Clinical trial NCT02053376
Conditions: Metastatic Biliary Tract Carcinoma
Keywords: gallbladder cancer, biliary cancer, bile duct cancer, hepatobiliary cancer, Biliary Tract Carcinoma Cholangiocarcinoma
Sponsor: Nathan Bahary, MD
Start date: 2014-01-01; Completion date: 2018-05-14
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Based on the facts of multiple pathways involvement in cholangiocarcinoma tumor genesis, including EGFR, Ras, Raf, VEGFR, and PDGFR, with evidence of overexpression of these proteins associated with tumor stage, prognosis and response to therapy. Multikinase inhibitor targeting multiple tumor pathways agent as regorafenib should be the ideal candidate for evaluating the anti-cancer activity for the disease as cholangiocarcinoma. More importantly, regorafenib likely holds promise in this disease setting with known effectiveness either as a single agent or in combination with cytotoxic chemotherapy agents in multiple solid tumors as above and the toxicity profile.

Detailed description:
Multiple pathways, including epidermal growth factor receptor (EGFR), Ras, Raf, Vascular Endothelial Growth Factor Receptors (VEGFR), and platelet-derived growth factor (PDGFR) appear to be involved in cholangiocarcinoma tumor genesis. Overexpression of these proteins has been shown to be associated with tumor stage, prognosis, and response to therapy. However, therapies targeting a single pathway have shown no clear benefit. A number of Phase 2 trials have been completed, or are underway, studying agents targeted to EGFR or VEGF - both as monotherapy and in combination with chemotherapy. These have shown varying increases in response rate, but have not found marked increases in progression-free or overall survival. This suggests that inhibition of multiple pathways simultaneously may be needed. Regorafenib, is an oral multikinase inhibitor targeting multiple tumor pathways, which has showed effectiveness as a single agent in multiple solid tumors.

Patients with advanced and metastatic biliary tract adenocarcinoma (cholangiocarcinoma) who had been treated with and failed first-line chemotherapy will be treated with regorafenib (120 mg) (160 mg for second and subsequent treatment cycles) orally once daily 21 days (3 weeks) on and 7 days (1 week) off in the 28-day (4-week) cycle.

Arms: arm 1: Patients with advanced and metastatic biliary tract adenocarcinoma (cholangiocarcinoma) who had been treated with and failed first-line chemotherapy will be treated with regorafenib (120 mg) (160 mg for second and subsequent treatment cycles) orally once daily 21 days (3 weeks) on and 7 days (1 week) off in the 28-day (4-week) cycle
Interventions: intervention 1: Regorafenib
Intervention descriptions: intervention 1: regorafenib (120 mg) (160 mg for second and subsequent treatment cycles)orally once daily 21 days (3 weeks) on and 7 days (1 week) off in the 28-day (4-week) cycle.

Protocol documents:
Prot_SAP_000.pdf: 
TITLE: A Phase 2 Trial of Regorafenib as A Single Agent in Advanced and Metastatic 
Biliary Tract Carcinoma/Cholangiocarcinoma Patients Who Have Failed First-line 
Chemotherapy 
 
UPCI #: 
13-100 
BB-IND#: 
Exempt 
Phase: 
2 
Version: 
5 
Version Date: 
08-07-2017 
Commercial Agent: 
Regorafenib 
 
Investigator: 
Nathan Bahary, MD, PhD 
 
Associate Professor of Medicine 
 
UPMC Cancer Pavilion 
 
5150 Centre Avenue, Fifth Floor 
 
Pittsburgh, PA  15232 
 
Phone: 412-864-7764 
 
Fax: 412-648-6579 
 
e-mail: baharyn@upmc.edu 
 
Biostatistician: 
Daniel Normolle, PhD 
 
Associate Professor of Biostatistics 
 
Director, UPCI Biostatistics Facility 
 
201 N. Craig Street, Suite 325 
 
Pittsburgh, PA  15213 
 
Phone: 412-383-1591 
 
Fax: 412-383-1535 
 
e-mail: dpn7@pitt.edu 
 
Source(s) of Support: 
Bayer Healthcare 
 
 
 
 


 
SYNOPSIS 
Title 
A Phase 2 Trial of Regorafenib as a Single Agent in Advanced 
and Metastatic Biliary Tract Carcinoma Patients Who Have 
Failed First-line Chemotherapy 
Clinical study phase 
Phase 2 single arm 
Study objective(s) 
Primary objective:  
To evaluate the progression-free survival (PFS) of patients with 
advanced or metastatic biliary cancer receiving ragorafenib 
following the failure of first-line chemotherapy. 
Secondary objectives: 
 
Overall response (OR), including complete and partial 
response, and disease Control rate (DCR). 
 
Overall survival (OS) 
 
Measurable changes in biomarkers [CA19-9 and CEA], in 
patients that were elevated at the time of study entry. 
 
Evaluation of safety and associated toxicities 
Background treatment 
Advanced and metastatic biliary tract carcinoma who have failed 
first-line chemotherapy. 
Indication 
Biliary Tract Carcinoma 
Diagnosis and main criteria 
for inclusion 
 
Histologically or cytologically confirmed diagnosis of biliary 
tract adenocarcinoma/cholangiocarcinoma; pathologic 
confirmation may be from the primary or a metastatic site 
 
Must have locally advanced or distant metastatic disease that 
is not surgically curable 
 
Failed first-line chemotherapy. 
 
Age ≥ 18 years. 
 
Life expectancy of at least 12 weeks (3 months). 
 
Performance status <  1 
 
Adequate liver, kidney, and bone marrow function as 
assessed by the following laboratory requirements: 
 Total bilirubin ≤ 3.0 x the upper limit of normal (ULN) 
 Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤ 5.0 x ULN 
 Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5.0 x ULN for 
subjects with intrahepatic involvement of their cancer) 
 Serum creatinine ≤ 1.5 x the ULN 
 International normalized ratio (INR)/partial thromboplastin 
time (PTT) ≤ 1.5 x ULN. 
Study design 
Patients with advanced and metastatic biliary tract 
adenocarcinoma (cholangiocarcinoma) who had been treated with 
and failed first-line chemotherapy will be treated with regorafenib 
(120 mg) orally once daily 21 days (3 weeks) on and 7 days (1 
week) off in the 28-day (4-week) cycle.  
Type of control 
Single arm uncontrolled 


Number of subjects 
Maximum of 37 patients. 
Plan for statistical analysis 
There will be no stratification. OR will be estimated at end of trial 
with 95% exact binomial confidence intervals. PFS and OS will 
be estimated by the Kaplan-Meier method, with appropriate 90% 
confidence intervals. Toxicity events will be tabulated. Change in 
CA19-9 and CEA will be characterized by their mean changes, 
with a nonparametric CDF-based 90% confidence interval. The 
study will have 83% power (using a one-sided test at α=0.10) to 
reject the null hypothesis (PFS<2.0 months) if the true median 
PFS is at least 3.5 months. 
 
Schema: 
Metastatic or locally 
advanced unresectable 
Cholangiocarcinoma with 
disease progression after 
standard chemotherapy  
Regorafenib 120 mg orally*, daily, 21 
days on and 7 days off, 28 days cycle 
*For those patients who show no regorafenib dose related toxicity 
after the dose level 120mg/day when at the end of cycle 1 
treatment, the dose level may escalate to 160mg/day for the second 
and subsequent cycles. 
Primary endpoint: PFS 


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TABLE OF CONTENTS 
Synopsis ...........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................3 
1.1 
Primary Objectives...................................................................................................3 
1.2 
Secondary Objectives...............................................................................................3 
2. 
BACKGROUND .................................................................................................................3 
2.1 
Study Disease(s).......................................................................................................3 
2.2 
Regorafenib ..............................................................................................................4 
2.3 
Rationale ..................................................................................................................6 
3. 
PATIENT SELECTION ......................................................................................................6 
3.1 
Eligibility Criteria ....................................................................................................6 
3.2 
Exclusion Criteria ....................................................................................................7 
3.3 
Withdrawal of patients from study treatment ..........................................................8 
3.4 
Screen Failures/Dropouts .........................................................................................9 
3.5 
Replacement ...........................................................................................................10 
4. 
TREATMENT PLAN ........................................................................................................10 
4.1 
Regorafenib Administration...................................................................................10 
4.2 
Examples of a low fat breakfast .............................................................................10 
4.3 
Prior and concomitant therapy ...............................................................................10 
4.4 
Treatment compliance ............................................................................................12 
4.5 
Duration of Follow Up ...........................................................................................12 
5. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................12 
5.1 
Hypertension ..........................................................................................................16 
5.2 
Liver Function Abnormalities ................................................................................17 
5.3 
Prevention/management strategies for diarrhea .....................................................18 
6. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................19 
6.1 
Adverse Events and Risks List ..............................................................................19 
6.2 
Definitions..............................................................................................................19 
6.3 
Reporting adverse events to the responsible IRB ..................................................20 
7. 
REGORAFENIB INFORMATION...................................................................................21 
7.1 
Drug information ...................................................................................................21 
7.2 
Ordering and accountability ...................................................................................21 
7.3 
Destruction and return............................................................................................21 
8. 
SPECIAL STUDIES ..........................................................................................................22 
8.1 
Pathology Material .................................................................................................22 
9. 
STUDY CALENDAR .................................................................................................. - 23 - 
10. 
MEASUREMENT OF EFFECT........................................................................................25 


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11. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................30 
11.1 
Data Safety Monitoring Plan .................................................................................30 
11.2 
Quality Control and Quality Assurance .................................................................31 
11.3 
Data Handling and Record-Keeping ......................................................................32 
11.4 
Institutional Review Board (IRB) Approval ..........................................................32 
11.5 
Ethical and Scientific Conduct of the Clinical Study ............................................32 
11.6 
Subject Informed Consent......................................................................................32 
12. 
STATISTICAL CONSIDERATIONS...............................................................................33 
12.1 
Data Analysis Plan .................................................................................................33 
12.2 
Justification of Design ...........................................................................................33 
12.3 
Premature termination of the study ........................................................................34 
13. 
REFERENCES ..................................................................................................................35 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................37 
 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To evaluate the progression-free survival (PFS) of patients with advanced or metastatic biliary 
tract carcinoma (cholangiocarcinoma) receiving ragorafenib following the failure of first-line 
chemotherapy. 
 
1.2 
Secondary Objectives 
 
 Overall response rate (ORR), including complete and partial response, and disease 
control rate (DCR) 
 Overall survival (OS)  
 Measurable changes in biomarkers [CA19-9 and CEA], in patients that were elevated at 
the time of study entry. 
 Evaluation of safety and associated toxicities 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Biliary tract adenocarcinoma (Cholangiocarcinoma, gallbladder carcinoma) is a relatively rare 
but aggressive neoplasm. There are about 7,000-10,000 new cases diagnosed per year in the 
United States. The incidence of intrahepatic cholangiocarcinoma is rising globally, and this 
rising rate has not been associated with an increase in the proportion of early stage disease. The 
five-year overall survival for advanced disease is only about 5%. It is also the second most 
common primary hepatic tumor but more lethal than HCC. Treatment outcomes and survival 
have improved little over the past three decades—a period in which successful new treatments 
have increased patient survival for many other cancers. 
 
As with most solid tumors, surgical resection represents the only curative therapy. However, the 
majority of patients with cholangiocarcinoma present with unresectable or metastatic disease. 
Currently, for these patients, first-line therapy consists of systemic chemotherapy with the 
combination of gemcitabine and cisplatin. Despite a described response rate of over 80%, 
median overall survival remained poor at 11.7 months. Other gemcitabine-based and 
flouropyrimidine-based chemotherapy regimens have been also used. In selected patients, local-
regional therapy e.g. chemoembolization with gemcitabine-based treatment has been applied as 
well. With all of these regimens, efficacy was limited with significant associated morbidities. 
There is no standard 2nd line therapy besides Phase 2 data. The mPFS (or TTP) of 2nd-line varies 
around 1.6-2.3 months (see refs: Oh SY, et al and Lee S, et al), and mOS varies between 4-6 
months. More effective therapies are definitely needed with better understanding of the 
mechanisms of this disease and therapy to treat it. 
 
Several signaling pathways have been identified that might play a role in the development of 


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cholangiocarcinoma. Over-expression of p53 has been found in 20 to 30 percent of tumors. 
BRAF mutations were seen in approximately 22 percent of intrahepatic cholangiocarcinomas. 
VEGF was also found to be overexpressed in a majority of patients with intrahepatic and 
extrahepatic cholangiocarcinoma. In several studies, abnormal expression of K-ras was seen in 
45 to 54 percent of intrahepatic cholangiocarcinomas, and 10 to 15 percent of extrahepatic 
cholangiocarcinomas. In one study, the incidence of K-ras gene mutations in patients with lymph 
node metastasis was seen to be higher than that in patients without, and patients with K-ras gene 
mutations showed a statistically significant worse survival rate than those without such 
mutations. 
 
2.2 
Regorafenib 
 
Regorafenib is a novel diphenylurea oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), 
stromal (PDGFR-β, FGFR1), and oncogenic kinases (KIT, RET, RAF) with potent preclinical 
antitumor activity and long-lasting anti-angiogenic activity as measured by dynamic contrast 
enhanced (DCE) – magnetic resonance imaging (MRI) (1). 
 
Regorafenib potently inhibits angiogenic kinases VEGFR 1-3, TIE2, PDGFR-β, and fibroblast 
growth factor receptor 1(FGFR1) in biochemical (IC50 between 4 and 311 nanomolar [nM]) and 
cellular (IC50 between 3 and ~200 nM) kinase phosphorylation assays. The VEGF, TIE2 and 
PDGF receptors are relevant to tumor angiogenesis (2, 3). PDGF receptors may also play a role 
in patients with chronic myeloproliferative cancers (4). 
 
Furthermore, it potently inhibits mutant oncogenic kinases KIT (cellular IC50 c-KITK642E = 22 
nM) and RET (cellular IC50 RETC634W ~10 nM), which play a role in human gastrointestinal 
stromal and thyroid cancers, respectively, and B-RAF, a member of the RAS/RAF/MEK/ERK 
signaling pathway (biochemical IC50 of wt B-RAF = 28nM and of B-RAFV600E = 19nM). In 
addition, it biochemically inhibits Raf-1 (IC50 = 2.5 nM) and the p38 MAPK (IC50 = 24 nM) (1). 
 
2.2.1 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). (1) 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. (1) These data suggest that regorafenib can target 
the tumor cell MAPK pathway (tumor cell survival) and tumor vasculature in some but not all 
tumors. 
 


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2.2.2 Clinical experience 
 
Two Phase 3 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 with 114 centers in 16 countries. Patients with documented metastatic 
colorectal cancer and progression during or within 3 months after the last standard therapy were 
randomized (in a 2:1 ratio; stratified by previous treatment with anti-VEGF therapy, time from 
metastatic disease diagnosis, and geographical area) to receive oral regorafenib, 160 mg once 
daily, plus best supportive care (BSC) or placebo plus BSC, with 3 weeks on and 1 week off as a 
cycle. The primary endpoint was overall survival. From April 30, 2010 to March 22, 2011, there 
were 1052 patients screened, 760 patients were randomized to receive regorafenib (n=505) or 
placebo (n=255); 753 patients initiated treatment (regorafenib n=500; placebo n=253). The 
primary endpoint of overall survival was met at a preplanned interim analysis. Median overall 
survival was 6.4 months in the regorafenib treatment arm versus 5.0 months in the placebo arm 
(HR of 0.77; 95% CI 0.64–0.94; one-sided p=0.0052). Treatment-related adverse events occurred 
in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The 
most common adverse events of grade three or higher related to regorafenib were hand-foot skin 
reaction (83 patients, 17%), fatigue (48, 10%), diarrhea (36, 7%), hypertension (36, 7%), and 
rash or desquamation (29, 6%). 
 
The efficacy and safety of regorafenib were examined in the Phase 3 GRID trial in patients with 
gastrointestinal stromal tumors (GISTs) who had exhausted all other treatment options. The 
study was conducted at 57 hospitals in 17 countries. Patients with histologically confirmed, 
metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were 
randomized in a 2:1 ratio (stratified by treatment line and geographical region) to receive either 
oral regorafenib, 160 mg daily, plus best supportive care (BSC) or placebo plus BSC, 3 weeks on 
and 1 week off as a cycle. 240 patients were screened and 199 were randomized to receive 
regorafenib (n=133) or matching placebo (n=66). Median PFS per independent blinded central 
review was 4.8 months (IQR 1.4–9.2) for regorafenib and 0.9 months (0.9–1.8) for placebo (HR 
0.27, 95% CI 0.19–0.39; p<0.0001). After progression, 56 patients (85%) assigned placebo 
crossed over to regorafenib. 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. Drug-related adverse events were reported in 130 (98%) patients that had 
regorafenib and 45 (68%) patients assigned to placebo. The most common regorafenib-related 
adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction 
(26 of 132, 20%), and diarrhea (seven of 132, 5%). 
 
Based on the facts of multiple pathways involvement in cholangiocarcinoma tumor genesis, 
including EGFR, Ras, Raf, VEGFR, and PDGFR, with evidence of overexpression of these 
proteins associated with tumor stage, prognosis and response to therapy. Multikinase inhibitor 
targeting multiple tumor pathways agent as regorafenib should be the ideal candidate for 
evaluating the anti-cancer activity for the disease as cholangiocarcinoma. More importantly, 
regorafenib likely holds promise in this disease setting with known effectiveness either as a 
single agent or in combination with cytotoxic chemotherapy agents in multiple solid tumors as 
above and the toxicity profile. 


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2.3 
Rationale 
 
As noted, multiple pathways, including EGFR, Ras, Raf, VEGFR, and PDGFR appear to be 
involved in cholangiocarcinoma tumor genesis. Overexpression of these proteins has been shown 
to be associated with tumor stage, prognosis, and response to therapy. However, therapies 
targeting a single pathway have shown no clear benefit. A number of Phase 2 trials have been 
completed, or are underway, studying agents targeted to EGFR or VEGF – both as monotherapy 
and in combination with chemotherapy. These have shown varying increases in response rate, 
but have not found marked increases in progression-free or overall survival. This suggests that 
inhibition of multiple pathways simultaneously may be needed. Regorafenib, is an oral 
multikinase inhibitor targeting multiple tumor pathways, which has showed effectiveness as a 
single agent in multiple solid tumors. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
 Histologically or cytologically confirmed diagnosis of biliary tract adenocarcinoma/ 
cholangiocarcinoma (including primary intra- and extrahepatic diseases); pathologic 
confirmation may be made from the primary or a metastatic site. 
 Must have locally advanced or distant metastatic disease that is not surgically curable. 
 Failed first-line chemotherapy (including systemic and local-regional therapy). 
 Age ≥ 18 years 
 Life expectancy  >12 weeks (3 months) 
 Performance status ECOG < 1 
 Adequate liver, kidney, and bone marrow function as assessed by the following 
laboratory requirements: 
 Total bilirubin ≤ 3.0 x the upper limits of normal (ULN) (biliary stenting or 
percutaneous biliary drainage are allowed for cancer related biliary obstruction) 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0 x ULN 
 Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5.0 x ULN for subjects with intrahepatic 
involvement of their cancer) 
 Serum creatinine ≤ 1.5 x the ULN 
 International normalized ratio (INR)/partial thromboplastin time (PTT) ≤ 1.5 x ULN. 
(Patients 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 stable based on a measurement that is 
pre-dose as defined by the local standard of care). 
 Platelet count ≥ 75,000 /mm3, 


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 Hemoglobin (Hb) ≥ 9 g/dL, 
 Absolute neutrophil count (ANC) ≥ 1500/mm3. 
 Blood transfusion to meet the inclusion criteria will not 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. 
 Patients (men and women) of childbearing potential must agree to use Double Barrier 
method of birth control beginning at the signing of the ICF until at least 3 months after 
the last dose of study drug.  
 Patients must be able to swallow and retain oral medication. 
 Patients must be able to understand and be willing to sign the written informed consent 
form. A signed informed consent form must be appropriately obtained prior to the 
conduct of any trial-specific procedure. 
3.2 
Exclusion Criteria 
 Previous assignment to treatment during this study. Subjects permanently withdrawn 
from study participation will not be allowed to re-enter study. 
 Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm 
Hg on repeated measurement) despite optimal medical management. 
 Active or clinically significant cardiac disease including: 
 Congestive heart failure – New York Heart Association (NYHA) > Class II. 
 Active coronary artery disease. 
 Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or 
digoxin. 
 Unstable angina (angina symptoms at rest), new-onset angina within 3 months before 
randomization, or myocardial infarction within 6 months before randomization. 
 Evidence or history of bleeding diathesis or coagulopathy. 
 Any hemorrhage or bleeding event ≥ Grade 3 within 4 weeks prior to prior to registration. 
 Patients 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 the study registration. 
 Previous exposure to VEGF inhibitor(s),  
 Patients with any previously untreated or concurrent cancer that is distinct in primary site 
or histology from biliary tract cancer except cervical cancer in-situ, treated basal cell 
carcinoma, or superficial bladder tumor. Patients surviving a cancer that was curatively 
treated and without evidence of disease for more than 3 years prior to registration are 


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allowed. All cancer treatments must be completed at least 3 years prior to prior to 
registration). 
 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. 
 Symptomatic metastatic brain or meningeal tumors. 
 Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
 Renal failure requiring hemo-or peritoneal dialysis. 
 Dehydration Grade ≥1  
 Patients with seizure disorder requiring medication. 
 Proteinuria  Grade 3 (> 3.5 g/24 hours, measured by urine protein: creatinine ratio on a 
random urine sample). 
 Active signs and symptoms of interstitial lung disease pleural effusion or ascites that 
causes respiratory compromise (≥Grade 2 dyspnea). 
 History of organ allograft (including corneal transplant). 
 Known or suspected allergy or hypersensitivity to any of the study drug classes. 
 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. 
 Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) other than study treatment 
regorafenib. However, the palliative XRT to non-targeted lesions is allowed. 
 Prior use of regorafenib. 
 Concurrent use of another investigational drug or device therapy (i.e., outside of study 
treatment) during, or within 28 days prior to registration  
 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to registration (biliary stenting or percutaneous biliary drainage are not included). 
 Use of any herbal remedy (e.g. St. John’s Wort [Hypericum perforatum]) 
 
3.3 
Withdrawal of patients from study treatment 
 
Patients must be withdrawn from the study treatment for the following reasons: 


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 Patients withdraw consent for study treatment and study procedures. A patient 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 patient will not suffer any disadvantage as 
a result. 
 Pregnancy 
 Subject is lost to follow-up 
 Disease Progression 
 Death 
Patients may be withdrawn from the study treatment for the following reasons: 
 The patient is non-compliant with study drug, trial procedures, or both; including the use 
of anti-cancer therapy not prescribed by the study protocol. 
 If, in the investigator's opinion, continuation of the trial would be harmful to the patient's 
well-being. 
 Severe allergic reaction to regorafenib (such as exfoliative erythroderma or Grade 3 or 4 
hypersensitivity reaction). 
 The development of a second cancer. 
 Development of an intercurrent illness or situation which would, in the judgment of the 
investigator, significantly affect assessments of clinical status and trial endpoints. 
 Deterioration of ECOG performance status to 4. 
 Use of illicit drugs or other substances that may, in the opinion of the investigator, have a 
reasonable chance of contributing to toxicity or otherwise skewing trial result. 
 
In all cases, the reason for removal from study must be recorded in the research data base and in 
the patient's medical records. 
 
Details for the premature termination of the study as a whole (or components thereof [e.g. 
centers, treatment arms, dose steps]) are provided in Section 12.3 (Premature termination of the 
study). 
 
3.4 
Screen Failures/Dropouts 
 
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has: already been registered, administered at least one dose of study 
drug. 
 
A patient who, for any reason (e.g. failure to satisfy the selection criteria; withdraws consent), 
prior to receiving first dose of study drug will be regarded a “screening failure”. 
 


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3.5 
Replacement 
 
No withdrawn patients will be replaced, ‘Drop out patients may be replaced. 
 
4. TREATMENT PLAN 
 
Patients with advanced and metastatic biliary tract adenocarcinoma (cholangiocarcinoma) who 
had been treated and failed first-line chemotherapy, ECOG PS 0-1, and adequate liver, kidney 
and bone marrow function will be treated with regorafnib (160 mg) orally once daily for 21 days 
on and 7 days off in a 28-day cycle. Tissue specimens collected at diagnosis may be submitted 
for molecular analyses or other studies. 
 
A maximum of 37 patients will be enrolled. 
 
4.1 
Regorafenib Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 6. Appropriate dose modifications are described in Section 5. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
The starting dose of regorafenib will be120 mg once daily for the first cycle.  However, for 
those patients who show no regorafenib dose related toxicity after the dose level 120mg/day 
when at the end of cycle 1 treatment, the dose level may escalate to 160mg/day for the 
second and subsequent cycles. Study medication will be administered on a 3 weeks on and 1 
week off schedule [3 weeks out of every 4]. 
 
At the startthree 40-mg regorafenib tablets [unless dose-reduced, Section 6] should be taken in 
the morning with approximately 8 fluid ounces (240 mL) of water after a low-fat (<30% fat) 
breakfast for cycle 1.  The number of regorafenib tablets of subsequent cycles should be taken 
based on the AE profile of the previous cycles. 
 
4.2 
Examples of a low fat breakfast 
 
Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly and 8 
ounces of skim milk. (Approximately 319 calories and 8.2 grams of fat) 
 
One cup of cereal (i.e., Special K), 8 ounces of skimmed 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). 
 
The patient will be requested to maintain a medication diary of each dose of medication. The 
medication diary will be returned to clinic staff at the end of each course 
 
4.3 
Prior and concomitant therapy 
 


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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 
research data base (including start/stop dates, dose frequency, route of administration, and 
indication). Specific caution should be taken when considering or administering a concomitant 
medication that is metabolized by the cytochrome enzymes CYP2C8, CYP2B6 and CYP2C9. 
Such concomitant medication should be avoided, if possible. 
 
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of 
regorafenib decreased the mean exposure of regorafenib, increased the mean exposure of the 
active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite 
M-2. Avoid concomitant use of regorafenib with strong CYP3A4 inducers (e.g. rifampin, 
phenytoin, carbamazepine, phenobarbital, and St. John’s Wort). 
 
Co administration of a strongCYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of 
Stivarga increased the mean exposure of regorafenib and decreased the mean exposure of the 
active metabolites M-2 and M-5. Avoid concomitant use of regorafenibwith strong inhibitors of 
CYP3A4 activity (e.g. clarithromycin, grapefruit juice, grapefruits, Seville oranges, itraconazole, 
ketoconazole, nefazadone, posaconazole, telithromycin, and voriconazole). 
 
Permitted concomitant therapies include: 
 Standard therapies for concurrent medical conditions. 
 Supportive care for any underlying illness. 
 Palliative radiation therapy is allowed if the target lesion(s) are not included within the 
radiation field and no more than 10% of the bone marrow is irradiated. 
 Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic growth factors 
may be used in the management of acute toxicity, such as febrile neutropenia, when 
clinically indicated or at the investigator’s discretion. However, they may not be 
substituted for a required dose reduction. Subjects are permitted to take chronic 
erythropoietin. 
 Treatment with nonconventional therapies (such as acupuncture), and vitamin/mineral 
supplements are permitted provided that they are reviewed by the investigator and are 
deemed acceptable. 
 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 is 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 28 days before starting study treatment 


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 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 its levels may 
be especially affected by regorafenib 
 Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum]) 
 
4.4 
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 patient may be discontinued from the trial for non-compliance with 
follow-up visits or study drug. 
 
4.5 
Duration of Follow Up 
 
Patients will be followed every 3 months (+/- 4 weeks) until death or study closure. Follow-up 
will be by either direct contact or medical record review. 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
Doses will be delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to protocol therapy according to the guidelines shown in the Dose 
Delays/Dose Modifications table that follows. Dose modifications will follow predefined dose 
levels. Dose adjustments for hematologic toxicity are based on the blood counts obtained in 
preparation for the day of treatment. 
 
Modifications of regorafenib will follow the following predefined dose levels: 
#Dose level +1 
 
160 mg, daily, orally 
Four 40-mg tablets of regorafenib 
Dose level 0 
(Standard starting dose) 120 mg, daily, orally 
Three 40-mg tablets of regorafenib 
Dose level –1 
80 mg, daily, orally 
Two 40-mg tablets of regorafenib 
Dose level -2  
40 mg, daily, orally 
One 40-mg tablet of regorafenib 
#Only for those patients with no regorafenib dose related toxicity after the 1st cycle dose level of 
regorafenib 120mg/day, the dose level may escalate to 160mg/day for the second and subsequent 


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cycles. 
 
If a patient 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. 
 
The following tables outline dose adjustments for toxicities related to study drug except hand-
foot skin reaction, hypertension, and liver function test abnormalities. 
 
Table 5-1: Recommended dose modification for toxicities except hand-foot-skin reaction, 
hypertension and ALT/ST/bilirubin 
NCI-CTCAE v4.0a 
Dose Interruption 
Dose 
Modificationb 
Dose for Subsequent 
Cycles 
Grade 0-2 
Treat on time 
No change 
No change 
Grade 3 
Delay until ≤ Grade 
2c,d 
Reduce by 1 dose level 
If toxicity remains < 
Grade 2, dose re-
escalation can be 
considered at the 
discretion of the 
treating (Sub-) 
investigator. If dose 
is re-escalated and 
toxicity (≥ Grade 3) 
recurs, institute 
permanent dose 
reduction. 
Grade 4 
Delay until ≤ Grade 2c 
Reduce by 2 dose 
levels. 
Permanent 
discontinuation 
can be considered at 
the treating 
(Sub-)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. 
d. For G3 AE for level of phosphate and magnesium only patient may continue tx at MD discretion.  MD will 
provide appropriate intervention, as needed. 
Note: these dose modifications are for the current cycle based on the grade of toxicity, there will not be re-
escalating in the same cycle. However, ‘re-escalation’ in subsequent cycles is possible, if toxicity remains grade 2 
or less, and will be ‘at the discretion of the treating (Sub-) investigator. 
 
Table 5-2: 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. 
 
Table 5.3 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 0-1b,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 


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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 
levelb,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. 
The maximum daily dose is 160 mg. 
 
Prior to starting regorafenib and at first occurrence of HFSR, independent of grade, prompt 
institutional supportive measures such as topical emollients, low potency steroids, or non-urea-
containing creams should be administered. Patients should be educated on 
prevention/management strategies for HFSR. 
 
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. 


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 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 
 
5.1 
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 8 weeks of treatment. If 
additional blood pressure measurements are done outside the study site, and the blood pressure is 
> 140 mmHg systolic or > 90 mmHg diastolic 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 5.4 outlines suggested dose reductions. 
 
Table 5-4: 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 mmHg: 
 
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 mmHga. When 
regorafenib is restarted, 
continue at the same dose 
level. 


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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 mmHg: 
 
Start anti-hypertensive 
medication 
 
AND/OR 
 
Increase current anti-
hypertensive medication 
 
AND/OR 
 
Add additional anti-hypertensive 
medications. 
Hold regorafenib until 
diastolic BP ≤ 90 mmHg 
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 
(e.g., 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. 
 
5.2 
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 5-5 should be followed. 
 
Regorafenib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia mayoccur 
in patients with Gilbert’s syndrome. 
 
Table 5-5: Dose modifications/interruption for ALT and/or AST and/or bilirubin 
increases related to study drug 
Observed elevations 
1st Occurrence 
Restart 
Re-occurrence 
AST and/or ALT ≤ 5 
X ULN (< G3) 
Continue dosing, 
with weekly 
monitoring of liver 
function until 
 
 


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transaminases return 
to <3 X ULN (≤ G1) 
or baseline. 
ALT and/or AST >5 X 
ULN (≥ G3) 
Interrupt dosing, 
with weekly 
monitoring until 
transaminases return 
to < 3 X ULN or 
baseline. 
If the potential benefit 
for reinitiating 
regorafenib is 
considered to outweigh 
the risk of 
hepatotoxicity: Reduce 
one dose level and 
measure serum liver 
tests weekly for at least 
4 weeks. 
Discontinue 
ALT and/or AST > 20 
X ULN (≥ G4) 
Discontinue 
 
 
ALT and/or AST > 3 
X ULN (≥ G2) with 
concurrent bilirubin > 
2 X ULN 
Discontinue 
treatment and 
measure serum liver 
tests weekly until 
resolution. 
Exception: patients 
with Gilbert’s 
syndrome who 
develop elevated 
transaminases 
should be managed 
as per the 
recommendations 
outlined above for 
ALT/AST 
elevations. 
 
 
During the first 2 cycles of treatment, ALT, AST and bilirubin must be monitored weekly. 
 
5.3 
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-diarrheas and optimized hydration status). 
 
Anti-diarrhea medications may be introduced if symptoms occur. Previous trials have shown that 
the diarrhea caused by TK inhibitors (e.g. sunitinib, sorafenib) 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. 
 


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6. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The AEs 
and the characteristics of an observed AE (Section 6.2) will determine whether the event requires 
expedited reporting in addition to routine reporting. 
 
All subjects who receive at least one dose of study treatment will be valid for the safety analysis. 
 
All observations pertinent to the safety of the study treatment will be recorded and included in 
the final report. 
 
Safety variables include the following: AEs, 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). 
 
AEs evaluation will be continued after the first 2 cycles. 
 
6.1 
Adverse Events and Risks List 
 
For this study, the applicable reference document is the most current version of the investigator’s 
brochure (IB), summary of product characteristics, and/or package insert. 
 
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. The investigator will routinely review any new distributions of the IB 
for relevant new safety information and incorporate into the informed consent form document as 
appropriate. 
 
6.2 
Definitions 
 
Adverse event: Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse event 
or suspected adverse reaction is considered "life-threatening" if, in the view of the investigator, 
its occurrence places the patient at immediate risk of death. It does not include an adverse event 
or suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
 
Serious adverse event or serious suspected adverse reaction: An adverse event or suspected 
adverse reaction is considered "serious" if, in the view of the investigator, it results in any of the 
following outcomes: death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 


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may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
Suspected adverse reaction: Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered "unexpected" if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application, as amended. For example, 
under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) 
if the investigator brochure listed only cerebral vascular accidents. "Unexpected," as used in this 
definition, also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
 
6.3 
Reporting adverse events to the responsible IRB 
 
In accordance with applicable policies of the University of Pittsburgh Institutional Review Board 
(IRB), the Investigator will report, to the IRB, any observed or volunteered adverse event that is 
determined to be 1) associated with the investigational drug or study treatment(s); 2) serious; 
and 3) unexpected. Adverse event reports will be submitted to the IRB in accordance with the 
respective IRB procedures. 
 
Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later 
than 10 calendar days following the investigator’s receipt of the respective information. Adverse 
events which are 1) associated with the investigational drug or study treatment(s); 2) fatal or 
life-threatening; and 3) unexpected will be reported to the IRB within 24 hours of the 
Investigator’s receipt of the respective information. 
 
Follow-up information to a reported adverse event will be submitted to the IRB as soon as the 
relevant information is available. If the results of the Investigator’s follow-up investigation show 
that an adverse event that was initially determined to not require reporting to the IRB does, in 
fact, meet the requirements for reporting; the Investigator will report the adverse event to the 
IRB as soon as possible, but in no event later than 10 calendar days, after the determination was 
made. 


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7. REGORAFENIB INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section6.1. 
 
7.1 
Drug information 
 
Regorafenib 40-mg tablets contains regorafenib and the inactive excipients microcrystalline 
cellulose, croscarmellose sodium, magnesium stearate, povidone, colloidal anhydrous silica, 
polyvinyl alcohol-part hydrolyzed, talk, titanium dioxide E171 (color index 77891), 
Macrogol/PEG 33350, lecithin (soy), iron oxide yellow – E172 (color index 77491), iron oxide 
red – E172. 
 
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. 
 
Regorafenib will be provided by Bayer as 40-mg tablets, which are coated, not divisible, gray-
orange-red, oval (length 16 mm, width 7 mm, thickness 4.9-5.6 mm), and 472 mg each in total 
weight. Tablets are in an immediate-release dosage form with rapid dissolution characteristics 
under the in vitro test conditions. 
 
7.2 
Ordering and accountability 
 
All study drugs will be stored in Investigational Drug Services in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practices (GMP) requirements and/or institutional 
standard operating procedures. 
 
7.3 
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 
Fax: 973-709-2193 


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 OR 
 
Mail: (VP of Medical Affairs named in contract) at 
Bayer HealthCare Pharmaceuticals 
6 West Belt 
Wayne, NJ  07470 
 
8. SPECIAL STUDIES 
 
Archival tissue specimens that were collected at time of diagnosis may be requested and used for 
correspondence molecular analyses, including: EGFR pathway genes, VEGFRs, PDGFR, and C-
Met. 
 
8.1 
Pathology Material 
 
Tissue specimens will be analyzed for the mutational status of EGFR, K-RAS and B-RAF. All 
testing will be performed as done for clinical samples in the Molecular Pathology Laboratory at 
the University of Pittsburgh Medical Center (UPMC). Tissue specimens, including formalin 
fixed paraffin embedded (FFPE) tissue blocks, or cell blocks, with representative tumor tissue, 
preferably from resection or core biopsy specimens, will be obtained from the site where the 
diagnostic material was collected. If tumor tissue or cell blocks are not available, unstained slides 
(a minimum of 20) will be requested. DNA sample preparation from microdissected tumor areas 
will follow standard techniques for DNA extraction using DNeasy Blood & Tissue Kits (Qiagen, 
Inc). Detection and quantitation of mutations in codons 12, 13 and 61 of K-RAS, and detection 
of the hotspot transversion mutation T1799A that causes the amino acid substitution V600E in 
BRAF will be performed by pyrosequencing analyses using the PyroMark Q24 (Qiagen, Inc). 
PCR and sequencing methods will be used for detection of the E19del and L858R mutations in 
the EGFR gene. Expression levels of EGFR will also be evaluated by immunohistochemistry 
with the EGFR pharmDx™ Kit (Dako, Inc). VEGFR, PDGFR and C-Met analyses will be 
performed based on UPMC pathology standard methods.  
 
Analysis of these samples may take place while the patient is receiving study treatment, but the 
results will not be communicated to the subject. The results will be used in the analysis of the 
final study data. 
 
 


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9. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. Scans and x-rays must be done 28 days prior 
to the start of therapy. In the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of the next cycle of therapy. 
 
There is a window of ±1 week available for scheduling treatment and/or procedures at the discretion of the Investigator/Sub-
investigator. This applies also if a course is missed or a subject's treatment and/or testing day(s) need to be rescheduled due to the 
subject’s inability to comply with the study calendar (i.e., hospitalizations, business, vacation plans, travel from long distances for 
study treatment, in advance of the scheduled date to allow ready access to the result(s), reduce financial burden on the subject [i.e. 
non-UPMC insurance coverage] or reduce travel inconvenience, illness, transportation issues, holidays, family emergencies, etc.). 
 
 
Screening 
Day 1 
(Cycles 1&2) 
Day 8 
(Cycles 1&2) 
Day 15 
(Cycles 1&2) 
Day 22 
(Cycles 1&2) 
Day 1 
(Cycle 3+) 
End of 
Treatmentd 
Follow 
upe 
History and Physical 
X 
X 
 
 
 
X 
X 
 
Weight 
X 
X 
 
 
 
X 
X 
 
Vital Signsh  
 
 
X 
X 
X 
 
 
 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Assessment 
 
Con meds 
 
X 
X 
X 
X 
X 
X 
 
Urine protein/Creatinine 
X 
 
 
 
 
 
 
 
Pregnancy testa 
X 
 
 
 
 
 
 
 
Blood testsb 
X 
X 
X 
X 
X 
X 
X 
 
PT/INR and PTTc 
X 
 
 
 
 
 
 
 
CEA, CA19-9i 
 
X 
 
 
 
X 
X 
 
Tumor Measurement 
(CT or MRI C/A/P) 
X 
 
 
 
 
Xf 
X 
 
Regorafenibg 
 
X 
X 
X 
 
X 
 
 


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Archived Tissue Sample 
Collection 
X 
 
 
 
 
 
 
 
Disease status and survival 
 
 
 
 
 
 
 
Xe 
 
a. 
WOCBP only, 7 days prior to the start of study drug 
b. Blood tests include: CBC with diff, platelets, Bilirubin, Alk Phos, AST, ALT, Total Protein, Albumin, Sodium, Potassium, Blood Glucose, Calcium, 
Phosphate, Magnesium, BUN/Creatinine,  no need to repeat if done within 3 days of cycle 1 day 1. 
c. 
PT/INR and PTT will be done for everyone at screening visit. For patients on anticoagulation therapy, it should be done weekly while  on the study 
drug. 
d. To occur 28 days (± 5 days) after the last dose of the study drug 
e. 
The follow-up for survival will be every 3 months (+/- 4 weeks) by review of medical records, or direct contact patient contact.s. 
f. 
Up to 3 days before day 1 of every odd cycle. 
g. 3 weeks on 1 week off. Patient to keep a drug diary and return diary and pill bottle day 1 of every cycle. 
h. If clinically significant toxicity exists then patient to see MD for physical exam. 
i. 
CEA, CA19-9 to be obtained prior to the start of study drug. 
 
Note: Starting day (day1) of the subsequent cycles may be delayed up to 1 week to accommodate the patients/physicians clinic needs. 
 


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10. MEASUREMENT OF EFFECT 
 
10.1 Antitumor Effect Measurement 
 
For the purposes of this study, patients will be re-evaluated for response every 2 cycles(up to 3 
days before day 1 of every odd cycle). In addition to a baseline scan, confirmatory scans should 
also be obtained following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
10.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with regorafenib. 
 
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
10.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or as ≥ 10 mm with CT scan, MRI, or calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 


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thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 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 as non-
measurable. 
 
Note: 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. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
10.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 


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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body 
scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, 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 be performed with breath-hold scanning techniques, if possible. 
 
PET-CT At present, the low dose or attenuation correction CT portion of a combined 
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 (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed. 
 
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 


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study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. 
 
10.1.4 Response Criteria 
 
10.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
10.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 


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unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Investigator). 
 
10.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 


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CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
10.1.5 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
10.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
10.1.7 Response Review 
 
All responses will be reviewed by PI and, simultaneous review of the patients’ files and 
radiological images.  
 
11. DATA REPORTING / REGULATORY REQUIREMENTS 
 
11.1 
Data Safety Monitoring Plan 
 
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, 
clinical research associates, data managers, and clinic staff meet monthly in disease center Data 
Safety Monitoring Boards (DSMB) to review and discuss study data to include, but not limited 
to, the following: 
 
 serious adverse events 
 subject safety issues 
 recruitment issues 
 accrual 


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 protocol deviations 
 unanticipated problems 
 breaches of confidentiality 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to 
the NCI Common Toxicity Criteria version 4. All study treatment associated adverse events that 
are serious, at least possibly related and unexpected will be reported to the IRB. Any 
modifications necessary to ensure subject safety and decisions to continue, or close the trial to 
accrual are also discussed during these meetings. If any literature becomes available which 
changes the risk/benefit ratio or suggests that conducting the trial is no longer ethical, the IRB 
will be notified in the form of an Unanticipated Problem submission and the study may be 
terminated. 
 
All study data reviewed and discussed during these meetings will be kept confidential. Any 
breach in subject confidentiality will be reported to the IRB in the form of an Unanticipated 
Problem submission. The summaries of these meetings are forwarded to the UPCI DSMC which 
also meets monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse events). 
DSMC progress reports, to include a summary of all serious adverse events and modifications, 
and approval will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will 
be reviewed twice a year rather than monthly by the disease center DSMB. 
 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to 
suspend accrual or further investigate treatment on any trial based on information discussed at 
these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research 
records. 
 
11.2 
Quality Control and Quality Assurance 
 
Independent monitoring of the clinical study for protocol and Guidelines on Good Clinical 
Practice compliance will be conducted periodically (i.e., at a minimum of annually) by qualified 
staff of the Education and Compliance Office – Human Subject Research, Research Conduct and 
Compliance Office, University of Pittsburgh. 
 
The Investigator (i.e., the study site principal investigator) and the University of Pittsburgh and 
University of Pittsburgh Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 


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11.3 
Data Handling and Record-Keeping 
 
The Investigator (i.e., the study site principal investigator) will maintain records in accordance 
with Good Clinical Practice. 
 
The investigator will retain the specified records and reports for up to 2 years after the marketing 
application is approved for the investigational drug; or, if a marketing application is not 
submitted or approved for the investigational drug, until 2 years after investigations under the 
IND have been discontinued and the FDA so notified. 
 
11.4 
Institutional Review Board (IRB) Approval 
 
The investigator (i.e., the study site principal investigator) will obtain, from the University of 
Pittsburgh Institutional Review Board (IRB), prospective approval of the clinical protocol and 
corresponding informed consent form(s); modifications to the clinical protocol and 
corresponding informed consent forms, and advertisements (i.e., directed at potential research 
subjects) for study recruitment, if applicable. 
 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s). In such circumstances, the 
investigator will promptly notify the University of Pittsburgh IRB of the deviation. 
 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR Parts 
50 and 21 CFR 56, and in conformance with applicable International Conference on 
Harmonization (ICH) Guidelines on Good Clinical Practice. 
 
11.5 
Ethical and Scientific Conduct of the Clinical Study 
 
The clinical study will be conducted in accordance with the current IRB-approved clinical 
protocol; ICH Guidelines on Guidelines on Good Clinical Practice; and relevant policies, 
requirements, and regulations of the University of Pittsburgh IRB, University of Pittsburgh and 
University of Pittsburgh Medical Center, Commonwealth of Pennsylvania, and applicable federal 
agencies. 
 
11.6 
Subject Informed Consent 
 
The investigator (i.e., the study site principal investigator) will make certain that an appropriate 
informed consent process is in place to ensure that potential research subjects, or their authorized 
representatives, are fully informed about the nature and objectives of the clinical study, the 
potential risks and benefits of study participation, and their rights as research subjects. The 
investigator, or a sub-investigator, will obtain the written, signed informed consent of each 
subject, or the subject’s authorized representative, prior to performing any study-specific 
procedures on the subject. The date and time that the subject, or the subject’s authorized 
representative, signs the informed consent form and a narrative of the issues discussed during the 
informed consent process will be documented in the subject’s case history. The investigator, or 


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sub-investigator, will retain the original copy of the signed informed consent form, and a copy 
will be provided to the subject, or to the subject’s authorized representative. 
 
The investigator will make certain that appropriate processes and procedures are in place to 
ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and 
that the subjects are informed of any new information that may affect their decision to continue 
participation in the clinical study. In the event of substantial changes to the clinical study or the 
risk-to-benefit ratio of study participation, the investigator will obtain the informed consent of 
enrolled subjects for continued participation in the clinical study. 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 
Data Analysis Plan 
 
12.1.1 Primary objective 
 
Evaluate the progression-free survival (PFS) of patients with advanced biliary cancer who had 
failed first-line chemotherapy when receiving regorafenib. The progression-free survival 
function will be estimated by the Kaplan-Meier method, with a 90% confidence interval. The 
estimated median PFS will be derived from the estimated progression free survival function. The 
null hypothesis that the median PFS is 2.0 months or less (see Justification of Design, below) 
will be tested using the two-sided 80% confidence interval around the median PFS. If the left 
side of the confidence interval does not include two months, the null hypothesis will be rejected 
(α=0.10). 
 
12.1.2 Secondary objectives  
 
 Overall response rate (ORR), including complete and partial response. The ORR at four 
months will be estimated with an exact 90% binomial confidence interval. 
 Overall survival (OS). The overall survival function will be estimated by the Kaplan-
Meier method, with a 90% confidence interval.  
 DCR (disease control rate) as ORR plus stable disease (SD) 
 Measurable changes in biomarkers (CA19-9 and CEA), in patients that were elevated at 
the time of registration. The means and standard deviation of both markers will be 
estimated at before and after treatment. The null hypothesis of no treatment effect will be 
tested using a paired-comparison t-test (α=0.10), or a rank sum test if there is evidence of 
significant non-normality in the differences. 
 Evaluation of safety and associated toxicities. Toxicities will be tabulated by grade and 
type. 
 
12.2 
Justification of Design 
 
The primary objective for this study is to evaluate the median progression-free survival (PFS) in 
patients with advanced or metastatic biliary tract carcinoma/cholangiocarcinoma treated with 


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regorafenib monotherapy. The monthly accrual is 2 patients, and it is assumed that accrual will 
require 19 months, and that the analysis will be performed 9 months after the last patient is put 
on study (that is, at month 28, patients who have not progressed will be treated as censored). A 
median PFS of 3.5 months or greater will be taken as evidence of activity in this patient 
population. The null hypothesis to be tested is that the median PFS is 2.0 months or lower. If the 
maximum of 37 patients is accrued, the study will  have 83% power (using a one-sided test with 
α=0.10) if the alternative hypothesis that median PFS for patients in this population treated with 
regorafenib is at least 3.5 months is true. 
 
12.3 
Premature termination of the study 
 
 If risk-benefit ratio becomes unacceptable owing to, for example: 
 
Safety findings from this study (e.g. SAEs) 
 
Results of parallel clinical studies 
 
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 at any time. 
 
 
 


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13. REFERENCES 
 
Abdalla EK, Vauthey JN. Curr Opin Gastroenterol. 2001 Sep;17(5):450-7. 
 
Khan SA, Toledano MB, Taylor-Robinson SD. Epidemiology, risk factors, and pathogenesis of 
cholangiocarcinoma. Biliary tract cancer.  HPB (Oxford). 2008;10(2):77-82. 
 
Wadsworth CA, Dixon PH, Wong JH, Chapman MH, McKay SC, Sharif A, Spalding DR, 
Pereira SP, Thomas HC, Taylor-Robinson SD, Whittaker J, Williamson C, Khan SA. 
 
Genetic factors in the pathogenesis of cholangiocarcinoma. Dig Dis. 2011;29(1):93-7. Epub 2011 
Jun 17. 
 
Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, 
Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. 
Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 
8;362(14):1273-81. 
 
Oh SY, Jeong CY, Hong SC, Kim TH, Ha CY, Kim HJ, Lee GW, Hwang IG, Jang JS, Kwon 
HC, Kang JH. Phase II study of second line gemcitabine single chemotherapy for biliary tract 
cancer patients with 5-fluorouracil refractoriness. Invest New Drugs. 2011 Oct;29(5):1066-72. 
 
Lee S, Oh SY, Kim BG, Kwon HC, Kim SH, Rho MH, Kim YH, Rho MS, Jeong JS, Kim HJ. 
Second-line treatment with a combination of continuous 5-fluorouracil, doxorubicin, and 
mitomycin-C (conti-FAM) in gemcitabine-pretreated pancreatic and biliary tract cancer. Am J 
Clin Oncol. 2009 Aug;32(4):348-52. 
 
Sugiyama H, Onuki K, Ishige K, et al. Potent in vitro and in vivo antitumor activity of sorafenib 
against human intrahepatic cholangiocarcinoma cells. J Gastroenterology 2011 46:779789 
 
Bengala C, Bertolini F, Malavasi N, et al. Sorafenib in patients with advanced biliary tract 
carcinoma: a phase II trial. B J Cancer 2010 102:68-72 
 
El-Khoueiry AB, Rankin CJ, Ben-Josef E, et al. SWOG 0514: a phase II study of sorafenib in 
patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest 
New Drugs. 2012 Aug;30(4):1646-51. 
 
Sohal D, Teitelbaum UR, Uehara T, Mykulowycz K, Watt CD, Damjanov N, Giantonio BJ, 
Carberry M, Wissel  PS, Jacobs-Small M, O'Dwyer PJ, Sepulveda A, Sun W. A phase II trial of 
gemcitabine, irinotecan, and panitumumab in advanced cholangiocarcinoma, with correlative 
analysis of EGFR, KRAS, and BRAF: An interim report. J Clin Oncol 30, 2012 (suppl; abstr 
4111) 
 
Mross K, Frost A, Steinbild S, et al. A phase I dose-escalation study of regorafenib (BAY 73-
4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced 
solid tumors. Clin Cancer Res 2012; 18(9):2658-67.  


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36 
 
 
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, 
Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, 
Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for 
previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, 
randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 
10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22. PMID: 23177514  
 
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, 
Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, 
Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, 
Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced 
gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, 
multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-
302. doi: 10.1016/S0140-6736(12)61857-1. Epub 2012 Nov 22. PMID: 23177515  
 
 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.