Clinical trial NCT02402036
Conditions: Colon Cancer
Sponsor: Georgetown University
Start date: 2015-02-01; Completion date: 2017-11-01
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an exploratory biomarker study. Patients with metastatic colorectal cancer will receive regorafenib, which is FDA approved in this setting, on day 1-21 of every consecutive 28 day cycle. Patients will be asked to undergo tumor biopsy at baseline and 2 weeks after starting regorafenib. Peripheral blood samples will be collected at baseline 2 weeks after starting regorafenib, after initiation of cycle 3, and every 4 weeks thereafter.

Detailed description:
Tumor tissue collected at baseline and 2 weeks after starting regorafenib will be analyzed for phosphoproteins and RNA. Peripheral blood samples will be collected and banked for protein, miRNA, and mutated DNA analysis.

Arms: arm 1: Regorafenib 120 mg orally daily for 21 days out of a 28 day cycle
Interventions: intervention 1: Regorafenib
Intervention descriptions: intervention 1: Regorafenib orally for 21 days every 28 day cycle

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
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STUDY TITLE  
  Regorafenib in Metastatic Colorectal Cancer: An Exploratory Biomarker Study  
 
 
 
 
Test drug(s):                                     Regorafenib 
 
[Study purpose:] 
                      Biomarker Study 
 
Clinical study phase:                      II 
 
Version no.:                                  2.3 
Date: July 17, 2017 
 
Amendment no.: 
 
                        Date: N/A 
 
NCT                                                NCT02402036 
 
Institution Study no.:                      2014-0133 
Principal Investigator: 
 
 
John Marshall, MD 
3800 Reservoir Rd NW 
Washington DC, 20007 
P: (202) 444-3958 
Co-Principal Investigator:   
Anton Wellstein MD, PhD 
Aiwu R. He MD, PhD 
Michael Pishvaian MD, PhD 
Anne Noonan MD 
Emanuel Petricoin PhD 
 


 
 
 
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Statistician:   
Hongkun Wang 
4000 Reservoir Rd NW 
Building D 
Washington DC 20007 
202-687-4146 
 
Participating Institutions: 
 
Angela Alistar, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
(P) 336-716-0457 
aalistar@wakehealth.edu 
 
 
 
 
Emil Lou, M.D., Ph.D 
Assistant Professor of Medicine 
University of Minnesota 
Division of Hematology, Oncology and Transplantation 
Mayo Mail Code 480 
420 Delaware Street SE 
Minneapolis, MN 55455 
Office: 612-625-7667 
E-mail: emil-lou@umn.edu 
 
 
 
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 


 
 
 
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Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in part 
or in full - to parties not associated with the clinical investigation, or its use for any other purpose, 
without the prior written consent of the Principal Investigator is not permitted. 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  Hence, 
the appearance of product names without these symbols does not imply that these names are not 
protected. 


 
 
 
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Synopsis 
 
Title 
Regorafenib in Metastatic Colorectal Cancer: An Exploratory 
Biomarker Study 
 
Clinical study phase 
Exploratory biomarker study 
Study objective(s) 
Primary objective: To prospectively identify and prioritize 
leading biomarkers in tumor tissue and/or serum that are 
potentially predictive of response to regorafenib in patients with 
metastatic colorectal cancer, and can be further validated in 
subsequent larger clinical trials. 
Secondary objective: To prospectively determine the molecular 
mechanisms by which Regorafenib can control colorectal tumors 
refractory to other treatments. 
[Background treatment] Regorafenib 120 mg orally (40 mg tablets x 3) daily for 21 days 
out of a 28 day cycle 
Indication 
Patients with a histological or cytological diagnosis of 
adenocarcinoma of the colon or rectum who have progressed on, 
or are ineligible for, standard treatment options other than 
regorafenib 
Diagnosis and main 
criteria for inclusion 
1. Patients with metastatic colorectal cancer who have progressed 
on, or are ineligible for, standard therapy such as 
fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and anti-
EGFR antibodies (where appropriate) but are suitable candidates 
for regorafenib treatment. 
2. Patients with radiographically measurable biopsy-accessible 
disease. 
3. Patients who are aged 18 years or older and have an Eastern 
Cooperative Oncology Group (ECOG) performance status of 0 or 
1. 
4. Patients with a life expectancy of at least 3 months. 
5. Patients with adequate bone marrow, liver, and renal function. 
6. Patient signed consent form. 


 
 
 
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Study design 
 
The study is an exploratory biomarker study conducted at the 
Georgetown Lombardi Comprehensive Cancer Center. Patients 
with metastatic colorectal cancer will receive regorafenib therapy, 
a treatment that is FDA approved for this setting, on day 1-21 of 
every consecutive 28 day cycle. Patients will be asked to undergo 
tumor biopsy in addition to providing peripheral blood samples 
prior to starting Regorafenib (at baseline).  A second tumor 
biopsy will be obtained 2 weeks (14-21 days) after starting 
regorafenib. Tumor tissue will be analyzed for phosphoproteins 
and RNA. Peripheral blood samples will be collected at baseline, 
2 weeks after starting regorafenib therapy and then, after 
initiation of cycle 3, every 4 weeks for the duration of regorafenib 
therapy. Specifically, peripheral blood will be collected and 
banked for protein, miRNA, and mutated DNA analysis.  A 
sample will also be obtained upon disease progression. 
Circulating biomarker (miRNA and mutated DNA) will be 
analyzed in the laboratory of Dr. Anton Wellstein at the 
Georgetown Lombardi Comprehensive Cancer Center. Caris 
Molecular Intelligence and Topologic Oligonucleotide Profiling 
will be performed by Caris Life Sciences. 
Type of control 
Uncontrolled study 
Number of subjects 
40 
Plan for statistical 
analysis 
For clinically relevant biomarker discovery, exploratory analyses 
of biomarkers will be performed to determine if a correlation can 
be established between the presence or change in the level of a 
marker species (“yes” or “no”) and the clinical response.  
Descriptive statistics, graphical methods, and statistical modeling, 
whichever is appropriate, may be used.  Chi-square test or 
Fisher’s exact test will be used to explore the association 
between categorical variables and the clinical response.  Kaplan-
Meier method will be used to explore the association between 
categorical variables and time-to-event response variables.  The 
analysis will be exploratory in nature.   


 
 
 
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Table of contents 
Synopsis ........................................................................................................................................... 4 
Table of contents .............................................................................................................................. 6 
List of abbreviations ........................................................................................................................ 9 
1. Background ............................................................................................................................. 11 
1.1 
Rationale of the study ..................................................................................................... 11 
1.2 
Regorafenib ..................................................................................................................... 12 
1.2.1 
Preclinical ................................................................................................................ 12 
1.2.2 
Clinical experience .................................................................................................. 12 
2. Study objectives ...................................................................................................................... 13 
2.1 
Primary objective: ........................................................................................................... 13 
2.2 
Secondary objective: ....................................................................................................... 13 
3. Investigator[s] and other study participants ............................................................................ 14 
4. Correlative Study design ........................................................................................................ 16 
4.1 
Study method overview: ................................................................................................. 16 
4.1.1 
Serum-based correlative .......................................................................................... 16 
4.1.2 
Tissue-based correlative .......................................................................................... 18 
4.2 
Methodology according to individual objectives ............................................................ 19 
4.2.1 
Primary Objective 1: ................................................................................................ 19 
4.2.2 
Primary Objective 2: ................................................................................................ 20 
4.2.3 
Secondary Objective 1: ............................................................................................ 21 
4.2.4 
Secondary Objective 2: ............................................................................................ 22 
5. Study population ..................................................................................................................... 23 
5.1 
Eligibility ........................................................................................................................ 23 
5.1.1 
Inclusion criteria ...................................................................................................... 23 
5.1.2 
Exclusion criteria ..................................................................................................... 24 
5.1.3 
Excluded therapies and medications, previous and concomitant ............................ 25 
5.2 
Withdrawal of subjects from study ................................................................................. 25 
5.2.1 
Withdrawal .............................................................................................................. 25 
5.2.2 
Screen Failures/Dropouts ........................................................................................ 26 
5.2.3 
Replacement ............................................................................................................ 26 
5.3 
Collaboration with Caris Life Sciences .......................................................................... 26 
5.3.1 
Personnel ................................................................................................................. 27 
5.3.2 
Patient Enrollment ................................................................................................... 27 
5.3.3 
Data Collection and Management ........................................................................... 27 
5.3.4 
Conference Calls ..................................................................................................... 28 
6. Treatment[s] ............................................................................................................................ 28 
6.1 
Blinding ........................................................................................................................... 28 
6.2 
Study Treatment .............................................................................................................. 28 
6.2.1 
Dose Reduction Levels ............................................................................................ 28 
6.2.2 
Prevention/management strategies for diarrhea ...................................................... 34 
6.3 
Drug logistics and accountability .................................................................................... 35 
6.4 
Treatment compliance ..................................................................................................... 35 
6.5 
Prior and concomitant therapy ........................................................................................ 35 
7. Detailed Study Plan ................................................................................................................ 36 


 
 
 
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7.1 
Screening ......................................................................................................................... 36 
7.2 
Study Procedures (details are provided in the events table (Page 42) ............................ 36 
7.2.1 
Subject assessments ................................................................................................. 36 
8. Endpoints ................................................................................................................................ 42 
8.1 
Primary endpoint: ............................................................................................................ 42 
8.1.1 
Level of serum miRNAs at baseline, 4 and 8 weeks of study treatment ................. 42 
8.2 
Secondary endpoints: ...................................................................................................... 42 
8.2.1 
Eight-week clinical benefit rate (CBR): .................................................................. 42 
8.2.2 
Objective response rate (ORR): ............................................................................... 42 
8.2.3 
Progression free survival (PFS): .............................................................................. 42 
8.2.4 
Overall survival (OS): ............................................................................................. 42 
8.2.5 
Safety: ...................................................................................................................... 42 
8.2.6 
Activation status of phosphoproteins in tissue specimens ...................................... 42 
8.2.7 
Presence mutated DNA in serum at baseline, 4 and 8 weeks of study treatment .... 42 
8.3 
Definitions ....................................................................................................................... 42 
8.3.1 
Measurable disease .................................................................................................. 43 
8.3.2 
Non-measurable disease .......................................................................................... 43 
8.3.3 
Target lesions ........................................................................................................... 43 
8.3.4 
Non-target lesions .................................................................................................... 43 
8.3.5 
Guidelines for Evaluation of Measurable Disease .................................................. 43 
8.3.6 
Response Criteria ..................................................................................................... 44 
8.4 
Safety .............................................................................................................................. 45 
8.4.1 
Data safety Monitoring Plan: ................................................................................... 45 
8.4.2 
Adverse events ......................................................................................................... 46 
8.4.3 
Definitions ............................................................................................................... 46 
8.4.4 
Classifications for adverse event assessment .......................................................... 47 
8.4.5 
Assessments and documentation of adverse events ................................................ 49 
8.4.6 
Pregnancies/Contraception ...................................................................................... 51 
9. Statistical methods and determination of sample size ............................................................ 51 
9.1 
Analysis sets .................................................................................................................... 51 
9.1.1 
Safety analysis set. ................................................................................................... 51 
9.2 
Variables ......................................................................................................................... 52 
9.2.1 
The primary endpoints for biomarker discovery: .................................................... 52 
9.2.2 
The secondary endpoints are: .................................................................................. 52 
9.3 
Statistical and analytical plans ........................................................................................ 52 
9.3.1 
Analysis for the Primary endpoints: ........................................................................ 52 
9.3.2 
Analysis for the secondary endpoints: ..................................................................... 53 
9.4 
Determination of sample size .......................................................................................... 53 
10. Data handling and quality assurance ...................................................................................... 53 
10.1 Data recording ................................................................................................................. 53 
10.2 Monitoring ...................................................................................................................... 53 
10.3 Data processing ............................................................................................................... 54 
10.4 Audit and inspection ....................................................................................................... 54 
10.5 Archiving ........................................................................................................................ 54 
11. Premature termination of the study......................................................................................... 54 
12. Ethical and legal aspects ......................................................................................................... 54 


 
 
 
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12.1 Ethical and legal conduct of the study ............................................................................ 54 
12.2 Subject information and consent ..................................................................................... 55 
12.3 Publication policy ........................................................................................................... 56 
12.4 Confidentiality ................................................................................................................ 56 
13. Reference list .......................................................................................................................... 56 
14. Appendices ............................................................................................................................. 58 
14.1 Examples of a low fat breakfast ...................................................................................... 58 
14.2 Caris Specimen Requirements ........................................................................................ 58 
14.3 Biopsy Flowchart ............................................................................................................ 59 
14.4 Blood Flowchart .............................................................................................................. 60 


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


 
 
 
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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. Background 
Colorectal cancer (CRC) is the third leading cause of cancer death in the United States (1,2). Surgery is the 
primary treatment modality is stage I-III CRC (2). In spite of surgery and adjuvant chemotherapy, 34% of 
patients with resected stage II and 27% of patients with resected stage III colorectal cancer will experience a 
recurrence within 5 years. Moreover, 19% of patients with CRC will present with metastatic disease (3). 
Despite of the advances in chemotherapy and surgery, metastatic CRC continues to be a dreadful disease with a 
5 year survival of approximately 11% (2). Chemotherapy is the mainstay of treatment of metastatic CRC. 
Chemotherapy treatment options include 5-fluorouracil (5-FU) based regimens such as the combinations of 
irinotecan or oxaliplatin with bolus and infusional 5-FU (FOLFIRI or FOLFOX, respectively) (4). The addition 
of monoclonal antibodies targeting vascular endothelial growth factor receptors (VEGFR) and epidermal 
growth factor receptors (EGFR; in KRAS wild-type tumors) has lead to clinically-relevant improvements in 
patient survival. Recently, bevacizumab was approved by the FDA for the treatment of patients with metastatic 
CRC (4). Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor 
(VEGF), which is an essential factor in controlling tumor-associated angiogenesis (5-8). Bevacizumab when 
combined with chemotherapy is associated with a 3-5 month improvement in overall survival compared to 
chemotherapy without bevacizumab (4). Regorafenib was also approved recently by the FDA and is associated 
with an improved in overall survival compared to best supportive care (9). Regorafenib has antiangiogenic 
activity in addition to activity again multiple other cellular targets (9). Angiogenesis directed therapy has 
provided a new therapeutic strategy for patients with metastatic colorectal cancer but is associated with side 
effects such as gastrointestinal perforation, arterial and possibly venous thromboembolism, proteinuria, 
nephrotic syndrome, hypertension, bleeding, and hypertension (4). Therefore, there  is considerable interest in 
predicting subgroups of patients who will respond to anti-angiogenic therapy in order to better individualize 
treatment and avoid unnecessary toxicity for patients who are resistant to treatment. A few studies have 
attempted to identify biomarkers that predict response to anti-angiogenic therapy, mostly bevacizumab.  Bates 
et al (10) evaluated a VEGF splice isoform that binds bevacizumab, VEGF(165)b to determine its predictive 
value. High VEGF (165)b appeared to predict resistance to bevacizumab therapy but this finding was not 
statistically significant. An exploratory analysis by Etienne-Grimaldi et al (11) also suggested that VEGF gene 
polymorphism might influence VEGF-A expression and serve as a marker of time to progression (TTP) in 
patients with metastatic breast cancer receiving bevacizumab containing therapy.  Similarly Gerger et al (12) 
suggested that germline variants in VEGF-dependent and -independent angiogenesis genes can predict survival 
and tumor response in patients with mCRC treated with first-line bevacizumab and oxaliplatin-based 
chemotherapy. Additionally, Goede et al (13) demonstrated that serum angiopoietin -2, a key regular of vascular 
remodeling in conjunction with VEGF, may be predictive of RR, PFS and survival. Angiopoietin-2 originates in 
the stroma and was significantly elevated in patients with metastatic CRC compared to healthy controls. An 
exploratory analysis by Duda et al (14) evaluated VEGF, placental growth factor (PIGF), soluble VEGF 
receptor 1 (sVEGFR-1) and s VEGFR-1 suggested that sVEGFR-1 may predict response and toxicity to 
neoadjuvant bevacizumab in combination with chemotherapy. Taken together, these studies suggest that the 
search for predictive biomarkers for regorafenib is feasible and may identify subgroups that are may be 
particularly sensitive to it.  
 
1.1 
Rationale of the study 
A phase III multinational trial (CORRECT trial) was conducted recently to evaluate the use of regorafenib 
versus placebo in patients with metastatic CRC who had progressed on all standard treatment options (9).  
Regorafenib was associated with a 1.4 month improvement in overall survival compared to placebo (hazard 
ratio, 0.77; 95% CI, 0.64–0.94; one-sided p=0.0052).  These results were well received as they provided an 


 
 
 
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additional treatment option for patients with metastatic colorectal cancer.  However, a few questions remained 
following the well-designed CORRECT trial. Kaplan-Meier curves for progression-free survival suggest that 
different patient subgroups may respond differently to treatment with regorafenib. Further exploration into the 
mechanism of action of regorafenib in patients with CRC is, therefore, necessary in order to be able to use the 
drug to its full potential.  A handful of human CRC xenograft animal model studies have described 
regorafenib’s mechanism of action but these mechanisms have not been described clinically. It is increasingly 
obvious that biomarkers for targeted cancer therapies, especially anti-angiogenesis compounds, are necessary. 
Therefore, we need to identify patient subgroups that may be particularly sensitive to regorafenib therapy and 
elucidate the mechanism of action of regorafenib in these subgroups. We are performing this pilot clinical 
trial in order to prospectively identify and prioritize leading biomarkers of activity for subsequent 
validation studies. 
1.2 
Regorafenib  
Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic activity as measured by 
dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI) (1).  
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 vitro biochemical or cellular assay results showed that 
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.  Results from in vivo animal model studies demonstrated that regorafenib had anti-angiogenic 
activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse 
xenograft models, including some for human colorectal carcinoma. 
1.2.1 
Preclinical 
In vivo, regorafenib exhibited anti-angiogenic and anti-proliferative effects in human colon and breast 
xenografts as demonstrated by a reduction in microvessel area, reduced Ki-67 staining, and reduced pERK1/2 
staining in tissue sections from tumor xenografts, and dose-dependent inhibition of growth in multiple xenograft 
models (breast, colon, renal, NSCLC, melanoma, pancreatic, thyroid, ovarian). (1)  Immunohistochemical ex-
vivo studies with a phospho –specific monoclonal anti-ERK 1 / 2 antibody demonstrated inhibition of the 
MAPK pathway five days after treatment with regorafenib in 2 of 3 tumor models examined (MDA-MB 231 
and BxPC-3), but not in NSCLC (H460). 
In addition, all tested human tumor xenografts (MDA-MB-231, H460, BxPC-3 and Colo-205) demonstrated a 
significant reduction in new blood vessels by histomorphometry as detected in tumor samples using a murine 
CD31 antibody. (1) These data suggest that regorafenib can target the tumor cell MAPK pathway (tumor cell 
survival) and tumor vasculature in some but not all tumors. 
1.2.2 
Clinical experience 
Two phase III global randomized studies have evaluated the efficacy of regorafenib. The CORRECT (Patients 
with metastatic colorectal cancer treated with regorafenib or placebo after failure of standard therapy) trial is an 
international, multicenter, randomized, double-blind, placebo-controlled study that enrolled 760 patients with 
mCRC whose disease has progressed after approved standard therapies. 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 


 
 
 
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survival, objective tumor response rate and disease control rate. The safety and tolerability of the two treatment 
groups were also compared. 
 
At a preplanned second interim analysis, there was a statistically significant survival benefit for regorafenib. 
The estimated hazard ratio for overall survival was 0.773 (95% confidence interval [CI], 0.635 to 0.941; 1-sided 
p = .0051). Patients treated with regorafenib had a median overall survival of 6.4 months, compared with 5.0 
months for placebo — a 29% increase in survival. In addition to improved overall survival, progression-free 
survival was superior; median progression-free survival was 1.9 months (95% CI, 1.88 to 2.17) for regorafenib 
and 1.7 months (95% CI, 1.68 to 1.74) for placebo. The estimated hazard ratio for progression-free survival was 
0.493 (95% CI, 0.418 to 0.581; 1-sided p< .000001). There was a substantial difference in disease control rate in 
the regorafenib and placebo groups (44% vs. 15%; p<.000001).  Regorafenib demonstrated comparable efficacy 
benefits across patient subgroups analyzed including age, number of metastases, number of lines of prior 
therapy, and kras status. 
The most frequent grade 3+ adverse events in the regorafenib group were hand–foot skin reaction (17%), 
fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%).  The efficacy and safety from 
the CORRECT study supported FDA approval in September 2012. 
The efficacy and safety of regorafenib were examined in the Phase III GRID trial in patients with 
gastrointestinal stromal tumors (GISTs) who had exhausted all other treatment options. The study involved 199 
patients with metastatic and/or unresectable GIST that had become resistant to imatinib and sunitinib. Patients 
were randomized 2:1 to regorafenib (160 mg orally once daily on a 3 weeks on/1 week off cycle) or placebo, 
plus best supportive care. 
The results showed that treatment with regorafenib led to a statistically significant 3.9-month improvement in 
progression-free survival (PFS), compared with placebo (4.8 months vs. 0.9 months; hazard ratio [HR] = 0.27;  
p <.0001). Overall survival was statistically similar between groups as expected due to a trial design that 
allowed crossover to regorafenib for disease progression (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 
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%).   The efficacy and safety of the GRID study 
data supported FDA approval February 2013. 
2. Study objectives 
2.1 
Primary objective:  
To prospectively identify and prioritize leading biomarkers in tumor tissue and/or serum that are potentially 
predictive of response to regorafenib in patients with metastatic colorectal cancer, and can be further validated 
in subsequent larger clinical trials. 
2.2 
Secondary objective:  
To prospectively determine the molecular mechanisms by which regorafenib can control colorectal tumors 
refractory to other treatments. 


 
 
 
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3. Investigator[s] and other study participants 
 
 
Principal Investigator 
 
John Marshall MD 
3800 Reservoir Rd NW 
Washington DC, 20007 
Email: marshal@georgetown.edu 
 
Co-Principal Investigators:  
 
Anton Wellstein MD, PhD 
3970 Reservoir Rd NW E501 
Washington, DC, 20007 
Email: wellstea@georgetown.edu 
Tel: 202-687-3672 
 
Aiwu R. He MD, PhD 
3800 Reservoir Rd NW 
Washington DC, 20007 
Email: Aiwu.r.he@gunet.georgetown.edu 
Tel: 202-444-2144 
 
Michael Pishvaian MD, PhD 
3800 Reservoir Rd NW 
Washington DC, 20007 
Email: pishvaim@gunet.georgetown.edu 
Tel: 202-444-2144 
 
Emanuel Petricoin PhD 
George Mason University 
10900 University Blvd 
Room 324 Bull Run Hall 


 
 
 
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Manassas VA 20110 
Email: epetrico@gmu.edu 
Tel: 703-993-8646 
 
Dr. Mariaelena Pierobon MD MPH 
George Mason University 
10900 University Blvd 
Room 324 Bull Run Hall 
Manassas VA 20110 
Email: mpierobo@gmu.edu 
 
Dr. Lance Liotta, MD PhD 
George Mason University 
10900 University Blvd 
Room 324 Bull Run Hall 
Manassas VA 20110 
Email: lliotta@gmu.edu 
 
Investigative Site 
Caris Life Sciences 
4610 South 44th Place 
Phoenix, AZ 85040 
Email: sreddy@carisls.com 
 
 
 


 
 
 
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4. Correlative Study design 
4.1 
Study method overview:  
The study will be conducted at the Georgetown Lombardi Comprehensive Cancer Center,  Wake Forest 
University, and Masonic Cancer Center, University of Minnesota,   and Caris Life Sciences.  Patients will 
each be allocated a unique anonymous study number which will be noted on all tumor and peripheral 
blood samples. 
 
Tumor Collection 
Patient will undergo tumor biopsy prior to starting Regorafenib (at baseline).  A second tumor biopsy will 
be obtained 2-3 weeks after starting Regorafenib. The timing of the biopsy was selected to allow for its 
completion before patients undergo dose reduction of regorafenib. Second biopsy can be waived in case 
of patient refusal, complications after the first biopsy or if the investigator deems the biopsy unsafe.  All 
tumor samples will be labeled with the date, protocol number, and protocol assigned patient number.  
Tumor samples obtained at Georgetown Hospital and other sites will be collected by the staff of the 
biospecimen bank. Two specimens will be placed in biopsy cassettes embedded in optimal cutting 
temperature compound (OCT) and snap frozen within 15 min in dry ice or liquid nitrogen and 
subsequently stored at -80 until further use. Once study is completed, the OCT embedded frozen core 
needle biopsy samples will be sent to the laboratory of Dr. Emanuel Petricoin at George Mason 
University for tissue-based laser capture microdissection and protein pathway activation mapping 
via reverse phase protein array analysis. The rest of the samples will be placed in formalin and then 
paraffin blocks will be formed to be sent to Caris for CMI testing. Only the baseline tumor samples 
should be sent to Caris (unless the baseline tumor sample did not have enough tissue to be analyzed, the 
second biopsy could be sent). Please see Appendix 14.1 for specimen requirements. 
 
 Blood Collection 
Peripheral blood samples (7 EDTA tubes) will be collected at baseline, 2 weeks (14-21 days) after 
starting regorafenib (the same day as the tumor biopsy), at the initiation of cycle 2and at the beginning of 
every cycle thereafter for the duration of regorafenib therapy, up to a total of 8 blood draws.  Blood 
samples will also be obtained upon disease progression. Samples will be collected in lavender-topped K2 
EDTA tubes. The peripheral blood samples from all participating sites  will be sent to Georgetown 
for storage and then distribution to Dr. Wellstein’s laboratory and Caris Life Sciences . Samples 
will be stored in a -80°C freezer. Analysis will be performed only after the last sample has been obtained, 
Samples from all participating sites will be shipped in a dry ice box to the Indvumid laboratory of then 
distribution to Dr. Anton Wellstein and Caris Life Sciences.  All blood samples will be labeled with the 
date, protocol number, and protocol assigned patient number.  Circulating biomarker studies and TOP 
will be performed in all patients. 
4.1.1 
Serum-based correlative 
4.1.1.1 
Serum-based correlative studies: Anton Wellstein MD, PhD, Narayan Shivapurkar 
PhD 
Hypothesis for correlative studies: Regorafenib has antiangiogenic activity in addition to activity again 
multiple other cellular targets (9). Angiogenesis directed therapy has provided a new therapeutic strategy 
for patients with metastatic colorectal cancer but is associated with side effects such as gastrointestinal 
perforation, arterial and possibly venous thromboembolism, proteinuria, nephrotic syndrome, 


 
 
 
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hypertension, bleeding, and hypertension (15). Therefore, there is considerable interest in predicting 
subgroups of patients who will respond to anti-angiogenic therapy in order to better individualize 
treatment and avoid unnecessary toxicity for patients who are resistant to treatment. A few studies have 
attempted to identify biomarkers that predict response to anti-angiogenic therapy, mostly bevacizumab.  
Bates et al (10) evaluated a VEGF splice isoform that binds bevacizumab, VEGF(165)b to determine its 
predictive value. High VEGF (165)b appeared to predict resistance to bevacizumab therapy but this 
finding was not statistically significant. An exploratory analysis by Etienne-Grimaldi et al (11) suggested 
that VEGF gene polymorphism may influence VEGF-A expression and serve as a marker of time to 
progression (TTP) in patients with metastatic breast cancer receiving bevacizumab containing therapy.  
Similarly Gerger et al (12) suggested that germline variants in VEGF-dependent and -independent 
angiogenesis genes can predict survival and tumor response in patients with mCRC treated with first-line 
bevacizumab and oxaliplatin-based chemotherapy. Additionally, Goede et al (13) demonstrated that 
serum angiopoietin -2, a key regular of vascular remodeling in conjunction with VEGF, may be 
predictive of RR, PFS and survival. Angiopoietin-2 originates in the stroma and was significantly 
elevated in patients with metastatic CRC compared to healthy controls.  
An exploratory analysis by Duda et al (14) that evaluated VEGF, placental growth factor (PIGF), soluble 
VEGF receptor 1 (sVEGFR-1) and s VEGFR-1 suggested that sVEGFR-1 might predict response and 
toxicity to neoadjuvant bevacizumab in combination with chemotherapy. This data indicate that 
biomarkers can potentially help in predicting patients who will respond to anti-angiogenic therapy. 
Regorafenib will be associated with a 1.4 month improvement in overall survival compared to placebo 
(hazard ratio, 0.77; 95% CI, 0.64–0.94; one-sided p=0.0052).  These results were well received as they 
provided an additional treatment option for patients with metastatic colorectal cancer.  However, a few 
questions remained following the well-designed CORRECT trial. Kaplan-Meier curves for progression-
free survival suggest that different patient subgroups may respond differently to treatment with 
regorafenib. Further exploration into the mechanism of action of regorafenib in patients with CRC is, 
therefore, necessary in order to be able to use the drug to its full potential.  A handful of human CRC 
xenograft animal model studies have described regorafenib’s mechanism of action but these mechanisms 
have not been described clinically. It is increasingly obvious that biomarkers for targeted cancer 
therapies, especially anti-angiogenesis compounds, are necessary. Therefore, we need to identify patient 
subgroups that may be particularly sensitive to regorafenib therapy and elucidate the mechanism of 
action of regorafenib in these subgroups. We are performing this pilot clinical trial in order to 
prospectively identify and prioritize leading biomarkers of activity for subsequent validation studies. We 
aim to identify biomarkers that can be assayed prior to starting regorafenib to predict if patients will 
respond to it. Additionally, we plan to measure those biomarkers serially to better define their role and 
describe the exact mechanism of action of regorafenib. We hypothesize that serum and tissue biomarkers 
can help predict which subgroups of patients that will respond to regorafenib monotherapy.  
4.1.1.2 
Topologic Oligonucleotide Profiling (TOP): Caris Life Sciences 
Exosomes (EXOs) are cell-specific, small double membrane extracellular microvesicles heterogeneous in 
size, ranging from 30 to 200 nm that are produced by different cell type (Schorey, Bhatnagar, 2008).  
Their classification has been based in their size, density, morphology (typical “cup-shaped” observed by 
electron microscopy) and the presence of common surface markers such as the CD63, CD81 and CD9 
tetraspanins, fusion proteins (Flotilin, Annexins, GTPases), endosome-associated proteins (Alix,TSG101) 
and heat shock proteins (Hsc70, Hsp 90). These markers are reported in all biological fluids analyzed in 
different organisms and are released to media by most cells when cultured. The mechanism proposed for 
EXOs production is the fusion of multivesicular bodies with the plasma membrane in an exocytic 
manner. This route could serve as a directional packaging system of signaling molecules, in fact growing 
evidence indicate there is enrichment of certain RNA species such as some mRNAs, miRNAs and other 
ncRNAs with exclusion of rRNAs. Also, proteomic analysis suggests the presence of particular 


 
 
 
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compositions related to tissue of origin and to physiological state. In this sense, the presence of certain 
surface markers has been linked to directed cell-cell communication processes and to the development of 
disease. Therefore, particular EXO cargos represent molecular signatures of pathological processes 
(Garcia-Contreeras, Ricordi, Robbins, Oltar, 2014).   
 
EXOs and microvesicles have been identified as potential sources for clinical disease biomarkers. They 
are particularly useful for this application because EXOs can be isolated from different body fluids 
collected by non-invasive (urine, saliva, breast milk, etc) or minimal-invasive (blood) methods (Hoorn, et 
al., 2014).  In addition, EXOs provide advantages versus classical methods for the identification of 
biomarkers such as the quantification of soluble proteins or RNA molecules in plasma for several 
reasons: 1) they provide protease/nuclease controlled environment increasing molecule stability at the 
time, 2) allow for concentration of specific molecules of interest in easy to isolate particles, and 3) a 
subset can be isolated using a specific anti-cell surface marker antibody followed by analysis of specific 
cargo proteins/RNAs. In fact, the EXO cargo of proteins, mRNAs, miRNAs and other ncRNAs is 
determined by the state of the cell-type of origin and has been associated with some pathological 
condition with changes that correlate with specific stages of the disease. EXOs not only serve as carriers 
of biomarkers of the disease, but can serve as methods for monitoring prognosis and early diagnosis of a 
disease. 
 
Exosome components present in the plasma from defined patient populations shall be processed with an 
oligonucleotide library to identify differentially binding oligonucleotides that are isolated using various 
techniques.  The recovered oligos are then mixed with the plasma from a control population and non-
binding oligos are retained.  The initial library has the potential to measure 1012 biological features, 
though after multiple rounds of exposing the library to selected positive and negative control input 
samples, an informative subset library may be obtained capable of characterizing a smaller number of 
biological features, e.g., 105 or 106.  The oligonucleotides that bind to the exosomes in the desired 
population are identified using sequencing resulting in a quantitative measure of molecular complexes for 
patients profiled.  Common trends between patients can be identified and bio-signatures can be defined 
across populations or subpopulation groups.  The oligonucleotide signature provides a unique and 
powerful method to stratify and characterize complex biological differences between patients. 
4.1.2 
Tissue-based correlative 
4.1.2.1 
Tissue-based correlative studies: Emanuel F Petricoin PhD, Mariaelena Pierobon, MD, 
MPH 
As described previously, regorafenib is a small molecule inhibitor of multiple membrane-bound and 
intracellular kinases. Moreover, in vitro biochemical or cellular assay results indicated that 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.  Preclinical studies have demonstrated in vivo that regorafenib exhibited anti-angiogenic and 
anti-proliferative effects in human colon and breast xenografts, reduced Ki-67 staining, and reduced 
phosphorylated ERK1/2 staining in tissue sections from tumor xenografts, Given that the mechanism of 
action of regorafenib is directed at protein kinase activity modulation, a direct analysis of protein 
phosphorylation and thus the protein signaling activation networks in patient tumor cells would be 
postulated to be highly predictive for drug response since protein phosphorylation is the major way that 
kinase-based cell signaling events occur. Given the large number of drug targets for regorafenib, assays 
that can quantify the activation/phosphorylation levels of many proteins simultaneously from 
microscopic amounts of cellular input are critical. Consequently, we will utilize the reverse phase protein 


 
 
 
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microarray (RPPA) technology that we (Petricoin) invented in our laboratories to map the activated 
signaling architecture of the regorafenib drug target portfolio and other immune cell/stroma signaling 
networks in laser capture microdissected tumor epithelium and patient-matched liver parenchyma in 
baseline and week-2 core needle biopsy samples. We are performing this pilot clinical trial in order to 
prospectively identify and prioritize leading biomarkers of activity for subsequent validation studies. We 
aim to identify biomarkers that can be assayed prior to starting regorafenib to predict if patients will 
respond to it. Additionally, we plan to measure those biomarkers serially to better define their role and 
describe the exact mechanism of action of regorafenib. We hypothesize that serum and tissue biomarkers 
can help predict which subgroups of patients that will respond to regorafenib monotherapy. 
4.1.2.2 
Caris Molecular Intelligence: Caris Life Sciences 
Molecular profiling has been used successfully to guide therapy selection in patients with advanced solid 
tumors.  
 Von Hoff et al. found a 27% response rate with molecularly selected therapies in a prospective 
trial of chemotherapy refractory cancer patients. [2]  
 Tsimberidou et al. at MD Anderson utilized molecular profiling to guide clinical trial enrolment 
to appropriate targeted therapies, based on the presence of a single genetic aberration, leading to a 
response rate of 27% in a population enrolled into matching clinical trials for which tumors 
expressed a molecular target, compared to 5% in those patients who were not treated according to 
a molecularly- defined targeted therapy [3]. This molecularly-targeted group, however, 
represented only 175 of the 1144 patients screened were treated with a molecularly targeted drug.  
 In a similar approach undertaken at the Princess Margaret Cancer Centre as part of the IMPACT 
trial, 678 patients were screened, leading to 43 patients receiving a treatment matched to their 
genotype – this represented 24% of the total number of patients with tumors that harbored 
mutations. [4]  
 
Caris Molecular Intelligence (CMI) is a CLIA certified biomedical laboratory service. Utilizing a recent 
FFPE tumor sample, Caris performs a broad biomarker profile, using state of the art molecular diagnostic 
tests and technologies, including immunohistochemistry, next-generation sequencing and in situ 
hybridization.   
 
The biomarker profile is assessed in relation to the latest and strongest published clinical evidence of 
oncology drug-biomarker associations. For each patient an individual list of drugs with more likely 
benefit or less likely benefit is produced. Drugs available in clinical trials, which could benefit the 
patient, are also listed. Linking the biomarker analyses with the available published clinical evidence 
enables the treating physicians to tailor evidence-based treatment plans for each patient in an efficient 
way.   
 
CMI is intended to increase the likelihood with which the physician can identify an effective therapy and 
avoid exposing the patient to unnecessary side effects. By using a multi-platform approach, CMI 
identifies more potential targets than sequencing alone and should therefore yield at least an equivalent 
degree of benefit in profile-matched therapy patients as the previous studies described earlier. 
4.2 
Methodology according to individual objectives  
4.2.1 
Primary Objective 1:  
To determine the value of serum miRNA in predicting clinical benefit from regorafenib. MicroRNA 
(miRNA) is a new class of small, non-coding RNA that can regulate the expression of multiple genes. 


 
 
 
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miRNAs have been implicated in a diverse number of cellular processes including cell proliferation, 
apoptosis, regulation of embryonic stem cell development, and cancer cell invasion. Recent studies have 
shown that, unlike other types of biomarkers, miRNAs in the circulation are remarkably stable making 
them robust and reliable biomarkers of cancer. Our group has published previously on the use of miRNA 
to predict response to therapy (16) miRNA can be assayed in serum and therefore is an attractive new 
investigational tool that can prove to be very helpful. We plan to correlate the changes in serum miRNA 
levels with the clinical benefit of regorafenib. MicroRNA level may identify patients that are more 
susceptible to the beneficial effect of regorafenib. We will conduct an exploratory analysis using a panel 
of 380 miRNA to determine if there is a lead miRNA/s that may offer predictive value in patients who 
are candidates for regorafenib.  
Methodology: We will use serum for miRNA quantification.  0.5 mL serum will be mixed with 10 vol of 
Qiazol lysis reagent and mixed by vortexing. The lysate will be extracted with CHCl3 and the aqueous 
phase will be further enriched for miRNA using the miRNeasy kit (Qiagen, Valencia, CA). The miRNA-
enriched fraction was eluted in RNase free water.  The miRNA will be converted to cDNA using 
miScriptII RT kit and miRNA expression profiling will be conducted using miScript miRNA PCR arrays 
in combination with the miScript SYBRgreen PCR kit on an ABI 7900 HT Real-Time PCR system 
(Applied Biosystems, Foster City, CA). We will assay miRNA at baseline, 4 and 8 weeks. Changes in the 
expression between the samples will be calculated using [delta][delta]Ct method with commercial 
software. The data will be expressed as fold up-regulation or down-regulation in miRNA expression 
compared to that at base level (time 0) serum sample. 
4.2.2 
Primary Objective 2:  
To evaluate the predictive value of resignaling pathways and angiogenesis using reverse phase 
microarray (RPPA) technology. Changes in protein levels and structure have also been shown to play 
critical roles in tumor development and progression, which are not reflected by genetic changes.  
Studying the levels and activation status of multiple protein pathways through changes such as protein 
phosphorylation or cleavage can greatly aid in understanding the causes and determining effective 
treatment of cancers.  Since regorafenib acts on protein kinase activity (the proteins are the drug target), 
measuring the activation levels of regorafenib drug targets and interconnected signaling pathways could 
provide a highly predictive marker set. This study will allow us to identify pathways that are inhibited or 
upregulated upon exposure to regorafenib by measuring signaling at baseline and at 2 week (14-21 days) 
post drug. Moreover, evaluation of the stroma signaling and immune checkpoint pattern in the 
surrounding liver parenchyma could provide a new opportunity to uncover new predictive markers. This 
knowledge will be correlated with clinical endpoints and will allow us to better understand potential 
mechanisms of action and resistance. For this study in particular, we will use the reverse phase protein 
microarray assay (RPPA) developed by our collaborator, Emanuel F Petricoin at George Mason 
University. RPPA is a high-throughput antibody-based technique that currently allows for the analysis of 
regorafenib targets and linked signaling. Examples of protein signaling that would be measured in this 
study (examples from 100-125 protein/phosphoproteins) include: 
a. RAS-RAF-ERK signaling:  
pARAF, pBRAF, pCRAF, pJNK/SPAK, pp38, pMEK, pERK, pELK, pCREB, and P90RSK; 
 
b. PI3K-AKT-mTOR signaling: 
pAKT, pmTOR, p4EBP1, p70S6K, pRSK, pGSK3, pFOXO, pSGK, and pPRAS; 
 
c. RTK signaling:  
pSHC, pFGFR, pVEGFR, pKIT, pRET, pTIE2, Tie2, pEphaA, pAbl, pPDGFR, pTYK2, pROS 


 
 
 
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pRON, pIGF, pEGFR, pHER2, and pHER3; 
 
d. JAK-STAT signaling:  
pJAK1, pJAK2, pSTAT3, pSTAT5, pSTAT2, and pSTAT1; and 
 
e. immune cell biology:  
pZAP70, pLCK, pCD3zeta, PDL-1, PD1, PDL2, B7-H3, B7-H4, LAG3, CX40L, CS40, CD3, and 
CD4. 
 
Tumor processing and phosphoprotein analysis will be performed by Emanuel Petricoin at George Mason 
University using LCM coupled to RPPA. Samples from all participating sites will be sent to 
Georgetown for storage and then distribution to George Mason University via FedEx medical 
shipment service after the last sample has been obtained or two years after the first sample has 
been obtained whichever occurs first. 
 
Methodology: An 18-20 gauge needle will be used to collect at least four 1-2 cm core tumor biopsies 
from each patient at each of the allocated time-points (baseline and at 2 weeks (14-21 days) post-
regorafenib treatment initiation), as per interventional radiology guidelines, Georgetown Department of 
Radiology.  Within 15 minutes, 2 of the 4 tumor samples taken will be placed into a biopsy cassette, 
embedding in optimal cutting temperature compound (OCT) and snap frozen on dry ice  and stored at -80 
until processed further. The OCT embedded biopsy material will be sent to George Mason University 
where the tissue will sectioned onto uncharged glass slides with a cryostat. The slides (7 μM) will be 
fixed in 70% ethanol; washed in purified water (Milli-Q); stained with Mayer's hematoxylin, followed by 
Scott's tap water substitute; and dehydrated by successive washes with increasing concentrations of 
ethanol, followed by final dehydration in xylene. Proteinase inhibitors (Roche, Indianapolis, IN) will be 
added to the water and 70% ethanol to minimize protein degradation. Approximately 20,000 cells from 
each sample will be captured onto caps (CapSure Macro LCM; Arcturus, Life Technologies, Carlsbad, 
CA) using a laser capture microscope (PixCell II; Arcturus, Life Technologies), and captured cells will 
stored at −80°C before extracting protein with a lysis buffer containing a 1:1 dilution of tissue protein 
extraction reagent (Pierce Biochemicals, Rockford, IL) and ×2 SDS loading buffer (Invitrogen, Carlsbad, 
CA) supplemented with 2.5% mercaptoethanol. An H and E FFPE slide from each sample will be 
provided to review the histological features. All samples will be collected and processed in accordance 
with approved Institutional Review Board tissue banking and use protocols at Georgetown University. 
RPPA analysis will be performed as previously described (17) and background subtracted, total protein 
normalized data will be generated as a continuous variable and reported via Excel. 
 
Statistical Analysis: Parametric and Non-parametric statistical analysis will be performed based on RPPA 
data distribution normalcy check based on responder vs. non-responder clinical designation. Analysis 
will be done using the both baseline and week 2 generated data. Moreover, changes in 
protein/phosphoprotein levels will be calculated between baseline and week 2 and the relative change in 
expression/activation will also be correlated with response. Spearman and Pearson correlations between 
proteins will be determined for both the responding and non-responding population and de novo network 
reconstruction produced from this data. 
 
4.2.3 
Secondary Objective 1:  
To determine if mutated DNA in serum could serve a predictive marker for clinical benefit to 
regorafenib. Quantitative assessment of mutated DNA in serum represents a new intriguing modality to 


 
 
 
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predict response to therapy. Several publications have described the use of mutated DNA in serum and its 
value as a predictive biomarker. Mutated DNA can be analyzed in 1-2 ml of serum and represents a non-
invasive modality to predict therapeutic benefit.  At least mutated BRAF and KRAS will be assayed as 
described by Pinzani et al 2010 and Diehl et al.  The results of such assays will be correlated with 
treatment benefit. Additionally, the time course change of these mutations will be followed to determine 
if they can be used as a method to early detect resistance when it occurs.  
Methodology: DNA will be purified from of 1µml of banked serum using the QIAamp circulating 
nucleic acid kit (Qiagen, catalogue no. 55114) following the manufacturer’s recommendations. 
Amplifiable DNA was quantified with quantitative PCR, using primers and conditions. The ligation 
assays will be performed as previously described (11) using the primers and probes described by Diehl et 
al (Nature Methods 2006). KRAS fragments containing codons 12 and 13 will be amplified with primers 
designed to yield a small PCR product (106 base pairs) to accommodate the degraded DNA found in 
serum. To confirm and further quantify samples containing KRAS mutations, BEAMing assays were 
used with the primers and probes described by Diehl et al 2006. The number of mutant fragments per ml 
of serum will be determined from the fraction of alleles containing the mutant allele (determined by 
BEAMing) and the number of alleles assessed per ml of serum will be determined by qPCR and 
correlated with the clinical benefit from regorafenib.  
 
 
4.2.4 
Secondary Objective 2: 
To correlate the presence of baseline gene expression with clinical outcomes of regorafenib: Given 
the genetic complexity of colorectal cancer, accurate identification of the somatic mutations that occur in 
a cancer cell, may be a useful tool in predicting response to various therapies. Han et al has demonstrated 
that targeted sequencing of cancer genes in colorectal cancer was feasible. A total of 526 somatic 
variations in 113 genes were found. The most commonly altered genes were the APC, TP3, KRAS, TTN, 
FVXW &, SMAD, MAFB, GNAS and SRC genes. While knowledge of these mutations is important, 
taking the next step to determine if the mutational profile of these tumors can be used to predict response 
to therapies is essential.  To this end we will send FFPE tissue for a commercially available predefined 
illumina TruSight tumor sequencing panel. The TruSight Tumor Sequencing panel is a comprehensive 
assay for examining the most relevant cancer genes involved in solid tumors. Combined with illumina's 
proven next generation technology, the TruSight Tumor panel delivers unmatched SNP, insertion, and 
deletion across the broadest regions of variation to enable a better understanding of biology leading to 
improved clinical studies. The genes involved with solid tumors will be carefully selected panel of 26 
genes from relevant publications and late phase pharmaceutical clinical trials. It looks beyond hot spots 
with 174 amplicons tiled over 82 exons in 26  genes associated with solid tumor progression, prognosis 
and targeted therapy for a more comprehensive view of tumor heterogeneity.  These genes include AKT, 
ALK, APC, BRAF, CDH1, CTNNB1, EGFR, ERBB2, FBXW7, FGFR2, FOXL2, GNAQ, GNAS, KIT, 
KRAS, MAP2K1, MET, MSH6, NRAS PDGFRA, PIK3CA, PTEN, SMAD4, SRC, STK11, and TP53. 
This provides a more comprehensive view of somatic variation in solid tumors enabling researchers to 
look beyond point mutations within hot spots in single genes. The protocol involves DNA extraction; 
Amplicon based library preparation and automated sequencing as recommended by illumina 
(www.illumina.com/trusight-tumor). The portion of the biopsies will be sent to the vendor for TruSight 
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5. Study population 
5.1 
Eligibility 
5.1.1 
Inclusion criteria 
 Patients with metastatic colorectal cancer who have progressed on, or are ineligible for standard therapy 
such as fluoropyrimidines, oxaliplatin, irinotecan, endotherlial growth factor (VEGF) inhibitors such as 
bevacizumab, and anti-EGFR antibodies where appropriate, but are suitable candidates for regorafenib 
treatment. 
 Patients with radiographically measurable biopsy-accessible disease. 
 Patients who have an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. 
 Age ≥ 18 years. 
 Life expectancy of at least 12 weeks (3 months). 
 Subjects must be able to understand and be willing to sign the written informed consent form.  Ideally, a 
signed informed consent form will be appropriately obtained prior to the conduct of any trial-specific 
procedure.  However, if patients have had standard of care assessments performed within the screening 
period, but before the consent was signed, these will be admissible. 
 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-transferase (AST)  ≤ 2.5 x ULN (≤ 5 x 
ULN for subjects with liver involvement of their cancer) 
o Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their 
cancer) 
o Serum creatinine  ≤ 1.5 x the ULN 
o For subjects with liver metastases, AST and ALT ≤ 5 X the upper normal limit of institution's 
normal range, and Non-fasting bilirubin 1.5 - 3.0 X the upper normal limit of institution's 
normal range are acceptable 
o As patients will undergo tissue biopsy, their international normalized ratio (INR)/ Partial 
thromboplastin time (PTT) has to be ≤ 1.5 x ULN. In addition, a platelet count > 100000 /mm3 
and absolute neutrophil count (ANC) ≥ 1500/mm3 is necessary.  
  
 Women of childbearing potential must have a negative serum pregnancy test performed within 7 days 
prior to the start of study drug.  Post-menopausal women (defined as no menses for at least 1 year) and 
surgically sterilized women are not required to undergo a pregnancy test.  Subjects (men and women) of 
childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until 
at least 3 months after the last dose of study drug.  The definition of adequate contraception will be 
based on the judgment of the principal investigator or a designated associate but is generally defined as a 
hormonal or barrier method of birth control, or abstinence. 
 Subject must be able to swallow and retain oral medication. 


 
 
 
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5.1.2 
Exclusion criteria 
 Previous assignment to treatment during this study.  Subjects permanently withdrawn from study 
participation will not be allowed to re-enter study. 
 Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm Hg [NCI-
CTCAE v4.0] on repeated measurement) despite optimal medical management. 
 
Active or clinically significant cardiac disease including: 
o Congestive heart failure – New York Heart Association (NYHA) > Class II. 
o Active coronary artery disease. 
o Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. 
o Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before 
randomization, or myocardial infarction within 6 months before randomization. 
 Evidence or history of bleeding diathesis or coagulopathy. 
 
 Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of study 
medication.  
 Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology 
from breast 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). 
 Patients with pheochromocytoma. 
 Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis 
B or C infection requiring treatment with antiviral therapy. 
 Ongoing infection > Grade 2 NCI-CTCAE v4.0. 
 Symptomatic metastatic brain or meningeal tumors.  NB. If a patient does not have known or 
symptomatic CNS metastases at screening, then brain imaging is not required for the purpose of this 
trial.  
 Presence of a non-healing wound, non-healing ulcer, or bone fracture. 
 Renal failure requiring hemo-or peritoneal dialysis. 
 Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.  
 Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version 4.0 Grade 2 
dyspnea). 
  History of organ allograft (including corneal transplant). 
  Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or 
excipients of the formulations given during the course of this trial. 
  Any malabsorption condition. 
  Women who are pregnant or breast-feeding. 
  Any condition which, in the investigator’s opinion, makes the subject unsuitable for trial participation. 


 
 
 
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  Substance abuse, medical, psychological or social conditions that may interfere with the subject’s 
participation in the study or evaluation of the study results. 
 Excluded therapies and medications: See section 5.1.3. 
5.1.3 
Excluded therapies and medications, previous and concomitant 
 Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic 
therapy, or tumor embolization) other than study treatment. The washout period between radiation 
therapy or tumor embolization is two weeks. Given the refractory nature of the study population, the 
washout period between study treatment and prior chemotherapy or biological therapy, will be 2 weeks 
prior to use of regorafenib. 
 Concurrent use of another investigational drug or device therapy (i.e., outside of study treatment) during, 
or within 4 weeks of trial entry . 
 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of 
study medication. 
 Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) . 
o However, prophylactic anticoagulation as described below is allowed: 
 Low dose warfarin (1 mg orally, once daily) with PT-INR  1.5 x ULN is permitted.  
Infrequent bleeding or elevations in PT-INR have been reported in some subjects taking 
warfarin while on regorafenib therapy.  Therefore, subjects taking concomitant warfarin 
should be monitored regularly for changes in PT, PT-INR or clinical bleeding episodes. 
 Prophylactic doses of heparin. 
 Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum]) 
5.2 
Withdrawal of subjects from study 
5.2.1 
Withdrawal 
Subjects must be withdrawn from the trial (treatment and procedures) for the following reasons:  
 Subject withdraws consent from study treatment and study procedures.  A subject must be removed from 
the trial at his/her own request or at the request of his/her legally acceptable representative.  At any time 
during the trial and without giving reasons, a subject may decline to participate further.  The subject will 
not suffer any disadvantage as a result. 
 Pregnancy.  Pregnancy will be reported as an SAE.  (Note: subjects who have been withdrawn from 
treatment with study drug because of pregnancy should not undergo CT scans [with contrast]/MRI or 
bone scans while pregnant.) 
 If, in the investigator's opinion, continuation of the trial would be harmful to the subject's well-being. 
 Subject is lost to follow-up. 
 Death. 
 
Subjects may be withdrawn from the study for the following reasons: 
 The subject is non-compliant with study drug, trial procedures, or both; including the use of anti-cancer 
therapy not prescribed by the study protocol. 


 
 
 
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 Severe allergic reaction to regorafenib (such as exfoliative erythroderma or Grade 3 or 4 hypersensitivity 
reaction). 
 The development of a second cancer.  
 Development of an intercurrent illness or situation which would, in the judgment of the investigator, 
significantly affect assessments of clinical status and trial endpoints. 
 Deterioration of ECOG performance status to 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 11 ( Premature termination of the study). 
5.2.2 
Screen Failures/Dropouts 
A subject who discontinues study participation prematurely for any reason is defined as a “dropout” if the 
subject has already been randomized; assigned to treatment/run-in/wash-out; or had at least one dose of study 
drug administered. 
A subject who, for any reason (e.g. failure to satisfy the selection criteria) terminates the study before the time 
point used for the definition of “dropout” (see above) is regarded a “screening failure”. 
5.2.3 
Replacement 
Subjects who withdraw from the study prior to undergoing the first biopsy will be replaced.  
5.3 
Collaboration with Caris Life Sciences 
The study will be conducted in collaboration with Wake Forest University, Masonic Cancer Center, University 
of Minnesota, , and Caris Life Sciences. Dr. John Marshall is the Principal Investigator for the study and will 
oversee the study including the data gathering, safety and reporting. Data will be shared amongst the 
collaborators for further analysis.  
 
Dr. Angela Alistar, and Dr. Emil Lou, will be the main study contacts at the perspective sites. Dr. Sandeep 
Reddy will be the main study contact at Caris Life Sciences. Patients will be recruited at all institutions for the 
study. The tissue and blood samples obtained at the collaborative sites will be mailed to Georgetown University 
as follows:  
1) Peripheral blood samples will be shipped on dry ice using Fed Ex medical shipments to  Georgetown 
University 
Indivumed Laboratory 
Georgetown University Medical Center 
Georgetown Lombardi Cancer Center 
Preclinical Science Building, Room LC6 
3900 Reservoir RD, NW 
Washington, D.C. 20016 
Tel: 202-687-1265 


 
 
 
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Fax: 202-687-5351 
 
2) Formalin-embedded tissue blocks will be shipped using Fed Ex medical shipments to Caris Life 
Sciences in Phoenix, Arizona for the molecular profile an. 
3)  
Monthly conference calls will be conducted between all institutions to follow up on the progress of the trial. Dr. 
Marshall will be responsible for coordination of the trial between all institutions. Study coordinators will notify 
Dr. Marshall upon the accrual of any patients in any institution.  
 
.  
5.3.1 Personnel 
At each site, personnel dedicated to this protocol will be: 
            - A study PI 
            - A research coordinator 
            - A data manager 
In addition, at Lombardi-Georgetown, there will be a dedicated “multi-institutional” research coordinator who 
will play the primary role in coordinating the trial between Lombardi-Georgetown and additional sites.  This 
coordinator will be the main point of contact for Dr. Marshall and the other site PIs for any study related 
concerns, and to screen each patient being considered for enrollment (Including “remote” screening for the 
patients being screened at other sites).  This coordinator will also be the point of contact for the data managers 
for data entry questions.  Finally, this coordinator will play a major role in regulatory coordination of the study, 
specifically by: 1) Reviewing and confirming all study-related adverse events; 2) Submitting all SAE reports to 
the Georgetown IRB (The research coordinators at the other sites will prepare SAE reports for patients treated 
at their respective sites, but the “multi-institutional” coordinator will submit the final report); 3) Gathering and 
preparing all primary source data for review/audit by Theradex, Inc. 
  
5.3.2 Patient Enrollment 
Enrollment at the sites will be competitive.  If a patient is being screened for enrollment, the local research 
coordinator must send an email within 24 - 48 hours containing the subject number, to the PI, and to the multi-
institutional coordinator.  If a patient is successfully screened, the local research coordinator must send all 
supporting documentation to the multi-institutional research coordinator (by email [hka10@georgetown.edu]).  
Patients should not start therapy until both PI and the multi-institutional coordinator have reviewed the patient’s 
records and confirmed that the patient is indeed eligible for enrollment. 
  
5.3.3 Data Collection and Management 
Patient data will be entered into the on-line accessible database.  This database is housed at Lombardi-
Georgetown, but is accessible anywhere there is internet access.  The data manager and research coordinator at 
each site will attend an on-line training session so that they may learn how to enroll data into the database.  All 
screening data should be entered prior to starting therapy, and all ongoing patient data should be entered within 
one week of each patient visit.  
  


 
 
 
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5.3.4 Conference Calls 
A monthly conference call will be held between Lombardi-Georgetown and the other sites to review patient 
enrollment, toxicity, and response assessment.  
  
 
 
6. Treatment[s] 
6.1 
Blinding 
Given the nature of this trial, patient or investigator blinding will not be necessary. 
6.2 
Study Treatment 
As Regorafenib is commercially available, patients will be provided a prescription and will fill it from 
retail or specialty pharmacies.   
Regorafenib is administered as monotherapy during the study; 120 mg qd will be administered for 3 
weeks on /1 week off.  One cycle is 28 days. 
 
Three 40-mg regorafenib tables should be taken in the morning with approximately 8 fluid ounces (240 
mL) of water after a low-fat (<30% fat) breakfast.   Some examples of low fat breakfasts are: 
 Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly and 8 
ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g of fat). 
 One cup of cereal (i.e. Special K), 8 ounces (240 mL) of skim milk, one piece of toast with jam (no 
butter or marmalade), apple juice, and one cup of coffee or tea (2 g fat, 17 g protein, 93 g of 
carbohydrate, 520 calories. 
6.2.1 
Dose Reduction Levels 
The starting dose of regorafenib is 120 mg once daily.  Patients will be asked to take regorafenib at their 
allocated dose 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 0 (standard 
starting dose) 
120 mg po qd 
Four 40-mg tablets of regorafenib 
Dose level - 1 
80 mg po qd  
Three 40-mg tablets of regorafenib 
Dose level - 2 
40 mg po qd  
Two 40-mg tablets of regorafenib 
 
If a subject experiences more than one toxicity, dose reduction should be carried out according to the toxicity 
with the highest grade  


 
 
 
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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 may be continued.  If a dose reduction has been performed, intra-subject dose re-escalation can be 
considered (up to the maximal 120 mg daily dose) at the discretion of the treating physician provided that the 
toxicity(ies) has resolved to baseline. 
 
The following tables outline dose adjustments for toxicities related to study drug except hand-foot skin reaction, 
hypertension and liver function test abnormalities.  
 
 
Table  6-1:  Recommended dose modification for toxicities except hand-foot-skin 
reaction, hypertension and ALT/ST/bilirubin 
NCI-CTCAE v4.0a 
Dose Interruption 
Dose  
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. 
 
 
The table above outlines dose adjustments for hematologic and non-hematologic toxicities related to 
regorafenib except HFSR and hypertension. 


 
 
 
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In addition to these recommended dose modifications, subjects who develop diarrhea, mucositis, anorexia or 
other events predisposing to fluid loss or inadequate fluid intake should be carefully monitored and rehydrated 
as clinically necessary.  This is in order to minimize the risk of postural hypotension and renal failure. 
 
 
 
 
 
 
 
 
 
Table  6-2: 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  6.3  Recommended dose modification for hand-foot-skin reactiona 
Grade of event  
(NCI-CTCAE v4.0) 
Occurrence 
Suggested Dose Modification 
Grade 1 
Any 
Maintain dose level and immediately institute 
supportive measures for symptomatic relief 
Grade 2 
 
1st occurrence 
Consider decreasing dose by one dose level and 
immediately institute supportive measures.  If no 
improvement, interrupt therapy for a minimum of 7 
days, until toxicity resolves to Grade 0-1 b, c 
No 
improvement 
within 7 days 
or 
2nd 
occurrence 
Interrupt therapy until toxicity resolves to Grade 0-
1.c 
When resuming treatment, treat at reduced dose 
level b 
3rd occurrence 
Interrupt therapy until toxicity resolves to Grade 0-
1. c 
When resuming treatment, decrease dose by one 
dose level. b, d 
4th occurrence 
Discontinue therapy 
Grade 3 
 
1st occurrence 
Institute 
supportive 
measures 
immediately. 
Interrupt therapy for a minimum of 7 days until 
toxicity resolves to Grade 0-1. c 
When resuming treatment, decrease dose by one 
dose level. b, d 
2nd occurrence 
Institute 
supportive 
measures 
immediately. 
Interrupt therapy for a minimum of 7 days until 
toxicity resolves to Grade 0-1. c When resuming 
treatment, decrease dose by one additional dose 
level b, d  
3rd occurrence 
Discontinue treatment permanently. 
a. More conservative management is allowed if judged medically appropriate by the 
investigator. 
b. If toxicity returns to Grade 0-1 after dose reduction, dose re-escalation is permitted at the 
discretion of the investigator if subject has completed one cycle at reduced dose without 
recurrence of event. 
c. If there is no recovery after a 4-week delay, treatment with regorafenib will be discontinued 
permanently. 
d. Subjects requiring > 2 dose reductions should go off protocol therapy. 
e. The maximum daily dose is 120 mg. 
 (For studies with combination therapy, consider including the following statement “The other study treatment 
may be continued”). 
 
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. 


 
 
 
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Recommended prevention/management strategies for skin toxicities consistent with HFSR are summarized 
below: 
Control of calluses 
Before initiating treatment with regorafenib: 
 Check condition of hands and feet. 
 Suggest a manicure/pedicure, when indicated. 
 Recommend pumice stone use for callus or ‘rough spot’ removal. 
During regorafenib treatment: 
 Avoid pressure points. 
 Avoid items that rub, pinch or create friction. 
Use of creams 
 Non-urea based creams may be applied liberally. 
 Keratolytic creams (e.g. urea-based creams, salicylic acid 6%) may be used sparingly and only to 
affected (hyperkeratotic) areas. 
 Alpha hydroxyl acids (AHA) based creams may be applied liberally 2 times a day.  Approximately 5% 
to 8% provides gentle chemical exfoliation. 
 Topical analgesics (e.g. lidocaine 2%) are to be considered for pain control. 
 Topical corticosteroids like clobetasol 0.05% should be considered for subjects with Grade 2 or 3 HFSR.  
Avoid systemic steroids. 
Tender areas should be protected as follows: 
 Use socks/gloves to cover moisturizing creams 
 Wear well-padded footwear 
 Use insole cushions or inserts (e.g. silicon, gel) 
 Foot soaks with tepid water and Epson salts 
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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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 
(e.g., 
malignant 
hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis) 
Per institutional guidelines 
Discontinue therapy 
a. Patients requiring a delay of >4 weeks should go off protocol therapy 
b. If BP remains controlled for at least one cycle, dose re-escalation permitted per 
investigator’s discretion. 
c. Patients requiring >2 dose reductions should go off protocol therapy. 
 


 
 
 
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Table  6-4:  Management of Treatment-Emergent Hypertension 
 
Liver Function Abnormalities 
For patients with observed worsening of serum liver tests considered related to regorafenib (i.e. where no 
alternative cause is evident, such as post-hepatic cholestasis or disease progression), the dose modification and 
monitoring advice in Table  6-5 should be followed. 
 
Regorafenib is a UGT1A1 inhibitor.  Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients 
with Gilbert’s syndrome. 
 
Table  6.5: Recommended measures and dose modifications in case of drug-related liver function test 
abnormalities 
Observed 
elevations 
of 
ALT and/or AST 
Occurrence 
Recommended measures and dose modification 
< 5 times upper limit of 
normal (ULN)  
(maximum Grade 2) 
Any occurrence 
Continue Regorafenib treatment. 
Monitor liver function weekly until transaminases return 
to < 3 times ULN (Grade 1) or baseline. 
>5 times ULN to < 20 times 
ULN 
(Grade 3) 
1st occurrence 
 
 
 
 
 
 
 
 
 
Interrupt Regorafenib treatment. 
Monitor transaminases weekly until return to < 3 times 
ULN or baseline. 
 
Restart: If the potential benefit outweighs the risk of 
hepatotoxicity, re-initiate Regorafenib treatment, reduce 
dose by 40 mg (one tablet), and monitor liver function 
weekly for at least 4 weeks. 
Re-occurrence 
Discontinue treatment with Regorafenib permanently. 
>20 times ULN  
(Grade 4) 
Any occurrence 
Discontinue treatment with Regorafenib permanently. 
>3 times ULN (Grade 2 or 
higher) 
with 
concurrent 
bilirubin >2 times ULN 
Any occurrence 
Discontinue treatment with Regorafenib permanently. 
 
Monitor liver function weekly until resolution or return 
to baseline. 
 
Exceptions: patients with Gilbert’s syndrome who 
develop elevated transaminases should be managed as 
per the above outlined recommendations for the 
respective observed elevation of ALT and/or AST. 
 
 
6.2.2 
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). 


 
 
 
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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. 
6.3 
Drug logistics and accountability 
Regorafenib is an FDA approved agent for metastatic colorectal cancer. It will be prescribed by the 
investigators or their staff. Patient will obtain it from their retail or specialty pharmacies. 
6.4 
Treatment compliance 
An adequate record of receipt, distribution, and return of all study drugs must be kept in the form of a Drug 
Accountability Form.  
Subject compliance with the treatment and protocol includes willingness to comply with all aspects of the 
protocol, and to have blood collected for all safety evaluations.  At the discretion of the principal investigator, a 
subject may be discontinued from the trial for non-compliance with follow-up visits or study drug. 
6.5 
Prior and concomitant therapy 
All medication that is considered necessary for the subject’s welfare, and which is not expected to interfere with 
the evaluation of the study treatment, may be given at the discretion of the investigator.  All medications 
(including contrast media) taken within 2 weeks prior to the start of the study and during the study must be 
recorded in the subject’s source documentation and in the CRF (including start/stop dates, dose frequency, route 
of administration, and indication).  Specific caution should be taken when considering or administering a 
concomitant medication that is metabolized by the cytochrome enzymes CYP2C8, CYP2B6 and CYP2C9.  
Such concomitant medication should be avoided, if possible. 
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the 
mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no 
change in the mean exposure of the active metabolite M-2.  Avoid concomitant use of Stivarga with strong 
CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) 
Co administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased 
the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5.  
Avoid concomitant use of Stivarga with strong inhibitors of CYP3A4 activity (e.g., clarithromycin, grapefruit 
juice, itraconazole, ketoconazole, nefazadone, posaconazole, telithromycin, and voriconazole). 
Permitted concomitant therapy includes: 
 Standard therapies for concurrent medical conditions. 
 Supportive care for any underlying illness. 
 Palliative radiation therapy is allowed if the target lesion(s) are not included within the radiation field 
and no more than 10% of the bone marrow is irradiated. 
 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 


 
 
 
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 As the study requires tissue biopsies, subjects that are therapeutically treated with an agent such as 
warfarin or heparin will not be allowed to participate in the trial.  However, patients that require 
anticoagulation after the biopsies are obtained can continue on the study. 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, cycloosporin, and digoxin).  Warfarin is 
metabolized by the cytochrome enzyme CYP2C9 and its levels may be especially affected by 
regorafenib 
 Use of any herbal remedy (e.g. St. John’s wort [Hypericum perforatum]) 
 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. 
 
7. Detailed Study Plan 
7.1 
Screening 
Screening will occur within 28 days prior to administration of the first dose of chemotherapy on Day 1. Signed 
informed consent will be obtained from the subject or the subject's legally acceptable representative before any 
study-specific procedures are undertaken. For procedures performed at screening and repeated, the later 
procedure performed prior to dosing will serve as a baseline for clinical assessment. A complete history and 
physical will be obtained at the screening visit. Additionally, labs will be reviewed/ordered during the screening 
visit, prior to the initiation of therapy. 
7.2 
Study Procedures (details are provided in the events table (Page 42) 
7.2.1 
Subject assessments  
Physical examinations (including neurological assessment), vital signs (vital sign determinations include heart 
rate, blood pressure and body temperature - Vital signs should be taken after a 5-minute resting period.  Labs 
will then be drawn once the vital signs are recorded), performance status, chemistry, hematology, medication 
review, and adverse event evaluations will be conducted at screening, on C1D1, C1D14, C2D1, C2D14,  D1 of 
every cycle starting C3, and at the off study visit. Study procedures may be performed 2 days before the 
scheduled visit date, due to unforeseen or unavoidable circumstances. 
 
Body weight will be recorded during every physical exam. The subject will wear lightweight clothing and no 
shoes during weighing. Height will be measured at the Screening Visit only; the subject will not wear shoes. 


 
 
 
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30 days after the patient’s “end of treatment” visit; a 30-day follow-up patient survival assessment will be made 
by phone. 
 
7.2.1.1 
Tumor Imaging and Response Evaluation 
 
Baseline imaging (CT scan) will be carried out for all cohorts within 28 days prior to regorafenib therapy——
and then must be performed every 8 weeks (as near to Day 1 as possible; every 2 cycles) following initiation of 
regorafenib treatment. 
 
7.2.1.2 
Medical History 
The following information will be collected during the Screening Visit: 
  
1) Complete medical history, including documentation of any clinically significant medical conditions  
2) History of tobacco and alcohol use  
3) Presence and severity of any symptoms/conditions associated with metastatic colorectal cancer  
4) Detailed oncology history, including:  
a. Date of primary cancer diagnosis  
b. Pathology (histology or cytology) of primary tumor  
c. Metastasis information (including the location)  
d. Surgical history  
e. Anti-cancer and radiation treatments administered (including dates and type of modality)  
7.2.1.3 
Research Samples  
Tumor biopsies will be obtained at baseline―prior to treatment initiation―and on day 14-21 of therapy (cycle 
1). Peripheral blood collection for research purposes will occur at baseline, on day 14-21 of therapy (on day of 
tumor biopsy; cycle 1) and then on D1 of each cycle starting C3 (i.e., every 4 weeks starting cycle 3) up to 8 
blood draws while taking regorafenib on study.  
7.2.1.4 
Pregnancy Test 
For female subjects of childbearing potential, a serum pregnancy test will be performed at the Screening Visit 
within 28 days of C1D1. Subjects considered not of childbearing potential must be documented as being 
surgically sterile or post-menopausal (for at least 1 year). The test results must be reviewed and determined to 
be negative prior to dosing. The test may be repeated at the discretion of the investigator at any time during the 
study. Should a female study subject become pregnant or suspect she is pregnant while participating in this 
study, she should inform the treating Investigator immediately. 
7.2.1.5 
Clinical Laboratory Tests 
All subjects will undergo the laboratory assessments outlined in the events table. 
 
1) Hematology and chemistry samples will be collected at the Screening Visit, on C1D1, C1D14, C2D1, 
C2D14,  D1 of every cycle starting C3, and at the off study visit. For Day 1 of each cycle after Cycle 1, 
hematology and chemistry samples may be collected up to 48 hours prior to the scheduled visit. 


 
 
 
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2) A CEA will be collected on Day 1 of every cycle 
 
Clinical laboratory samples for this study will be assessed using the certified laboratories at Georgetown 
University and affiliated Medstar Hospitals; OR any CLIA-certified laboratory such as LabCorp or Quest is 
acceptable. The PI or sub-investigator will review, initial and date all laboratory results. Any laboratory value 
outside the reference range that is considered clinically significant by the investigator will be followed as 
appropriate. Clinically significant laboratory values will be recorded as adverse events if they meet the criteria 
as specified in Section 9.4. 
7.2.1.6 
Imaging and Response Evaluation 
Imaging studies should include a diagnostic CT scan of the chest, abdomen, and pelvis with PO and IV contrast 
(unless medically contraindicated). Patients may undergo other modalities such as an MRI instead of a CT scan 
at the treating physician’s discretion if appropriate (such as patient allergy to CT contrast, extremity tumors, 
bone metastases requiring bone scans, etc). 
Response evaluation will occur every 8 weeks (as measured from Cycle 1, Day 1), and at the off study visit (if 
not performed within the last four weeks). Tumor response and/or disease progression will be assessed by the 
modality(ies) used prior to treatment. Patients will continue to remain on study as long as there is no evidence 
of progression of disease and the therapy is adequately tolerated. 
7.2.1.7 
Adverse Event Evaluation 
The Principal Investigator or Sub-investigators will assess adverse events, laboratory data and vital signs 
throughout the study. Adverse events will be assessed by NCI CTCAE Version 4.0. 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf 
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on a routine 
basis throughout the study. The investigator will assess and record any adverse event in detail including the date 
of onset, event diagnosis (if known) or sign/symptom, severity, time course, duration and outcome, relationship 
of the adverse event to study drug, and any action(s) taken. For serious adverse events not considered "probably 
related" to study drug, the investigator will provide an "Other" cause of the event. For adverse events to be 
considered intermittent, the events must be of similar nature and severity. Adverse events, whether in response 
to a query, observed by site personnel, or reported spontaneously by the subject will be recorded. All adverse 
events will be followed to a satisfactory conclusion. 
7.2.1.8 
Research Sample Handling Details 
All tumor and blood samples will be labeled with the date, protocol number, and protocol assigned patient 
number. 
 
At baseline (before starting Regorafenib), patients will each be asked to undergo  
 peripheral blood draw (7 K2 EDTA lavender top tubes) 
 tumor biopsies 
 
Two –three weeks (14-21 days) after starting Regorafenib, 
 Peripheral blood draw (7 K2 EDTA lavender top tubes) 
 A second tumor biopsies (optional) 
 


 
 
 
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7.2.1.9 
Peripheral blood samples  
Further peripheral blood samples (7 K2 EDTA lavender top tubes) will be collected after initiation of cycle 2, 
and then at the beginning of every treatment cycle  for the duration of regorafenib therapy, up to a total of 8 
blood draws. 
Specifically, peripheral blood will be collected and banked for miRNA, and mutated DNA analysis. 
A peripheral blood sample (7 K2 EDTA lavender top tubes)will also be obtained upon disease progression.  
The peripheral blood samples will be sent to  Georgetown University Medical Center  for storage then 
distribution to Dr. Wellstein’s lab and Caris Life Sciences (4610 South 44th Place, Suite 100, Phoenix, 
Arizona 85040; Email: mbaker@carisls.com; Phone: 602-792-2407) for storage and distribution. 
7.2.1.10   Tumor Biopsies 
The second tumor biopsy (at 2-3 weeks) can be waived in case of patient refusal, complications after the first 
biopsy or if the investigator deems the biopsy unsafe.  
 
Tumor samples obtained at Georgetown Hospital and other sites will be collected by the staff of the 
biospecimen bank. Two specimens will be placed in biopsy cassettes embedded in optimal cutting temperature 
compound (OCT) and snap frozen within 15 min in dry ice or liquid nitrogen and subsequently stored at -80 
until further use. The OCT embedded frozen core needle biopsy samples will be Samples will be stored in the 
Georgetown University laboratory then shipped to the laboratory of Dr. Emanuel Petricoin (George Mason 
University, 10920 George Mason Circle , Room 2006 Institute of Advanced Biomedical Research , Manassas 
VA 20110; Email: epetrico@gmu.edu; Phone: 703-993-8646) via FedEx medical shipment service after the last 
sample has been obtained or two years after the first sample has been obtained whichever occurs first.  Once at 
George Mason University tissue-based laser capture microdissection and protein pathway activation mapping 
via reverse phase protein array analysis will take place. The rest of the samples will be placed in formalin and 
then paraffin blocks will be formed to be sent to Caris for CMI testing. Only the baseline tumor samples should 
be sent to Caris. Please see Appendix 14.1 for specimen requirements. 


 
 
 
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EVENTS TABLE and STUDY CALENDAR 
 
 
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy. Scans and x-rays must be done ≤ 4 weeks prior to the start of 
therapy. Unless otherwise noted, a standard window of -1 day to + 2 days will be considered acceptable for all testing and evaluations (will not be 
considered study deviation). In the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next dose of therapy. 
 
 
 
Screening 
Day -28 
to -1 
C1D1 & 
C2D1 
Day 1 - 21 of every 
Cycle; starting C1 
C1 
D 14-
21 
C1D14 
& 
C2D14 
Day 1 of each cycle 
starting cycle 2 
Every  
8 
weeks 
Disease progression 
or end of treatment8 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
 
 
X 
X 
 
X 
β-HCG1  
X 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
 
 
X 
X 
 
X 
Vital signs 
X 
X 
 
 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
X 
 
X 
Performance status 
X 
X 
 
 
X 
X 
 
X 
Oral Regorafenib 
 
X 
X 
 
X 
X 
 
 
CBC with diff 
X 
X 
 
 
X 
X 
 
X 
Serum chemistries 2 
X 
X 
 
 
X 
X 
 
X 
PT/INR/PTT7 
X 
 
 
 
 
 
 
 
CEA3 
X 
X 
 
 
 
X 
 
X 
Adverse event evaluation 
X 
X 
 
 
X 
X 
 
X 
Radiological evaluation and 
tumor measurement 4 
X 
 
 
 
 
 
X 
X5 
Research Biopsy 
X 
 
 
X 
 
 
 
 
Research serum samples6 
X 
 
 
X 
 
X 
 
X 
1 A serum pregnancy test (women of child bearing potential) at screening only.  However, the test may be repeated at the discretion of the investigator at any 
time during the study. 
2 Serum chemistry will include sodium, potassium, chloride, BUN, bicarbonate creatinine, AST, ALT, total bilirubin, direct bilirubin, albumin, total protein and 
alkaline phosphatase 
3 CEA should be taken on D1 monthly 


 
 
 
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4 Tumor measurements will be obtained by CT scan (or MRI at physician discretion) using RECIST criteria.  If patient insurance will not cover a CT/MRI scan 
within 14 days of regorafenib treatment then a scan within 4 weeks of treatment is acceptable. 
5 Only if not performed within the last 4 weeks 
6 Patients will undergo peripheral blood collection for research purposes every 4 weeks for up to 8 blood draws (if still actively on study for that long) 
7 PT/INR/PTT is only performed at screening unless especially required at 4 weeks by the investigator.  
8 30 days after the patient’s “end of treatment” visit, a 30-day follow-up patient survival assessment will be made by phone. 
 


 
 
 
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8. Endpoints 
8.1 
Primary endpoint: 
8.1.1 
Level of serum miRNAs at baseline, 4 and 8 weeks of study treatment 
8.2 
Secondary endpoints:  
8.2.1 
Eight-week clinical benefit rate (CBR): 
Defined as proportion of patients who achieve completed response (CR) any time + partial response (PR) any 
time + stable disease (SD) at 8-week and will be measured every eight weeks based on the RECIST criteria 
version 1.1. 
8.2.2 
Objective response rate (ORR): 
Will follow the RECIST criteria version 1.1 and will be defined as partial response (PR) or complete response 
(CR).  Patients who are lost to follow-up without a valid response assessment will be classified as non-
responders. 
8.2.3 
Progression free survival (PFS): 
Defined as the number of days from study entry until progression or death; patients who are alive and free from 
progression on the date of closing follow-up will be censored on that date. 
8.2.4 
Overall survival (OS): 
Defined as the time in days from study entry until death; patients who are alive on the date of closing follow-up 
will be censored on that date.  All events of death will be included.  
8.2.5 
Safety: 
Assessed by determining the percent of subjects who experience unacceptable (Grade 3/4) adverse events and 
by describing the safety profiles; adverse events will be summarized by the common terminology criteria for 
adverse events (CTCAE version 4.0). 
8.2.6 
Activation status of phosphoproteins in tissue specimens  
At baseline and 2-3 weeks into treatment; as measured by RPMA assay 
8.2.7 
Presence mutated DNA in serum at baseline, 4 and 8 weeks of study treatment 
8.3 
Definitions 
Response and progression will be evaluated in this study using the new international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Committee. Changes in only the largest 
diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria. Note: Lesions are 
either measurable or non-measurable using the criteria provided below.  


 
 
 
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8.3.1 
Measurable disease  
Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral 
CT scan. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).  
 
8.3.2 
Non-measurable disease  
 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with conventional 
techniques or <10 mm using spiral CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable. 
 
8.3.3 
Target lesions  
All measurable lesions up to a maximum of five lesions per organ and 10 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) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all 
target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor response.  
8.3.4 
Non-target lesions  
 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at 
baseline. Non-target lesions include measurable lesions that exceed the maximum numbers per organ or total of 
all involved organs as well as non-measurable lesions. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up. 
8.3.5 
Guidelines for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 
weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used to assess the antitumor effect of a treatment.  
 
Clinical Lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable 
lymph nodes). 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 These techniques should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. This 
applies to tumors of the chest, abdomen, and pelvis. Head and neck tumors and those of extremities usually 
require specific protocols.  
 


 
 
 
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Ultrasound (US) When the primary endpoint of the study is objective response evaluation, US should not be 
used to measure tumor lesions. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions, and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical examination.  
 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation has not yet been 
fully and widely validated. Their uses in this specific context require sophisticated equipment and a high level 
of expertise that may only be available in some centers. Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in reference centers. However, such 
techniques may be useful to confirm complete pathological response when biopsies are obtained.  
 
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. 
8.3.6 
Response Criteria 
Evaluation of target lesions: 
8.3.6.1 
Complete Response (CR):  
Disappearance of all target lesions 
8.3.6.2 
Partial Response (PR):  
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the 
baseline sum LD 
8.3.6.3 
Progressive Disease (PD):  
At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more new lesions 
8.3.6.4 
Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the 
smallest sum LD since the treatment started 
8.3.6.5 
Clinical benefit rate (CBR):  
Objective responses (complete or partial response [PR] as well as stable disease [SD] ≥ 8 weeks) 
8.3.6.6 
Progression free survival (PFS):  
Time from randomization until objective tumor progression or death from any cause 
8.3.6.7 
Overall survival (OS):  
Time from randomization until death from any cause 


 
 
 
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8.3.6.8 
Objective response rate:  
Proportion of patients with tumor size reduction of a predefined amount and for a minimum time period 
 
8.4 
Safety 
All subjects who receive at least one dose of study treatment will be valid for the safety analysis.  
All observations pertinent to the safety of the study treatment will be recorded and included in the final report. 
Safety variables include the following: AEs, laboratory changes (complete blood counts, electrolytes, chemistry, 
and coagulation), changes in vital signs (blood pressure, heart rate, respiratory rate, and temperature) and ECG 
and, in some instances, changes in chest x-ray images, as produced at the investigator’s discretion (e.g., for 
evaluation for pneumonia). 
All AEs whether considered drug-related or not, will be reported in  with a diagnosis, start/stop dates, action 
taken, whether treatment was discontinued, any corrective measures taken, outcome, and other possible causes.  
For all events, the relationship to treatment and the intensity of the event will be determined by the investigator. 
This trial will use the NCI-CTCAE v4.0 criteria for assessment of toxicity and SAE reporting with regard to 
toxicity grade. 
8.4.1 
Data safety Monitoring Plan: 
The Georgetown Lombardi Comprehensive Cancer Center will be responsible for the data and safety 
monitoring of this multi-site trial.  As this study is an investigator initiated exploratory study utilizing an FDA 
approved drug it is considered a moderate risk study which requires real-time monitoring by the PI and study 
team and semi-annual reviews by the LCCC Data and Safety Monitoring Committee (DSMC). 
 
The Principal Investigator and the Co-Investigators will review the data including safety monitoring at their 
weekly institution based disease group meetings and on monthly teleconferences.   
 
All Severe Adverse Events (SAEs) are required to be reported to the IRB.  Based on SAEs, the IRB retains the 
authority to suspend further accrual pending more detailed reporting and/or modifications to further reduce risk 
and maximize the safety of participating patients. 
 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and Safety Monitoring 
Committee every 6 months from the time the first patient is enrolled on the study. Results of the DSMC 
meetings will be forwarded to the IRB with recommendations regarding need for study closure.  
 
DSMC recommendations should be based not only on results for the trial being monitored as well as on data 
available to the DSMC from other studies.  It is the responsibility of the PI to ensure that the DSMC is kept 
apprised of non-confidential results from related studies that become available.  It is the responsibility of the 
DSMC to determine the extent to which this information is relevant to its decisions related to the specific trial 
being monitored. 
 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB.  If the DSMC 
recommends a study change for patient safety or efficacy reasons the trial PI must act to implement the change 


 
 
 
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as expeditiously as possible.  In the unlikely event that the trial PI does not concur with the DSMC 
recommendations, then the LCCC Associate Director of Clinical Research must be informed of the reason for 
the disagreement.  The trial PI, DSMC Chair, and the LCCC AD for Clinical Research will be responsible for 
reaching a mutually acceptable decision about the study and providing details of that decision to the IRB.  
Confidentiality must be preserved during these discussions.  However, in some cases, relevant data may be 
shared with other selected trial investigators and staff to seek advice to assist in reaching a mutually acceptable 
decision. 
 
If a recommendation is made to change a trial for reasons other than patient safety or efficacy the DSMC will 
provide an adequate rationale for its decision. If the DSMC recommends that the trial be closed for any reason, 
the recommendation will be reviewed by the Associate Director for Clinical Research at G-LCCC.  Authority to 
close a trial for safety reasons lies with the IRB, with the above described input from DSMC and the AD for 
Clinical Research.    
8.4.2 
Adverse events 
Investigators should refer to the Safety Information section of the current IB for regorafenib , including the 
DCSI (development core safety information), for the expected side effects of , regorafenib.  As with any agent, 
there is always the potential for unexpected AEs, including hypersensitivity reactions.  The IB will be updated if 
any new relevant safety data are obtained. 
Therapeutic monitoring should be performed following dose selection or modification of regorafenib , in a 
manner consistent with the local clinical standard of care.  In general, subjects should be closely monitored for 
side effects of all concomitant medications regardless of the path of drug elimination. 
All concomitant medications must be recorded in the subject’s source documentation. 
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. 
8.4.3 
Definitions 
Definition of adverse event (AE) 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject 
after providing written informed consent for participation in the study.  Therefore, an AE may or may not 
be temporally or causally associated with the use of a medicinal (investigational) product. 
A surgical procedure that was planned prior to the start of the study by any physician treating the subject should 
not be recorded as AE (however, the condition for which the surgery is required may be an AE if worsens 
compared to baseline). 
 
 Conditions that started before signing of informed consent and for which no symptoms or treatment are 
present until signing of informed consent are recorded as medical history (e.g. seasonal allergy without 
acute complaints). 
 Conditions that started before signing of informed consent and for which symptoms or treatment are 
present after signing of informed consent, at unchanged intensity, are recorded as medical history 
(e.g. allergic pollinosis). 


 
 
 
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 Conditions that started or deteriorated after signing of informed consent will be documented as adverse 
events. 
Definition of serious adverse event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the following criteria (a –
 f): 
a. Results in death. 
b. Is life-threatening. 
The term ‘life-threatening’ in the definition refers to an event in which the patient was at risk of death at 
the time of the event, it does not refer to an event which hypothetically might have caused death if it 
were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization. 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at least one of the 
following exceptions is met: 
- The admission results in a hospital stay of less than 12 hours. 
- The admission is pre-planned.  
(i.e. elective or scheduled surgery arranged prior to the start of the study) 
- The admission is not associated with an AE. 
(e.g., social hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization may fulfill the criterion 
of ‘medically important’ and as such may be reportable as an SAE dependent on clinical judgment.  In 
addition, where local regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedence. 
d. Results in persistent or significant disability / incapacity. 
Disability means a substantial disruption of a person’s ability to conduct normal life’s functions. 
e. Is a congenital anomaly / birth defect. 
f. Is another medically important serious event as judged by the investigator 
8.4.4 
Classifications for adverse event assessment 
 
All AEs will be assessed and documented by the investigator according to the categories detailed below. 
8.4.4.1 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in Section 8.4.3. 
8.4.4.2 
Intensity 
The intensity of the AE is classified according to the CTCAE v4.0.  Grade refers to the severity (intensity) of 
the AE: 
CTCAE v4 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention is not indicated. 


 
 
 
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CTCAE v4 Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; limiting to age-
appropriate instrumental activities of daily living (ADL; instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc). 
CTCAE v4 Grade 3: Severe or medically significant but not immediately life threatening; hospitalization 
or prolongation of hospitalization is indicated; disabling; limiting to self care ADL (self care ADL refers 
to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden). 
CTCAE v4 Grade 4: life-threatening consequences; urgent intervention is indicated. 
CTCAE v4 Grade 5: death due to an AE. 
8.4.4.3 
Causal relationship  
The assessment of the causal relationship between an AE and the administration of treatment is a clinical 
decision based on all available information. 
The assessment is based on the question whether there was a “reasonable causal relationship” to the study 
treatment in question. 
Possible answers are “yes” or “no”. 
An assessment of “no” would include: 
1. The existence of a clear alternative explanation, e.g. mechanical bleeding at surgical site. 
Or 
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no indication that the drug 
caused disorientation that may have caused the event; cancer developing a few days after the first drug 
administration. 
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is associated with the use of 
the study treatment. 
Factors to be considered in assessing the relationship of the AE to study treatment include: 
- The temporal sequence from drug administration:  The event should occur after the drug is given.  The 
length of time from drug exposure to event should be evaluated in the clinical context of the event. 
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction (re-challenge): 
- Subject’s response after de-challenge or subjects response after re-challenge should be considered in the 
view of the usual clinical course of the event in question. 
- Underlying, concomitant, intercurrent diseases:   
Each event should be evaluated in the context of the natural history and course of the disease being treated 
and any other disease the subject may have. 
- Concomitant medication or treatment:  
The other drugs the subject is taking or the treatment the subject receives should be examined to determine 
whether any of them may be suspected to cause the event in question. 
- The pharmacology and pharmacokinetics of the study treatment:  
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) of the study treatment, 
coupled with the individual subject’s pharmacodynamics should be considered. 


 
 
 
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[Causal relationship to protocol-required procedure(s)] 
The assessment of a possible causal relationship between the AE and protocol-required procedure(s) is based on 
the question whether there was a “reasonable causal relationship” to protocol-required procedure(s). 
Possible answers are “yes” or “no”. 
8.4.4.4 
Action taken with study treatment  
Any action on study treatment to resolve the AE is to be documented using the categories listed below. 
8.4.4.5 
Other specific treatment(s) of adverse events 
 ־None 
 ־Remedial drug therapy 
8.4.4.6 
Outcome 
The outcome of the AE is to be documented as follows:  
 ־Recovered/resolved 
 ־Recovering/resolving 
 ־Recovered/resolved with sequelae 
 ־Not recovered/not resolved 
 ־Fatal 
 ־Unknown 
8.4.5 
Assessments and documentation of adverse events 
8.4.5.1 
Reporting of serious adverse events 
The definition of serious adverse events (SAEs) is given in Section 8.4.3. 
Each serious adverse event must be followed up until resolution or stabilization, by submission of updated 
reports to the designated person. An isolated laboratory abnormality that is assigned grade 4, according to CTC 
definition, is not reportable as an SAE; unless the investigator assesses that the event meets standard ICH 
criteria for an SAE.  CTC grade 4 baseline laboratory abnormalities that are part of the disease profile should 
not be reported as an SAE, specifically when they are allowed or not excluded by the protocol 
inclusion/exclusion criteria.   
 
When required, and according to local law and regulations, serious adverse events must be reported to the 
Ethics Committee and Regulatory Authorities.  
 
All serious adverse events should be reported to Bayer within 24 hours.  In the event of such an event, the 
investigator should refer to the Pharmacovigilance section of the contract for reporting procedures. 
 
The Investigator may report serious adverse drug reactions (SADRs) using either: 
 
An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html   
 
OR 


 
 
 
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 A MedWatch form available at http://www.fda.gov/medwatch/  
 
All reports shall be sent electronically to:  
 
Electronic Mailbox:  
DrugSafety.GPV.US@bayer.com  
 
Facsimile:    
 
(973) 709-2185  
 
Address: 
 
 
Global Pharmacovigilance - USA  
Mail only: 
 
 
Bayer HealthCare Pharmaceuticals Inc. 
 
P.O. Box 915  
 
Whippany, NJ 07981-0915  
 
Address:   
 
 
100 Bayer Boulevard, Whippany, NJ 07981  
FDX or UPS only    
  
 
Reports for all Bayer products can also be phoned in via our Clinical Communications Dept:  
 
Phone:  
 
 
1-888-842-2937 
 
8.4.5.2 
Expected adverse events 
For this study, the applicable reference document is the most current version of the investigator’s brochure (IB) 
/ summary of product characteristics. 
Overview listings of frequent events that have occurred so far in the clinical development are shown in the 
current IB.  If relevant new safety information is identified, the information will be integrated into an update of 
the IB and distributed to all participating sites. 
The expectedness of AEs will be determined by Bayer according to the applicable reference document and 
according to all local regulations. 
8.4.5.3 
Adverse events of special safety interest 
As with any new chemical entity, there is always potential for unexpected adverse events, including 
hypersensitivity reactions. 
Based on data studies with regorafenib and from current knowledge of the pharmacological properties of other 
small molecule tyrosine kinase inhibitors in this drug class, as soon as there is reasonable suspicion of any of 
the following AEs, the investigator should immediately notify the sponsor as outlined in Section 7.4.1.4.  
Reportable adverse events include: 
 Acute renal failure (NCI-CTCAE version 4.0 ≥ grade 3) or severe proteinuria (NCI-CTCAE version 4.0 
≥ grade 3) 
 Interstitial lung disease 
 Acute cardiac failure 
 Clinically significant bleeding (NCI-CTCAE version 4.0 ≥ grade 3) 
 Stevens-Johnson Syndrome and erythema multiforme 


 
 
 
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 Hepatic failure 
 Reversible posterior leukoencephalopathy syndrome 
 Gastrointestinal perforation or fistula 
 
8.4.6 
Pregnancies/Contraception 
 
The effects of regorafenib on the developing human fetus at the recommended therapeutic dose are unknown.  
Regorafenib was embryo-lethal and teratogenic in rats and rabbits at exposures lower than human exposures at 
the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. 
For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal 
or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.  
The investigator must report to Bayer any pregnancy occurring in a study subject, or in his partner, during the 
subject’s participation in this study.  The report should be submitted within the same timelines as an SAE, 
although a pregnancy per se is not considered an SAE.   
For a study subject, the outcome of the pregnancy should be followed up carefully, and any abnormal outcome 
of the mother or the child should be reported. 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar information on 
course and outcome, subject to the partner’s consent. 
For all reports, the forms provided are to be used. 
 
9.   Statistical methods and determination of sample size 
9.1 
Analysis sets 
9.1.1 
Safety analysis set.   
 
The safety analysis set includes all enrolled patients who receive at least one dose of study medication. 
 
9.1.1.1 
  Full analysis set. 
 
The full analysis set includes all enrolled patients 
 
9.1.1.2 
  Response analysis set 
 
All enrolled patients who are eligible, receive study treatment, have baseline assessments and at least 1 on-study 
tumor assessment will be considered evaluable for response. Patients who are treated and removed from study 
prior to on-study tumor assessment because of disease progression will be considered evaluable for efficacy and 
counted as failures. 
 


 
 
 
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9.2 
Variables 
9.2.1 
The primary endpoints for biomarker discovery:   
1) Level of serum miRNAs at baseline, 4 and 8 weeks of study treatment 
9.2.2 
The secondary endpoints are: 
1) Eight-week clinical benefit rate (CBR), defined as proportion of patients who achieve completed 
response (CR) any time + partial response (PR) any time + stable disease (SD) at 8-week.  
2) Objective response rate (ORR), will follow the RECIST criteria and will be defined as partial response 
(PR) or complete response (CR).  Patients who are lost to follow-up without a valid response assessment 
will be classified as non-responders. 
3) Progression free survival (PFS), defined as the number of days from study entry until progression or 
death. Patients who are alive and free from progression on the date of closing follow-up will be censored 
on that date. 
4) Overall survival (OS), defined as the time in days from study entry until death.  Patients who are alive 
on the date of closing follow-up will be censored on that date.  All events of death will be included.  
5)  Safety will be assessed by determining the percent of subjects who experience unacceptable (Grade 3/4) 
adverse events and by describing the safety profiles. Adverse events will be summarized by the common 
terminology criteria for adverse events (CTCAE version 4.0). 
6) Activation status of phosphoproteins in tissue specimens at baseline and 2-3 weeks into treatment as 
measured by RPMA assay.  
7) Presence and level of mutated DNA in serum at baseline, 4 and 8 weeks of study treatment.  
9.3 
Statistical and analytical plans 
Demographic and baseline characteristics will be summarized in all subjects using descriptive statistics.  
 
9.3.1 
Analysis for the Primary endpoints: 
 
The analysis will be exploratory in nature. There will be no adjustment for multiplicity to be utilized.  
 
For clinically relevant biomarker discovery, exploratory analyses of biomarkers will be performed to 
determine if a correlation can be established between the presence or change in the level of a marker species 
(“yes” or “no”) and the clinical response. Our main goal is to identify biomarkers that, when assayed at 
baseline, can predict the patient’s response to regorafenib. Descriptive statistics, graphical methods, and 
statistical modeling including repeated measure models, whichever is appropriate, may be used.  The expression 
of biomarker levels within patients at different time points will be analyzed using paired t-test or the non-
parametric Wilcoxon Signed Rank test to see whether any changes between different time points are apparent. 
Chi-square test or Fisher’s exact test will be used to explore the association between categorical variables and 
the clinical response.  We may also use Cox models for association of biomarker variables (categorical or 
continuous) and time-to-event variables. Kaplan-Meier method will be used to explore the association between 
categorical variables and time-to-event response variables.  ROC (Receiver Operating Characteristic) curves 
will also be plotted to examine the sensitivity and specificity of the identified biomarkers. 
 


 
 
 
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9.3.2 
Analysis for the secondary endpoints: 
 
The clinical benefit rate (CBR) will be estimated with 95% exact binomial confidence interval.  
 
The objective response rate (ORR) will be computed for all subjects with at least one measurable lesion at 
baseline. 
 
The progression free survival (PFS), as well as overall survival (OS), will be estimated and presented by the 
method of Kaplan and Meier (1958) and 95% confidence interval will be presented for the estimated PFS 
survival rate and for the median. 
 
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be presented using 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All 
on-study AEs, treatment-related AEs, SAEs, and treatment-related SAEs will be tabulated using worst grade per 
NCI CTCAE v 4.0 criteria by system organ class and preferred term. On-study lab parameters including 
hematology, chemistry, liver function, and renal function will be summarized using worst grade NCI CTCAE v 
4.0 criteria. For continuous safety variables, mean, standard deviation, and 95% confidence interval will be 
calculated at baseline and each visit. 
 
Descriptive statistics (N, percentage for categorical variables and N, mean, std, median, min, max for 
continuous variables) will be used to summarize the activation status of phosphoproteins, presence and level of 
mutated DNA in serum at baseline, 4 and 8 weeks of study treatment. Repeated measures models may be used 
to explore the relationship between the level of mutated DNA in serum with clinical response. 
 
9.4 
Determination of sample size 
The study is exploratory in nature. The sample size is not based on certain statistical power for significance 
testing.  However, a sample size of 40 could demonstrate an effect size of 0.5 using a 1 degree of freedom Chi-
Square test with 80% power at a significance level of 5%. If the biomarkers we are looking for exhibit big 
changes/big-effect size, then this sample size would be sufficient for us to perform the analysis. It is estimated 
40 patients will be enrolled at Georgetown University.  
 
 
10.  Data handling and quality assurance 
10.1 
Data recording 
Clinical and laboratory data will be collected at the Georgetown Lombardi Cancer Center and entered into 
electronic case report forms (CRF) using LCCC’s web-based CRFs.  
10.2 
Monitoring 
The study will be monitored by the Georgetown Lombardi Comprehensive Cancer Center multi-site coordinator 
and data safety monitoring board (DSMC).  


 
 
 
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10.3 
Data processing 
Data will be submitted to the Georgetown Lombardi Cancer Center for final analysis. Since the Georgetown 
Lombardi Cancer Center is the lead institution in the trial, it will be responsible for accuracy of the data 
processing and presentation.  
 
10.4 
Audit and inspection 
Inspections by regulatory health authority representatives i.e. FDA and IEC(s)/IRB(s) are possible.  The 
investigator should notify Bayer immediately of any such inspection. 
. 
10.5 
Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they are readily 
available upon authorities’ request. 
Patient (hospital) files will be archived according to local regulations and in accordance with the maximum 
period of time permitted by the hospital, institution or private practice. 
11. Premature termination of the study 
 If risk-benefit ratio becomes unacceptable owing to, for example, 
o Safety findings from this study (e.g. SAEs) 
o Results of any interim analysis 
o Results of parallel clinical studies 
o Results of parallel animal studies  
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity). 
 If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol compliance) does not 
suggest a proper completion of the trial within a reasonable time frame. 
The investigator has the right to close his/her center at any time. 
For any of the above closures, the following applies: 
 Closures should occur only after consultation between involved parties. 
 All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; head of study 
center) must be informed as applicable according to local law. 
 In case of a partial study closure, ongoing subjects, including those in post study follow-up, must be 
taken care of in an ethical manner. 
Details for individual subject's withdrawal can be found in Section 5.2.1. 
12. Ethical and legal aspects 
12.1 
Ethical and legal conduct of the study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of this study, 
are designed to ensure that the investigator abide by Good Clinical Practice (GCP) guidelines and under the 


 
 
 
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guiding principles detailed in the Declaration of Helsinki.  The study will also be carried out in keeping with 
applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating centers before start of 
the study, according to GCP, local laws, regulations and organizations.  When necessary, an extension, 
amendment or renewal of the EC/IRB approval must be obtained and also forwarded to Bayer. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study conduct; the 
investigator may not modify or alter the procedures described in this protocol.   
Modifications to the study protocol will not be implemented by the investigator without discussion and 
agreement by Bayer.  However, the investigator may implement a deviation from, or a change of, the protocol 
to eliminate an immediate hazard(s) to the trial subjects without prior IEC/IRB/Bayer approval/favorable 
opinion.  As soon as possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical institution.  Any deviations 
from the protocol must be explained and documented by the investigator. 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with Title 
21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  The Principal Investigator is 
responsible for personally overseeing the treatment of all study patients.  The Principal Investigator must assure 
that all study site personnel, including sub-investigators and other study staff members, adhere to the study 
protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study 
completion. 
The Principal Investigator at each institution or site will be responsible for assuring that all the required data 
will be collected and properly documented. 
12.2 
Subject information and consent 
Each subject / legal representative or proxy consenter will have ample time and opportunity to ask questions 
and will be informed about the right to withdraw from the study at any time without any disadvantage and 
without having to provide reasons for this decision. 
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign the informed consent 
form and has done so, may he/she enter the study.  Additionally, the investigator and other information provider 
(if any) will personally sign and date the form.  The subject / legal representative or proxy consenter will 
receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally required, in the 
patient’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are performed, the 
study record or subject’s clinical record must clearly show that informed consent was obtained prior to these 
procedures. 
 
 
If the patient is not capable of providing a signature, a verbal statement of consent can also be given in the 
presence of an impartial witness (independent of Bayer and the investigator).  This is to be documented by a 
signature from the informing physician as well as by a signature from the witness. 
The informed consent form and any other written information provided to subjects / legal representatives or 
proxy consenters will be revised whenever important new information becomes available that may be relevant 
to the subject’s consent, or there is an amendment to the protocol that necessitates a change to the content of the 
subject information and / or the written informed consent form.  The investigator will inform the subject / legal 
representative or proxy consenter of changes in a timely manner and will ask the subject to confirm his/her 


 
 
 
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participation in the study by signing the revised informed consent form.  Any revised written informed consent 
form and written information must receive the IEC/IRB`s approval / favorable opinion in advance of use. 
12.3 
Publication policy 
Bayer recognizes the right of the investigator to publish results upon completion of the study.  However, the 
investigator must send a draft manuscript of the publication or abstract to Bayer at least thirty days in advance 
of submission in order to obtain approval prior to submission of the final version for publication or congress 
presentation.  This will be reviewed promptly and approval will not be withheld unreasonably.  In case of a 
difference of opinion between Bayer and the investigator(s), the contents of the publication will be discussed in 
order to find a solution which satisfies both parties. All relevant aspects regarding data reporting and 
publication will be part of the contract between Bayer and the investigator/institution 
The Principal Investigator should ensure that the information regarding the study be publicly available on the 
internet at www.clinicaltrials.gov. 
12.4 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws 
and/or regulations, will not be made publicly available. 
Should direct access to medical records require a waiver or authorization separate from the subject’s statement 
of informed consent, it is the responsibility of the Investigator to obtain such permission in writing from the 
appropriate individual. 
13.  Reference list 
(1) Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010 Sep-Oct;60(5):277-300. 
(2) Siegel R, Desantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship 
statistics, 2012. CA Cancer J Clin 2012 Jul;62(4):220-241. 
(3) Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, et al. Annual report to the nation 
on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, 
screening, and treatment) to reduce future rates. Cancer 2010 Feb 1;116(3):544-573. 
(4) Benson AB,3rd, Bekaii-Saab T, Chan E, Chen YJ, Choti MA, Cooper HS, et al. Metastatic colon cancer, 
version 3.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw 2013 Feb 1;11(2):141-52; 
quiz 152. 
(5) Gerger A, El-Khoueiry A, Zhang W, Yang D, Singh H, Bohanes P, et al. Pharmacogenetic angiogenesis 
profiling for first-line Bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal 
cancer. Clin Cancer Res 2011 Sep 1;17(17):5783-5792. 
(6) Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus 
irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004 Jun 
3;350(23):2335-2342. 
(7) Hurwitz HI, Yi J, Ince W, Novotny WF, Rosen O. The clinical benefit of bevacizumab in metastatic 
colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with 
chemotherapy in previously untreated metastatic colorectal cancer. Oncologist 2009 Jan;14(1):22-28. 


 
 
 
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(8) Suenaga M, Matsusaka S, Ueno M, Yamamoto N, Shinozaki E, Mizunuma N, et al. Predictors of the 
efficacy of FOLFIRI plus bevacizumab as second-line treatment in metastatic colorectal cancer patients. Surg 
Today 2011 Aug;41(8):1067-1074. 
(9) Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for 
previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, 
placebo-controlled, phase 3 trial. Lancet 2013 Jan 26;381(9863):303-312. 
(10) Bates DO, Catalano PJ, Symonds KE, Varey AH, Ramani P, O'Dwyer PJ, et al. Association between 
VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with 
bevacizumab. Clin Cancer Res 2012 Nov 15;18(22):6384-6391. 
(11) Etienne-Grimaldi MC, Formento P, Degeorges A, Pierga JY, Delva R, Pivot X, et al. Prospective analysis 
of the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-based therapy in 
metastatic breast cancer patients. Br J Clin Pharmacol 2011 Jun;71(6):921-928. 
(12) Gerger A, LaBonte M, Lenz HJ. Molecular predictors of response to antiangiogenesis therapies. Cancer J 
2011 Mar-Apr;17(2):134-141. 
(13) Goede V, Coutelle O, Neuneier J, Reinacher-Schick A, Schnell R, Koslowsky TC, et al. Identification of 
serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with 
bevacizumab-containing therapy. Br J Cancer 2010 Oct 26;103(9):1407-1414. 
(14) Duda DG, Willett CG, Ancukiewicz M, di Tomaso E, Shah M, Czito BG, et al. Plasma soluble VEGFR-1 
is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced 
rectal cancer. Oncologist 2010;15(6):577-583. 
(15) Chung YS, Maeda K, Sowa M. Prognostic value of angiogenesis in gastro-intestinal tumours. Eur J Cancer 
1996 Dec;32A(14):2501-2505. 
(16) Shivapurkar N, Mikhail S, Navarro R, Bai W, Marshall J, Hwang J, et al. Decrease in blood miR-296 
predicts chemotherapy resistance and poor clinical outcome in patients receiving systemic chemotherapy for 
metastatic colon cancer. Int J Colorectal Dis 2012 Aug 15. 
 (17) Wulfkuhle JD, Berg D, Wolff C, Langer R, Tran K, Illi J, et al.  Molecular analysis of HER2 signaling in 
human breast cancer by functional protein pathway activation mapping. Clin Cancer Res. 2012 Dec 
1;18(23):6426-35. 
 


 
 
 
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14.  Appendices 
14.1 
Examples of a low fat breakfast 
Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly and 8 ounces of skim 
milk.  (Approximately 319 calories and 8.2 grams of fat) 
 
One cup of cereal (i.e. Special K), 8 ounces of skimmed milk, one piece of toast with jam (no butter or 
marmalade), apple juice, and one cup of coffee or tea (2 g fat, 17 g protein, 93 g of carbohydrate, 520 calories). 
 
14.2 
Caris Specimen Requirements 
 
 
 
 
 
 
 
 
 
 


 
 
 
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14.3 
Biopsy Flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wake Forest University  
Paraffin blocks biopsy 
sent to Caris: 
 
Caris Life Sciences: 
4610 South 44th Place 
Suite 100 
Phoenix, Arizona 85040 
email:mbaker@carisls.com 
602-792-2407 
Georgetown University 
University of Minnesota 
Paraffin blocks biopsy 
sent to Caris: 
 
Caris Life Sciences: 
4610 South 44th Place 
Suite 100 
Phoenix, Arizona 85040 
email:mbaker@carisls.com 
602-792-2407 
 
The OCT embedded frozen core needle biopsy 
samples y sent to Georgetown for storage: 
 
Indivumed Laboratory 
Georgetown University Medical Center 
Georgetown Lombardi Cancer Center 
Preclinical Science Building, Room LC6 
2900 Reservoir RD, NW 
Washington, D.C. 20016 
Tel: 202-687-1265 
Fax: 202-687-5351 
 
The OCT embedded frozen core needle biopsy 
samples sent to George Mason University: 
 
10920 George Mason Circle 
10900 University Blvd., Room 2006 
Institute of Advanced Biomedical Research 
324 Bull Run Hall 
Manassas, Virginia 20110 
epetrico@gmu.edu 
703-993-8646
Paraffin blocks biopsy 
sent to Caris: 
 
Caris Life Sciences: 
4610 South 44th Place 
Suite 100 
Phoenix, Arizona 85040 
email:mbaker@carisls.com 
602-792-2407 
 


 
 
 
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14.4 
Blood Flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wake Forest University  
University of Minnesota 
One blood sample 
sent to Caris: 
 
Caris Life Sciences: 
4610 South 44th Place 
Suite 100 
Phoenix, Arizona 85040 
email:mbaker@carisls.com 
602-792-2407 
 
Blood samples sent to Georgetown 
University: 
 
Indivumed Laboratory 
Georgetown University Medical Center 
Georgetown Lombardi Cancer Center 
Preclinical Science Building, Room LC6 
2900 Reservoir RD, NW 
Washington, D.C. 20016 
Tel: 202-687-1265 
Fax: 202-687-5351 
 
Blood sample sent to Dr. Wellstein’s laboratory at 
Georgetown University