Conditions: Cancer of the Bile Duct
Keywords: biliary liver Refractory Advanced Biliary Cancers gallbladder cancer carcinoma intra-hepatic biliary system extra-hepatic biliary system gall bladder unresectable locally advanced metastatic disease Bile Duct Diseases Gallbladder Diseases regorafenib stivarga Bay 73-4506 multikinase inhibitor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
The main purpose of this study is to see if regorafenib can help control or decrease cancer size in patients with cancer of the bile duct. Researchers also want to find out if regorafenib is safe and tolerable.

Detailed description:

Arms:
arm 1: Regorafenib is administered as monotherapy during the study. 160 mg once daily (QD) will be administered for 3 weeks on /1 week off. One cycle is 28 days.

Interventions: intervention 1: Regorafenib
Intervention descriptions: intervention 1: Four 40 mg regorafenib tables should be taken in the morning with approximately 8 fluid ounces (240 mL) of water after a low-fat (\<30% fat) breakfast.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Multi Institutional Phase II Trial of Single Agent Regorafenib in Refractory 
Advanced Biliary Cancers 
 
NCT02115542 
 
Version 2.0 
April 5, 2017 


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Title page 
 
Multi institutional phase II trial of single agent regorafenib in refractory advanced biliary 
cancers.  
 
 
 
 
 
 
 
 
Test drug(s): 
Regorafenib 
[Study purpose:] 
Efficacy 
Clinical study phase: 
II 
Version no.: 
2.0 
Date: 
01/27/2015     
Amendment no.: 
4.0 
Date: 
04/05/2017     
Institution Study no.: 
YYYYY 
Principal Investigator: 
Richard Kim M.D. Assistant Professor H. Lee Moffitt Cancer Center 
12902 Magnolia Drive FOB-2 Tampa, FL 33647 
Participating Institutions:       
 
                                            Hanna Sanoff M.D 
                                            University of North Carolina 
                                            Chapel Hill, NC 
                                             
 
                                            Andrew Poklepovic M.D 
                                            VCU Massey Cancer Center 
                                            Richmond, VA 
                                             
 
                                            Andrew Nixon PhD 
                                            Duke University 
                                            Durham, NC 
Research Nurse:  TBD  
Data Manager:  TBD 


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Statistician:  Jongphil Kim PhD. Assistant Member, Department of Biostatistics, Moffitt Cancer 
Center & Research Institute tel:  813-745-6908 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Principal Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 


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Synopsis 
 
Title 
Multi institutional phase II trial of single agent regorafenib in 
refractory advanced biliary cancers.  
Clinical study phase 
Phase II  
Study objective(s) 
Primary Objective  
• To determine the 6 month overall survival in patients with 
advanced refractory BC receiving regorafenib. 
 
Secondary Objectives 
• 
To determine the frequency and severity of adverse 
events and tolerability of the regimen in patients with 
advanced refractory BC receiving regorafenib  
• 
To evaluate the disease control rate (CR + PR+ SD) as 
defined by the RECIST 1.1 criteria in patients with 
advanced refractory biliary cancers (BC) receiving 
regorafenib at 8 weeks. 
• 
To determine the progression-free survival in patients 
with advanced refractory BC receiving regorafenib  
Exploratory Objectives 
• 
To explore potential correlations between blood 
biomarkers and clinical outcome 
 


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Background treatment 
The outcome of patients with advanced biliary cancer remains 
dismal with the current standard of care options. There is 
currently an unmet medical need for patients with advanced BC 
who have failed one prior systemic therapy. 
The second line setting therefore offers a unique opportunity to 
evaluate the activity of relevant molecularly targeted therapies 
and to identify potential predictive biomarkers. The fact that 
aberrant activation of the Ras/Raf/MAPK pathway occurs in 
more than 60% of BC indicates the importance of these 
pathways in biliary carcinogenesis and highlights potential new 
strategies in the treatment of this disease.  Furthermore anti-
angiogenic agents such as the VEGF-antagonist bevacizumab, 
and the multikinase inhibitor sorafenib have been tested in BC in 
the first line setting with modest activity.  
Regorafenib is an oral multi-kinase inhibitor that targets both 
receptor tyrosine kinases (RTKs), as well as the tumor cell 
proliferation/survival 
signaling 
pathway 
kinases 
(RAS/RAF/MEK/ERK). In addition, regorafenib inhibits VEGFR-
2/3, TIE-2, c-KIT, and PDGFR-ß receptor phosphorylation. 
Given the pivotal role of VEGF, the Ras/Raf/MAPK pathway, and 
PDGFR- ß in biliary cancer biology, evaluation of the regorafenib 
in the second line setting represents a rational approach. 
Indication 
Patients with advanced biliary tumor who have failed at least one 
prior line of systemic therapy. 
Diagnosis and main 
criteria for inclusion 
• Patients 
must 
have 
histologically 
or 
cytologically 
documented carcinoma primary to the intra- or extra-
hepatic biliary system or gall bladder with clinical and/or 
radiologic evidence of unresectable locally advanced or 
metastatic disease. Patients with ampullary carcinoma 
are not eligible. 
• Patients must have failed no more than 2 prior line of 
systemic chemotherapy for advanced biliary cancer. 
Patients who received adjuvant chemotherapy and had 
evidence of disease recurrence within 6 months of 
completion of the adjuvant treatment are also eligible. If 
patient received adjuvant treatment and had disease 
recurrence after 6 months, patients will only be eligible 
after failing one line of systemic chemotherapy used to 
treat the disease recurrence. 
 
• Patients must have measurable disease, as defined by 
RECIST 1.1 criteria. 
• Patients must not have been treated with any VEGF 
inhibitors.  
Study design 
This is a multi-institutional phase II single arm single-stage 
design trial using regorafenib as a single agent. 


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Type of control 
Patients will receive regorafenib 160 mg QD (21 days on and 7 
days off). After 2 cycles (1cycle= 28 days), response and 
progression will be evaluated using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guidelines (version 1.1). 
Number of subjects 
39 
Plan for statistical 
analysis 
Overall survival (OS) will be defined as the time from starting on 
trial to date of death due to any cause. The final analysis will be 
conducted after the follow-time of the last patient exceeds 6 
months. OS at 6 months is the primary endpoint of the trial and 
will be estimated using the Kaplan-Meier method. The two-sided 
95% confidence interval (CI) for median OS will be computed 
using log-log transformation. The sample size was determined 
based on the Simon’s two-stage minimax design. With one-sided 
10% of type I error rate and 90% power, a sample of evaluable 
39 patients will be evaluated; 28 in first stage and additional 11 
patients in second stage. If 8 or more out of 28 survive 6 months 
or more, the study goes on the second stage. The experimental 
treatment will be deemed to have good activity if ≥16 out of 39 
patients survive 6 months or more. 
 


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Table of contents 
Title page .................................................................................................................................... 1 
Synopsis ..................................................................................................................................... 3 
Table of contents ........................................................................................................................ 6 
List of abbreviations .................................................................................................................... 8 
1. 
Introduction .......................................................................................................................... 9 
1.1 
Background .................................................................................................................. 9 
1.2 
Rationale of the study ................................................................................................. 11 
1.3 
Regorafenib ................................................................................................................ 11 
1.3.1 
Preclinical ............................................................................................................ 12 
1.3.2 
Clinical experience .............................................................................................. 12 
2. 
Study objectives ................................................................................................................. 13 
3. 
Investigator[s] and other study participants ........................................................................ 14 
4. 
Study design ...................................................................................................................... 14 
4.1 
Eligibility ..................................................................................................................... 14 
4.1.1 
Inclusion criteria .................................................................................................. 14 
4.1.2 
Exclusion criteria ................................................................................................. 16 
4.1.3 
Excluded therapies and medications, previous and concomitant ......................... 18 
4.2 
Withdrawal of subjects from study .............................................................................. 18 
4.2.1 
Withdrawal .......................................................................................................... 18 
4.2.2 
Screen Failures/Dropouts .................................................................................... 19 
4.2.3 
Replacement ....................................................................................................... 19 
5. 
Treatment[s] ...................................................................................................................... 19 
5.1 
Treatments to be administered ................................................................................... 19 
5.1.1 
Regorafenib ........................................................................................................ 20 
5.1.2 
Dosage and administration: ................................................................................. 20 
5.1.3 
Study Treatment .................................................................................................. 20 
5.1.4 
Dose Modification for management of adverse events ........................................ 20 
5.1.4.1 
Dose Reduction Levels ................................................................................ 20 
5.1.4.2 
Prevention/management strategies for diarrhea .......................................... 30 
5.2 
Drug logistics and accountability ................................................................................. 30 
5.2.1 
Accountability ...................................................................................................... 30 
5.2.2 
Destruction and Return ....................................................................................... 30 
5.3 
Treatment compliance ................................................................................................ 31 
5.4 
Prior and concomitant therapy .................................................................................... 31 
6. 
Procedures and variables .................................................................................................. 32 
6.1 
Calendar ..................................................................................................................... 32 
6.2 
Safety ......................................................................................................................... 34 
6.2.1 
Adverse events ................................................................................................... 34 
6.2.1.1 
Definitions .................................................................................................... 35 
6.2.1.2 
Classifications for adverse event assessment .............................................. 36 
6.2.1.2.1 
Seriousness .......................................................................................... 36 
6.2.1.2.2 
Intensity ................................................................................................ 36 
6.2.1.2.3 
Causal relationship ............................................................................... 37 
6.2.1.2.4 
Action taken with study treatment ......................................................... 38 
6.2.1.2.5 
Other specific treatment(s) of adverse events ...................................... 38 
6.2.1.2.6 
Outcome ............................................................................................... 38 
7. 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ............................................ 39 


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7.1 
Measurability of Lesions ............................................................................................. 39 
7.2 
Objective Status at Each Disease Evaluation ............................................................. 40 
7.3 
Best Response ........................................................................................................... 42 
8. 
Statistical methods and determination of sample size ........................................................ 42 
8.1 
Sample Size Determination ........................................................................................ 42 
8.2 
Statistical Analysis ...................................................................................................... 43 
9. 
Safety Monitoring ............................................................................................................... 43 
9.1 
Adverse events ........................................................................................................... 44 
9.2 
Serious adverse events .............................................................................................. 45 
9.3 
Reporting of serious adverse events ........................................................................... 45 
9.4 
Adverse events of special safety interest .................................................................... 46 
9.5 
Pregnancies ............................................................................................................... 46 
9.6 
Further safety ............................................................................................................. 47 
10. Premature termination of the study .................................................................................... 47 
11. Data recording ................................................................................................................... 47 
11.1 Institutional Review Board (IRB) Approval and Consent ............................................. 47 
11.2 Required Documentation ............................................................................................ 48 
11.3 Registration Procedures ............................................................................................. 49 
11.4 Data Management and Monitoring/Auditing ................................................................ 49 
11.5 Adherence to the Protocol .......................................................................................... 50 
11.6 Emergency Modifications ............................................................................................ 50 
11.7 Record Retention ........................................................................................................ 50 
11.8 Obligations of Investigators ........................................................................................ 51 
12. Ethical and legal aspects ................................................................................................... 51 
12.1 Ethical and legal conduct of the study ........................................................................ 51 
12.2 Subject information and consent ................................................................................ 52 
12.3 Publication policy ........................................................................................................ 53 
12.4 Confidentiality ............................................................................................................. 53 
13. Correlative studies ............................................................................................................. 54 
13.1 Required Participation ................................................................................................ 54 
13.2 Details on Potential Biomarker Studies by Specimen ................................................. 54 
13.3 Special Instructions .................................................................................................... 56 
13.4 Shipping ..................................................................................................................... 56 
14. Reference list ..................................................................................................................... 57 


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List of abbreviations 
 
ADL 
Activities of Daily Living  
ALT 
Alanine aminotransferase 
Ang 
Angiopoietin 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BID 
bis in die, twice daily  
 
B-Raf 
B isoform of Rapidly Accelerated Fibrosarcoma protein 
BUN 
Blood Urea Nitrogen 
c-KIT 
Stem Cell Factor Receptor Tyrosine Kinase 
CR 
Complete Response 
C-RAF 
C isoform of Rapidly Accelerated Fibrosarcoma protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCE 
Dynamic Contrast Enhanced 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
ERK 
Extracellular Signal-regulated Kinases 
FDA 
Food and Drug Administration 
FGFR 
Fibroblast Growth Factor Receptor 
FLT3 
FMS-like Tyrosine Kinase 3 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HCC 
Hepatocellular Carcinoma 
HFSR 
Hand-foot-skin reaction 
IB 
Investigator’s Brochure 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IR 
Immediate Release 
IRB 
Institutional Review Board 
MAPK 
Mitogen Activated Protein Kinase 
MEK 
MAP Kinase / ERK Kinase 1 
NM 
Nano molar 
NYHA 
New York Heart Association 


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PD 
Progressive Disease 
PDGFR-β 
Platelet Derived Growth Factor Receptor-beta 
PFS 
Progression free survival 
PO 
per oris, oral 
PR 
Partial Response 
PS 
Performance Status 
PTT 
Partial thromboplastin time 
QD 
quaque die, once daily 
RAF 
Rapidly Accelerated Fibrosarcoma 
RAS 
Rat sarcoma 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria for Solid Tumors 
RET 
Rearranged during transfection 
RTK 
Receptor Tyrosine Kinase 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TIE2 
Tyrosine kinase with Immunoglobulin and Epidermal Growth Factor (EGF) 
homology domain 2 
TK 
Tyrosine Kinase 
TTP 
Time to Progression 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
 
1. Introduction 
1.1 
Background 
Biliary cancer (BC) typically includes intra and extrahepatic cholangiocarcinoma and 
cancers of the gallbladder.  In the United States, an estimated 2600 intrahepatic 
cholangiocarcinomas were diagnosed in 2010.[1]
,[2] In addition, about 10,000 cases of 
extrahepatic bile duct cancer are diagnosed annually in the United States, two-thirds of 
which are gallbladder cancers.[1] Unfortunately, most patients have advanced disease at 
presentation and relapse despite surgery.[3] 
Data regarding chemotherapy have historically been disappointing in advanced BC, but 
new combinations show promise. ABC-02, a randomized phase III study recently 
published by Valle et al, enrolled more than 300 patients and compared gemcitabine plus 
cisplatin with gemcitabine alone.[4] The median overall survival (OS) and progression-free 
survival (PFS) were greater for gemcitabine plus cisplatin than for gemcitabine alone 
without significantly increased toxicity (OS: 11.7 v 8.2 months; log-rank P = .002; PFS: 8.5 


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v 6.5 months;  P = .003). This drug combination set a new international standard of care 
for advanced biliary tract cancers. However, the survival for advanced BCs still rarely 
exceeds one year. This has led to a search for molecular targets for therapy. However, 
advances have been slow in part because of the tumor heterogeneity of BCs.[5] 
 
VEGF Pathway 
The vascular endothelial growth factor (VEGF)/VEGF receptor tyrosine kinase (RTK) 
signaling pathway plays a pivotal role in tumor angiogenesis by promoting vascular and 
lymphatic 
endothelial 
cell 
proliferation, 
survival, 
and 
invasion, 
resulting 
in 
neovascularization, tumor growth, and metastasis.[6] 
VEGF has been found to be overexpressed in biliary tract cancers and has thus been 
suggested as a potential prognostic marker and therapeutic target.[7, 8] VEGF expression 
in biliary tract cancer has also been found to be an independent negative predictive 
marker. [9] Increased VEGF expression has been reported to be associated with 
significant vascularization of human intrahepatic cholangiocarcinomas, as assessed by 
microvessel density. In comparison, hypovascularity of cholangiocarcinoma may be 
related to a downregulation of VEGF together with an upregulation of the angiogenesis 
inhibitor thrombospondin-1.[10] Interestingly, VEGF-A expression was more frequently 
encountered in peripheral cholangiocarcinoma (69 vs 25%, p < 0.0001) and correlated 
with increased vascular density.[11] This could suggest a potential benefit for 
antiangiogenic therapies in peripheral cholangiocarcinomas. 
Based on the pre-clinical data, VEGF inhibitors have been studied in bile duct cancers. 
Bevacizumab, a monoclonal antibody to VEGF, has been used in combination with 
gemcitabine/oxaliplatin or erlotinib and has shown promising results.[12, 13] The 
combination of gemcitabine and oxaliplatin with the addition of bevacizumab for first line 
treatment showed impressive overall survival of 12.7 months and progression free survival 
of 7.0 months. [12] Bevacizumab has also been studied in combination with erlotinib as a 
second line treatment.[14] The results were modest with response rate of 13% and overall 
survival of 4 months.    
Tyrosine kinase inhibitors (TKI) of VEGF have also been tested in advanced biliary tract 
tumors. Sorafenib, a small molecule inhibitor of several protein kinases including VEGFR 
has been studied as first line treatment in biliary cancers. So far there have been 2 studies 
using sorafenib in advanced biliary cancers.[15, 16] The results were moderately effective 
but with a high rate of toxicity.  
Raf-MEK-ERK Pathway 
The Raf-MEK-ERK signaling pathway controls fundamental cellular processes including 
proliferation, differentiation and survival.[17] This pathway is an important mediator of 
response to growth signals and angiogenic factors, and is often aberrantly activated in 
human tumors due to the presence of activated RAS, mutant BRAF, or overexpression of 
growth factor receptors.[18] Activated RAS triggers the phosphorylation and activation of 
the RAF kinase, which then phosphorylates MEK1 and MEK2 on two serine residues. [19] 
Because this pathway is frequently dysregulated in human cancers, intense efforts are 
under way to develop selective inhibitors of the ERK pathway as anticancer drugs. In 
preclinical data, MEK inhibitors have been shown to improve survival in mice with KRAS 
mutant BC. [20] However, the frequency of RAS and RAF mutations in biliary cancer is still 


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unclear.  In one study evaluating 69 patients with BC, 31 (45%) patients had KRAS 
mutations.[21] Other studies have shown RAS mutation in BC ranging from 3-54% [22, 23]  
Incidence of BRAF mutation in BC is unclear as well. In one study, BRAF mutations were 
identified in 22% of human cholangiocarcinoma samples. Significantly, these mutations 
were mutually exclusive of KRAS alterations, which occurred in 45% of tumors within the 
same series.[21] BRAF mutations are frequently associated enhanced sensitivity to MEK 
inhibition and may constitute a key survival mechanism for those cells.[24, 25] A better 
understanding of the frequency and impact of BRAF mutations in cholangiocarcinoma is 
needed since other studies have found no BRAF mutations in BC. [26] 
Downstream of BRAF, the MAPK pathway appears active in 75% of BC, as evidenced by 
P-MAPK immunostaining.[27] Expression profiling across a panel of seven human BC cell 
lines demonstrated expression of a number of RAS/MAPK pathway components and have 
demonstrated sensitivity to MEK inhibitors.[28]  
The PDGFR pathway also appears to be a potential target in BC. It has been 
hypothesized that PDGFR activation mediates resistance apoptosis. Data in human cells 
has shown increased sensitivity to apoptotic agents once the PDGFR- ß /c-kit pathway 
was targeted.[29] 
 
1.2 
Rationale of the study 
 
The outcome of patients with advanced biliary cancer remains dismal with the current 
standard of care options. There is currently an unmet medical need for patients with 
advanced BC who have failed one prior systemic therapy. 
The second line setting therefore offers a unique opportunity to evaluate the activity of 
relevant molecularly targeted therapies and to identify potential predictive biomarkers. The 
fact that aberrant activation of the Ras/Raf/MAPK pathway occurs in more than 60% of BC 
indicates the importance of these pathways in biliary carcinogenesis and highlights 
potential new strategies in the treatment of this disease.[30]  Furthermore anti-angiogenic 
agents such as the VEGF-antagonist bevacizumab, and the multikinase inhibitor sorafenib 
have been tested in BC in the first line setting with modest activity.  
Regorafenib is an oral multi-kinase inhibitor that targets both receptor tyrosine kinases 
(RTKs), as well as the tumor cell proliferation/survival signaling pathway kinases 
(RAS/RAF/MEK/ERK). In addition, regorafenib inhibits VEGFR-2/3, TIE-2, c-KIT, and 
PDGFR-ß receptor phosphorylation.  Given the pivotal role of VEGF, the Ras/Raf/MAPK 
pathway, and PDGFR- ß in biliary cancer biology, evaluation of the regorafenib in the 
second line setting represents a rational approach. 
 
 
. 
1.3 
Regorafenib  
Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic 
activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging 
(MRI).  
Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular 
kinases involved in normal cellular functions and in pathologic processes such as 


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oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.  In in 
vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 
and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, 
PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, 
SAPK2, PTK5, and Ab1 at concentrations of regorafenib that have been achieved 
clinically.  In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat 
tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several 
mouse xenograft models including some for human colorectal carcinoma. 
1.3.1 
Preclinical 
In vivo, regorafenib exhibited anti-angiogenic and anti-proliferative effects in human colon 
and breast xenografts as demonstrated by a reduction in microvessel area, reduced Ki-67 
staining, and reduced pERK1/2 staining in tissue sections from tumor xenografts, and 
dose-dependent inhibition of growth in multiple xenograft models (breast, colon, renal, 
NSCLC, melanoma, pancreatic, thyroid, ovarian).[31]  Immunohistochemical ex-vivo 
studies with a phospho –specific monoclonocal anti-ERK 1 / 2 antibody demonstrated 
inhibition of the MAPK pathway five days after treatment with regorafenib in 2 of 3 tumor 
models examined (MDA-MB 231 and BxPC-3), but not in NSCLC (H460). 
In addition, all tested human tumor xenografts (MDA-MB-231, H460, BxPC-3 and Colo-
205) demonstrated a significant reduction in new blood vessels by histomorphometry as 
detected in tumor samples using a murine CD31 antibody.[31] These data suggest that 
regorafenib can target the tumor cell MAPK pathway (tumor cell survival) and tumor 
vasculature in some but not all tumors. 
1.3.2 
Clinical experience 
Two phase III global randomized studies have evaluated the efficacy of regorafenib. The 
CORRECT (Patients with metastatic colorectal cancer treated with regorafenib or placebo 
after failure of standard therapy) trial is an international, multicenter, randomized, double-
blind, placebo-controlled study that enrolled 760 patients with mCRC whose disease has 
progressed after approved standard therapies. [32]Metastatic colorectal cancer patients 
were randomized to regorafenib plus best supportive care (BSC) or placebo plus BSC. 
Treatment cycles consisted of 160 mg of regorafenib (or matching placebo) once daily for 
three weeks on / one week off plus BSC. The primary endpoint of this trial was overall 
survival. Secondary endpoints included progression-free survival, objective tumor 
response rate and disease control rate. The safety and tolerability of the two treatment 
groups were also compared. 
 
At a preplanned second interim analysis, there was a statistically significant survival 
benefit for regorafenib. The estimated hazard ratio for overall survival was 0.773 (95% 
confidence interval [CI], 0.635 to 0.941; 1-sided p = .0051). Patients treated with 
regorafenib had a median overall survival of 6.4 months, compared with 5.0 months for 
placebo — a 29% increase in survival. In addition to improved overall survival, 
progression-free survival was superior; median progression-free survival was 1.9 months 
(95% CI, 1.88 to 2.17) for regorafenib and 1.7 months (95% CI, 1.68 to 1.74) for placebo. 
The estimated hazard ratio for progression-free survival was 0.493 (95% CI, 0.418 to 
0.581; 1-sided p< .000001). There was a substantial difference in disease control rate in 
the regorafenib and placebo groups (44% vs. 15%; p<.000001).  Regorafenib 


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demonstrated comparable efficacy benefits across patient subgroups analyzed including 
age, number of mets, number of lines of prior therapy, and kras status. 
The most frequent grade 3+ adverse events in the regorafenib group were hand–foot skin 
reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension 
(7%).  The efficacy and safety from the CORRECT study supported FDA approval in 
September 2012. 
The efficacy and safety of regorafenib were examined in the Phase III GRID trial in 
patients with gastrointestinal stromal tumors (GISTs) who had exhausted all other 
treatment options. 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. 
The results showed that treatment with regorafenib led to a statistically significant 3.9-
month improvement in progression-free survival (PFS), compared with placebo (4.8 
months vs. 0.9 months; hazard ratio [HR] = 0.27;  p <.0001). Overall survival was 
statistically similar between groups as expected due to a trial design that allowed 
crossover to regorafenib for disease progression.  The median survival period without 
tumor growth among patients on regorafenib was 4.8 months while for the control group 
on placebo it was less than a month. The overall disease control rate combining partial 
responses with durable stable disease for at least 12 weeks was 53% with regorafenib 
compared with 9% in the control group. The most common grade ≥3 adverse events 
associated with regorafenib were hand-foot skin reaction (56.1%), hypertension (48.5%), 
and diarrhea (40.9%).   GRID study data is currently under FDA review. 
 
2. Study objectives 
 
Primary Objective  
• To determine 6 month overall survival in patients with advanced refractory BC receiving 
regorafenib. 
 
Secondary Objectives 
• 
To determine the frequency and severity of adverse events and tolerability of the 
regimen in patients with advanced refractory BC receiving regorafenib  
• 
To evaluate the disease control rate (CR + PR+ SD) as defined by the RECIST 1.1 
criteria in patients with advanced refractory biliary cancers (BC) receiving 
regorafenib at 8 weeks. 
• 
To determine the progression-free survival in patients with advanced refractory BC 
receiving regorafenib  
 
Exploratory Objective 
• 
To explore potential correlations between blood biomarkers and clinical benefit 
 


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3. Investigator[s] and other study participants 
 
 
Nishi Kothari M.D. 
 
H. Lee Moffitt Cancer Center 
           Tampa, Fl 
 
           Hanna Sanoff M.D 
           University of North Carolina 
           Chapel Hill, NC 
                                             
            
 
           
 
           Tanios Sabb M.D 
           Ohio State University 
           Columbus, Oh 
 
           Andrew Poklepovic M.D 
           VCU Massey Cancer Center 
           Richmond, VA 
 
 
          Andrew Nixon PhD 
          Duke University 
          Durham, NC 
 
 
 
 
4. Study design 
This is a multi-institutional single arm, Simon’s two-stage trial using regorafenib as a 
single agent in patients who have failed at least one prior line of systemic therapy in 
advanced biliary tumors. 39 patients will be accrued. Patients will receive regorafenib 160 
mg QD (21 days on and 7 days off). After 2 cycles (1cycle= 28 days), response and 
progression will be evaluated using the new international criteria proposed by the revised 
Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Primary 
endpoint is 6 month overall survival.  
 
 
4.1 
Eligibility 
4.1.1 
Inclusion criteria 
 
 
• Patients must have histologically or cytologically documented carcinoma primary to 
the intra- or extra-hepatic biliary system or gall bladder with clinical and/or 
radiologic evidence of unresectable, locally advanced or metastatic disease. 
Patients with ampullary carcinoma are not eligible. 
• Patients must have failed no more than 2 prior line of systemic chemotherapy for 
advanced biliary cancer. Patients who received adjuvant chemotherapy and had 


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evidence of disease recurrence within 6 months of completion of the adjuvant 
treatment are also eligible. If patient received adjuvant treatment and had disease 
recurrence after 6 months, patients will only be eligible after failing one line of 
systemic chemotherapy used to treat the disease recurrence. 
• Age ≥ 18 years. 
• Eastern Cooperative Oncology Group (ECOG) Performance Status Assessment of 
0 or 1  
• Measurable and non-measurable disease will be allowed.  
• Patients must not have been treated with any VEGF inhibitors.  
• Life expectancy of at least 12 weeks (3 months). 
• For patients who have received prior cryotherapy, radiofrequency ablation, 
therasphere, ethanol injection, transarterial chemoembolization (TACE) or 
photodynamic therapy, the following criteria must be met: 28 days have elapsed 
since that therapy (lesions that have not been treated with local therapy must be 
present and measureable 
• 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. 
• All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 
Grade 1 or less at the time of signing the Informed Consent Form (ICF). 
• Adequate bone marrow, liver and liver function as assessed by the following 
laboratory requirements: 
o Total bilirubin ≤ 2.0 x the upper limits of normal (ULN) 
o Alanine aminotransferase (ALT) and aspartate amino-transferease (AST)  
≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) 
o Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver 
involvement of their cancer) 
o Serum creatinine  ≤ 1.5 x the ULN 
o Calculated creatinine clearance > 30 ml/min. 
 
Calculated creatinine clearance = (140 – age) x t (kg) x [0.85 (if 
female)] 
 
 
 
 
 
 
72 x creatinine (mg/dL) 
 
o International normalized ratio (INR)/ Partial thromboplastin time (PTT) ≤  
1.5 x ULN. (Subjects who are therapeutically 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 


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stable based on a measurement that is pre-dose as defined by the local 
standard of care. 
 
Platelet count ≥ 75,000 /mm3,  
 
hemoglobin (Hb) ≥ 9 g/dL,  
 
absolute neutrophil count (ANC) 1000/mm3.  
 
 Blood transfusion to meet the inclusion criteria will  be allowed. 
• Women of childbearing potential must have a negative serum pregnancy test 
performed within 7 days prior to the start of study drug.  Post-menopausal women 
(defined as no menses for at least 1 year) and surgically sterilized women are not 
required to undergo a pregnancy test. 
• Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 3 months after the 
last dose of study drug.  The definition of adequate contraception will be based on 
the judgment of the principal investigator or a designated associate. 
• Subject must be able to swallow and retain oral medication. 
4.1.2 
Exclusion criteria 
• Previous assignment to treatment during this study.  Subjects permanently 
withdrawn from study participation will not be allowed to re-enter study. 
• Other investigational treatment during or within 21 days before starting study 
treatment 
• Child Pugh B or C 
• 
Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure 
> 90 mm Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal 
medical management. 
• 
Active or clinically significant cardiac disease including: 
o Congestive heart failure – New York Heart Association (NYHA) > Class II. 
o Active coronary artery disease. 
o Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers or digoxin. 
o Unstable angina (anginal symptoms at rest), new-onset angina within 3 
months, or myocardial infarction within 6 months. 
• Evidence or history of bleeding diathesis or coagulopathy. 
 


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• Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to 
start of study medication.  
• Subjects with thrombotic, embolic, venous, or arterial events, such as 
cerebrovascular accident (including transient ischemic attacks) deep vein 
thrombosis or pulmonary embolism within 6 months of informed consent. 
• No active malignancy except for nonmelanoma skin cancer or in situ cervical 
cancer.  Subjects surviving a cancer that was curatively treated and without 
evidence of disease for more than 3 years before the trial are allowed. All cancer 
treatments must be completed at least 3 years prior to study entry (i.e., signature 
date of the informed consent form). 
• Patients with phaeochromocytoma. 
• Known history of human immunodeficiency virus (HIV) infection or current chronic 
or active hepatitis B or C infection requiring treatment with antiviral therapy. 
• Ongoing infection > Grade 2 NCI-CTCAE v4.0. 
• Symptomatic metastatic brain or meningeal tumors. 
• Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
• Renal failure requiring hemo-or peritoneal dialysis. 
• Patients with seizure disorder requiring medication. 
• Persistent proteinuria ≥ Grade 3 NCI-CTCAE v4.0 (> 3.5 g/24 hrs, measured by 
urine protein:creatinine ratio on a random urine sample). 
• Interstitial lung disease with ongoing signs and symptoms at the time of informed 
consent.  
• Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE 
version 4.0 Grade 2 dyspnea). 
•   History of organ allograft (including corneal transplant). 
•   Known or suspected allergy or hypersensitivity to any of the study drugs, study 
drug classes, or excipients of the formulations given during the course of this trial. 
•   Any malabsorption condition. 
•   Women who are pregnant or breast-feeding. 
•   Any condition which, in the investigator’s opinion, makes the subject unsuitable for 
trial participation. 
•   Substance abuse, medical, psychological or social conditions that may interfere 
with the subject’s participation in the study or evaluation of the study results. 


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4.1.3 
Excluded therapies and medications, previous and concomitant 
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) other than study 
treatment  
• Prior use of regorafenib or other anti VEGF drugs. 
• Concurrent use of another investigational drug or device therapy (i.e., outside of 
study treatment) during, or within 21 days of trial entry (signing of the informed 
consent form). 
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
before start of study medication. 
• Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum]) 
4.2 
Withdrawal of subjects from study 
4.2.1 
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. 
• 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. 
• Progression of disease 
• 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. 


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• 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 3 or 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 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. 
4.2.2 
Screen Failures/Dropouts 
A subject who discontinues study participation prematurely for any reasons except death, disease 
progression and severe toxicity is defined as a dropout. 
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see above) is regarded a 
“screening failure”. 
4.2.3 
Replacement 
Dropout patients will need to be replaced.  
Patients will be considered inevaluable for the primary endpoint of 6 month of OS if they 
are not able to complete first cycle.   Inevaluable patients will be replaced 
5. Treatment[s] 
5.1 
Treatments to be administered 
All patients will receive regorafenib  
 
Arm 1: Regorafenib 
 
 
Agent  
Dose 
Route   Day 
Schedule* 
 
 
Regorafenib 
160mg   
PO 
 QD 
21 days 
 
One cycle = 28days  
 


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5.1.1 
Regorafenib 
Regorafenib tablets will be packaged in high density polyethylene bottles with a white child 
resistant closure and induction seal.  Each bottle includes 30 tablets and a 3-gram 
desiccant.  The bottles will have a label affixed containing study identification, product 
identification, and quantity of tablets.  Once the drug has been received it must be kept in 
a secure, dry location.  Study drug must be stored in its original bottle at a temperature not 
above 25°C (77°F). 
The study drug must be exclusively used for the investigation specified in this protocol and 
it will only be accessible to authorized staff. 
5.1.2 
Dosage and administration: 
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 –coating contains the following inactive ingredients: ferric oxide red, ferric oxide 
yellow, lecithin (soy), polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. 
5.1.3 
Study Treatment 
Regorafenib is administered as monotherapy during the study, 160 mg qd will be 
administered for 3 weeks on /1 week off.  One cycle is 28 days. 
 
Four 40-mg regorafenib tables should be taken in the morning with approximately 8 fluid 
ounces (240 mL) of water after a low-fat (<30% fat) breakfast.   Some examples of low fat 
breakfasts are: 
• Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon 
of jelly and 8 ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g 
of fat). 
• One cup of cereal (i.e. Special K), 8 ounces (240 mL) of skim milk, one piece of 
toast with jam (no butter or marmalade), apple juice, and one cup of coffee or tea 
(2 g fat, 17 g protein, 93 g of carbohydrate, 520 calories. 
5.1.4 
Dose Modification for management of adverse events 
5.1.4.1 
Dose Reduction Levels 
The starting dose of regorafenib is 160 mg once daily.  Study medication will be 
administered on a 3 weeks on/1week 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 


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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 
(standard starting 
dose) 
160 mg po qd 
Four 40-mg tablets of regorafenib 
Dose level - 1 
120 mg po qd  
Three 40-mg tablets of regorafenib 
Dose level - 2 
80 mg po qd  
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 treatment 
 
If more than 2 dose reductions are required, regorafenib will be discontinued and patient 
will need to come off of the trial.   If a dose reduction has been performed, intra-subject 
dose re-escalation can be considered (up to the maximal 160 mg daily dose) at the 
discretion of the treating physician provided that the toxicity(ies) has resolved to baseline. 
 
The following tables outline dose adjustments for toxicities related to study drug except 
hand-foot skin reaction, hypertension and liver function test abnormalities.  
 
 
Table 6-1:  Recommended dose modification for toxicities except hand-foot-skin 
reaction, hypertension and ALT/ST/bilirubin 
NCI-CTCAE v4.0a 
Dose Interruption 
Dose  
Modification b 
Dose for 
Subsequent 
Cycles 
Grade 0-2 
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 
 


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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 
unless subject is deriving clinical benefit. 
*   Modify according to study specific cycle length 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 6-2: Grading for Hand-Foot-Skin-Reaction 


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Grade 1 
Grade 2 
Grade 3 
NCI-CTCAE v4.0 
Palmar-plantar 
erythrodysesthesia 
syndromea 
Minimal skin changes 
or dermatitis 
(e.g., erythema, 
edema, or 
hyperkeratosis) 
without pain 
Skin changes 
(e.g., peeling, 
blisters  bleeding, 
edema, or 
hyperkeratosis) 
with pain 
Severe skin 
changes (e.g., 
peeling, blisters, 
bleeding, edema, 
or hyperkeratosis) 
with pain 
Further description / 
examples of skin 
changes 
Numbness, 
dysesthesia / 
paresthesia tingling, 
painless swelling, or 
erythema of the hands 
and/or feet 
Painful erythema 
and swelling of the 
hands and/or feet 
Moist 
desquamation, 
ulceration, 
blistering, or 
severe pain of the 
hands and/or feet 
Effect on activities 
Does not disrupt 
normal activities 
Limiting 
instrumental 
activities of daily 
life (e.g., preparing 
meals, shopping 
for groceries or 
clothes, using the 
telephone, 
managing money) 
Limiting self-care 
activities of daily 
life (e.g., bathing, 
dressing and 
undressing, 
feeding self, using 
the toilet, taking 
medications) and 
not bedridden 
a. Palmer-planter erythrodysesthesia syndrome is a disorder characterized by redness, 
marked 
    discomfort, swelling, and tingling in the palms of hands or the soles of the feet. 
 


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Table 6.3  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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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: 
• 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 


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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 6.4 outlines suggested dose reductions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 6-4:  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 patient already on anti-
hypertensive medication, 
titrate up the dose. 
• Continue regorafenib 
 
• If symptomatic, hold regorafenib 
until symptoms resolve AND 
diastolic BP ≤ 90 mm Hga. When 
regorafenib is restarted, continue 
at the same dose level. 
 
3 
 
Systolic BP ≥ 160 
mmHg or 
diastolic BP ≥ 100 
mmHg 
OR 
More than one drug or 
more 
intensive therapy than 
previously used 
indicated 
Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
Start anti-hypertensive 
medication  
 
AND/OR 
Increase current anti-
hypertensive medication 
 
AND/OR  
Add additional anti-
hypertensive medications.   
• Hold regorafenib until diastolic BP 
≤ 90 mm Hg, and if symptomatic, 
until symptoms resolve.a 
 
• When regorafenib is restarted, 
continue at the same dose level. 
 
• If BP is not controlled with the 
addition of new or more intensive 
therapy, reduce by 1 dose level.b 
 
• If Grade 3 hypertension recurs 
despite dose reduction and 
antihypertensive therapy, reduce 
another dose level.c 
4 
 
Life-threatening 
consequences 
(eg, malignant 
hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis) 
Per institutional guidelines 
Discontinue therapy 
a. Patients requiring a delay of >4 weeks should go off protocol therapy 
b. If BP remains controlled for at least one cycle, dose re-escalation permitted per 
investigator’s discretion. 
c. Patients requiring >2 dose reductions should go off protocol therapy. 
 


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Liver Function Abnormalities 
For patients with observed worsening of serum liver tests considered related to 
regorafenib (i.e. where no alternative cause is evident, such as post-hepatic cholestasis or 
disease progression), the dose modification and monitoring advice in Table 6-5 should be 
followed. 
 
Regorafenib is a UGT1A1 inhibitor.  Mild, indirect (unconjugated) hyperbilirubinemia may 
occur in patients with Gilbert’s syndrome. 
 
 
Alanine or aspartate aminotransferase (AST/ALT): for any grade increase in AST or ALT, 
the investigator needs to ensure that it is not due to biliary obstruction or the introduction 
of new drugs. Biliary obstruction should be ruled out by imaging if needed. If the elevation 
of AST or ALT is due to biliary obstruction, and the biliary obstruction is treated, the study 
drug may be restarted at the same dose level upon return of the AST and ALT to baseline 
or grade 2. 
 
For any grade increase in bilirubin, the investigator needs to ensure that it is not due to 
biliary obstruction or the introduction of new drugs. Biliary obstruction should be ruled out 
by imaging if needed. If the elevation of bilirubin is due to biliary obstruction, and the biliary 
obstruction is treated, the study drug may be restarted at the same dose level upon return 
of the bilirubin to baseline or Grade 1.  
 
 
 
 
Table 6-5:  Dose modifications/interruption for ALT and/or AST and/or bilirubin 
increases related to study drug 
Observed elevations 
1st Occurrence 
Restart 
Re-occurrence 
ALT and/or AST >5 X 
ULN (≥ G3) 
If patient had Grade 
0 or 1 AST or ALT 
increase at 
baseline, hold the 
drug until AST or 
ALT returns to 
Grade 1 or baseline.  
If patient had Grade 
2 (asymptomatic) 
AST or ALT 
increase at 
baseline, continue 
treatment at same 
dose and follow 
AST or ALT weekly 
for 4 weeks. Hold 
Reduce one dose level 
and measure serum 
liver tests weekly for at 
least 4 weeks. 
Discontinue 


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the drug if patient 
develops symptoms 
or if AST or ALT > 
10 x IULN; 
restart treatment 
with one dose level 
reduction when AST 
or ALT returns to 
baseline AND 
patient is 
asymptomatic 
 
ALT and/or AST > 20 
X ULN (≥ G4) 
Discontinue 
 
 
Bilirubin ( G=2) 
If patient had a 
normal bilirubin at 
baseline, hold the 
drug until bilirubin 
returns to Grade 1 
or baseline 
 
If patient had Grade 
1 bilirubin at 
baseline, continue 
treatment at same 
dose and follow 
bilirubin weekly for 4 
weeks. Hold the 
drug if patient 
develops symptoms 
or if bilirubin > 2 x 
ULN and AST or 
ALT > 5 x ULN 
Restart treatment 
when bilirubin 
returns to grade 1 or 
baseline and patient 
is asymptomatic.  
Restart with one dose 
reduction 
Discontinue 
Bilirubin ( G=3) 
Discontinue 
 
Discontinue 
During the first 2 cycles of treatment, ALT, AST and bilirubin must be monitored every 2 
weeks. 


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Bilirubin and AST/ALT: for any grade increase in bilirubin AST or ALT, the investigator 
needs to ensure that it is not due to biliary obstruction or the introduction of new drugs. 
Biliary obstruction should be ruled out by imaging if needed. If the elevation of AST or ALT 
is due to biliary obstruction, and the biliary obstruction is treated, the study drug may be 
restarted at the same dose level upon return of the AST and ALT to baseline or grade 2. 
 
 
 
 
 
5.1.4.2 
Prevention/management strategies for diarrhea 
Diarrhea can be a common side effect of regorafenib.  The same dose-modification 
algorithm used for skin toxicities can be used to address these toxicities.  However, the 
preventive/management strategies for diarrhea should be consistent with local standards 
(e.g., anti-diarrheals and optimized hydration status). 
Anti-diarrhea medications may be introduced if symptoms occur.  Previous trials have 
shown that 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. 
5.2 
Drug logistics and accountability 
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practices (GMP) requirements and the 
instructions given by the clinical supplies department of the Institution and will be 
inaccessible to unauthorized personnel. 
5.2.1 
Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI Drug Accountability Record or another comparable drug 
accountability form. (See the CTEP website at http://ctep.cancer.gov/protocolDevelopment  
for the “Policy and Guidelines for Accountability and Storage of Investigational Agents” or 
to obtain a copy of the drug accountability form.) 
5.2.2 
Destruction and Return 
At the end of the study, unused supplies of regorafenib should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form. The certificate of destruction should be sent to Bayer. 
A completed “Unused Study Drug Disposition Form Destruction or Return Confirmation” 
should be sent to Bayer at the following address:   
E-mail: Karen.marini@bayer.com 
  OR  


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Fax: 973-709-2193 
  OR 
Mail: (VP of Medical Affairs named in contract) at 
Bayer HealthCare Pharmaceuticals 
6 West Belt 
Wayne, NJ   07470 
5.3 
Treatment compliance 
An adequate record of receipt, distribution, and return of all study drugs must be kept in 
the form of a Drug Accountability Form.  
Subject compliance with the treatment and protocol includes willingness to comply with all 
aspects of the protocol, and to have blood collected for all safety evaluations.  At the 
discretion of the principal investigator, a subject may be discontinued from the trial for 
non-compliance with follow-up visits or study drug. 
5.4 
Prior and concomitant therapy 
All medication that is considered necessary for the subject’s welfare, and which is not 
expected to interfere with the evaluation of the study treatment, may be given at the 
discretion of the investigator.  All medications (including contrast media) taken within 2 
weeks prior to the start of the study and during the study must be recorded in the subject’s 
source documentation and in the CRF (including start/stop dates, dose frequency, route of 
administration, and indication).  Specific caution should be taken when considering or 
administering a concomitant medication that is metabolized by the cytochrome enzymes 
CYP2C8, CYP2B6 and CYP2C9.  Such concomitant medication should be avoided, if 
possible. 
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of 
Stivarga 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 Stivarga with strong CYP3A4 inducers (e.g. 
rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) 
Co administration of a strongCYP3A4 inhibitor (ketoconazole) with a single 160mg dose of 
Stivarga increased the mean exposure of regorafenib and decreased the mean exposure 
of the active metabolites M-2 and M-5.  Avoide concomitant use of Stivarga with strong 
inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, 
ketoconazole, nefazadone, posaconazole, telithromycin, and voriconazole). 
 
Permitted concomitant therapy includes: 
• Standard therapies for concurrent medical conditions. 
• Supportive care for any underlying illness. 
• Palliative radiation therapy is allowed if the target lesion(s) are not included within 
the radiation field and no more than 10% of the bone marrow is irradiated. 


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• 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 (day5 of cycle 1 and day 1 of each cycle) 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. 
The following are not permitted: 
• Other investigational treatment during or within 21 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 
• Subjects taking narrow therapeutic index medications should be monitored 
proactively (e.g. warfarin, phenytoin, quinidine, carbamazepine, Phenobarbital, 
cyclosporine, and digoxin).  Warfarin is metabolized by the cytochrome enzyme 
CYP2C9 and it’s levels may be especially affected by regorafenib 
• Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum]) 
6. Procedures and variables 
6.1 
Calendar 
 
 
 
 


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Required studies must be done within 28 days prior to starting on the treatment. 
 
1 Protocol treatment and parameters will continue at these intervals until progression of 
disease or until patient has met any of the guidelines in Section 4.2.1 
2 After off treatment following disease progression, physical assessments (with lab tests 
performed at the discretion of the treating investigator) should take place every 3 
months for up to two years or death. 
3 Sodium, potassium, chloride, CO2, calcium, magnesium, phosphorus, blood urea 
nitrogen [BUN], creatinine, glucose, albumin, total protein, alkaline phosphatase, 
bilirubin [total and direct], AST, ALT 
 
Cycle 1   +/- 2 Days 
 
Cycle 2   +/- 2 Days 
 
 
Cycle 31       +/- 2 Days 
REQUIRED 
STUDIES 
Pre-
Study 
Wk 
1 
 
Wk 
2 
 
Wk
3 
 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Pre-
Progressio
n Follow-
Up 1 
Post-
Progression 
Follow-Up 2 
PHYSICAL  1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and 
Physical Exam 
(informed 
consent) 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
Weight and 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
Toxicity 
Notation 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X # 
X # 
Blood Pressure 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
LABORATORY
  1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC, 
Differential, 
Platelets 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
CA-19-9 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Serum 
Chemistry  3 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
U/A 7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS AND 
SCANS 1, 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI for 
Disease 
Assessment  5 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample ( 
for 
correlatives)6 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Regorafenib   
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 


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4 To be performed every 8 weeks until progression.  Must be performed using same 
method as prestudy. 
5 Scan must be performed +/- 1 week of each assessment. 
6 Draw 1 x10mls EDTA tubes at baseline, Cycle 3 Day 1 (+/- 2 days), and at the 
treatment discontinuation visit if patient continues on after cycle 3 day1. ( see section 
13.) 
7.   Spot urine must not show 2+ or more protein in urine or the patient will 
require a repeat urine analysis.  If repeat urinanalysis shows 2+ protein or more, a 
24-   hour urine collection will be required and must show total protein excretion 
<3500 mg/24 hours 
 
 
# Toxicity should be evaluated until resolution of any adverse events.  
 
6.2 
Safety 
All subjects who receive at least one dose of study treatment will be valid for the safety 
analysis.  
All observations pertinent to the safety of the study treatment will be recorded and 
included in the final report. 
Safety variables include the following: AEs, laboratory changes (complete blood counts, 
electrolytes, chemistry, and coagulation), changes in vital signs (blood pressure, heart 
rate, respiratory rate, and temperature) and ECG and, in some instances, changes in 
chest x-ray images, as produced at the investigator’s discretion (e.g., for evaluation for 
pneumonia). 
All AEs whether considered drug-related or not, will be reported with following information:  
start/stop dates, action taken, whether treatment was discontinued, any corrective 
measures taken, outcome, and other possible causes.  For all events, the relationship to 
treatment and the intensity of the event will be determined by the investigator. 
This trial will use the NCI-CTCAE v4.0 criteria for assessment of toxicity and SAE 
reporting with regard to toxicity grade. 
6.2.1 
Adverse events 
Investigators should refer to the Safety Information section of the current IB for 
regorafenib, including the DCSI (development core safety information), for the expected 
side effects of, regorafenib.  As with any agent, there is always the potential for 
unexpected AEs, including hypersensitivity reactions.  The IB will be updated if any new 
relevant safety data are obtained. 
Therapeutic monitoring should be performed following dose selection or modification of 
regorafenib, in a manner consistent with the local clinical standard of care.  In general, 
subjects should be closely monitored for side effects of all concomitant medications 
regardless of the path of drug elimination. 
All concomitant medications must be recorded in the subject’s source documentation. 


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Subjects must be carefully monitored for AEs.  This monitoring also includes clinical 
laboratory tests.  Adverse events should be assessed in terms of their seriousness, 
intensity, and relationship to the study drug, or other chemotherapy/treatment. 
6.2.1.1 
Definitions 
Definition of adverse event (AE) 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable 
and unintended sign [including abnormal laboratory findings], symptom or disease) 
in a patient or clinical investigation subject after providing written informed consent 
for participation in the study.  Therefore, an AE may or may not be temporally or 
causally associated with the use of a medicinal (investigational) product. 
A surgical procedure that was planned prior to the start of the study by any physician 
treating the subject should not be recorded as AE (however, the condition for which the 
surgery is required may be an AE if worsens compared to baseline). 
 
• Conditions that started before signing of informed consent and for which no 
symptoms or treatment are present until signing of informed consent are recorded 
as medical history (e.g. seasonal allergy without acute complaints). 
• Conditions that started before signing of informed consent and for which symptoms 
or treatment are present after signing of informed consent, at unchanged intensity, 
are recorded as medical history (e.g. allergic pollinosis). 
• Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. 
Definition of serious adverse event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
a. Results in death. 
b. Is life-threatening. 
The term ‘life-threatening’ in the definition refers to an event in which the patient 
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe. 


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c. Requires inpatient hospitalization or prolongation of existing hospitalization. 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE 
if at least one of the following exceptions is met: 
- The admission results in a hospital stay of less than 12 hours. 
- The admission is pre-planned.  
(i.e. elective or scheduled surgery arranged prior to the start of the study) 
- The admission is not associated with an AE. 
(e.g. social hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an 
SAE dependent on clinical judgment.  In addition, where local regulatory 
authorities specifically require a more stringent definition, the local regulation 
takes precedence. 
d. Results in persistent or significant disability / incapacity. 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
e. Is a congenital anomaly / birth defect. 
f. Is another medically important serious event as judged by the investigator. 
6.2.1.2 
Classifications for adverse event assessment 
 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
6.2.1.2.1 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 6.2.1.1 
6.2.1.2.2 
Intensity 
The intensity of the AE is classified according to the CTCAEv4.0.  Grade refers to the 
severity (intensity) of the AE: 
CTCAEv4 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention is not indicated. 
CTCAEv4 Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; 
limiting to age-appropriate instrumental activities of daily living (ADL; instrumental 
ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc). 
CTCAEv4 Grade 3: Severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of hospitalization is indicated; disabling; 


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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. 
6.2.1.2.3 
Causal relationship  
The assessment of the causal relationship between an AE and the administration of 
treatment is a clinical decision based on all available information. 
 
The causality assessment should be done separately for each study treatment. 
The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study treatment in question. 
Possible answers are “yes” or “no”. 
An assessment of “no” would include: 
1. The existence of a clear alternative explanation, e.g. mechanical bleeding at 
surgical site. 
or 
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; 
cancer developing a few days after the first drug administration. 
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is 
associated with the use of the study treatment. 
Factors to be considered in assessing the relationship of the AE to study treatment 
include: 
- The temporal sequence from drug administration:  The event should occur after the 
drug is given.  The length of time from drug exposure to event should be evaluated in 
the clinical context of the event. 
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): 
- Subject’s response after de-challenge or subjects response after re-challenge should 
be considered in the view of the usual clinical course of the event in question. 
- Underlying, concomitant, intercurrent diseases:   
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have. 
- Concomitant medication or treatment:  
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them may be suspected to cause the event in 
question. 


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- The pharmacology and pharmacokinetics of the study treatment:  
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of 
the study treatment, coupled with the individual subject’s pharmacodynamics should 
be considered. 
[Causal relationship to protocol-required procedure(s)] 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal 
relationship” to protocol-required procedure(s). 
Possible answers are “yes” or “no”. 
6.2.1.2.4 
Action taken with study treatment  
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. 
The study treatment action should be recorded separately for each study treatment. 
 ־Drug withdrawn 
 ־Drug interrupted 
 ־Dose reduced 
 ־Dose not changed 
 ־Dose increased 
 ־Not applicable 
 ־Unknown 
6.2.1.2.5 
Other specific treatment(s) of adverse events 
 ־None 
 ־Remedial drug therapy 
6.2.1.2.6 
Outcome 
The outcome of the AE is to be documented as follows:  
 ־Recovered/resolved 
 ־Recovering/resolving 
 ־Recovered/resolved with sequelae 
 ־Not recovered/not resolved 
 ־Fatal 
 ־Unknown 


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7.   CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
This study will use the RECIST 1.1 guidelines 
7.1 
Measurability of Lesions 
 
a.  
Measurable disease  
 
 
Measurable disease is defined differently for lymph nodes compared 
with other disease and will be addressed in a separate section 
below. 
 
1. 
Lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 2.0 cm  by 
chest x-ray, by ≥ 1.0 cm  with CT or MRI scans, or ≥ 1.0 cm 
with calipers by clinical exam. All tumor measurements must 
be recorded in decimal fractions of centimeters (or 
millimeters). 
 
The defined measurability of lesions on CT scan is based on 
the assumption that CT slice thickness is 0.5 cm or less.  If 
CT scans have slice thickness greater than 0.5 cm, the 
minimum size for a measurable lesion should be twice the 
slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically 
enlarged and measurable if it measures ≥ 1.5 cm in SHORT 
AXIS (greatest diameter perpendicular to the long axis of the 
lymph node) when assessed by scan (CT scan slice 
recommended being no greater than 0.5 cm). 
 
b.    
Non-measurable disease:  All other lesions (or sites of disease), 
including small lesions (longest diameter < 1.0 cm or pathologic 
lymph nodes with ≥ 1.0 cm to < 1.5 cm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered non-measurable as are previously 
radiated lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used 
and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should by 
performed with breath-hold scanning techniques, if possible.  
 
2. 
PET-CT:  At present, the low dose or attenuation correction 
CT portion of a PET-CT is not always of optimal diagnostic 
CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT, 
then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with 
conventional CT. 
 


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3. 
Ultrasound: Ultrasound is not useful in assessment of lesion 
size and should not be used as a method of measurement. 
 
4. 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as malignant 
lesions (neither measurable nor non-measurable) since they 
are, by definition simple cysts. 
 
5. 
If a target lesion becomes very small some radiologists 
indicate that it is too small to measure.  If the lesion is 
actually still present, a default measurement of 0.5 cm 
should be applied.  If the radiologist believes the lesion has 
gone, a default measurement of 0.0cm should be   
 
7.2 
Objective Status at Each Disease Evaluation   
Objective Status is to be recorded at each evaluation. All measurable 
lesions up to a maximum of 2 lesions per organ 5 lesions in total, 
representative of all involved organs, should be identified as target lesions 
at baseline. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-
target lesions.  Measurements must be provided for target measurable 
lesions, while presence or absence must be noted for non-target 
measurable and non-measurable disease.   
 
For studies that use disease progression as an endpoint, whole body 
scanning at specific intervals is necessary to determine that progression is 
NOT present outside of the “target” areas. Therefore, in these studies it is 
not acceptable to image only the “target” areas of the body in follow-up 
scans. For study-specific imaging requirements, see the Study Calendar in 
Section 9.0.   
 
a.  
Complete Response (CR):  Complete disappearance of all target 
and non-target lesions (with the exception of lymph nodes 
mentioned below).  No new lesions.  No disease related symptoms.   
Any lymph nodes (whether target or non-target) must have 
reduction in short axis to < 1.0 cm.  All disease must be assessed 
using the same technique as baseline. 
 
b. 
Partial Response (PR): Applies only to patients with at least one 
measurable lesion. Greater than or equal to 30% decrease under 
baseline of the sum of appropriate diameters of all target 
measurable lesions.  No unequivocal progression of non-
measurable disease.  No new lesions.  All target measurable lesions 
must be assessed using the same techniques as baseline. 
 
c.  
Stable: Does not qualify for CR, PR, Progression or Symptomatic 
Deterioration.  All target measurable lesions must be assessed 
using the same techniques as baseline. 
 
d.  
Progression: One or more of the following must occur:  20% 
increase in the sum of appropriate diameters of target measurable 
lesions over smallest sum observed (over baseline if no decrease 
during therapy) using the same techniques as baseline, as well as 
an absolute increase of at least 0.5 cm.  Unequivocal progression of 
non-measurable disease in the opinion of the treating physician (an 


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explanation must be provided).  Appearance of any new lesion/site.  
Death due to disease without prior documentation of progression 
and without symptomatic deterioration (see Section 10.2e). 
 
 
Notes regarding new lesions:  FDG-PET imaging can complement 
regular scans in identifying new lesions according to the following 
algorithm.  
 
1. 
Negative FDG-PET at baseline, with a positive FDG-PET at 
follow-up is a sign of progression based on a new lesion. 
2. 
No FDG-PET at baseline and a positive FDG-PET at follow-
up corresponding to a potential new site of disease must 
have a confirmation by anatomical assessment (e.g. CT, 
MRI, x-ray) as new site of disease to be considered 
progressive disease.  In such a case, the date of progressive 
disease will be the date of the initial abnormal FDG-PET.   
e.   
Symptomatic deterioration:  Global deterioration of health status 
requiring discontinuation of treatment without objective evidence of 
progression.  Efforts should be made to obtain objective evidence of 
progression after discontinuation. 
 
f.  
Assessment 
inadequate, 
objective 
status 
unknown.  
Progression 
or 
symptomatic 
deterioration 
has 
not 
been 
documented, and one or more target measurable lesions have not 
been assessed or inconsistent assessment methods were used. 
 
g.  
Objective status notes: 
 
1.  
Non-measurable and non-target measurable disease do not 
affect Objective Status  in determination of CR (must be 
absent--a patient who otherwise has a CR, but who has non-
measurable or non-target measurable disease present or not 
assessed, will be classified as having a PR). However, non-
measurable 
and 
non-target 
lesions 
are 
included in 
determination of progression (if new sites of disease develop 
or if unequivocal progression occurs in the opinion of the 
treating physician).  
 
2.   
An objective status of PR or stable cannot follow one of CR.  
Stable can follow PR only in the rare case that tumor 
increases too little to qualify as progression, but enough that 
a previously documented 30% decrease no longer holds. 
 
3.    
In cases for which initial flare reaction is possible 
(hypercalcemia, increased bone pain, erythema of skin 
lesions), objective status is not progression unless either 
symptoms persist beyond 4 weeks or there is additional 
evidence of progression.   
 
4.  
Lesions that appear to increase in size due to presence of 
necrotic tissue will not be considered to have progressed.  
 
5.   
For bone disease documented on bone scan only, increased 
uptake does not constitute unequivocal progression. 
However, increase in the soft tissue component of a lesion 
as measured by CT or MRI would constitute progression. 
 
6.   
Appearance of new pleural effusions does not constitute 
unequivocal progression unless cytologically proven of 
neoplastic origin, since some effusions are a toxicity related 


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to therapy or other medical conditions. Increase in the size of 
an existing effusion does not constitute unequivocal 
progression, since the fluid status of the patient could alter 
the size of the effusion.  
 
7.   
If CR determination depends on a lesion for which the status 
is unclear by the required tests, it is recommended the 
residual lesion be investigated with biopsy or fine needle 
aspirate.   
7.3 
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four 
weeks apart documented before progression or symptomatic 
deterioration. 
 
b.  
PR: Two or more objective statuses of PR or better a minimum of 
four weeks apart documented before progression or symptomatic 
deterioration, but not qualifying as CR. 
 
c.  
Unconfirmed CR:  One objective status of CR documented before 
progression or symptomatic deterioration but not qualifying as CR or 
PR. 
 
d.  
Unconfirmed PR:  One objective status of PR documented before 
progression or symptomatic deterioration but not qualifying as CR, 
PR or unconfirmed CR. 
 
e.  
Stable/no response:  At least one objective status of stable/no 
response documented at least 6 weeks after registration and before 
progression or symptomatic deterioration, but not qualifying as 
anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 
weeks of registration, not qualifying as anything else above.   
 
g. 
Symptomatic deterioration: Objective status of symptomatic 
deterioration within 12 weeks of registration, not qualifying as 
anything else above.   
 
h. 
Inadequate assessment, response unknown:  Progression or 
symptomatic deterioration greater than 12 weeks after registration 
and no other response category applies. 
 
 
8. Statistical methods and determination of sample size 
8.1 
Sample Size Determination  
Overall Survival (OS) at 6 month is the primary endpoint on this study. OS is defined in 
section 8.2. Dropouts/screen failures defined in section 4.2.2 and those who are lost 


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follow-up prior to 6 months from starting on trial except death are not evaluable for the 
primary endpoint, and they will be replaced by new patients. The study will test the null 
hypothesis of ≤30% of OS at 6 month against the alternative of ≥50% of OS at 6 month 
(HR = 0.578 under exponential model). The sample size was determined, based on the 
Simon’s two-stage minimax design. With one-sided 10% of type I error rate and 90% 
statistical power, a sample of evaluable 39 will be evaluated: 28 in first stage and 
additional 11 in second stage. If 8 or more out of 28 survive 6 months or more, the study 
goes on the second stage.. REGORAFENIB will be deemed to have good activity if ≥16 
out of 39 patients survive 6 months or more from starting on trial. The continuation of 
accrual may be allowed while the analysis for early stopping being conducted.  We expect 
to accrue 2 or more patients per month among 6-7 participating institutions and will follow 
up patients 6 months or more.  
Dropouts/screen failures defined in section 4.2.2 and those who are lost follow-up prior to 6 
months from starting on trial except death, disease and severe toxicity are not evaluable for the 
primary endpoint, and they will be replaced by new patients 
 
8.2 
Statistical Analysis 
 
Overall survival (OS) is defined as the time from starting on trial to date of death due to 
any cause and progression-free survival (PFS) is defined as the duration of time from start 
of treatment to time of progression or death, whichever comes first. The final analysis will 
be conducted after the follow-time of the last patient exceeds 6 months. The primary 
endpoint of the study is OS at 6 month. The experimental treatment will be deemed to 
have good activity if ≥16 out of 39 evaluable patients survive 6 months or more. OS will be 
estimated using the Kaplan-Meier method and the two-sided 95% confidence interval (CI) 
for median OS will be computed using log-log transformation.  
The secondary endpoints in this study include the disease control response (DCR) defined 
as (CR + PR+ SD), toxicity, and PFS. DCR rate will be reported with 95% CI computed by 
the Clopper-Pearson method. The frequency and severity of adverse events and 
tolerability of the regimen will be summarized using descriptive statistics. PFS with 95% CI 
will be estimated. As exploratory objective, the association between biomarkers and 
clinical outcomes (DCR rate, OS and PFS) will be examined using multiple logistic 
regression and the multivariable Cox regression model. A p-value of <0.05 will be 
considered statistically significant. Frequency and severity of adverse events will be 
summarized using descriptive statistics. 
 
9.  Safety Monitoring  
Safety assessments will consist of monitoring and recording all adverse events and 
serious adverse events, the regular monitoring of hematology and blood chemistry 
parameters and regular physical examinations. Adverse events will be evaluated 
continuously throughout the study. Safety and tolerability will be assessed according to the 
NIH/NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) that 
is available at: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
The PMC monitors its assigned ongoing research protocols for: adverse event reporting, 
data and safety monitoring, and internal audit findings. The PMC, upon review of any 


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agenda item, may approve the study for continuation, require revisions, suspend or close 
a protocol. 
Investigators of studies, which are designated to be reviewed by the PMC for data and 
safety monitoring, shall provide a statistical report of the study’s progress and summary of 
adverse events and deviations based on the phase of the study and the associated risk of 
the study or 
more often if applicable. The external DSMB (if applicable) shall forward its report for high-
risk studies designated for external review at least annually or more often if applicable. 
 
Internal Monitoring Plan 
 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. Regulatory documents 
and case report forms will be reviewed routinely according to Moffitt’s Monitoring Policies. 
9.1 
Adverse events 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. An adverse event is 
the appearance or worsening of any undesirable sign, symptom, or medical condition 
occurring after starting the study drug even if the event is not considered to be related to 
study drug. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after starting study drug. Abnormal laboratory 
values or test results constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, or require therapy. The occurrence of 
adverse events should be sought by non-directive questioning of the patient at each visit 
during the study. Adverse events also may be detected when they are volunteered by the 
patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
• 
The severity grade (grade 1-4, or mild/moderate/severe)  
• 
Its relationship to the study drug(s) (suspected/not suspected)  
• 
Its duration (start and end dates or if continuing at final exam)  
• 
Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 
medication taken; non-drug therapy given; hospitalization/prolonged 
hospitalization) 
• 
Whether it constitutes a serious adverse event (SAE) 
  
All adverse events should be treated appropriately. Such treatment may include changes 
in study drug treatment including possible interruption or discontinuation, starting or 
stopping concomitant treatments, changes in the frequency or nature of assessments, 
hospitalization, or any other medically required intervention. Once an adverse event is 
detected, it should be followed until its resolution, and assessment should be made at 
each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study drug, the interventions required to treat it, and the outcome.  
  
Information about common side effects already known about the investigational drug can 
be found in the Investigator’s Brochure or will be communicated between Investigator 
Brochure updates in the form of Investigator Notifications. This information will be included 
in the patient informed consent and should be discussed with the patient during the study 
as needed. 
 


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9.2 
Serious adverse events 
  
A serious adverse event is an undesirable sign, symptom or medical condition which: 
• 
is fatal or life-threatening  
• 
results in persistent or significant disability/incapacity  
• 
constitutes a congenital anomaly/birth defect  
• 
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for routine treatment or monitoring of the studied indication 
• 
is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed 
above 
  
Information about all serious adverse events will be collected and recorded. To ensure 
patient safety, each serious adverse event must be reported to the PI and to Bayer 
expeditiously.  Moffitt Cancer Center and all participating sites will report SAEs by 
completing an SAE report in ONCORE, the electronic data capture system and a 
Medwatch Form online at http://www.fda.gov/medwatch The SAE must be reported by 
email (affiliate.research@moffitt.org) to the MCRN within 2 working days. 
9.3 
Reporting of serious adverse events 
The definition of serious adverse events (SAEs) is given in Section 6.2.1.1. 
Each serious adverse event must be followed up until resolution or stabilization, by 
submission of updated reports to the designated person. An isolated laboratory 
abnormality that is assigned grade 4, according to CTC definition, is not reportable as an 
SAE; unless the investigator assesses that the event meets standard ICH criteria for an 
SAE.  CTC grade 4 baseline laboratory abnormalities that are part of the disease profile 
should not be reported as an SAE, specifically when they are allowed or not excluded by 
the protocol inclusion/exclusion criteria.   
 
When required, and according to local law and regulations, serious adverse events must 
be reported to the Ethics Committee and Regulatory Authorities.  
 
All serious adverse events should be reported to Bayer within 24 hours.  In the event of 
such an event, the investigator should refer to the Pharmacovigilance section of the 
contract for reporting procedures. 
 
The Investigator may report serious adverse events (SAEs) as described below. 
 
 
 A MedWatch form available at http://www.fda.gov/medwatch/  
 
All reports shall be sent electronically to:  
 
Electronic Mailbox:   
DrugSafety.GPV.US@bayer.com  
 
Facsimile:    
 
(973) 709-2185  
 
Address: 
 
 
Global Pharmacovigilance - USA  
Mail only: 
 
 
Bayer HealthCare Pharmaceuticals Inc. 


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P.O. Box 1000  
 
Montville, NJ 07045-1000  
 
Address:   
 
 
340 Changebridge Road  
FDX or UPS only   
 
Pine Brook, NJ  07058  
 
Reports for all Bayer products can also be phoned in via our Clinical 
Communications Dept:  
 
Phone:  
 
 
1-888-765-3203-2937 
 
9.4 
Adverse events of special safety interest 
As with any new chemical entity, there is always potential for unexpected adverse events, 
including hypersensitivity reactions. 
Based on data from phase I/II studies with regorafenib and from current knowledge of the 
pharmacological properties of other small molecule tyrosine kinase inhibitors in this drug 
class, as soon as there is reasonable suspicion of any of the following AEs, the 
investigator should immediately notify the sponsor as outlined in Section 7.6.1.4.  
These events are: 
• Acute renal failure (NCI-CTCAE version 4.0 ≥ grade 3) or severe proteinuria (NCI-
CTCAE version 4.0 ≥ grade 3) 
• Interstitial lung disease 
• Acute cardiac failure 
• Clinically significant bleeding (NCI-CTCAE version 4.0 ≥ grade 3) 
• Stevens-Johnson Syndrome and erythema multiforme 
• Hepatic failure 
 
9.5 
Pregnancies 
The investigator must report to Bayer any pregnancy occurring in a study subject, or in his 
partner, during the subject’s participation in this study.  The report should be submitted 
within the same timelines as an SAE, although a pregnancy per se is not considered an 
SAE.   
For a study subject, the outcome of the pregnancy should be followed up carefully, and 
any abnormal outcome of the mother or the child should be reported. 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar 
information on course and outcome, subject to the partner’s consent. 
For all reports, the forms provided are to be used. 


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9.6 
Further safety 
Progressive disease 
If progressive disease leads to signs and symptoms that meet the criteria for an SAE 
(i.e., hospitalization, disability, death, or important medical event), the signs and symptoms 
should be reported as an SAE and not the underlying progressive disease. 
Death 
If any subject dies during the trial or within 30 days of the end-of-treatment visit, the 
investigator will inform Bayer and record the cause of death in detail (using the SAE Form) 
within 24 hours. 
10.  Premature termination of the study 
• If risk-benefit ratio becomes unacceptable owing to, for example, 
o Safety findings from this study (e.g. SAEs) 
o Results of any interim analysis 
o Results of parallel clinical studies 
o Results of parallel animal studies  
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity). 
• 
If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame. 
The investigator has the right to close his/her center at any time. 
For any of the above closures, the following applies: 
• 
Closures should occur only after consultation between involved parties. 
• 
All affected institutions (e.g. IEC(s)/IRB(s); competent authority (ies); study center; 
head of study center) must be informed as applicable according to local law. 
• 
In case of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner. 
Details for individual subject's withdrawal can be found in Section 4.2.1. 
11.   Data recording 
11.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function 
in accordance with federally mandated regulations.  The IRB should 
approve the consent form and protocol. 
 


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In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations.  Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient 
understands the implications of participating in the study, the patient will be 
asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
11.2 
Required Documentation 
 
Before the study can be initiated at any site, the site will be required to provide 
regulatory documentation to the Moffitt Clinical Research Network (MCRN) at  Moffitt 
Cancer Center. 
Sites must provide a copy of their informed consent to the MCRN coordinating 
center for review and approval prior to submission of any documents to the site’s IRB. 
Any changes re- quested by the site’s IRB must be provided to the MCRN staff for 
review and approval prior to resubmission to the IRB. 
 
The MCRN Coordinating Center must receive the following trial specific documents 
either by hardcopy, fax, or email before a site can be activated for any trial: 
 
1. IRB Approval Letter that includes the protocol version and date 
2. FDA Related Forms 1572/1571/310 as appropriate 
3. Signed Protocol Title Page 
4. IRB Approved Consent Form 
5. Site Delegation of Responsibility Log 
6. Signed  Financial Interest Disclosure Forms (principal and sub investigators) 
7. Updated  Investigator/Personnel  documents  (CVs,  licenses,  Conflict  of  
Interest statements, etc) as needed 
8. Updated Laboratory Documents (certifications, normal ranges, etc) as 
needed Signed protocol specific Task Order 
 
 
A study initiation visit (or teleconference) will be held prior to the start of any study 
related activity at the site. Attendance i s  r e q u i r e d  f o r :   
• 
The site PI and appropriate research staff 
• 
Moffitt PI and MCRN research coordinator is required 
 


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The requirements of the protocol and all associated procedures and processes will be 
reviewed and agreed upon prior to the activation of the study. The MCRN 
utilizes the EDC system, OnCore. OnCore training will be scheduled if 
indicated with the appropriate staff from the site.  
 
11.3 
Registration Procedures 
All subjects must be registered with the MCRN Coordinating Center to be able to 
participate in a trial. The participating site must fax or email the completed study 
specific eligibility checklist and registration forms, supporting documents and signed 
informed consent to the Coordinating Center. Unsigned or incomplete forms will be 
returned to the site. Once documents are received, the MCRN Research Coordinator 
will review them to confirm eligibility and to complete the registration process. If 
eligibility can not be confirmed, the research coordinator will query the site for 
clarification or additional documents as needed. Subjects failing to meet all study 
eligibility requirements will not be registered and will be unable to participate in the 
trial. 
 
Upon completion of registration, the MCRN Research Coordinator will provide the 
participating site with the study sequence number and randomization information if 
indicated. Within 24-48 hours after registration, It is the site’s responsibility to: 
• 
Enter the demographic and on-study patient information into the OnCore 
database 
• 
Order investigational agent(s) if indicated per protocol 
 
 
It is the responsibility of the participating Investigator or designee to inform the 
subject of the research treatment plan and to conduct the study in compliance 
with the protocol as agreed upon with Moffitt Cancer Center and approved by the 
site’s IRB. 
To register a patient send the completed signed eligibility checklist along with 
supporting documentation to the MCRN via email at affiliate.research@moffitt.org or 
via fax at 813-745-5666, Monday through Friday between 8:00AM and 
5:00PM(EST). 
 
11.4 
Data Management and Monitoring/Auditing 
All participating sites are required to enter and submit data through the Oncology 
Research Management software (OnCore) electronic data system.Data will be 
monitored for subject eligibility and protocol compliance, as well as for accuracy and 
completeness, 
 
To obtain access to OnCore, the site research staff must complete an OnCore 
Access Request Form and a Moffitt Information Systems Confidentiality Agreement 
and submit both to the Coordinating Center. Once the completed forms are received, 
the site coordinator will receive a VPN access key, logon/password, and information on 
how to access OnCore using the VPN. The MCRN Coordinating Center will provide 
OnCore training to the site once initial access is granted and on an ongoing basis as 


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needed. Written instructions  will be provided electronically for each site to download 
prior to the initial training with updates sent as appropriate.  
 
11.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study patient requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol 
 
 
11.6 
Emergency Modifications 
Moffitt Cancer Center and Affiliate investigators may implement a deviation from, 
or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects 
without prior H. Lee Moffitt Cancer Center or  their respective institution’s 
approval/favorable opinion.  
 
 
For Institutions Relying on Moffitt's IRB: 
For any such emergency modification implemented, a Moffitt IRB modification 
form must be completed by Moffitt Research Personnel within five (5) business 
days of making the change. 
 
 
For Institutions Relying on Their Own IRB: 
For Affiliate investigators relying on their own institution’s IRB, as soon as possible 
after the modification has been made, the implemented deviation or change and 
the reasons for it should be submitted to: To Moffitt  Principal Investigator for 
agreement and the Affiliate institution’s IRB for review and approval. (Once IRB‟s 
response is received, this should be forwarded to the  MCRN). 
 
11.7 
Record Retention 
 
Study documentation includes all eCRFs, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator. In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 


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Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
 
11.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding 
clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the eCRFs. 
Periodically, monitoring visits will be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of 
data. At the completion of the study, all eCRFs will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the 
data. 
 
12. Ethical and legal aspects 
12.1 
Ethical and legal conduct of the study 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the investigator abide by Good 
Clinical Practice (GCP) guidelines and under the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs 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 the EC/IRB 
approval must be obtained and also forwarded to Bayer. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.   
Modifications to the study protocol will not be implemented by the investigator without 
discussion and agreement by Bayer.  However, the investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial 
subjects without prior IEC/IRB/Bayer approval/favorable opinion.  As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed 


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protocol amendment should be submitted to the IEC/IRB/head of medical institution.  Any 
deviations from the protocol must be explained and documented by the investigator. 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients.  The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and properly documented. 
12.2 
Subject information and consent 
Each subject / legal representative or proxy consenter will have ample time and 
opportunity to ask questions and will be informed about the right to withdraw from the 
study at any time without any disadvantage and without having to provide reasons for this 
decision. 
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study.  Additionally, the 
investigator and other information provider (if any) will personally sign and date the form.  
The subject / legal representative or proxy consenter will receive a copy of the signed and 
dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures 
are performed, the study record or subject’s clinical record must clearly show that 
informed consent was obtained prior to these procedures. 
1. If the patient is not capable of providing a signature, a verbal statement of consent can 
also be given in the presence of an impartial witness (independent of Bayer and the 
investigator).  This is to be documented by a signature from the informing physician as 
well as by a signature from the witness. 
2. For minors or adults under legal protection, consent shall be given by the legal 
guardian(s).  The consent of a minor or adult under legal protection shall also be 
requested where such a person is able to express his/her own will.  His/her refusal or 
the withdrawal of his/her consent may not be disregarded. 
3. In emergency situations, when prior consent of the patient is not possible, the consent 
of the patient’s legal representative(s) or proxy consenter, if present, should be 
requested.  The patient should be informed about the study as soon as possible and 
his/her consent to continue the study should be requested. 
The informed consent form and any other written information provided to subjects / legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an 


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amendment to the protocol that necessitates a change to the content of the subject 
information and / or the written informed consent form.  The investigator will inform the 
subject / legal representative or proxy consenter of changes in a timely manner and will 
ask the subject to confirm his/her participation in the study by signing the revised informed 
consent form.  Any revised written informed consent form and written information must 
receive the IEC/IRB`s approval / favorable opinion in advance of use. 
12.3 
Publication policy 
Bayer recognizes the right of the investigator to publish results upon completion of the 
study.  However, the investigator must send a draft manuscript of the publication or 
abstract to Bayer at least thirty days in advance of submission in order to obtain approval 
prior to submission of the final version for publication or congress presentation.  This will 
be reviewed promptly and approval will not be withheld unreasonably.  In case of a 
difference of opinion between Bayer and the investigator(s), the contents of the publication 
will be discussed in order to find a solution which satisfies both parties. All relevant 
aspects regarding data reporting and publication will be part of the contract between 
Bayer and the investigator/institution 
The Principal Investigator should ensure that the information regarding the study be 
publicly available on the internet at www.clinicaltrials.gov. 
12.4 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. 
Should direct access to medical records require a waiver or authorization separate from 
the subject’s statement of informed consent, it is the responsibility of the Investigator to 
obtain such permission in writing from the appropriate individual. 
 


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13. Correlative studies  
13.1 
Required Participation 
Regorafenib is a multi-kinase inhibitor that is believed to block tumor growth through effects 
on both tumor cells and the angiogenic compartment.  At present, there is no way to predict 
which patients will benefit from this compound.  Biomarker studies will be performed to 
investigate the mechanisms by which regorafenib works in an attempt to identify markers 
predictive of drug benefit in patients with advanced biliary tumors. In the current study, both 
genetic and non-genetic biomarker analyses are planned on blood  specimens.  Utmost care 
will be taken to protect patient identity during biomarker analyses. Collection, processing, 
handling, and shipping of biomarker samples will be performed as described in the laboratory 
manual 
 
13.2 
Details on Potential Biomarker Studies by Specimen 
 
Plasma samples: The Duke Molecular Reference Laboratory at Duke University Medical 
Center is one of several core facilities for CALGB. It acts as a molecular profiling laboratory 
for blood-based biomarkers of targeted therapies, particularly targeted anti-angiogenic 
agents.  Drs. Andrew Nixon and Herbert Hurwitz serve as co-directors of the facility and 
direct the overall research of the laboratory.  The laboratory has quality control procedures 
in place to address many of the issues involved in clinical trials research including sample 
quantity, sample integrity, and sample heterogeneity. The services provided align with our 
programmatic focus around the interrogation of blood and urine samples by either multiplex 
or standard ELISA technologies.  Each study utilizes unique combinations of cancer 
therapeutics, affecting multiple signaling pathways.  The optimal design for this study 
addresses the specific drug targets of the study as well as attempting to capture the relevant 
co- and counter-regulated proteins.  Based on our experience, we have chosen important 
pathway components, identified the appropriate assay, built multiplex panels, and 
established QA/QC parameters regarding these assays. 
 
In the past, the gold standard for detection of growth factors and cytokines in blood was the 
use of ELISAs; however, multiplex technology offers an attractive alternative approach for 
cytokine and growth factor analysis. This novel technology allows for the measurement of 
multiple analytes simultaneously from a single sample.  The advantages of multiplex 
technology compared to traditional ELISA assays are conservation of patient sample, 
increased sensitivity, and significant savings in cost, time and labor.  Furthermore, all plate 
designs are validated in order to 1) limit cross-reactivity of the antibodies 2) optimize 
sensitivity and specificity and 3) maximize the linearity of the assay’s dynamic range. 
 
Several systems exist, the plate-based platforms being the Meso Scale Discovery (MSD) 
multiplex system and the SearchLight system, produced by Aushon Biosystems (formerly of 
ThermoFisher Scientific). The assay design in both cases is similar to a sandwich ELISA, 


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except multiple capture antibodies are pre-spotted into individual wells of a 96-well plate. 
Samples or standards are added which bind to the specific capture antibodies and are 
detected using various outputs.  Over the past 2 years, we have optimized the design of 
customized multiplex ELISA plates via extensive collaborations with the SearchLight.  We 
have devoted considerable effort to this and have developed an appropriately designed 
panel for the simultaneous evaluation of up to 40 regulators of tumor and normal 
angiogenesis.  Table 1 lists the analytes that can be evaluated. Modifications to this list may 
occur during patient accrual, but the programmatic theme related to angiogenesis will 
remain constant.  Standard ELISA assays are also included to evaluate soluble TGF
RIII 
and IGF-1 as additional blood markers.   
 
All multiplex plate designs have been validated in order to limit cross-reactivity of the 
antibodies, optimized for sensitivity and specificity, and maximize the linearity of the assay’s 
dynamic range. The CVs of the multiplex arrays are approximately 15-20%, depending on 
the particular assay. Any study samples that fall outside the linear portion of the standard 
curve are retested. Samples that read below the limit of detection are retested, if possible. 
Samples that read above the linear portion of the standard curve are serially diluted and 
retested to obtain accurate measurements.  Any analyte that does not meet the 
aforementioned criteria will result in the sample being re-evaluated. Analytes of interest that 
are not available in our multiplex plates can be evaluated using commercial ELISA kits or 
“home-brew” ELISAs. 
 
 
Table 1.  Plasma-based marker identification 
Soluble 
Angiogenic 
Factors* 
Matrix-Derived 
Angiogenic 
Factors 
Markers of 
Coagulation 
Markers of 
Vascular 
Activation and 
Inflammation 
bFGF 
MMP2 
Tissue Factor 
Gro- 
HGF 
MMP9 
PAI-1 Active 
IL-6 
PlGF 
TGF
1
 
PAI-1 Total 
IL-8 
VEGF-A 
TGF
2
 
CRP 
P-selectin 
VEGF-C 
Osteopontin 
D-dimer 
E-selectin 
VEGF-D 
TSP1 
Von Willebrand  
Factor 
SDF-1 
 
ANG-2 
TSP2 
ICAM-1 
PDGF-AA 
BMP9 
 
VCAM-1 
PDGF-BB 
sEndoglin 
 
MCP-1 
IGFBP1 
PEDF 
 
E-cadherin 
IGFBP2 
 
 
 
IGFBP3 
 
 
 
sVEGFR1 
 
 
 
sVEGFR2 
 
 
 
*Standard ELISA assays will also be included to evaluate soluble TGFbRIII, and 
IGF-1 as additional blood markers.  
 
Lastly, all samples have appropriate chain-of-custody documentation to ensure compliance 
with FDA and IRB regulations.  We have systems in place detailing the location, transfer, 


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and use of any and all human research subject samples. Any discrepancies or omissions in 
flow sheets and/or sample labels are resolved upon receipt of the sample in the lab.  All 
sample and data handling procedures will be fully compliant with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA). We have sample handling protocols that 
provide step-by-step details for sample isolation, sample handling, and sample 
receipt/shipment.  Samples are housed in ultra low temperature freezers (-80°C).  The 
freezers are monitored daily and are equipped with an alarm system designed to alert 
laboratory personnel upon freezer malfunction. Additionally, we have implemented a 
secondary, independent alarm system on all ultra low freezers currently used to store all 
patient samples.  Use of these redundant systems greatly reduces the chance of freezer 
failure, which could potentially result in the loss of irreplaceable samples from hundreds of 
clinical trial patients.  
 
 
 
13.3 
Special Instructions 
 
For plasma samples: 
 
1. Draw 1 x10mls EDTA tube 
2. Invert tubes 10 times to mix blood 
3. Centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge manufacturer’s 
instructions) 
4. Remove plasma from each tube and transfer equally into two separate clean 15ml 
polypropylene tubes 
5. Repeat centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions) 
6. Aliquot approximately 1.0ml of plasma from each tube into each 2.0ml cryovial.  For the EDTA, 
aliquot into pink capped cryovial.  Total of 3 pink capped cryovials needed for EDTA plasma.  
For the sodium citrate, aliquot into blue capped cryovial.  Total of 2 blue capped cryovials 
needed for sodium citrate plasma. 
7. Label and freeze at -80°C* (see labeling instructions below) 
 
 
13.4 
  Shipping 
• 
All biomarker samples (whole blood, plasma, serum and urine) must be 
shipped on dry ice by overnight delivery Monday through Thursday (no holidays) to the 
following address: 
 
Attention: 
Phase I Biomarker Laboratory 
 
 
 
 
 
ATTN:  Andrew Nixon, PhD 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
 


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14. Reference list 
 
[1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 
2010;60:277-300. 
[2] Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic 
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