment, scans will then be 
performed every eight weeks (+/- 2 weeks). A contrast-enhanced MRI of the 
abdomen and pelvis and an uncontrasted CT scan of the chest may be 
substituted if clinically necessary; however, subsequent studies must be 
performed using the same imaging modality throughout the study period. 
Scans will be submitted for Central Radiology review per Section 10.1.4. 
 
Every effort will be made to obtain imaging studies and tumor assessments 
every 8 weeks (+/- 2 weeks) until documented progression for subjects who 
had a complete response, partial response, or stable disease, and/or 
discontinued study therapy due to toxicity or reasons other than progressive 
disease.   
 
4.3.9. Archived Tissue and Blood-based Biomarkers 
 
Tissue and serum will be collected and made available for analysis for 
exploratory biomarker correlates by LCI.  For subjects who have archived 
tissue, the subject agrees to tissue collection being included in this study by 
signing the informed consent form. Tissue will be requested after 
confirmation of study eligibility.  Subjects may be asked to undergo an 
optional core biopsy after providing additional written informed consent.  
Subjects will not be excluded from this study if they choose not to undergo the 
optional core biopsy. Core biopsy samples will be collected per standard 


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operating procedures and submitted fresh within 15 minutes of collection to 
the Carolinas Medical Center Pathology Laboratory where they will be snap 
frozen and stored at -80°C or moved to the Carolinas HealthCare System 
Biospecimen Repository (BSR) until biomarker testing. Core biopsy samples 
collected at investigational sites other than the Coordinating Site will be 
processed and shipped on the day of collection, fresh, on dry ice to Carolinas 
Medical Center Pathology Laboratory:  
 
 
William Ahrens, M.D. 
Carolinas Medical Center 
Pathology Laboratory 
1000 Blythe Boulevard 
Charlotte, NC 28203 
Phone: (704) 355-0519 
 
Archived paraffin or fresh frozen tissue samples will be from investigational 
sites other than the Coordinating Site and stored in the CHS BSR for later 
study.  Although not formally part of the initial protocol, biomarkers related to 
the angiogenic, RAS-RAF and Mek-Erk pathways, may be tested at a later 
date.  These include, but are not limited to the presence of KRAS, NRAS, 
HRAS, BRAF, p53, KDR, KIT, FGFR1, and PDGFRA mutations.  
Additionally, archived tissue will be examined for Mucin1 (MUC1) at the 
University of North Carolina at Charlotte.  
 
Plasma and serum from subjects will be collected using two ethylene diamine 
tetraacetic (EDTA) (10 mL) tubes and one serum collection tube. Samples 
will be  processed within one hour of collection, if possible, but may be kept 
at 4°C for no longer than 4 hours before processing and then stored at -80°C 
until future testing.  Samples will be stored at the CHS BSR.  
 
Samples will be collected at scheduled intervals, according to the schedule in 
Section 5. Baseline samples will be collected after subject eligibility 
confirmation, but prior to administration of the first dose of regorafenib. One 
serum sample will be stored in the CHS BSR for later study while the second 
serum sample, if possible to obtain, will be provided to the University of 
North Carolina at Charlotte for MUC1 analysis. Exploratory biomarker arrays 
may be used to detect changes in baseline, on-treatment and post-treatment 
levels of sVEGFR-1, sVEGFR-2, sVEGF, HGF, SCF, PLGF, sTie-2, IL16, 
TGF-β1, PDGF-AA, PDGF-BB, angiopoietin-1, and FGF levels.  
 


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Specimen collection and processing data will be recorded in the CTMS. All 
specimens will be labeled appropriately with the protocol number, subject ID 
number, and date of collection.  
 
Future tissue and blood-based biomarkers not described in this protocol may 
also be examined.   
 
4.3.10. Subsequent Therapy and Survival Status 
 
Once subjects complete their Off Treatment visit, they will be followed until 
all treatment-related toxicities have resolved, returned to baseline, stabilized, 
or are deemed irreversible.  Subject’s cancer therapies following completion 
of treatment on this study and survival status will be documented.   
 
Subjects (or their family members or designees) may be contacted by 
telephone, in writing, or during clinic visits after treatment discontinuation for 
collection of long-term follow-up data every month until death or lost to 
follow-up. Long-term follow-up clinical information may also be obtained 
through chart reviews. 
 
 


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5. STUDY CALENDAR (see footnotes on next page) 
Required 
Procedures 
Screening 
Study Week 
Off 
Treatment 
Follow-up 
0 
1 
2 
3 
4 
5 
6 
8 
10 h 
12 h 
14 h 
16 h 
 
Within 28 
days of 
treatment 
initiation 
Start 
C#1 
 
 
 
Start 
C#2 
 
 
Start 
C#3 
 
Start 
C#4 
 
Start 
C#5 
Within 30 
days of last 
drug dose 
Every 
month 
until death 
or LTF 
Informed Consent 
and HIPAA waiver 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(urine) a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs with 
Blood Pressurek 
Xj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Office Visit 
Xj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event 
Assessment 
Xj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
Medications 
Xj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dose Assessment b 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Basic Study Labs c 
Xj 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
LDH, CA 19-9 d 
 
Xj 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
Amylase, Lipase & 
Coagulation Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Scan e 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Translational Blood 
Biomarkersi 
 
Xj 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Archived Tissue 
Collection f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Core Biopsy g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subsequent 
Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


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a:  In women of child-bearing potential 
b:  Dose escalation can be considered up to 160 mg maximum dose, per section 6.1.1.2. 
c:  Screening and Week 0 (if applicable): Complete blood count, basic metabolic panel, and liver function tests; then subsequent visits: complete blood count and comprehensive 
metabolic panel per sections 4.3.7.  
d:  Week 0, then every 4 weeks per section 4.3.7. 
e:  Screening scan should be within 28 days prior to treatment initiation, then every 8 weeks.  Radiography with tumor measurements and central radiology review will  
     be done per section 4.3.8. 
f:  If available; attempt to collect archived tissue can be made at any time after subject eligibility confirmation. 
g:  Optional; may be requested at any time if subject consents. 
h:  After week 16, the schedules for weeks 10-16 repeat themselves for subjects who are still on study (i.e. week 18 as per week 10 schedule, week 20 as per week 12, etc.) 
i:  Screening biomarker specimens must be collected after eligibility confirmation, but prior to the first dose of regorafenib. 
j:  Must be performed within 7 days before treatment initiation. 
k: Vital signs to include: temperature, pulse rate, respiratory rate, oxygen saturation rate and blood pressure. 


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6. 
TREATMENT PLAN 
 
6.1. Drug Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications are  
described in Section 7.   
 
No investigational or commercial agents or therapies other than regorafenib may be 
administered with the intent to treat the subject's malignancy.  Medication that is 
considered necessary for the subject’s welfare, and which is not expected to interfere 
with the evaluation of the study treatment, may be given at the discretion of the 
Investigator.  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 strong CYP3A4 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). 
6.1.1. Regorafenib Dosage and Administration 
 
6.1.1.1. 
Initial Regorafenib Dosage and Administration (Cycle 1) 
 
Regorafenib will be started within 7 days of the eligibility date .  
Regorafenib is administered orally as monotherapy at 120 mg daily  
for 21 days on /7 days off.  Subjects will take three 40-mg 
regorafenib oral tablets (total dose 120 mg) each morning with a 
low-fat breakfast and approximately 8 fluid ounces (240mL) of 


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water for 21 days.  Under the direction of the Investigator, subjects 
may take regorafenib at a time other than the morning, as long as it 
is taken with a low-fat meal as above, and it is taken at the same 
time each day.     
Subjects will not take regorafenib the following 7 days.  One cycle 
is 28 days.  Cycle start may be delayed up to 5 days. 
 
6.1.1.2. 
Regorafenib Dose Escalation (Cycle 2 and Subsequent Cycles) 
 
After the first cycle of therapy on study and at the start of cycle 2, 
subjects who have no worse than grade 1 toxicity (CTCAE v4) will 
have a dose escalation up to 160 mg daily, taken for 21 days 
followed by 7 days off.  Subjects with clinically significant grade 2 
or higher toxicity considered possibly, probably, or definitely 
related to regorafenib, OR, in the Investigator’s opinion, may 
adversely impact the safety of the subject will not have a dose 
escalation (excluding alopecia, non-refractory nausea/vomiting, 
non-refractory hypersensitivity and nonclinical and asymptomatic 
laboratory abnormalities).  Subjects who undergo dose escalation 
up to 160 mg will take four 40 mg regorafenib oral tablets each 
morning as per section 6.1.1.1.  Dose reduction for toxicity will 
follow standard protocol guidelines (see section 7.2).   
 
Dose escalation by 1 level (i.e. from dose level -1 to dose level 0, 
or from dose level -2 to dose level -1) can be considered as above 
at the treating Investigator’s discretion at the beginning of each 
subsequent 28 day cycle for any subject who has no worse than 
clinically-significant grade 1 toxicity.  Doses beyond 160 mg are 
not permitted.   Dose reduction for toxicity will follow standard 
protocol guidelines, whether or not dose escalation had previously 
occurred. 
 
6.1.2.  Regorafenib Drug Supply 
 
Regorafenib tablets for oral administration are formulated as light pink oval 
shaped tablets debossed with “BAYER” on one side and “40” on the other.  
Each tablet contains 40 mg of regorafenib in the anhydrous state, which 
corresponds to 41.49 mg of regorafenib monohydrate, and the following 
inactive ingredients: cellulose microcrystalline, croscarmellose sodium, 
magnesium stearate, povidone, and colloidal silicon dioxide.   The film –


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coating contains the following inactive ingredients: ferric oxide red, ferric 
oxide yellow, lecithin (soy), polyethylene glycol 3350, polyvinyl alcohol, talc, 
and titanium dioxide. 
 
Regorafenib will be supplied by Bayer HealthCare through their Investigator 
Sponsored Study (ISS) Portal located at the following website: 
 
http://www.iss.bayer.com/ 
 
The Sponsor-Investigator will provide Portal access to the investigational 
pharmacist(s) for the purpose of managing drug supply and shipment.  
 
The LCI investigational pharmacy will receive regorafenib tablets 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). Temperature 
excursions of 15-30°C (59-86°F) are acceptable.  
 
The study drug must be exclusively used for the investigation specified in this 
protocol and it will only be accessible to authorized staff. 
 
Bottles dispensed to subjects will be labeled as “Investigational” and subjects 
should comply with the following directions: 
 
• Store tablets in the original bottle, once opened use within 28 days 
• Take tablet at the same time daily, with breakfast containing less than 
30% fat (Appendix A) 
• Swallow tablet whole 
• If dose is missed, do not take 2 doses in one day 
 
6.2. Treatment Compliance 
An adequate record of receipt, distribution, and return of all study drugs must be 
documented on a Drug Accountability Form. 
Study drug will be dispensed to subjects, and the pills bottles returned to LCI Clinical 
Trials staff according to LCI standard operating procedures. IDS Pharmacy staff will 
report the number of pills in the bottles returned to LCI Clinical Trials. The number 


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of pills the subjects take per cycle will be derived from these pill counts rather than 
reported by the subjects on a pill diary.  
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 Sponsor-Investigator, a subject may be discontinued from the 
trial for non-compliance with follow-up visits or study drug. 
6.3. Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment will continue 
until one of the following criteria applies: 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s), 
• 
Subject decides to withdraw from the study, or 
• 
General or specific changes in the subject's condition render the subject 
unacceptable for further treatment in the judgment of the Investigator. 
 
6.4. Drug Accountability 
All study drugs will be stored at the investigational pharmacy in accordance with 
Good Clinical Practice (GCP) and Good Manufacturing Practices (GMP) 
requirements and will be inaccessible to unauthorized personnel. 
An adequate record of receipt, distribution, and destruction of all study drugs must be 
documented on a Drug Accountability Form. The Investigator, or a responsible party 
designated by the Investigator, will maintain a careful record of the inventory using 
the Drug Accountability Form. 
6.5. Destruction  
At the end of the study, unused supplies of regorafenib will be destroyed according to 
LCI IDS pharmacy policies. Destruction will be documented in the Drug 
Accountability Form and sent to Bayer at the following address: 
 
Email: joy.wang1@bayer.com  
Mail:  Joy Wang  
Bayer HealthCare Pharmaceuticals 
100 Bayer Boulevard 
Whippany, NJ 07981 
Phone: (862) 404-5333 
 


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7. 
TREATMENT-RELATED ADVERSE EVENTS 
 
7.1. Adverse Events Related to Regorafenib 
 
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 AEs in the following 
sections, the Investigator should immediately notify the appropriate agencies as 
outlined in Section 9. 
 
 
7.2. Prevention and Management of Adverse Events 
 
7.2.1. Dose Modifications for Adverse Events 
The starting dose of regorafenib is 120 mg once daily (starting dose 
level -1) but with a planned dose escalation (to dose level 0) with cycle 
2 if less than grade 2 clinically significant toxicity (per the 
Investigator) is experienced (see section 6.1.1.2).  Study medication will 
be administered on a 21 days on/7 days off schedule (3 weeks out of every 
4). Doses will be delayed or reduced for clinically significant hematologic 
and non-hematologic toxicities that are related to protocol therapy 
according to the guidelines shown in the Dose Delays/Dose Modifications 
table that follows.  Dose modifications will follow predefined dose levels. 
Dose adjustments for hematologic toxicity are based on the blood counts 
obtained in preparation for the day of treatment. 
 
The modifications of regorafenib will follow the following predefined dose levels: 
Dose level 0 
160 mg po daily 
Four 40-mg tablets of regorafenib 
Dose level -1 
120 mg po daily  
Three 40-mg tablets of regorafenib 
Dose level -2 
80 mg po daily  
Two 40-mg tablets of regorafenib 
 
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 treatments.  If 
treatment is held for more than 4 weeks due to toxicity or if dose 
reductions beyond dose level -2 are necessary, then treatment will be 
permanently discontinued. 
 


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7.2.2. Dose Adjustments for Adverse Events (other than hand-foot-skin 
 reaction, hypertension and liver function test abnormalities) 
 
The following tables outline dose adjustments for toxicities related to 
study drug except hand-foot skin reaction, hypertension and liver function 
test abnormalities.  
 
Table 7.1:  Recommended dose modification for toxicities except hand-foot-skin reaction, 
hypertension and ALT/AST/Total Bilirubin 
NCI-CTCAE 
v4.0a 
Dose Interruption 
Dose  
Modificationb 
Dose for Subsequent Cycles 
Grade 0-1 
Treat on time 
No change 
Dose escalation or No 
change (see section 6.1.1.2) 
Grade 2 
Treat on time 
No change 
No change 
Grade 3 
Delay until ≤ Grade 
2c 
Reduce by 1 dose 
level 
If toxicity remains < Grade 
2, dose re-escalation can be 
considered at the discretion 
of the treating Investigator. If 
dose is re-escalated and 
toxicity (≥ Grade 3) recurs, 
institute permanent dose 
reduction. 
Grade 4 
Delay until ≤ Grade 
2c 
Reduce by 1 dose 
level. 
Permanent 
discontinuation 
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 nonclinical and 
asymptomatic laboratory abnormalities. 
c. If no recovery after a 4 week delay*, treatment should be permanently discontinued  
 


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The table above outlines dose adjustments for hematologic and non-
hematologic toxicities related to regorafenib except HFSR and 
hypertension.  In addition to these recommended dose modifications, 
subjects who develop diarrhea, mucositis, anorexia or other events 
predisposing to fluid loss or inadequate fluid intake should be carefully 
monitored and rehydrated as clinically necessary.  This is in order to 
minimize the risk of postural hypotension and renal failure. 
 
7.2.3. Grading and Dose Adjustments for Hand-Foot-Skin Reaction (HSFR) 
 
 
 
Table 7.2: 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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At first occurrence of HFSR, independent of grade, prompt institution of supportive 
measures such as topical emollients, low potency steroids, or urea-containing creams 
should be administered. 
Recommended prevention/management strategies for skin toxicities consistent with 
HFSR are summarized below: 
Control of calluses 
Before initiating treatment with regorafenib: 
Table 7.3  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 immediately institute 
supportive measures for symptomatic relief 
Grade 2 
 
1st occurrence 
Consider decreasing dose by one dose level and 
immediately institute supportive measures.  If no 
improvement, interrupt therapy for a minimum of 7 
days, until toxicity resolves to Grade 0-1 b, c 
No improvement 
within 7 days or 2nd 
occurrence 
Interrupt therapy until toxicity resolves to Grade 0-
1.c 
When resuming treatment, treat at reduced dose 
level b 
3rd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-
1. c 
When resuming treatment, decrease dose by one 
dose level. b, d 
4th occurrence 
Discontinue therapy 
Grade 3 
 
1st occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity 
resolves to Grade 0-1. c When resuming treatment, 
decrease dose by one dose level. b, d 
2nd occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity 
resolves to Grade 0-1. c When resuming treatment, 
decrease dose by one additional dose level b, d  
3rd occurrence 
Discontinue treatment permanently. 
a. More conservative management is allowed if judged medically appropriate by the Investigator. 
b. If toxicity returns to Grade 0-1 after dose reduction, dose re-escalation is permitted at the discretion of the 
Investigator if subject has completed one cycle at reduced dose without recurrence of event. 
c. If there is no recovery after a 4-week delay, treatment with regorafenib will be discontinued permanently. 
d. Subjects requiring > 2 dose reductions should go off protocol therapy. 
e. The maximum daily dose is 160 mg. 


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• Check condition of hands and feet. 
• Suggest a manicure/pedicure, when indicated. 
• Recommend pumice stone use for callus or ‘rough spot’ removal. 
 
During regorafenib treatment: 
• Avoid pressure points. 
• Avoid items that rub, pinch or create friction. 
 
Use of creams 
• Non-urea based creams may be applied liberally. 
• Keratolytic creams (e.g. urea-based creams, salicylic acid 6%) may be 
used sparingly and only to affected (hyperkeratotic) areas. 
• Alpha hydroxyl acids (AHA) based creams may be applied liberally 2 
times a day.  Approximately 5% to 8% provides gentle chemical 
exfoliation. 
• Topical analgesics (e.g. lidocaine 2%) are to be considered for pain 
control. 
• Topical corticosteroids like clobetasol 0.05% should be considered for 
subjects with Grade 2 or 3 HFSR.  Avoid systemic steroids. 
Tender areas should be protected as follows: 
• Use socks/gloves to cover moisturizing creams 
• Wear well-padded footwear 
• Use insole cushions or inserts (e.g. silicon, gel) 
• Foot soaks with tepid water and Epson salts 
 
7.2.4. Grading and Dose Adjustments for Hypertension 
Hypertension is a known AE associated with regorafenib treatment.  Subject will have their 
blood pressure measured at least weekly at the study site during the first 6 weeks of treatment.  If 
additional blood pressure measurements are done outside the study site, and the blood pressure is 
> 140 mm Hg systolic or > 90 mm Hg diastolic (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 7.4 outlines suggested dose 
reductions. 
 


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Table 7.4:  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 subject 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. Subjects 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. 


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7.2.5. Dose Adjustments for Liver Function Test Abnormalities 
 
For subjects with observed worsening of serum liver tests considered 
related to regorafenib (i.e. where no alternative cause is evident, such as 
post-hepatic cholestasis or disease progression), the dose modification and 
monitoring advice in Table 7.5 should be followed. 
 
Regorafenib is a UGT1A1 inhibitor.  Mild, indirect (unconjugated) 
hyperbilirubinemia may occur in subjects with Gilbert’s syndrome. 
 
Table 7.5:  Dose modifications/interruption for ALT and/or AST and/or Total Bilirubin 
increases related to study drug 
Observed elevations 
1st Occurrence 
Restart 
Re-occurrence 
 
baseline G0  G1 
 
or 
 
baseline G1  G2 
 
 
 
Treat on time and check 
AST, ALT and bilirubin 
2x/week for 2 weeks 
followed by weekly 
assessments for at least 4 
weeks. 
 
 
 
Treat on time and 
check AST, ALT 
and bilirubin 
2x/week for 2 weeks 
followed by weekly 
assessments for at 
least 4 weeks. 
 
baseline G0  G2 
  
 
 
Delay until ≤  G1 and 
check AST, ALT, 
bilirubin 2x/week. 
 
 
 
Reduce 1 dose 
level and check 
AST, ALT, 
bilirubin 2x/week 
for 2 weeks 
followed by 
weekly 
assessments for at 
least 4 weeks.a 
 
 
 
Discontinue 
c.   Subjects requiring >2 dose reductions should go off protocol therapy. 


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Baseline any grade  G3  
Delay until ≤  G1 if 
baseline was G0 or G1 
OR until G2 if baseline 
was G2. 
 
Check AST, ALT, 
bilirubin 2x/week. 
 
If ALT or AST > 8 x 
ULN with a concomitant 
rise in bilirubin (of any 
degree) compared to 
previous bilirubin values, 
consider permanent 
discontinuation at the 
first occurrence. 
 
Reduce 1 dose 
level and check 
AST, ALT, 
bilirubin 2x/week 
for 2 weeks 
followed by 
weekly 
assessments for at 
least 4 weeks.a 
 
Discontinue 
Before regorafenib initiation and during the first 2 cycles of treatment, ALT, AST and bilirubin 
must be monitored at least every 2 weeks. 
a: If toxicity returns to ≤ Grade 1 after dose reduction, dose re-escalation is permitted at the discretion of the treating Investigator per Section 
6.1.1.2 for first occurrence only. 
 
7.2.6. Prevention and Management of 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) and 
at the Investigator’s discretion. 
 
Anti-diarrhea medications may be introduced if symptoms occur.  
Previous trials have shown that the diarrhea could be managed with 
loperamide.  The recommended dose of loperamide is 4 mg at first onset, 
followed by 2 mg every 2 to 4 hours until diarrhea-free for 12 hours. 
 
7.3. Adverse Event Grading 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for AE reporting.  All Levine Cancer Institute staff will 
have access to a copy of the CTCAE version 4.0.  
 
Grade refers to the severity (intensity) of the AE: 


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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. 
 
CTCAEv4 Grade 5: death due to an AE 
7.4. Adverse Event Attribution 
 
The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study treatment in question. AEs are considered to be “not 
related” or “related” to the study drug according to the following definitions: 
 
Not Related:  Evidence exists that the AE has an etiology other than the study drug 
(eg, pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication).  This includes events that are considered remotely or unlikely related to 
study drug. 
 
Related:  A temporal relationship exists between the event onset and administration 
of the study drug.  It cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies.  In the case of cessation or reduction of 
the dose, the event abates or resolves and reappears upon rechallenge.  It should be 
emphasized that ineffective study drug treatment should not be considered as causally 
related in the context of AE reporting.  This includes events that are considered 
possibly, probably, or definitely related to study drug. 
Final attribution should be stated as follows (choose only one): 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 


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Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.5. Adverse Event Action and Outcome 
Any action on study treatment to resolve the AE is to be documented using the 
categories listed below: 
• 
Drug withdrawn 
• 
Drug interrupted 
• 
Dose reduced 
• 
Dose not changed 
• 
Dose increased 
• 
Not applicable 
• 
Unknown 
 
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 
 
8. 
DATA AND SAFETY MONITORING PLAN 
 
8.1. Safety Monitoring 
 
This trial will be monitored according to the processes in effect for all Levine Cancer 
Institute Investigator- Initiated Trials and will abide by standard operating procedures 
set forth by both the Carolinas Medical Center Office of Clinical and Translational 
Research and the Levine Cancer Institute Clinical Trials Department.  It is the 
responsibility of the Sponsor-Investigator to monitor the safety data for this study.  
On at least a monthly basis, the Sponsor-Investigator, Study Statistician and Protocol 
Coordinator will meet to monitor subject consents, enrollment and retention, safety 
data for all subjects [including adverse events (AE’s) for all grades and attributions, 
serious adverse events (SAE’s)], study drug administration, and validity/integrity of 
the data.  SAEs will be reported to the IRB per their requirements.  Major protocol 
deviations that result in a threat to subject safety or the integrity of the study will be 
reported to the IRB per their requirements. Following each meeting, a status will be 


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generated and kept on file in the LCI Clinical Trials Office with study records.  The 
Sponsor-Investigator will submit reports to the LCI Data and Safety Monitoring 
Committee according to the overarching LCI Data and Safety Monitoring Plan. 
 
8.2. Data Quality Assurance 
 
This study will be organized, performed, and reported in compliance with the study 
protocol, standard operating procedures (SOPs) of Levine Cancer Institute and 
Carolinas Medical Center Office of Clinical and Translational Research, the FDA, 
and other applicable regulations and guidelines (e.g. GCP).  
 
Data will be collected on electronic CRFs in the CTMS.  
 
Subjects will be monitored by Levine Cancer Institute Research Monitors routinely 
for data quality. This monitoring will be done by comparing source documentation to 
the CRFs. Any variation between the two data sets will be discussed with the Protocol 
Coordinator or Sponsor-Investigator. 
 
The study database will be reviewed and checked for omissions, apparent errors, and 
values requiring further clarification using computerized and manual procedures. 
Data queries requiring clarification will be generated and addressed by the 
appropriate study team member and/or Sponsor- Investigator. Only authorized 
personnel will make corrections to the study database and all corrections will be 
documented in an electronic audit trail. 
 
8.3. Communication Between Investigational Sites 
Investigational sites will be required to report AEs for all grades and attributions, 
SAEs, study drug administration, or any other problem that could affect the 
validity/integrity of the study data to the Sponsor-Investigator.  All investigational 
sites will report AEs using the eCRFs and SAEs using the SAE reporting function in 
the CTMS to the Sponsor-Investigator. AEs will be reported promptly of the 
Investigator learning of the event.  SAEs will be reported within 24 hours, or next 
business day, of the Investigator learning of the event. Study drug administration or 
any other problem should be communicated to the Protocol Coordinator and/or 
Sponsor-Investigator by email or phone as soon as possible but within 2 business 
days of the Investigator learning of the event. 
 
 


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9. 
SAFETY DATA COLLECTION, RECORDING AND REPORTING 
 
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 and SAEs (whether related to regorafenib or 
not), laboratory changes (complete blood counts, electrolytes, chemistry, and coagulation), 
changes in vital signs (blood pressure, heart rate, respiratory rate, and temperature) and, in 
some instances, changes in radiologic  images. These assessments should be performed 
according to the Study Calendar.  Adverse events will be evaluated continuously 
throughout the study. Safety and tolerability, relationship to treatment and intensity will be 
assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. All adverse events (Grades 1 – 5) will be determined by the Investigator and 
recorded in the eCRF. 
 
9.1. Unanticipated Problem Definition 
 
An UAP is any incidence, experience or outcome that is unexpected, given the 
information provided in research-related documentation (e.g. Investigator’s brochure, 
informed consent) and the study population characteristics that is related or possibly 
related to participation in the research study and places the participant at an increased 
risk.   
 
9.2. Adverse Event (AE) Definition 
 
An adverse event is any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related, including the following: An 
adverse event occurring in the course of the use of a drug in professional practice; an 
adverse event occurring from drug overdose whether accidental or intentional; an 
adverse event occurring from drug withdrawal; and any failure of expected 
pharmacological action. Pre-existing conditions that increase in frequency or severity 
or change in nature during or as a consequence of use of a drug in human clinical 
trials are also considered adverse events.  Adverse events may also include pre or 
post-treatment complications that occur as a result of protocol mandated procedures 
(e.g., invasive procedures such as biopsies). 
 
Any continuing medical condition or clinically significant laboratory abnormality 
with an onset date before the first date of study drug administration should be 
considered pre-existing and should be documented. 


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An AE does not include: 
• 
relapse or progression of the underlying malignant disease; however, the 
associated signs, symptoms, or diagnoses should be recorded as adverse events 
(e.g., “jaundice” due to new or increasing liver metastases, or “tumor pain” or 
“bone pain” due to progressive disease); 
• 
medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
 
transfusion).  The condition that leads to the procedure is the adverse event; 
• 
situations where an untoward medical occurrence has not occurred (e.g., 
 
hospitalization for elective surgery, social and/or convenience admissions); 
• 
overdose of either study drug or concomitant medication without any signs or 
 
symptoms unless the subject is hospitalized for observation; and 
• 
pregnancy (Pregnancy during treatment should be reported as an SAE and on the 
      eCRF) 
 
Laboratory abnormalities are usually not recorded as adverse events; however, signs 
and/or symptoms that are associated with laboratory findings requiring study 
withdrawal, dose modification, or medical intervention (e.g., anemia requiring 
transfusions or hyperglycemia requiring treatment) or other abnormal assessments 
(e.g., ECG, radiographs, vital signs) must be recorded as adverse events if they meet 
the definition of an adverse event .  In addition, laboratory abnormalities marked as 
clinically significant by the Investigator should also be recorded as adverse events on 
the eCRF.  The Investigator will record the most severe grade of the clinically 
significant laboratory abnormality and will evaluate its relationship to the study drug 
and clinical condition if/when a clinically significant laboratory abnormality occurs.   
 
The relationship to study drug therapy should be assessed using the following 
definitions: 
 
Not Related:  Evidence exists that the AE has an etiology other than the study drug 
(eg, pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication).  This includes events that are considered unrelated or unlikely related to 
study drug. 
 
Related:  A temporal relationship exists between the event onset and administration 
of the study drug.  It cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies.  In the case of cessation or reduction of 
the dose, the event abates or resolves and reappears upon rechallenge.  It should be 
emphasized that ineffective study drug treatment should not be considered as causally 


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related in the context of AE reporting.  This includes events that are considered 
possibly, probably, or definitely related to study drug. 
 
All adverse events (including event name, grade, start/stop date and attribution) will 
be documented in the medical record and on the case report form for this protocol.  
AEs will be captured from the time of enrollment through 30 days after the date of the 
last study drug administration.  
 
The Investigator is responsible for verifying and providing source documentation for 
all adverse events and assigning the attribution for each event for all subjects enrolled 
on the trial. 
 
9.3 Adverse Drug Reaction (ADR) Definition 
All noxious and unintended responses to a medicinal product related to any dose 
should be considered adverse drug reactions. The phrase “responses to a medicinal 
product” means in view of the investigator and/or company that a causal relationship 
between a medicinal product and an adverse event is at least a reasonable possibility 
and that the adverse event is associated with the use of the drug. 
 
9.4. “Serious Adverse Event (SAE)” Definition 
A Serious Adverse Event includes any event that: 
• Results in death. 
 
• Is life-threatening. 
NOTE: The term ‘life-threatening’ refers to an event during which the subject was 
at immediate risk of death from the adverse event.  It does not refer to an event 
which hypothetically might have caused death if it had been more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
NOTE: In general, hospitalization means that the subject has been detained at the 
hospital or emergency ward for observation or treatment that would not have been 
appropriate in the physician’s office or out-patient setting.  Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious.  When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered 
serious.  Hospitalization for elective treatment planned prior to study enrollment 
is neither an SAE nor an AE. 
• Results in persistent or significant disability or incapacity. 


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NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. 
sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
• Is a congenital anomaly or birth defect. 
 
• Is an important medical event.  
An event may be considered an important medical event when, based upon 
appropriate medical judgment, it may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in the 
definition.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. 
SAEs will be captured from the time of enrollment through 30 days after the date 
of the last study drug administration. SAEs will be followed until clinical 
recovery is complete and laboratory tests have returned to baseline, until 
progression has been stabilized, or until there has been acceptable resolution of 
the event. This may at times, cause the follow-up period for SAEs to be greater 
than 30 days.  This 30-day time period applies even if the subject is taken off 
study and enrolled onto another protocol during this time period. Similarly, the 
Sponsor-Investigator is responsible for following the subject during the required 
follow-up period even if the subject lives elsewhere or has been released from his 
or her care and is being treated under another service at LCI. 
Laboratory abnormalities: 
Laboratory abnormalities that meet the definition of a serious adverse event will 
be recorded as such on the CRF and reported appropriately. The Investigator will 
record the most severe grade of the clinically significant laboratory abnormality 
and will evaluate its relationship to the study drug and clinical condition if/when a 
clinically significant laboratory abnormality occurs. 
 
Planned hospitalizations: 
Elective surgeries that have been planned prior to subject enrollment in the study 
or for conditions existing prior to study enrollment do not need to be captured as 


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SAEs, unless complications occur or the conditions are worse that the subject’s 
baseline. They should however, be clearly documented on the case report form. 
Development of new cancers: 
Secondary malignancies are defined as new cancers, not transformations or 
progression of original disease. 
Secondary malignancies during 30 day time period: 
Any secondary malignancy diagnosed within 30 days of the last dose, regardless 
of attribution, must be reported as an SAE. 
Secondary malignancies after the 30 day time period: 
Any secondary malignancy diagnosed greater than 30 days after last day of study 
drug and thought to be possibly, probably or definitely related to drug must be 
reported as an SAE 
Deaths: 
Deaths during 30 day time period: 
Any death, expected or unexpected, occurring within 30 days of the last dose of 
study drug, regardless of attribution, must be reported as an SAE. 
Deaths after the 30 day time period: 
Deaths occurring greater than 30 days after last day of study drug and thought to 
be possibly, probably or definitely related to drug must be reported within 24 
hours of knowledge of the event. 
 
All SAEs (including event name, grade, start/stop date and attribution) will be 
documented in the medical record and on the case report form for this protocol. 
The Investigator is responsible for verifying and providing source documentation 
for all SAEs and assigning the attribution for each event for all subjects enrolled 
on the trial. 
 
9.5. Serious Adverse Drug Reaction (SADR) Definition 
 


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A Serious Adverse Drug Reaction is an event that meets any of the criteria for 
seriousness as previously defined and has a possible causal relationship to the study 
drug. 
 
The Sponsor-Investigator is responsible for judging whether it is a reasonable 
possibility that the study drug caused the serious adverse event. 
 
9.6. “Unexpected” Definition 
An SAE or SADR is to be considered unexpected if the event is not listed in the 
current Investigator Brochure or is not listed in the severity or specificity observed.  
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. 
9.7. SAE Reporting Requirements 
 
All Serious Adverse Events must be reported to the Sponsor-Investigator within 
24 hours, or next business day, of awareness via the CTMS with a notification to 
the Protocol Coordinator and Sponsor-Investigator.  Also, all SAEs must be 
reported to Bayer within 24 hours, or next business day, of the Principal 
Investigator’s awareness and must include the following minimum information:  
1.  The name and contact information of the reporter 
2.  The name of the study drug(s) 
3.  A description of the reported SAE 
4.  A patient identified by one or more of the following:  
a.  Patient initials 
b.  Patient number  
c.  Knowledge that a patient who experienced the adverse event exists 
d.  Age 
e.  Sex 
5.  An investigator assessment of study drug causality.   
 
Additional data which would aid the review and causality assessment of the case 
include but are not limited to:   
• 
The date of onset 
• 
The severity 
• 
The time from administration of study drug(s) to start of the event 
• 
The duration and outcome of the event 
• 
Any possible etiology for the event 
• 
The final diagnosis or syndrome, if known 
• 
Action(s) taken, if any 
 


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Expedited Reporting of Other Safety Information: 
The Investigator/ Sponsor shall report to Bayer within 24 hours, or next business day, 
of the investigator’s awareness of other events such as:   
 
• 
An adverse event related to study specific procedures  
• 
Any new and important event related to treatment with the study drug(s). 
• 
Any pregnancy during which a female patient was exposed to the study drug(s) 
• 
Any pregnancy in the partner of a male patient, where the male patient was 
exposed to study drug at the time of conception or conception occurred within 
two weeks of the last dose of study drug(s). 
• 
Any other relevant safety information including but not limited to reports on drug 
interaction, overdose, or medication error occurring at any time during the 
treatment phase. 
 
All SAEs will be reported to Bayer HealthCare via MedWatch forms (FDA Form 
3500) within 24 hours, or next business day, of the Sponsor-Investigator learning of 
the event. 
 
All reports shall be sent electronically to:  
 
Electronic Mailbox: DrugSafety.GPV.US@bayer.com   
Address: 100 Bayer Boulevard  
               Whippany, NJ 07981 
Phone: (862) 404-5333 
 
 
  
All events occurring during the conduct of a protocol and meeting the definition of 
an UAP or SAE that are related to the study drug (serious adverse drug reactions) 
and unexpected must be reported to the IRB of record within 10 working days of the 
Sponsor-Investigator learning of the event. 
 
9.8. Deviation Reporting to the IRB 
 
Protocol deviations involving the informed consent process, subject safety, or 
adversely impacting data integrity will be reported promptly to the IRB but no later 
than two weeks from the time of identification of the protocol deviation by the 
Sponsor-Investigator.  
 
9.9. Deviation Reporting to the Funding Company 
Protocol deviations involving subject safety will be reported to Bayer HealthCare 
promptly but no later than two weeks from the time of identification of the protocol 
deviation by the Sponsor-Investigator. 
   
 


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10. MEASUREMENT OF EFFECT 
 
10.1. Anti-tumor Effect  
Response and progression will be evaluated in this study using the revised response 
evaluation criteria in solid tumors (RECIST) guideline version 1.1.22 
 
10.1.1. Definitions 
 
Evaluable for toxicity.  All subjects will be evaluable for toxicity from the 
time of their first treatment with regorafenib. 
 
Evaluable for objective response.  Only those subjects who have measurable 
disease present at baseline, have received at least one dose of study therapy, 
and have had their disease re-evaluated (either clinically or radiologically) 
will be considered evaluable for objective response.  These subjects will have 
their response classified according to the definitions stated below.   
 
10.1.2. Disease Parameters 
Target lesions: When more than one measurable lesion is present at baseline 
all lesions up to a maximum of five lesions total (and a maximum of two 
lesions per organ) representative of all involved organs should be identified as 
target lesions and will be recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be 
the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. Lymph nodes merit 
special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which 
are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  ≥ 15 mm by CT scan or MRI. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the 
node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in 
the plane in which the image is obtained (for CT scan this is almost always the 
axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). 
The smaller of these measures is the short axis. All other pathological nodes 
(those with short axis ≥ 10 mm but <15 mm) should be considered non-target 


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lesions. Nodes that have a short axis <10 mm are considered non-pathological 
and should not be recorded or followed. A sum of the diameters (longest for 
non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to 
be included in the sum, then as noted above, only the short axis is added into 
the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of 
the disease. 
Non-target lesions: All other lesions (or sites of disease) including 
pathological lymph nodes should be identified as non-target lesions and 
should also be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). 
10.1.3. Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers.  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 is preferred to evaluation by clinical 
examination when both methods have been used to assess the antitumor effect 
of a treatment.  The Sponsor-Investigator or designee will be responsible for 
performing tumor measurements.  The tumor measurements will be 
documented on the eCRF. 
10.1.4. Central Radiology Review 
Scans will be evaluated by Central Radiology at screening and every 8 weeks 
for each subject. The Central Radiologist will be notified by the applicable 
study team member when central review of scans for a subject is due. For 
subjects receiving their scans at an office other than Charlotte Radiology, the 
Coordinator will request the images be burned to a disc and de-identified, and 
mail to the following address: 
 
Attn: Richard Redvanly, M.D. 
Charlotte Radiology 
1000 Blythe Boulevard, Suite 4 
Charlotte, NC 28203 


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Phone: (704) 365-0343 
 
Tumor logs and the Central Radiology Review request form accompany 
Central Radiology Review requests. 
 
Central radiology review of scans performed for screening is NOT required to 
be completed prior to subject enrollment.  
 
Scan data will be abstracted and entered into the eCRF. 
10.2. Response Criteria 
 
Response will be evaluated using RECIST 1.1 Criteria. 
 Complete Response: 
• Target lesion: Disappearance of all target lesions. Any pathological lymph  
 
 
nodes (whether target or non-target) must have reduction in short axis to  
 
 
<10 mm. 
• Non-target lesion: Disappearance of all non-target lesions. All lymph nodes   
 
must be non-pathological in size (<10 mm short axis). 
 
Partial Response: 
• Target lesion: At least a 30% decrease in the sum of diameters of target, 
 
taking as reference the baseline sum diameters. 
• Non-target lesion: Not applicable 
 
Stable Disease: 
• Target lesion: Neither sufficient shrinkage to qualify for a partial response,  
 
 
nor sufficient increase to qualify for progressive disease, taking as reference   
 
the smallest sum diameters while on study. 
• Non-target lesion: Not applicable. 
 
Progressive Disease: 
• Target lesion: At least a 20% increase in the sum of diameters of target  
 
 
lesions, taking as reference the smallest sum on study (this includes the  
 
 
baseline sum if that is the smallest on study). In addition to the relative  
 
 
increase of 20%, the sum must also demonstrate an absolute increase of at 
 
least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 


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• Non-target lesion: Unequivocal progression (as described in RECIST version   
 
1.1) of existing non-target lesions. (Note: the appearance of one or more new   
 
lesions is also considered progression). 
 
Non-Complete Response / Non-Progressive Disease: 
• Target lesion: Not applicable 
• Non-target lesion: Persistence of one or more non-target lesion(s) 
 
 
Summary of RECIST: 
 
 
 
 
 
 
 
 
 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. This means 
that subjects with CR may not have a total sum of the diameters of ‘zero’. 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as ‘symptomatic deterioration’. Every effort should be made to document 
objective progression even after discontinuation of treatment. Symptomatic 
deterioration is not a descriptor of an objective response: it is a reason for stopping 
study therapy.  It is included as part of the criteria for determination of Progression 
Free Survival.  The objective response status of such subjects is to be determined by 
evaluation of target and non-target disease. 
Target 
Lesions 
Non-target Lesions 
New Lesions 
Overall 
Response 
Best Response for this 
Category also requires 
CR 
CR 
No 
CR 
Documented at least once 
 4 weeks from baseline 
CR 
Non-CR/Non-PD 
No 
PR 
Documented at least once 
 4 weeks from baseline 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented at least once 
 4 weeks from baseline 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in nontarget lesions may be accepted as disease progression. 


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For equivocal findings of progression (e.g. very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled  assessment, progression is 
confirmed, the date of progression should be the earlier date when progression was 
suspected. 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1. Sample Size 
A total of 32 participants will be enrolled to this study.  The primary objective is to 
evaluate the 16-week progression free survival rate.  The CONKO-003 study reported 
a median OS with best supportive care in this subject population to be 2.3 months.14  
Therefore, the null hypothesis assumes a median PFS of 6 weeks. This corresponds to 
a 16-week PFS rate of approximately 0.15.  A single-stage design will be used to test 
the hypothesis that the 16-week PFS rate is less than or equal to 0.15.  If at least 8 of 
the 32 subjects are alive and progression free at 16 weeks, the null hypothesis will be 
rejected (based on an exact binomial test) and regorafenib therapy may be considered 
for further evaluation in this subject population.  Assuming a one-sided alpha = 0.10 
significance level, this sample size will provide at least 90% power to reject the null 
hypothesis, assuming the true 16-week progression free survival rate is 0.35.   An 
increase in the 16-week PFS rate of 0.20 in the context of this Phase II study is 
considered clinically relevant. 
11.2. Endpoint Definitions 
 
11.2.1. 16-Week Progression Free Survival 
 
Progression free survival will be calculated from a recorded binary variable 
determined for each subject indicating whether or not the patient experienced 
disease progression or death from any cause during the 16 week period 
following the start of treatment. Disease progression can be objectively 
determined as per Section 10.2 or progression can be subjective as determined 
by the Investigator. Evidence for subjective progressions must be documented 
in the medical records. The binary variable described above will be calculated 
for the primary objective. 
 
11.2.2. Progression Free Survival 
 
PFS is defined as the duration of time from enrollment to the study to time of 


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progression or death.  Disease progression can be objectively determined as 
per Section 10.2 or progression can be subjective as determined by the 
investigator.  Evidence for subjective progressions must be documented in the 
medical records.  For surviving subjects who do not have documented disease 
progression, PFS will be censored at the date of last radiologic assessment.  
For subjects who receive subsequent anti-cancer therapy prior to documented 
disease progression, PFS will be censored at the date of last radiologic 
assessment prior to the commencement of subsequent therapy.  Subjects who 
experience a PFS event immediately following an interval equal to two or 
more scheduled CT assessments will be censored at the date of the last 
assessment prior to the first missed assessment. 
 
11.2.3. Overall Survival 
 
Overall survival is defined as the duration from enrollment date to the date of 
death from any cause.  Subjects who are alive or lost to follow-up at the time 
of the analysis will be censored at the last known date they were alive. 
 
11.2.4. Overall Response 
 
Overall response will be determined for each patient as a binary variable 
indicating whether or not the patient achieved a best overall response of CR or 
PR as determined by RECIST 1.1 criteria.  For the purposes of response 
determination, a confirmatory scan for CR and PR is not required.  
 
11.2.5. Disease Control 
 
Disease control will be determined for each patient as a binary variable 
indicating whether or not the patient achieved a best overall best response of 
CR, PR, or stable disease as determined by RECIST 1.1 criteria.  
 
11.2.6. Safety Endpoints 
 
Safety endpoints will include treatment administration (cycles delivered, 
cumulative dose administration, and relative dose intensity), AEs, SAEs, 
deaths while on study therapy, and laboratory determinations. 
 
11.3. Analysis Populations 
 


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Efficacy and safety analyses will be conducted on the population of subjects who 
begin regorafenib treatment.  Analysis of overall response rate will be conducted on 
those patients in the efficacy population with measurable disease present at baseline.  
The date of initiation of regorafenib treatment will be the enrollment date. 
 
11.4. Analysis Methods 
 
11.4.1. Timing of Analysis 
 
While not planned as a formal multistage analysis, we will be evaluating 
safety and efficacy in data reviews throughout the course of the study. The 
analysis for the primary objective will occur after all 32 patients have either 
progressive disease, died, or have at least 16 weeks of follow up time after the 
treatment start date. Preliminary analysis of the secondary endpoints 
(including PFS and OS) will also be done at the time of the primary analysis. 
However, an updated PFS analysis will also occur once the PFS censoring rate 
for all enrolled patients reaches 20% or after all patients have at least 1 year of 
follow up time (whichever occurs first). Additionally, for the purposes of OS, 
patients will continue to be followed until the OS censoring for all enrolled 
patients reaches 20% or after all patients have at least 3 years of follow up 
time (whichever occurs first), and the final analysis will be conducted after 
this milestone is reached.    
 
11.4.2. Subject Disposition 
 
An accounting of all consenting subjects will be provided at the end of the 
study. This will include a breakdown of subjects who consented, were treated, 
discontinued treatment, died, and were lost to follow-up or withdrew consent. 
 
11.4.3. Baseline Subject and Disease Characteristics 
 
A summary of subject demographics and disease-related characteristics will 
be completed and subject medical history will be assessed. 
 
 
11.4.4. Efficacy Analyses 
 
11.4.4.1. Primary Analysis 
 
The frequency and proportion of subjects alive and progression free 


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after 16 weeks will be calculated, along with a 95% Clopper Pearson 
confidence interval. A one-sided exact binomial test of proportions, 
with α = 0.10, will be carried out, testing the null hypothesis that the 
16-week progression free survival probability is less than 15%. 
Based on the sample size calculations described in Section 11.1, if at 
least 8 subjects are alive and progression free at 16 weeks, the null 
hypothesis can be rejected. 
 
11.4.4.2. Secondary Analyses 
 
Overall and progression free survival will be analyzed using Kaplan 
Meier techniques.  Medians, 25th, and 75th percentiles will be 
estimated.  Selected landmarks for OS (1, 3, 6, and 9 month survival 
rates) and PFS (1, 3, and 6 month PFS rates) will from the Kaplan 
Meier curve. Tumor response and disease control rates will be 
estimated with proportions and associated 95% Clopper Pearson 
confidence intervals will be calculated. 
 
11.4.5. Safety Analyses 
 
Incident rates for adverse events, SAEs, and deaths while on study therapy 
will be summarized. Laboratory data will be analyzed quantitatively using 
methods for longitudinal data. 
 
11.4.6. Exploratory Analyses 
 
Cox proportional hazards models and logistic regression will be used to assess 
the correlation between baseline characteristics and biomarker expression 
levels with clinical outcomes. 
 
11.5. Interim Analyses 
 
No interim analyses are planned for this study. 
 
 
12. STUDY COMPLETION AND TERMINATION 
 
12.1. Completion 
 


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The study will be considered complete when one or more of the following conditions 
is met: 
• 
All subjects have completed all study visits. 
• 
All subjects have discontinued from the study. 
• 
The IRB, LCI DSMC, Sponsor-Investigator or Bayer HealthCare discontinues 
the study because of safety considerations. 
• 
The Sponsor-Investigator defines an administrative or clinical cut-off date. 
 
12.2. Termination 
 
The study will be terminated when one or more of the following conditions occur: 
If risk-benefit ratio becomes unacceptable owing to, for example: 
• 
Safety findings from this study (e.g. SAEs) 
• 
Results of any interim analysis 
• 
Results of parallel clinical studies 
• 
Results of parallel animal studies (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 Sponsor-Investigator has the right to close the trial at any site and at any time. 
For any of the above closures, the following applies: 
• 
Closures should occur only after consultation between involved parties. 
• 
All affected institutions must be informed as applicable according to local  
       law.   
• 
In case of a partial study closure, ongoing subjects, including those in follow-  
       up, must be taken care of in an ethical manner. 
 
Details for individual subject's withdrawal can be found in Section 3.4. 
 
13. RETENTION OF RECORDS 
 
Essential documentation (e.g. adverse events, records of study drug receipt and 
dispensation), including all IRB correspondence, will be retained for at least 2 years after 
the investigation is completed.  Documentation will be readily available upon request. 
 
 
14. ETHICAL AND LEGAL ISSUES 
 
14.1. Ethical and Legal Conduct of the Study 
 


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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). 
 
Documented approval from appropriate agencies (e.g. DSMC, IRB) will be obtained 
for all participating centers before start of the study, according to GCP, local laws, 
regulations and organizations.  When necessary, an extension, amendment or renewal 
of IRB approval must be obtained and forwarded to Bayer HealthCare. 
 
Strict adherence to all specifications laid down in this protocol is required for all 
aspects of study conduct; the Investigators may not modify or alter the procedures 
described in this protocol.   
 
Modifications to the study protocol will not be implemented by the Sponsor-
Investigator without discussion and agreement by Bayer Healthcare.  However, the 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to the trial subjects without prior approval from 
applicable agencies.  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 appropriate agencies.  Any deviations from the protocol must be 
explained and documented by the Investigator. 
 
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites 
in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration 
of Helsinki.  The Sponsor-Investigator is responsible for personally overseeing the 
treatment of all study subjects.  The Sponsor-Investigator must assure that all study 
site personnel, including sub-investigators and other study staff members, adhere to 
the study protocol and all applicable regulations and guidelines regarding clinical 
trials both during and after study completion. 
 
The Sponsor-Investigator will be responsible for assuring that all the required data 
will be collected and properly documented. 
 
 
14.2. Confidentiality 
 


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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. 
 
 
15. PUBLICATION POLICY 
 
The Sponsor-Investigator must send a draft manuscript of the publication or abstract to 
Bayer HealthCare prior to submission of the final version for publication or congress 
presentation. All relevant aspects regarding data reporting and publication will be part of 
the contract between Bayer HealthCare and the Sponsor-Investigator. 
 
The Sponsor-Investigator will ensure that the information regarding the study be publicly 
available on the internet at www.clinicaltrials.gov.  


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REFERENCES 
 
1. 
Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit 
with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a 
randomized trial. Journal of Clinical Oncology. June 1, 1997 1997;15(6):2403-2413. 
2. 
Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB. Phase III Study 
of Gemcitabine in Combination With Fluorouracil Versus Gemcitabine Alone in Patients 
With Advanced Pancreatic Carcinoma: Eastern Cooperative Oncology Group Trial 
E2297. Journal of Clinical Oncology. August 1, 2002 2002;20(15):3270-3275. 
3. 
Heinemann V, Quietzsch D, Gieseler F, et al. Randomized phase III trial of gemcitabine 
plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. Aug 20 
2006;24(24):3946-3952. 
4. 
Rocha Lima CM, Green MR, Rotche R, et al. Irinotecan Plus Gemcitabine Results in No 
Survival Advantage Compared With Gemcitabine Monotherapy in Patients With Locally 
Advanced or Metastatic Pancreatic Cancer Despite Increased Tumor Response Rate. 
Journal of Clinical Oncology. September 15, 2004 2004;22(18):3776-3783. 
5. 
Oettle H, Richards D, Ramanathan RK, et al. A phase III trial of pemetrexed plus 
gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic 
cancer. Annals of Oncology. October 1, 2005 2005;16(10):1639-1645. 
6. 
Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared 
with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase 
III trial of the Swiss Group for Clinical Cancer Research and the Central European 
Cooperative Oncology Group. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. Jun 1 2007;25(16):2212-2217. 
7. 
Louvet C, Labianca R, Hammel P, et al. Gemcitabine in Combination With Oxaliplatin 
Compared With Gemcitabine Alone in Locally Advanced or Metastatic Pancreatic 
Cancer: Results of a GERCOR and GISCAD Phase III Trial. Journal of Clinical 
Oncology. May 20, 2005 2005;23(15):3509-3516. 
8. 
Abou-Alfa GK, Letourneau R, Harker G, et al. Randomized Phase III Study of Exatecan 
and Gemcitabine Compared With Gemcitabine Alone in Untreated Advanced Pancreatic 
Cancer. Journal of Clinical Oncology. September 20, 2006 2006;24(27):4441-4447. 
9. 
Philip PA, Benedetti J, Corless CL, et al. Phase III Study Comparing Gemcitabine Plus 
Cetuximab Versus Gemcitabine in Patients With Advanced Pancreatic Adenocarcinoma: 
Southwest Oncology Group–Directed Intergroup Trial S0205. Journal of Clinical 
Oncology. August 1, 2010 2010;28(22):3605-3610. 
10. 
Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine Plus Bevacizumab Compared 
With Gemcitabine Plus Placebo in Patients With Advanced Pancreatic Cancer: Phase III 
Trial of the Cancer and Leukemia Group B (CALGB 80303). Journal of Clinical 
Oncology. August 1, 2010 2010;28(22):3617-3622. 


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11. 
Moore MJ, Goldstein D, Hamm J, et al. Erlotinib Plus Gemcitabine Compared With 
Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of 
the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical 
Oncology. May 20, 2007 2007;25(15):1960-1966. 
12. 
Von Hoff FF, Arena FP, Chiorean EB, et al. Results of a randomized phase III trial 
(MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for 
patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 
correlates. Journal of Clinical Oncology 31, 2013 (suppl; abstr 4005). 
13. 
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. The New England Journal Of Medicine. 2011;364(19):1817-1825. 
14. 
Pelzer U, Schwaner I, Stieler J, et al. Best supportive care (BSC) versus oxaliplatin, 
folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced 
pancreatic cancer: a phase III-study from the German CONKO-study group. European 
Journal Of Cancer (Oxford, England: 1990). 2011;47(11):1676-1681. 
15. 
Grothey A, Cutsem EV, Sobrero A, et al. Regorafenib monotherapy for previously 
treated metastatic colorectal cancer (CORRECT): an international, multicentre, 
randomised, placebo-controlled, phase 3 trial. The Lancet. //26;381(9863):303-312. 
16. 
Demetri GD, Reichardt P, Kang Y-K, et al. Efficacy and safety of regorafenib for 
advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): 
an international, multicentre, randomised, placebo-controlled, phase 3 trial. The Lancet. 
//26;381(9863):295-302. 
17. 
Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): A new oral 
multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with 
potent preclinical antitumor activity. International Journal of Cancer. 2011;129(1):245-
255. 
18. 
Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human 
carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53(4):549-
554. 
19. 
Chu GC, Kimmelman AC, Hezel AF, DePinho RA. Stromal biology of pancreatic cancer. 
Journal of Cellular Biochemistry. 2007;101(4):887-907. 
20. 
Kindler HL, Ioka T, Richel DJ, et al. Axitinib plus gemcitabine versus placebo plus 
gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind 
randomised phase 3 study. The Lancet Oncology. 3// 2011;12(3):256-262. 
21. 
Mross K, Frost A, Steinbild S, et al. A Phase I Dose–Escalation Study of Regorafenib 
(BAY 73–4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in 
Patients with Advanced Solid Tumors. Clinical Cancer Research. May 1, 2012 
2012;18(9):2658-2667. 
22. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). European journal of cancer (Oxford, 
England : 1990). 2009;45(2):228-247. 


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23. 
Curry J, Thompson K, Rao S, et al. The Use of a Novel MUC1 Antibody to Identify 
Cancer Stem Cells and Circulating MUC1 in Mice and Patients with Pancreative Cancer. 
Journal of Surgical Oncology. 2013 Jun;107(7):713-22.   
 
 
 


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APPENDICES 
 
APPENDIX A:  EXAMPLES OF A LOW-FAT MEAL 
Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly and 8 
ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g of fat). 
One cup of cereal (i.e. Special K), 8 ounces (240 mL) of skim milk, one piece of toast with jam 
(no butter or marmalade), apple juice, and one cup of coffee or tea (2 g fat, 17 g protein, 93 g of 
carbohydrate, 520 calories). 
 
 
 
 
 
 
 


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APPENDIX B:  PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
5 
Dead.