Conditions: Metastatic Pancreatic Adenocarcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
This phase II trial studies how well regorafenib and gemcitabine hydrochloride work as second-line therapy (treatment given when initial treatment doesn't work) in treating patients with pancreatic cancer that has spread to other parts of the body. Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving regorafenib together with gemcitabine hydrochloride may kill more tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the efficacy (progression-free survival) of regorafenib and gemcitabine (gemcitabine hydrochloride) in previously treated patients with metastatic pancreatic cancer.

SECONDARY OBJECTIVES:

I. To assess the safety of regorafenib in combination with gemcitabine. II. To assess response rate (RR). III. To assess overall survival (OS).

OUTLINE:

Patients receive regorafenib orally (PO) once daily (QD) on days 1-21 and gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up to 30 days and then every 3 months thereafter.

Arms:
arm 1: Patients receive regorafenib PO QD on days 1-21 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Regorafenib intervention 2: Gemcitabine Hydrochloride
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol document:
Prot_SAP_001.pdf: 
A PHASE II STUDY OF SECOND-LINE 
THERAPY WITH REGORAFENIB PLUS 
GEMCITABINE IN METASTATIC 
PANCREATIC CANCER
Case Comprehensive Cancer Center 
11100 Euclid Avenue, Wearn 152 
Cleveland, Ohio 44106-5065 


 
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2 
CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
 
STUDY NUMBER:  CASE5214 
 
ClinicalTrials.gov NCT#: NCT02383433 
 
STUDY TITLE:   
SECOND-LINE 
THERAPY 
WITH 
REGORAFENIB 
PLUS 
GEMCITABINE IN METASTATIC PANCREATIC CANCER – A 
PHASE II STUDY 
 
 
 
 
PRINCIPAL INVESTIGATOR: Davendra P. S. Sohal, MD, MPH 
 
 
 
 
Department of Solid Tumor Oncology 
Taussig Cancer Institute 
 
 
 
 
Cleveland Clinic 
9500 Euclid Avenue  
 
 
 
Cleveland, OH – 44195 
 
 
 
 
 
 
 
CO-PRINCIPAL INVESTIGATOR (OTHER SITE): 
 
 
 
 
 
Jennifer Eads, MD 
Assistant Professor of Medicine 
Division of Hematology and Oncology 
University Hospitals Seidman Cancer Center 
Case Western Reserve University 
Case Comprehensive Cancer Center 
11100 Euclid Ave, Lakeside 1200 
Cleveland, OH 44106 
 
 
 
 
CO-PI: 
Mark Kofi Kyei, MD 
 
Regional Oncology 
Taussig Cancer Institute  
Cleveland Clinic 
5001 Rockside Road 
Independence, OH – 44131 


 
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CO- INVESTIGATORS:  
Alok A. Khorana, MD 
 
 
 
 
Robert Pelley, MD 
 
 
 
 
Bassam Estfan, MD 
 
 
 
 
Michael McNamara, MD 
 
 
 
 
Marc Shapiro, MD 
 
 
 
 
Dale Shepard, MD 
 
 
 
All at: Department of Solid Tumor Oncology 
Taussig Cancer Institute 
 
 
 
 
Cleveland Clinic 
9500 Euclid Avenue  
 
 
 
Cleveland, OH – 44195 
 
CO- INVESTIGATORS:  
Neal Meropol, MD 
 
 
 
 
Smitha Krishnamurthi, MD 
 
 
 
 
Joel Saltzman, MD 
 
 
 
 
Joseph Gibbons, MD 
 
 
 
 
Michael Gibson, MD 
 
 
 
All at: Division of Hematology and Oncology 
 
 
 
 
University Hospitals Seidman Cancer Center 
 
 
 
 
Case Western Reserve University 
 
 
 
 
Case Comprehensive Cancer Center 
 
 
 
 
11100 Euclid Ave,  
 
 
 
 
Cleveland, OH 44106 
 
STATISTICIAN:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
 
 
 
 
SUPPLIED AGENT 
 
Regorafenib 
 
 
 
OTHER AGENT  
 
Gemcitabine 


 
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TABLE OF CONTENTS 
 
SCHEMA 
List of Abbreviations 
 
1.0  
INTRODUCTION  
 
1.1 
Background on Metastatic Pancreatic Cancer 
1.2  
Rationale of the Study 
1.3       Background on Regorafenib 
1.4       Background on Gemcitabine 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
 
3.0 
STUDY DESIGN 
4.0  
PATIENT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Eligibility and Baseline Evaluation 
 
6.1.1 Regorafenib 
 
 
6.1.2 Gemcitabine 
 
6.2  
General Concomitant Medications and Supportive Care Guidelines 
6.3 
Duration of Therapy 
6.4 
Duration of Follow Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
8.1 
Adverse Events and Potential Risk List  
 
8.1.1 Regorafenib 
 
8.1.2 Gemcitabine 
8.2 
Definitions 


 
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8.2.1 Adverse Events 
 
8.2.2 Significance of an Adverse Event 
 
8.2.3 Serious Adverse Events 
 
8.2.4 Expectedness 
 
8.2.5 Attribution 
8.3 
Reporting Procedures for All Adverse Events 
8.4 
Serious Adverse Event Reporting Procedures 
 
8.4.1 Reporting 
 
8.4.2 FDA Reporting 
 
8.4.3 Multi-Center Trials 
8.5 
Data Safety Toxicity Committee    
 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Regorafenib 
9.2 
Gemcitabine 
 
 10.0 
CORRELATIVE / SPECIAL STUDIES 
 
 11.0 
STUDY PARAMETERS AND CALENDAR 
 11.1  
Study Parameters 
 11.2  
Calendar 
 
 12.0 
MEASUREMENT OF EFFECT  
 12.1 
Antitumor Effect – Solid Tumors  
 
 13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
 13.1 
Data Reporting 
 13.2 
Regulatory Considerations  
 
 
 14.0 
STATISTICAL CONSIDERATIONS 
 
 
REFERENCES 
 
 
      
 
  


 
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SCHEMA 
 
 
Informed Consent, 
Eligibility work-up: 
H&P, labs, data review 
 Regorafenib 120 mg, PO daily for 21 days – Cycle 1 
(If no dose related toxicities) 
Regorafenib 160 mg, PO daily for 21 days on subsequent cycles 
Gemcitabine 800 mg/m2 to 1000mg/m2 over 30 minutes on days 1, 
8, 15 of each 28-day cycle 
Follow until off-study, 
due to death, progression or toxicity 
Follow until death for survival 


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


 
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IRB 
Institutional Review Board 
MAPK 
Mitogen Activated Protein Kinase 
MEK 
MAP Kinase / ERK Kinase 1 
NM 
Nano molar 
NYHA 
New York Heart Association 
PD 
Progressive Disease 
PDGFR-β 
Platelet Derived Growth Factor Receptor-beta 
PFS 
Progression free survival 
PO 
per oris, oral 
PR 
Partial Response 
PS 
Performance Status 
PTT 
Partial thromboplastin time 
QD 
quaque die, once daily 
RAF 
Rapidly Accelerated Fibrosarcoma 
RAS 
Rat sarcoma 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria for Solid Tumors 
RET 
Rearranged during transfection 
RTK 
Receptor Tyrosine Kinase 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TIE2 
Tyrosine kinase with Immunoglobulin and Epidermal Growth Factor 
(EGF) homology domain 2 
TK 
Tyrosine Kinase 
TTP 
Time to Progression 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
 
 


 
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1.0 
INTRODUCTION 
 
1.1 
Background on Metastatic Pancreatic Carcinoma 
 
Pancreatic adenocarcinoma is an aggressive gastrointestinal cancer with an estimated 
annual incidence of over 45,000 cases in the United States, and is also expected to 
account for over 38,000 deaths in the United States in 2013 making it the fourth leading 
cause of cancer death for both men and women. Five-year survival rate is around 6 %. 
The incidence of diagnosis peaks in the seventh and eighth decade of life [1, 2]. 
Pancreatic adenocarcinoma is characterized by extensive local growth and early 
metastasis, making surgical control of disease uncommon. As a result, chemotherapeutic 
agents are often employed in an effort to control growth and spread of the cancer, as well 
as to prolong life and maximize function for patients with pancreatic cancer. 
 
 
1.2 
Rationale of the Study 
 
Currently, the most widely used first line regimens for metastatic pancreatic cancer in the 
US involves gemcitabine, which is a nucleoside analog, either alone or in combination 
with erlotinib, an inhibitor of epidermal growth factor receptor-associated tyrosine 
kinase. Median survival with gemcitabine based regimen ranges approximately between 
5.2-7.2 months. Recently, two new combination therapies consisting of 5-FU/LV plus 
oxaliplatin and irinotecan (FOLFIRINOX) and Nab-paclitaxel plus gemcitabine have 
been added to the first line treatment regimen for metastatic pancreatic cancer. 
FOLFIRINOX was approved by the FDA in 2010 after a large randomized phase 3 trial 
showed significant improvement in overall survival compared to gemcitabine 
monotherapy (11.1 vs 6.8 months, p < 0.001) [3]. There are, however, many concerns 
about the toxicity of the FOLFIRINOX regimen. The grade 3/4 toxicity rates were 12.3% 
for diarrhea, 15.6% for nausea, 17.2% for vomiting, 24% for fatigue, 47.9% for 
neutropenia, and 5.7% for febrile neutropenia. Patients who were enrolled in the study 
had an ECOG performance status of 0-1. Therefore, this regimen has not been completely 
adapted by the medical oncology community. Gemcitabine with nab-paclitaxel is another 
regimen that has been shown to improve outcomes in the first-line setting, compared with 
gemcitabine monotherapy, with a median overall survival of 8.5 months vs. 6.7 months 
(HR=0.72, p<0.001) [4]. Unfortunately, results from clinical studies on the use of 
biologics in pancreatic cancer have been disappointing. One of the studies was a phase III 
study, CALGB 80303, comparing Bevacizumab plus gemcitabine with gemcitabine plus 
placebo had a median OS of 5.8 months for Bevacizumab/gemcitabine and 5.9 months 
for gemcitabine/placebo [5]. Progression free survival (PFS) was 3.8 months versus 2.9 
months (p=0.07) [5].   


 
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There is no optimal treatment for patients whose disease progress after their initial 
treatment. This is, in part, due to lack of adequate clinical trials in this patient population. 
Pancreatic cancer is now becoming the second most common cause of all cancer deaths 
with a median 5 year survival of only 6%. Historically, combination systemic therapy has 
been shown to be more beneficial than single agent therapy albeit with increased 
toxicities. Regorafenib in preclinical studies showed some activity in reducing blood 
vessel formation in pancreatic cancer cell lines. Therefore, we propose this current study 
to assess the safety and clinical benefit of the combination of regorafenib and 
gemcitabine as well as to develop other therapeutic options.  
 
 
1.3    Background on Regorafenib 
 
Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic 
activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging 
(MRI) [6]. Regorafenib is a small molecule inhibitor of multiple membrane-bound and 
intracellular kinases involved in normal cellular functions and in pathologic processes such 
as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in 
vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 
and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, 
PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, 
BRAFV600E, SAPK2, PTK5, and Ab1 at concentrations of regorafenib that have been 
achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in 
a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in 
several mouse xenograft models including some for human colorectal carcinoma. 
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) [6]. 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 [6]. 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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Two phase III global randomized studies have evaluated the efficacy of regorafenib. The 
CORRECT (Patients with metastatic colorectal cancer treated with regorafenib or placebo after 
failure of standard therapy) trial is an international, multicenter, randomized, double-blind, 
placebo-controlled study that enrolled 760 patients with mCRC whose disease has progressed 
after approved standard therapies. Metastatic colorectal cancer patients were randomized 
to regorafenib plus best supportive care (BSC) or placebo plus BSC. Treatment cycles 
consisted of 160 mg of regorafenib (or matching placebo) once daily for three weeks on / one 
week off plus BSC. The primary endpoint of this trial was overall survival. Secondary 
endpoints included progression-free survival, objective tumor response rate and disease control 
rate. The safety and tolerability of the two treatment groups were also compared [7]. 
 
At a preplanned second interim analysis, there was a statistically significant survival benefit for 
regorafenib. The estimated hazard ratio for overall survival was 0.773 (95% confidence 
interval [CI], 0.635 to 0.941; 1-sided p = .0051). Patients treated with regorafenib had a median 
overall survival of 6.4 months, compared with 5.0 months for placebo — a 29% increase in 
survival. In addition to improved overall survival, progression-free survival was superior; 
median progression-free survival was 1.9 months (95% CI, 1.88 to 2.17) for regorafenib and 
1.7 months (95% CI, 1.68 to 1.74) for placebo. The estimated hazard ratio for progression-free 
survival was 0.493 (95% CI, 0.418 to 0.581; 1-sided p< .000001). There was a substantial 
difference in disease control rate in the regorafenib and placebo groups (44% vs. 15%; 
p<.000001). Regorafenib demonstrated comparable efficacy benefits across patient subgroups 
analyzed including age, number of mets, number of lines of prior therapy, and KRAS status [7]. 
The most frequent grade 3+ adverse events in the regorafenib group were hand–foot skin 
reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%) 
[7]. The efficacy and safety from the CORRECT study supported FDA approval in September 
2012. 
The efficacy and safety of regorafenib were examined in the Phase III GRID trial in patients 
with gastrointestinal stromal tumors (GISTs) who had exhausted all other treatment options. 
The study involved 199 patients with metastatic and/or unresectable GIST that had become 
resistant to imatinib and sunitinib. Patients were randomized 2:1 to regorafenib (160 mg orally 
once daily on a 3 weeks on/1 week off cycle) or placebo, plus best supportive care [8]. 
The results showed that treatment with regorafenib led to a statistically significant 3.9-month 
improvement in progression-free survival (PFS), compared with placebo (4.8 months vs. 0.9 
months; hazard ratio [HR] = 0.27; p <.0001). Overall survival was statistically similar between 
groups as expected due to a trial design that allowed crossover to regorafenib for disease 
progression (85% for placebo and 31% regorafenib randomized patients). The median survival 
period without tumor growth among patients on regorafenib was 4.8 months while for the 
control group on placebo it was less than a month. The overall disease control rate combining 


 
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partial responses with durable stable disease for at least 12 weeks was 53% with regorafenib 
compared with 9% in the control group. The most common grade ≥3 adverse events associated 
with regorafenib were hand-foot skin reaction (56.1%), hypertension (48.5%), and diarrhea 
(40.9%) [8].  The efficacy and safety of the GRID study data supported FDA approval 
February 2013. 
 
1.4 
Background on Gemcitabine 
 
 
Gemcitabine (2’,2’-difluorodeoxycytidine: dFdC) is a nucleoside analogue that has a 
broad spectrum of antitumor activity in solid tumors and leukemia [9]. A prodrug with 
high membrane permeability and a high affinity for deoxycytidine kinase, gemcitabine is 
converted intracellularly to its active metabolite, difluorodeoxycytidine triphosphate 
(dFdCTP). dFdCTP achieves higher intracellular concentrations and is retained 
significantly longer than the triphosphate of other pyrimidine analogues though feedback 
inhibition of cytidine deaminase, the enzyme responsible for its degradation. It competes 
with dCTP for incorporation into DNA, where it acts as chain terminator [9]. The drug 
also depletes intracellular deoxynucleoside triphosphate pools, presumably by inhibiting 
ribonucleotide reductase. Responses to gemcitabine as a single agent have been shown in 
several common solid tumors in phase II studies. Dose ranged from 800 to 1,250 mg/m2 
weekly for 3 weeks every 28 days, and toxicity was considered tolerable [10]. A phase III 
trial in patients with advanced pancreatic cancer demonstrated that gemcitabine 1,000 
mg/m2 weekly was more effective than 5-FU in producing clinical benefit, as measured 
by a specific scale [11]. Other outcomes including response rate, time to progression and 
overall survival also favored gemcitabine in this study. 
 
 
 
 


 
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2.0  
OBJECTIVES 
 
2.1  
Primary Objective 
 
To assess the efficacy (progression-free survival) of regorafenib and gemcitabine in 
previously treated patients with metastatic pancreatic cancer. 
 
2.2 
Secondary Objective(s) 
 
 To assess the safety of regorafenib in combination with gemcitabine 
 To assess response rate (RR), 
 To assess overall survival (OS) 
 
 


 
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3.0  
STUDY DESIGN 
 
Previously treated histologically confirmed metastatic pancreatic cancer will be eligible for this 
study. Study is a single arm non-randomized open label phase II study. 
 
Regorafenib will be given daily at 120 mg orally for 21 days out of 28 days for the first cycle and 
for those patients who do not experience any regorafenib dose related toxicities; the dose may be 
escalated to 160 mg daily for the subsequent cycles of treatments. Patients will take Regorafenib 
along with food (low-fat meal) 
 
Gemcitabine will be given intravenously at a starting dose of 800 mg/m2 and increased to a 
maximum dose of 1000 mg/m2 over 30 minutes per each dose on days 1, 8, 15 of each 28-day 
cycle as tolerated. 
 
Radiographic imaging will be performed at baseline and after every 2 cycles.  
Response to treatment will be evaluated based on RECIST 1.1 criteria  
Treatment will continue until disease progression, unacceptable toxicity or decision of 
patient/physician. 
 


 
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4.0 
PATIENT SELECTION 
 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. The 
checklist must be completed for each patient and must be signed and dated by the treating 
physician.  
 
Patient’s Name _____________________________________________________________ 
 
Medical Record # ___________________________________________________________ 
 
Research Nurse /  
Study Coordinator Signature: _________________________________ Date __________ 
 
Treating Physician [Print] ____________________________________________________ 
 
Treating Physician Signature: ________________________________ Date __________ 
 
 
4.1 
Inclusion Criteria 
 
 
4.1.1 Patients must have histologically or cytologically confirmed metastatic pancreatic 
adenocarcinoma (or any mixed pathology if adenocarcinoma is predominant).  
4.1.2 Patients must have measurable disease, defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm with 
conventional techniques or as >10 mm with spiral CT scan. 
4.1.3 Prior Therapies: Patients must have received at least one prior systemic chemotherapy 
regimen for metastatic pancreatic cancer. They should have experienced disease 
progression or intolerable toxicity from that regimen. 
4.1.3.1 Patients who have received prior non-gemcitabine-based systemic chemotherapy 
for metastatic disease at any time 4 weeks prior to enrollment, or those who are beyond 12 
months of exposure to gemcitabine-based chemotherapy regimen are allowed. 
4.1.3.2 Prior chemotherapy, radiation therapy, concurrent chemoradiation are allowed if 
used for treatment of non-metastatic disease. 
4.1.3.3 Any chemotherapy must have been completed 4 weeks prior to enrollment. 
4.1.3.4 Any radiotherapy must have been completed 2 weeks prior to enrollment. 


 
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4.1.4  Age ≥ 18 years. Because the dosing and toxicity data for Regorafenib are not currently 
available in patient population <18 years, children are excluded from this study. 
4.1.5 ECOG performance status 0-1 
4.1.6 Life expectancy of at least 12 weeks (3 months). 
4.1.7  Subjects must be able to understand and be willing to sign the written informed consent 
form. A signed informed consent form must be appropriately obtained prior to the 
conduct of any trial-specific procedure. 
4.1.8  All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 
or less at the time of signing the Informed Consent Form (ICF). 
4.1.9 Adequate bone marrow, liver and renal function as assessed by the following laboratory 
requirements: 
o Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) 
o Alanine aminotransferase (ALT) and aspartate amino-transferease (AST) ≤ 2.5 x 
ULN (≤ 5 x ULN for subjects with liver involvement of their cancer) 
o Alkaline phosphastase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver 
involvement of their cancer) 
o Lipase ≤ 1.5 x the ULN 
o Serum creatinine ≤ 1.5 x the ULN 
o International normalized ratio (INR)/ Partial thromboplastin time (PTT) 
 1.5 x 
ULN. (Subjects who are therapeutically treated with an agent such as warfarin or 
heparin will be allowed to participate provided that no prior evidence of 
underlying abnormality in coagulation parameters exists. Close monitoring of at 
least weekly evaluations will be performed until INR/PTT is stable based on a 
measurement that is pre-dose as defined by the local standard of care. 
 Platelet count ≥ 100000 /mm3, hemoglobin (Hb) ≥ 9 g/dL, absolute 
neutrophil count (ANC) ≥ 1500/mm3. Blood transfusion to meet the 
inclusion criteria will not be allowed. 
4.1.10 Women of childbearing potential must have a negative serum pregnancy test performed 
within 7 days prior to the start of study drug. Post-menopausal women (defined as no 
menses for at least 1 year) and surgically sterilized women are not required to undergo a 
pregnancy test. 
4.1.11 Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 3 months after the last 
dose of study drug. The definition of adequate contraception will be based on the 
judgment of the principal investigator or a designated associate. 


 
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4.1.12 Subject must be able to swallow and retain oral medication. 
 


 
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4.2 
Exclusion Criteria 
 
The presence of any of the following will exclude a patient from study enrollment. 
 
4.2.1 Chemotherapy within 4 weeks prior to entering the study, radiotherapy within 2 weeks 
prior to entering the study or failure to recover from adverse events to Grade 1 or less due 
to agents administered more than 4 weeks earlier. 
4.2.2 Use of any other investigational agents. 
4.2.3 Previous assignment to treatment during this study. Subjects permanently withdrawn 
from study participation will not be allowed to re-enter study. 
4.2.4 Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm 
Hg [NCI-CTCAE v4.0] on repeated measurement) despite optimal medical management. 
4.2.5 
Active or clinically significant cardiac disease including: 
o Congestive heart failure – New York Heart Association (NYHA) > Class II. 
o Active coronary artery disease. 
o Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or 
digoxin. 
o Unstable angina (anginal symptoms at rest), new-onset angina within 3 months 
before randomization, or myocardial infarction within 6 months before 
randomization. 
4.2.6  Evidence or history of bleeding diathesis or coagulopathy. 
 
4.2.7 Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start 
of study medication.  
4.2.8 Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular 
accident (including transient ischemic attacks) deep vein thrombosis or pulmonary 
embolism within 6 months of  informed consent. 
4.2.9 Subjects with any previously untreated or concurrent cancer that is distinct in primary site 
or histology from pancreatic cancer except cervical cancer in-situ, treated basal cell 
carcinoma, or superficial bladder tumor. Subjects surviving a cancer that was curatively 
treated and without evidence of disease for more than 3 years before randomization are 
allowed. All cancer treatments must be completed at least 3 years prior to study entry 
(i.e., signature date of the informed consent form). 
4.2.10 Patients with phaeochromocytoma. 


 
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4.2.11 Known history of human immunodeficiency virus (HIV) infection or current chronic or 
active hepatitis B or C infection requiring treatment with antiviral therapy. 
4.2.12 Any infection requiring ongoing intravenous antibiotics for management.. 
4.2.13 Symptomatic metastatic brain or meningeal tumors. Treated and stable, asymptomatic 
brain metastases, as long as treatment was greater than 4 weeks prior to informed consent, are 
allowed. 
4.2.14 Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
4.2.15 Renal failure requiring hemo-or peritoneal dialysis. 
4.2.16 Dehydration Grade >1 NCI-CTCAE v4.0. 
4.2.17 Patients with seizure disorder requiring medication. 
4.2.18 Persistent proteinuria  Grade 3 NCI-CTCAE v4.0 (> 3.5 g/24 hrs, measured by urine 
protein:creatinine ratio on a random urine sample). 
4.2.19 Interstitial lung disease with ongoing signs and symptoms at the time of informed 
consent.  
4.2.20 Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version 
4.0 Grade 2 dyspnea). 
4.2.21 History of organ allograft (including corneal transplant). 
4.2.22 Known or suspected allergy or hypersensitivity to any of the study drugs, study drug 
classes, or excipients of the formulations given during the course of this trial. 
4.2.23 Any malabsorption condition. 
4.2.24 Women who are pregnant or breast-feeding. 
4.2.25 Any condition which, in the investigator’s opinion, makes the subject unsuitable for trial 
participation. 
4.2.26 Substance abuse, medical, psychological or social conditions that may interfere with the 
subject’s participation in the study or evaluation of the study results. 
 
4.3 
Inclusion of Women and Minorities  
 
 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial 
 
 


 
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5.0 
REGISTRATION or RANDOMIZATION, if applicable 
 
All subjects who have been consented are to be registered in the OnCore Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be recorded. 
 
All subjects will be registered through Taussig Cancer Institute, Cleveland Clinic and will be 
provided a study number by referring to the OnCore Database. Patient numbers are to be 
assigned in numerical order. 
 
 


 
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6.0  
TREATMENT PLAN 
 
 
6.1 
Eligibility and Baseline Evaluation 
 
After obtaining written informed consent and ensuring all eligibility requirements are met, 
based on clinical history and physical examination, laboratory tests for marrow and organ 
function, imaging studies and laparoscopic evaluation for extent of disease, as outlined in 
section 4.0, patients will be enrolled onto the study. A chemotherapy port will be placed to 
allow central venous administration of chemotherapeutic agents. 
 
 
6.1.1 Regorafenib 
Regorafenib tablets will be packaged in high density polyethylene bottles with a white child 
resistant closure and induction seal. Each bottle includes 30 40-mg tablets (for randomized 
studies) or 28 40-mg tablets (for open-label studies) 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). 
 
 
Oral Regorafenib 120 mg daily for 21 days of the first 28-day cycle taken along with food (low-
fat meal). For those patients who tolerate the first cycle of treatment without any regorafenib 
dose related toxicities, the dose of regorafenib may be escalated to 160 mg/day for the second 
and subsequent cycles (3 weeks on and 1 week off; every 4 week cycle). 
The study drug must be exclusively used for the investigation specified in this protocol and it 
will only be accessible to authorized staff. 
 
Dose escalation criteria are given below: 
 
Cycle 
Each cycle 28 days 
Adverse Event 
Regorafenib 
Days 1-21 
Gemcitabine 
Days 1, 8, 15 
1 
N/A 
120 mg/day baseline 
800 mg/m2 baseline 
2 onward 
No ≥grade 2 toxicity 
in cycle 1 
160 mg/day baseline, 
refer to 6.4.2 for dose 
modification 
1000 mg/m2 baseline, 
refer to 6.4.2 for dose 
modification 
2 onward 
Any ≥grade 2 
toxicity in cycle 1 
120 mg/day baseline, 
refer to 6.4.2 for dose 
modification 
800 mg/m2 baseline, 
refer to 6.4.2 for dose 
modification 


 
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This is a phase II open labeled study.  
One treatment cycle is 28 days. 
 
Four 40-mg regorafenib tablets should be taken in the morning with approximately 8 fluid 
ounces (240 mL) of water after a low-fat (<30% fat) meal.  Some examples of low fat meal are: 
 Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of 
jelly and 8 ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g of fat). 
 One cup of cereal (i.e. Special K), 8 ounces (240 mL) of skim milk, one piece of toast 
with jam (no butter or marmalade), apple juice, and one cup of coffee or tea (2 g fat, 17 g 
protein, 93 g of carbohydrate, 520 calories.  
 
6.1.2 Gemcitabine 
Gemcitabine will be administered at a starting dose of 800 mg/m2 and escalated to 1000 mg/m2 
as tolerated by study patients after a stable dose of regorafenib is achieved for 1 cycle, as a 30-
minute intravenous infusion, on days 1, 8 and 15 of each 28-day cycle.  
 
6.2 
General Concomitant Medications and Supportive Care Guidelines 
 
Concomitant medicines will be administered to counter the expected common side-effects of 
chemotherapy. These may include anti-emetic, anti-allergy, and anti-diarrhea medicines, as 
well as growth factors for bone marrow support. These will be ordered by the treating 
physician per the patient’s condition and prior history 
Further intravenous medicines and fluids may also be used per the treating physician’s 
recommendations. Oral medicines can be prescribed for use at home, as deemed appropriate 
by the treating physician. These may include anti-emetics, analgesics, anti-pyretics, anti-
diarrheals, pancreatic enzyme supplements, appetite stimulants, antacids, H2-blockers, 
proton pump inhibitors, anxiolytics, anti-depressants, sleep aids, and other common 
medicines as needed. Referral to health care providers from other specialties, such as 
palliative medicine, nutrition, psychology, psychiatry, home care services, etc., may be made 
as needed per the patient’s clinical situation. 
 
All medication that is considered necessary for the subject’s welfare, and which is not expected 
to interfere with the evaluation of the study treatment, may be given at the discretion of the 
investigator.  All medications (including contrast media) taken within 2 weeks prior to the start 
of the study and during the study must be recorded in the subject’s source documentation and in 
the CRF (including start/stop dates, dose frequency, route of administration, and indication).  
Specific caution should be taken when considering or administering a concomitant medication 
that is metabolized by the cytochrome enzymes CYP2C8, CYP2B6 and CYP2C9.  Such 
concomitant medication should be avoided, if possible. 


 
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Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of 
regorafenib decreased the mean exposure of regorafenib, increased the mean exposure of the 
active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite 
M-2.  Avoid concomitant use of regorafenib with strong CYP3A4 inducers (e.g. rifampin, 
phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) 
 
Co administration of a strongCYP3A4 inhibitor (ketoconazole) with a single 160mg dose of 
regorafenib increased the mean exposure of regorafenib and decreased the mean exposure of the 
active metabolites M-2 and M-5.  Avoid concomitant use of regorafenib with strong inhibitors of 
CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazadone, 
posaconazole, telithromycin, and voriconazole). 
 
Permitted concomitant therapy includes: 
 Standard therapies for concurrent medical conditions. 
 Supportive care for any underlying illness. 
 Palliative radiation therapy is allowed if the target lesion(s) are not included within the 
radiation field and no more than 10% of the bone marrow is irradiated. 
 Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic growth factors 
may be used in the management of acute toxicity, such as febrile neutropenia, when 
clinically indicated or at the investigator’s discretion. However, they may not be 
substituted for a required dose reduction.  Subjects are permitted to take chronic 
erythropoietin. 
 Treatment with nonconventional therapies (such as acupuncture), and vitamin/mineral 
supplements are permitted provided that they do not interfere with the study endpoints, in 
the opinion of the investigator. 
 Bisphosphonates 
 Subjects who are therapeutically treated with an agent such as warfarin or heparin will be 
allowed to participate provided that their medication dose and INR/PTT are stable.  Close 
monitoring (day5 of cycle 1 and day 1 of each cycle) is mandatory.  If either of these 
values are above the therapeutic range, the doses should be modified and the assessments 
should be repeated weekly until they are stable. 
 For subject receiving regorafenib in combination with chemotherapy consider adding the 
following:  
o A standard antiemetic regimen for the prophylaxis of acute emesis is 
recommended on the day of chemotherapy at least 30 minutes prior to the 
administration of chemotherapy.  Such a regimen may include a serotonin (5-
HT3) antagonist (e.g. granisetron or ondansetron) with or without a 
corticosteroid (e.g. dexamethasone).  The investigators should also consider 
providing subjects with a standard antiemetic regimen for treatment of delayed or 
breakthrough emesis as needed. 


 
CASE 5214 PH II, REGORAFENIB, GEMCITABINE  
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The following are not permitted: 
 Other investigational treatment during or within 30 days before starting study treatment 
 Systemic antitumor therapy, including cytotoxic therapy, signal transduction inhibitors, 
immunotherapy, and hormonal therapy 
 Bone marrow transplant or stem cell rescue 
 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 cytocrome enzyme CYP2C9 and its levels may 
be especially affected by regorafenib 
 Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum]) 
 Please note:  Patients should be seen frequently / early during treatment as per 
Prescribing Information 
 Liver function tests should be obtained before initiation of regorafenib and monitored at 
least every 2 weeks during first 2 months of treatment.  Thereafter liver function should 
be monitored monthly or more frequently as clinically indicated 
 Monitor blood pressure weekly for the first 6 weeks of treatment and every cycle or more 
frequently as clinically indicated. 
 
6.3  
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment with regorafenib and 
gemcitabine will continue or until one of the following criteria applies: 
 
 Disease progression, 
 Intercurrent illness that prevents further administration of treatment, 
 The investigator considers it, for clinical reasons, to be in the best interest of the patient.  
 Unacceptable treatment-related toxicity, NCI CTCAE version 4.0, that fails to resolve 
with usual supportive measures,  
 General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator,  
 Patient decision to withdraw from treatment (partial consent) or from the study (full 
consent), 
 Pregnancy during the course of the study for a child-bearing participant, or 
 Death. 
 
The date and reason for discontinuation must be documented. Every effort should be 
made to complete the appropriate assessments.  
 


 
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Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons:  
 Subject withdraws consent from study treatment and study procedures. A subject must be 
removed from the trial at his/her own request or at the request of his/her legally 
acceptable representative. At any time during the trial and without giving reasons, a 
subject may decline to participate further. The subject will not suffer any disadvantage as 
a result. 
 Pregnancy. Pregnancy will be reported as an SAE. (Note: subjects who have been 
withdrawn from treatment with study drug because of pregnancy should not undergo CT 
scans [with contrast]/MRI or bone scans while pregnant.) 
 If, in the investigator's opinion, continuation of the trial would be harmful to the subject's 
well-being. 
 Subject is lost to follow-up. 
 Death. 
Subjects may be withdrawn from the study for the following reasons: 
 The subject is non-compliant with study drug, trial procedures, or both; including the use 
of anti-cancer therapy not prescribed by the study protocol. 
 Severe allergic reaction to regorafenib (such as exfoliative erythroderma or Grade 3 or 4 
hypersensitivity reaction). 
 The development of a second cancer.  
 Development of an intercurrent illness or situation which would, in the judgment of the 
investigator, significantly affect assessments of clinical status and trial endpoints. 
 Deterioration of ECOG performance status to 4. 
 Use of illicit drugs or other substances that may, in the opinion of the investigator, have a 
reasonable chance of contributing to toxicity or otherwise skewing trial result. 
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable. 
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's medical 
records. 
Details for the premature termination of the study as a whole (or components thereof 
[e.g. centers, treatment arms, dose steps]) are provided in Section Adverse Events 
 
6.4 
Duration of Follow Up 
 


 
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Patients will be followed from the time of enrollment until death, or patient decision to 
withdraw from the study. The study calendar, in section 11, describes the schedule of follow-
up. 
 
6.5    Drug logistics and accountability 
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practices (GMP) requirements and the instructions 
given by the clinical supplies department of the Institution and will be inaccessible to 
unauthorized personnel. 
6.5.1  Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the agent (investigational or free of charge) using the 
NCI Drug Accountability Record or another comparable drug accountability form. (See the 
CTEP website at http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the drug 
accountability form.) 
6.5.2 
Destruction and Return 
Unused, expired and returned 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 
Mail: (VP of Medical Affairs named in contract) at 
Bayer HealthCare Pharmaceuticals 
100 Bayer Boulevard 
Whippany, NJ 07981 
6.5.3 
Treatment compliance 
An adequate record of receipt, distribution, and return of all study drugs must be kept in the form 
of a Drug Accountability Form.  
Subject compliance with the treatment and protocol includes willingness to comply with all 
aspects of the protocol, and to have blood collected for all safety evaluations.  At the discretion 
of the principal investigator, a subject may be discontinued from the trial for non-compliance 
with follow-up visits or study drug. 
 


 
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7.0  
DOSING DELAYS / DOSE MODIFICATIONS 
The starting dose of regorafenib is 120 mg once daily. Study medication will be 
administered on a 3 weeks on/1 week off schedule [3 weeks out of every 4]. 
Doses will be delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to protocol therapy according to the guidelines shown in the Dose 
Delays/Dose Modifications table that follows. Dose modifications will follow predefined 
dose levels. Dose adjustments for hematologic toxicity are based on the blood counts 
obtained in preparation for the day of treatment. 
 
The modifications of regorafenib will follow the following predefined dose levels: 
Dose level +1 
160 mg po 
qd 
Four 40-mg tablets of regorafenib 
Dose level 0 
(starting dose) 
120 mg po 
qd  
Three 40-mg tablets of regorafenib 
Dose level - 1 
80 mg po 
qd  
Two 40-mg tablets of regorafenib 
 
If a subject experiences more than one toxicity, dose reduction should be according to the 
toxicity with the highest grade  
In the case of two or more toxicities of the same grade, the investigator may dose reduce 
according to that deemed most causally related to study treatment. 
 If more than 2 dose reductions are required, regorafenib only will be discontinued and the rest of 
the study treatment (gemcitabine) may be continued. If a dose reduction has been performed, 
intra-subject dose re-escalation can be considered (up to the maximal 160 mg daily dose) at the 
discretion of the treating physician provided that the toxicity(ies) has resolved to baseline. 
 
The following tables outline dose adjustments for toxicities related to study drug except hand-
foot skin reaction, hypertension and liver function test abnormalities.  


 
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Table 7-1: 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 
Reduce by 1 dose level 
If toxicity remains < 
Grade 2, dose re-
escalation can be 
considered at the 
discretion of the treating 
investigator. If dose is 
re-escalated and toxicity 
(≥ Grade 3) recurs, 
institute permanent dose 
reduction. 
Grade 4 
Delay until ≤ Grade 2c 
Reduce by 1 dose level. 
Permanent 
discontinuation 
can be considered at 
treating investigator’s 
discretion. 
 
a. NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events, 
  version 4.0 
b. Excludes alopecia, non-refractory nausea/vomiting, non-refractory hypersensitivity and nonclinical and 
asymptomatic laboratory abnormalities. 
c. If no recovery after a 4 week delay*, treatment should be permanently discontinued unless subject is 
deriving clinical benefit. 
 
 
 
Other Toxicities 
Any treatment-emergent toxicities other than the ones described above will be managed by 
the treating physician as appropriate. Dose delays and modifications, and treatment cessation 
will be at the discretion of the treating physician and/or the Principal Investigator. All 
adverse events will be documented and measures to manage/treat/mitigate them will be 
documented as well. This is described further in section 8.0. 
 
In addition to these recommended dose modifications, subjects who develop diarrhea,  
mucositis, anorexia or other events predisposing to fluid loss or inadequate fluid intake 
should be carefully monitored and rehydrated as clinically necessary.  This is in order to  
minimize the risk of postural hypotension and renal failure. 
 
 


 
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Table 7-2: Grading for Hand-Foot-Skin-Reaction 
 
Grade 1 
Grade 2 
Grade 3 
NCI-CTCAE v4.0 
Palmar-plantar 
erythrodysesthesia 
syndrome 
Minimal skin changes or 
dermatitis 
(e.g., erythema, edema, 
or hyperkeratosis) 
without pain 
Skin changes 
(e.g., peeling, blisters  
bleeding, edema, or 
hyperkeratosis) with 
pain 
Severe skin changes 
(e.g., peeling, 
blisters, bleeding, 
edema, or 
hyperkeratosis) with 
pain 
Further description / 
examples of skin 
changes 
Numbness, dysesthesia / 
paresthesia tingling, 
painless swelling, or 
erythema of the hands 
and/or feet 
Painful erythema and 
swelling of the hands 
and/or feet 
Moist desquamation, 
ulceration, blistering, 
or severe pain of the 
hands and/or feet 
Effect on activities 
Does not disrupt normal 
activities 
Limiting 
instrumental 
activities of daily life 
(e.g., preparing 
meals, shopping for 
groceries or clothes, 
using the telephone, 
managing money) 
Limiting self-care 
activities of daily life 
(e.g., bathing, 
dressing and 
undressing, feeding 
self, using the toilet, 
taking medications) 
and not bedridden 
a. Palmer-planter erythrodysesthesia syndrome is a disorder characterized by redness, marked 
    discomfort, swelling, and tingling in the palms of hands or the soles of the feet. 
 


 
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Table 7.3 Recommended dose modification for hand-foot-skin reactiona 
Grade of event  
(NCI-CTCAE v4.0) 
Occurrence 
Suggested Dose Modification 
Grade 1 
Any 
Maintain dose level and immediately institute 
supportive measures for symptomatic relief 
Grade 2 
 
1st occurrence 
Consider decreasing dose by one dose level and 
immediately institute supportive measures.  If no 
improvement, interrupt therapy for a minimum of 7 
days, until toxicity resolves to Grade 0-1 b, c 
No improvement 
within 7 days or 
2nd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1.c 
When resuming treatment, treat at reduced dose level b 
3rd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-1. c 
When resuming treatment, decrease dose by one dose 
level. b, d 
4th occurrence 
Discontinue regorafenib therapy. The other study 
treatment may be continued 
Grade 3 
 
1st occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves 
to Grade 0-1. c When resuming treatment, decrease dose 
by one dose level. b, d 
2nd occurrence 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves 
to Grade 0-1. c When resuming treatment, decrease dose 
by one additional dose level b, d  
3rd occurrence 
Discontinue regorafenib treatment permanently. The 
other study treatment may be continued 
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 other study treatment may 
be continued. 
e. The maximum daily dose is 160 mg. 
  
 
At first occurrence of HFSR, independent of grade, prompt institution of supportive 
measures such as topical emollients, low potency steroids, or urea-containing creams 
should be administered. 
Recommended prevention/management strategies for skin toxicities consistent with HFSR are 
summarized below: 
Control of calluses 
Before initiating treatment with regorafenib: 
 Check condition of hands and feet. 


 
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 Suggest a manicure/pedicure, when indicated. 
 Recommend pumice stone use for callus or ‘rough spot’ removal. 
During regorafenib treatment: 
 Avoid pressure points. 
 Avoid items that rub, pinch or create friction. 
Use of creams 
 Non-urea based creams may be applied liberally. 
 Keratolytic creams (e.g. urea-based creams, salicylic acid 6%) may be used sparingly and 
only to affected (hyperkeratotic) areas. 
 Alpha hydroxyl acids (AHA) based creams may be applied liberally 2 times a day.  
Approximately 5% to 8% provides gentle chemical exfoliation. 
 Topical analgesics (e.g. lidocaine 2%) are to be considered for pain control. 
 Topical corticosteroids like clobetasol 0.05% should be considered for subjects with 
Grade 2 or 3 HFSR.  Avoid systemic steroids. 
Tender areas should be protected as follows: 
 Use socks/gloves to cover moisturizing creams 
 Wear well-padded footwear 
 Use insole cushions or inserts (e.g. silicon, gel) 
 Foot soaks with tepid water and Epson salts 
 
Hypertension 
Hypertension is a known AE associated with regorafenib treatment.  Subject will have their 
blood pressure measured at least weekly at the study site during the first 6 weeks of treatment.  If 
additional blood pressure measurements are done outside the study site, and the blood pressure is 
> 140 mm Hg systolic or > 90 mm Hg diastolic (NCI CTCAE v4.0), then the subject must 
contact study personnel.  The management of hypertension, including the choice of 
antihypertensive medication, will be performed according to local standards and to the usual 
practice of the investigator.  Every effort should be made to control blood pressure by medical 
means other than study drug dose modification.  If necessary, Table 6-4 outlines suggested dose 
reductions. 
 
 
 
 
 


 
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Table 7-4:  Management of Treatment-Emergent Hypertension 


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


 
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For patients with observed worsening of serum liver tests considered related to regorafenib 
(i.e. where no alternative cause is evident, such as post-hepatic cholestasis or disease 
progression), the dose modification and monitoring advice in Table 6-5 should be followed. 
 
Regorafenib is a UGT1A1 inhibitor.  Mild, indirect (unconjugated) hyperbilirubinemia may 
occur in patients with Gilbert’s syndrome. 
 
Table 7.5: Dose Modification/interruption for alanine aminotransferase and/or aspartate 
aminotransferase increases related to study drug 
Increases in 
ASL/ALT (per 
NCI-CTCAE v 
4.0) 
1st Occurrence 
Restart 
Recurrence 
AST and/or 
ALT < 5 X 
ULN (<Grade 
3) 
Continue dosing, 
with weekly 
monitoring of 
liver function 
until 
transaminases 
return to < 3 X 
ULN (< Grade 1) 
or baseline. 
 
 
ALT and/or 
AST > 5 X 
ULN (> Grade 
3) 
Interrupt dosing, 
with weekly 
monitoring until 
transaminases 
return to < 3 X 
ULN or baseline. 
If the potential 
benefit of 
reinitiating 
regorafenib is 
considered to 
outweigh the 
risk of 
hepatotoxicity: 
reduce 1 dose 
level and 
measure serum 
transaminases 
weekly for at 
least 4 weeks. 
Discontinue 
ALT and/or 
AST > 20 X 
ULN (> Grade 
4) 
Discontinue 
 
 
ALT and/or 
AST > 3 X 
ULN (> Grade 
2) with 
concurrent 
bilirubin > 2 X 
ULN 
Discontinue 
treatment and 
measure serum 
transaminases 
weekly until 
resolution. 
Exception: 
subjects with 
Gilbert's 
syndrome who 
 
 


 
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Prevention/management strategies for diarrhea 
Diarrhea can be a common side effect of regorafenib .  The preventive/management strategies for 
diarrhea should be consistent with local standards (e.g., anti-diarrheals and optimized hydration 
status). 
Anti-diarrhea medications may be introduced if symptoms occur.  Previous trials have shown 
that the diarrhea could be managed with loperamide.  The recommended dose of loperamide is 4 
mg at first onset, followed by 2 mg every 2 to 4 hours until diarrhea-free for 12 hours. 
Myelosuppression (Hematological Toxicities) 
ANC should be ≥ 1000/mm3 and platelets should be > 75,000/mm3 prior to each 
administration of medications.  
Dose modification of gemcitabine will be allowed for subsequent doses based on the nadir 
counts when treatment is held. 
Dose Modification of Gemcitabine for subsequent doses: 
ANC (cells/mm3) 
Platelets ( cells/mm3) 
Gemcitabine (mg/m2) 
≥ 1000 
≥ 75,000 
Continue previous dose level 
500-999 
50,000-74,999 
Reduce dose by 20% 
<500 
<50,000 
Reduce dose by 40% 
 
CBC will be checked weekly for all cycles of Gemcitabine. 
 
Hold for a maximum of 3 weeks.  Perform blood counts weekly until 
they return to ≥1000 (ANC) and ≥75000 (platelets), to allow resumption of 
gemcitabine.  If counts do not recover to these levels  despite 4 weeks of holding 
gemcitabine, discontinue protocol therapy. 
 
G-CSF can be administered if persistent neutropenia ≤500/mm3 for 
more than 7 days with no fever, or neutropenia with temperature ≥38.50C. 
Non-Hematological Toxicities from Gemcitabine 
Permanently discontinue gemcitabine for any of the following: 
 Unexplained dyspnea or other evidence of severe pulmonary toxicity 
develop elevated 
transaminases 
should be 
managed as per 
the 
recommendations 
outlined above 
for ALT/AST 
elevations. 


 
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 Severe hepatic toxicity 
 Hemolytic-uremic syndrome 
 Capillary leak syndrome 
 Posterior reversible encephalopathy syndrome 
Withhold Gemcitabine or reduce dose by 50% for other severe (Grade 3 or 4) non-
hematological toxicity until resolved. No dose modifications are recommended for alopecia, 
nausea, or vomiting. 
 


 
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8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
The following is a list of AEs (Section 8.1) and the reporting requirements associated with 
observed AEs (Sections 8.3 and 8.4).  
 
Investigators should refer to the Safety Information section of the current IB for regorafenib, 
including the DCSI (development core safety information), for the expected side effects of 
regorafenib. As with any agent, there is always the potential for unexpected AEs, including 
hypersensitivity reactions. The IB will be updated if any new relevant safety data are obtained. 
Therapeutic monitoring should be performed following dose selection or modification of 
regorafenib, in a manner consistent with the local clinical standard of care. In general, subjects 
should be closely monitored for side effects of all concomitant medications regardless of the path 
of drug elimination. 
All concomitant medications must be recorded in the subject’s source documentation. 
Subjects must be carefully monitored for AEs. This monitoring also includes clinical laboratory 
tests. Adverse events should be assessed in terms of their seriousness, intensity, and relationship 
to the study drug, or other chemotherapy/treatment. 
 
8.1 
Adverse Events and Potential Risks  
 
8.1.1 Regorafenib 
Common: Hand-Foot-Skin reaction, Hypertension, Liver function abnormalities, Diarrhea 
Rare: Myocardial infarction/ischemia, Taste disturbances, GERD, Tremor 
 
8.1.2 Gemcitabine 
Common: Myelosuppression, Dyspnea, Pulmonary toxicity, Hepatic toxicity, Hemolytic 
Uremic Syndrome, Peripheral edema 
Rare: Paresthesias, Increased creatinine, Bronchospasm, TTP 
 
 
8.2 
Definitions  
 
8.2.1 
Adverse Events  
 
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 


 
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have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; 
the collection of identifiable private information in the research; an underlying disease, 
disorder, or condition of the subject; and/or other circumstances unrelated to the research or 
any underlying disease, disorder, or condition of the subject. In general, adverse events that 
are at least partially the result of (a) or (b) would be considered related to the research, 
whereas adverse events solely related to (c) or (d) would be considered unrelated to the 
research.  
 
External adverse events are adverse events experienced by subjects enrolled in multicenter 
clinical trials at sites other than the site(s) over which the Institutional Review Board has 
jurisdiction.  
Internal adverse events are adverse events experienced by subjects enrolled at the site(s) 
under the IRB’s jurisdiction for either multicenter or single-center research projects.  
 
8.2.2 The significance of an adverse event is used to describe the patient/event outcome or 
action criteria associated with events that pose a threat to a patient’s life or functioning (i.e., 
moderate, severe or life threatening). Based on the National Cancer Institute Guidelines for 
the Cancer Therapy Evaluation Program, severity can be defined by the following grades of 
events: 
 
 
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical 
intervention; asymptomatic laboratory findings only; marginal clinical relevance) 
 
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; non-
invasive intervention; transfusion; elective interventional radiological procedure; therapeutic 
endoscopy or operation). 
 
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms requiring 
hospitalization or invasive intervention; transfusion; elective interventional radiological 
procedure; therapeutic endoscopy or operation). 
 
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, life-
threatening metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis; life–threatening physiologic consequences; need for intensive care or 
emergent invasive procedure; emergent interventional radiological procedure, therapeutic 
endoscopy or operation). 


 
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Grades 5 are fatal adverse event resulting in death.   
 
8.2.3  Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that results 
in any of the following outcomes:  
 Results in death.  
 Is a life-threatening adverse experience. The term life-threatening in the definition of 
serious refers to an adverse event in which the subject was at risk of death at the time 
of the event. It does not refer to an adverse event which hypothetically might have 
caused death if it were more severe.  
 Requires inpatient hospitalization or prolongation of existing hospitalization. Any 
adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (i.e., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a serious 
adverse event dependent on clinical judgment. In addition where local regulatory 
authorities specifically require a more stringent definition, the local regulation takes 
precedent.  
 Results in persistent or significant disability/incapacity. The definition of disability 
is a substantial disruption of a person’s ability to conduct normal life’s functions. 
 Is a congenital anomaly/birth defect.  
 Is an important medical event. Important medical events that may not result death, 
be life-threatening, or require hospitalization may be considered a serious adverse 
experience when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject 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 disease or disorders, or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
8.2.4 Expectedness 
Adverse Events can be Expected or Unexpected. 
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 


 
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subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject.  
 
8.2.5 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug. Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
 
8.3  
Reporting Procedures for All Adverse Events 
All participating investigators will assess the occurrence of AEs throughout the subject’s 
participation in the study. Subjects will be followed for toxicity for 30 days after treatment has 
been discontinued or until death, whichever occurs first. The clinical course of each event will be 
followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  
The investigator is responsible for ensuring that all adverse events observed by the investigator 
or reported by the subject which occur after the subject has signed the informed consent are fully 
recorded in the subject’s case report form, subject’s medical records, and/or any other 
institutional requirement. Source documentation must be available to support all adverse events.  
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an adverse event.  
 
The investigator will provide the following for all adverse events: 
 Description of the event 
 Date of onset and resolution 
 Grade of toxicity  
 Attribution of relatedness to the investigational agent 
 Action taken as a result of the event 
 Outcome of event 
 
In this study, descriptions and grading scales found in the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 available at http://ctep.cancer.gov will be utilized for 


 
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AE reporting.  
Investigative sites will report adverse events to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. 
 
8.4  
Serious Adverse Event Reporting Procedures 
Serious adverse events that occur beginning with the signing of the informed consent form, 
during treatment, or within 30 days of the last dose of treatment must be reported to the Site 
Principal Investigator. 
Investigative sites will report serious adverse events to their respective IRB according to the 
local IRB’s policies and procedures in reporting serious adverse events. SAEs will be reported in 
OnCore. 
 
8.4.1 FDA Reporting 
In accordance with 21 CFR 312.32, the Taussig Cancer Institute Principal Investigator is 
responsible for notifying the FDA of SAEs that are serious, unexpected (not listed in the 
Investigator Brochure) and judged to be related (i.e., possible, probable, definite) to the study 
drug.  
 
8.5  
Data Safety Toxicity Committee 
It is the Case Comprehensive Cancer Center’s Principal Investigator’s responsibility to ensure 
that ALL serious adverse events are reported to the Case Comprehensive Cancer Center’s Data 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
Sponsor or other Regulatory body.  
 
 
 
 
 
 
 
 
 
 


 
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9.0  
PHARMACEUTICAL INFORMATION   
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 8.0.   
 
 
9.1 
Gemcitabine 
 
9.1.1 Gemcitabine 
 
Chemical Name:    
Gemcitabine, Nucleoside Analogue 
 
Other Names:     
Gemzar 
 
Classification:      
Antineoplastic 
 
Molecular Formula:  
Nucleoside analogue in which the hydrogen atoms on the 2’ 
carbon of deoxycytidine are replaced by fluorine atoms 
 
 
Mode of Action:    
The triphosphate analogue of gemcitabine replaces cytidine, during 
DNA replication. That process arrests tumor growth, as only one 
additional nucleoside can be attached to the "faulty" nucleoside, 
resulting in apoptosis. 
Other target of gemcitabine is the enzyme ribonucleotide reductase 
(RNR). The diphosphate analogue binds to RNR active site and 
inactivates the enzyme irreversibly. Once RNR is inhibited, the cell 
cannot produce the deoxyribonucleotides required for DNA 
replication and repair, and cell apoptosis is induced 
 
 
Metabolism:   
Metabolized intracellularly by nucleoside kinases to the active 
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleoside 
metabolites 
 
 
Product description: 
Gemcitabine 
is 
commercially 
available. 
Using 
standard 
Pharmacy policies and procedures for chemotherapeutic agents, 
drug will be prepared for intravenous administration to patients.  
 
 


 
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9.2  
Regorafenib 
 
 9.2.1  Regorafenib 
  
Chemical Name:    
Regorafenib 
 
Other Names:     
Stivarga 
 
Classification:      
Antineoplastic 
 
Mode of Action:    
Regorafenib is a multikinase inhibitor; it targets kinases involved 
with tumor angiogenesis, oncogenesis, and maintenance of the 
tumor microenvironment which results in inhibition of tumor 
growth. Specifically, it inhibits VEGF receptors 1-3, KIT, 
PDGFR-alpha, PDGFR-beta, RET, FGFR1 and 2, TIE2, DDR2, 
TrkA, Eph2A, RAF-1. BRAF, BRAFV600E, SAPK2, PTK5, and 
Abl. 
 
Metabolism:   
Hepatic via CYP3A4 and UGT1A9, primarily to active 
metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) 
 
Product description: 
Regorafenib is commercially available. For this study, however, 
it will be supplied by the manufacturer. Using standard 
Pharmacy policies and procedures for chemotherapeutic agents, 
drug will be supplied to patients. 
 
 


 
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10.0 
CORRELATIVE / SPECIAL STUDIES 
 
 
NA 
 
 
 
 


 
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11.0  STUDY PARAMETERS AND CALENDAR  
 
11.1 
Study Parameters 
 
11.1.1 Screening Evaluation  
 
Screening studies and evaluations will be used to determine the eligibility of each subject for 
study inclusion. All evaluations must be completed < 28 days prior to administration of 
protocol therapy.  
 Informed Consent 
 Demographics 
 Medical History  
 Complete physical examination  
 Height 
 Weight 
 Vital signs including: Temperature, Pulse, Blood Pressure, Respiratory rate 
 Concomitant Medications Assessment including all prescription medicines 
 ECOG Performance Status ≤ 1 
 Baseline Symptoms Assessment 
 Laboratory Studies: 
 Complete Blood Count (CBC) with differential 
 Serum 
Chemistries: 
albumin, 
alkaline 
phosphatase, 
total 
bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium. Calculated creatinine clearance 
will be done if creatinine and/or BUN are abnormal.   
 ß-hCG for women of childbearing potential 
 CT or MRI scan of chest, abdomen, and pelvis with and without contrast  
 
11.1.2 All Follow-up visits and procedures are described in the Study Calendar. 
      
Lost to Follow-Up 
 
If the patient does not show up for the scheduled follow-up visit, all reasonable efforts will 
be made to contact the patient or appropriate family member or personal caregiver to re-
schedule follow-up. If patient is deceased, this information will be captured. If patient is 
unable to follow up in clinic, appropriate reasons will be captured. In this case, or if patient 
withdraws consent, permission will be sought to continue contact by telephone, letter, or 
email to capture survival data. Appropriate databases, such as the Social Security Death 
Index, may be searched to gather survival data. 
 


 
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11.2 
Study Calendar 
 
 
 
Cycles 1&2 (Every 28 
days per cycle) 
Cycles 3 onward 
(Every 28 days per 
cycle) 
End of 
treatment 
Every 2 
months ± 1 
week 
 
Screen 
Day 
1* 
Day 
8±1 
Day 
15±1 
Day 
1±1 
Day 
8±1 
Day 
15±1 
4 weeks (± 
3 days) 
from last 
treatment 
visit 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
History1 
X 
X 
 
X 
X 
 
X 
X 
X7 
ECOG PS 
X 
X 
X 
X 
X 
 
X 
X 
X7 
AE 
assessment6 
 
X 
X 
X 
X 
 
X 
X 
 
Physical 
exam2 
X 
X 
 
X 
X 
 
X 
X 
X7 
Height 
X 
 
 
 
 
 
 
 
 
Weight  
X 
X 
 
X 
X 
 
X 
X 
X7 
Vitals3  
X 
X 
X 
X 
X 
 
X 
X 
X7 
CBC  
X 
X 
X 
X 
X 
X 
X 
X 
 
LFTs4 
X 
X 
X 
X 
X 
 
X 
X 
 
BMP, 
amylase and 
lipase 
X 
X 
 
X 
X 
 
X 
X 
 
Urinalysis 
and urine 
protein 
X 
X 
 
X 
X 
 
X 
 
 
aPTT and 
PT/INR 
X 
X 
 
X 
X 
 
X 
 
 
CA 19.9 
X 
X 
 
 
X 
 
 
X 
X7 
β-hCG 
X 
 
 
 
 
 
 
 
 
CT or MRI5 
X 
 
 
 
 
 
 
X 
X7 
RECIST 1.1 
Evaluation6 
X 
Scans for response evaluation to be performed 
every 8 weeks (+/-3 days) 
X 
X7 
Gemcitabine  
 
X 
X 
X 
X 
X 
X 
 
 
Regorafenib 
 
X – to be taken daily for the first 21 days of 
each 28-day cycle 
 
 
Survival 
data 
 
X 
 
 
 
 
X 
X 
Abbreviations: ECOG PS: ECOG Performance Status. AE: Adverse Event. CBC: Complete Blood Count, with differential. 
BMP: Basic Metabolic Panel, including bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, sodium. LFTs: 
Liver Function Tests, albumin, alkaline phosphatase, total bilirubin, total protein, SGOT [AST], SGPT [ALT]. 
*Cycle 1, Day 1 assessments need not be performed if the screening assessments were performed within 7 days. 
1. Complete or focused clinical history, as determined appropriate by treating physician. 


 
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2. Complete or focused physical examination, as determined appropriate by treating physician. 
3. Include temperature, pulse, and blood pressure. Monitor blood pressure weekly for the first 6 weeks of treatment and every 
cycle or more frequently as clinically indicated.  
4. Liver function tests (albumin, alkaline phosphatase, total bilirubin, total protein, SGOT [AST], SGPT [ALT]) should be 
obtained before initiation of regorafenib and monitored at least weekly during first 2 months of treatment. Thereafter liver 
function should be monitored monthly or more frequently as clinically indicated 
5. Contrast enhanced CT or MRI of the chest, abdomen and pelvis based on treating physician’s preference. It is 
recommended (but not required) to obtain the same study as was performed at screening throughout a patient’s course. PET 
scans are NOT acceptable alternatives. 
6. Response will be assessed using RECIST 1.1 criteria after 2 cycles of treatment. Imaging (CT or MRI) will be repeated 
every 2 cycles (every 8 weeks (+/-3 days)). 
7. To be performed only up to disease progression or initiation of new cancer-directed therapy. Once disease progression is 
established, or a new cancer-directed therapy is initiated, only survival data will be captured. 
 


 
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12.0  MEASUREMENT OF EFFECT  
 
12.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks 
(+/-3 days). In addition to a baseline scan, confirmatory scans should also be obtained 8 
weeks (+/-3 days) following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new 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. For primary brain tumors, response and progression 
will be evaluated using the RANO criteria [J Clin Oncol 28: 1963-1972.2010]. 
 
12.1.1  Definitions 
 
Evaluable for toxicity All patients will be evaluable for toxicity from the time of their first 
treatment with the study drugs.  
 
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.  
 
 
12.1.2  Disease Parameters  
 
Measurable Disease Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter for non-nodal lesions and short axis for nodal 
lesions to be recorded) as > 20 mm by chest x-ray, as > 10 mm with CT scan, or > 10 mm 
with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 


 
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Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  
 
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 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 reproducible 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. 


 
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12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination 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-holding 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 


 
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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 is not 
routine 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 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. Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26: 1148-1159, 2008]. In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 
FDG-PET While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 


 
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assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FGD-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
12.1.4 Response Criteria 
 
12.1.4.1 
Evaluation of Target lesions 
 
Response 
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 diameters of 
target lesions, taking as reference the baseline sum of 
diameters. 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  


 
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Note: the appearance of one or more new lesions is 
also considered progression. 
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. 
 
 
12.1.4.2 
Evaluation of Non-Target lesions 
 
Response 
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 
 
[Incomplete response/ 
Stable Disease (SD)] 
 
 
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 
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 Principal Investigator).  
 
12.1.4.3 
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 


 
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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.  
 
 


 
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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesion 
New Lesions 
Overall Response 
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. 
 
12.1.5  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. 
 
 
12.1.6  Overall and Progression-Free Survival 
 
Overall Survival will be calculated as time in days from enrollment (signing of the informed 
consent) to death.  
 
Progression-free Survival will be calculated as time in days from enrollment (signing of the 
informed consent) to the earlier of: 
 Death, or 
 Disease progression, by clinical, imaging, or laparoscopic parameters. 
 


 
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13.0 
RECORDS TO BE KEPT / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
 
The OnCore Database will be utilized, as required by the Case Comprehensive Cancer 
Center, to provide data collection for both accrual entry and trial data management. OnCore 
is a Clinical Trials Management System housed on secure servers maintained at Case 
Western Reserve University. OnCore properly used is compliant with Title 21 CFR Part 11. 
Access to data through OnCore is restricted by user accounts and assigned roles. Once 
logged into the OnCore system with a user ID and password, OnCore defines roles for each 
user which limits access to appropriate data. User information and password can be obtained 
by contacting the OnCore Administrator at oncore-registration@case.edu. 
 
OnCore is designed with the capability for study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification. This study will utilize electronic Case 
Report Form completion in the OnCore database. A calendar of events and required forms 
are available in OnCore. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws.  
13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures. 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
subject’s financial responsibility. Subjects must also be notified that they are free to discontinue 
from the study at any time. The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. 


 
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13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or allow the 
sponsor, a regulatory authority, or Institutional Review Board access to subject’s medical 
information that includes all hospital records relevant to the study, including subjects’ medical 
history. 
 
13.2.3  Retention of records 
 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with national and international regulations. No 
records will be destroyed until the Principal Investigator confirms destruction is permitted.  
 
13.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform audits 
or inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.  
13.2.5 Data Safety and Monitoring Plan 
 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI regulations.  


 
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14.0   STATISTICAL CONSIDERATIONS 
 
All clinical data will be captured in the OnCore database system. 
All pertinent baseline demographic and disease characteristics will be captured. Medical and 
surgical history, with detailed information on pancreatic cancer treatment history, including 
surgery, chemotherapy, and radiation therapy, will be gathered. During the study, detailed 
treatment data, clinical, laboratory and radiologic data, and adverse event and efficacy data will 
be collected. 
Categorical data will be summarized as frequency counts and percentages, measured data will be 
summarized using means, standard deviations, medians, and time-to-event data will be 
summarized using the Kaplan-Meier method. Chi-square tests, t-tests and ANOVA methods (or 
their non-parametric counterparts), and the logrank test or proportional hazards models will be 
used for univariable comparisons that might be performed. Multivariable methods such as 
logistic regression and proportional hazards will be used to adjust for potential confounders. 
No interim analyses planned. 
The primary efficacy outcome is progression-free survival (PFS). Limited data are available on 
PFS in metastatic pancreatic cancer that has progressed on prior chemotherapy. A recent 
comprehensive analysis estimated that the median PFS with other combination chemotherapy 
care in this setting is between 1.6 and 2.9 months [11]. We will consider a median PFS of 4 
months with regorafenib and gemcitabine as supportive of further investigation. The study will 
be conducted at the Cleveland clinic main campus and all its ten (10) regional oncology sites. 
Based our current tumor registry data, 50-60 new patients with stage IV pancreatic cancer are 
seen each year at the main campus alone, therefore, the estimated accrual time for the study is 
18-24 months, and the follow-up time is 6-12 months. With 80% power and a one-sided alpha of 
0.10 to detect this improvement in median PFS from 2.85 months to 4 months, 40 patients are 
needed for this study. 
 
 
 
 


 
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