A Randomized Phase II Trial to Evaluate the Efficacy of Supportive Therapy With Ginseng for Patients on Treatment With Regorafenib
Phase: PHASE2
Conditions: Colorectal Cancer, Palliative Medicine, Supportive Care
Sponsor: Wake Forest University Health Sciences

 
 
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Protocol Title 
A Randomized, Phase II Trial to Evaluate the Efficacy of Supportive Therapy with Ginseng for 
Patients on Treatment with Regorafenib: HCRN GI14-191  
 
Sponsor-Investigator 
Rodwige J. Desnoyers, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
Co-Investigators  
Angela Alistar, MD 
Atlantic Health System 
 
George Yacoub 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
Richard P. McQuellon, Ph.D., HSP-P 
Professor of Medicine and Director 
Psychosocial Oncology and Cancer Patient Support Programs 
 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 
Statistician 
Ralph D’Agostino, PhD 
Department of Biostatistical Sciences 
Wake Forest School of Medicine 
 
Funding Support Provided By 
Bayer HealthCare Pharmaceuticals, Inc. 
 
 
Investigational New Drug (IND) ID#: 128760 
 
Initial Protocol Version Date: 02FEB2016 
Protocol Amendment Version Date: 
28JUN2016 
27FEB2017 
 
 
 

 
 
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PROTOCOL SIGNATURE PAGE 
 
Protocol Title: A Randomized, Phase II Trial to Evaluate the Efficacy of Supportive Therapy 
with Ginseng for Patients on Treatment with Regorafenib 
 
VERSION DATE: 27FEB2017 
 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable ethical review board(s). 
 
 
 
 
 
 
 
 
 
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PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date. Scan and email 
the completed form to HCRN and keep a record for your files. 
 

 
 
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SYNOPSIS 
 
TITLE 
A Randomized, Phase II Trial to Evaluate the Efficacy of Supportive Therapy 
with Ginseng for Patients on Treatment with Regorafenib 
SHORT TITLE 
Efficacy of Ginseng for Patients on Regorafenib 
PHASE  
Phase II 
OBJECTIVES 
Primary Objective: Assess fatigue with the Multidimensional Fatigue Symptom 
Inventory-Short Form (MFSI-SF) and Patient-Reported Outcomes Measurement 
Information System (PROMIS) form for each group (Regorafenib + No Ginseng vs. 
Regorafenib + Ginseng) to determine if 2000 mg of American Ginseng for 8 weeks 
has an impact on the fatigue score 
 
Secondary Objectives:  
1) Assess the effect of Ginseng on adherence to Regorafenib for CRC subjects with 
good performance status 
2) Assess the toxicities of the combination of Regorafenib and Ginseng for CRC 
subjects with good performance status 
3) Assess the retention of subjects to the combination of Regorafenib and Ginseng 
for CRC subjects with good performance status 
4) Evaluate response rate and overall survival 
STUDY DESIGN 
Randomized 
ESTIMATED 
NUMBER OF 
SUBJECTS  
90: 60 randomized to regorafenib + ginseng and 30 to regorafenib + no ginseng 
KEY ELIGIBILITY 
CRITERIA  
Inclusion criteria: 
1. Subjects must be able to understand and be willing to sign the written informed 
consent and HIPAA authorization for release of personal health information. A 
signed informed consent form must be appropriately obtained prior to the conduct 
of any trial-specific procedure. 
NOTE:  HIPAA authorization may be included in the informed consent or 
obtained separately. 
2. Age ≥ 18 years at the time of consent. 
3. Life expectancy of at least 12 weeks (3 months). 
4. ECOG Performance Status of 0 or 1 within 28 days prior to registration. 
5. Histological or cytologically confirmed stage IV adenocarcinoma of the colon.  
6. Adequate bone marrow, liver and renal function as assessed by the following 
laboratory values obtained within 7 days prior to registration for protocol therapy. 
a. Absolute neutrophil count (ANC) count > 1,500/mm3 
b. Hemoglobin (Hgb) > 9g/dL 
c. Platelet count > 100,000/mm3 
d. Total bilirubin ≤ 1.5 × the upper limit of normal (ULN).  
e. Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 
x ULN (≤ 5 × ULN for subjects with liver involvement of their cancer) 
f. Alkaline phosphatase limit ≤ 2.5 × ULN (≤ 5 × ULN for subjects with liver 
involvement of their cancer) 
g. Serum creatinine ≤ 1.5 × the ULN 

 
 
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h. International normalized ratio (INR)/ Partial thromboplastin time (PTT) < 1.5 
× ULN. (Subjects who are prophylactically treated with an agent such as 
warfarin or heparin will be allowed to participate if no prior evidence of 
underlying abnormality in coagulation parameters exists. Close monitoring of 
at least weekly evaluations will be performed until INR/PTT is stable based on 
a measurement that is pre-dose as defined by the local standard of care.)  
7. 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. The definition of adequate contraception 
will be based on the judgment of the site investigator. 
8. Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 2 months after the 
last dose of study drug. The definition of adequate contraception will be based on 
the judgment of the treating physician or a designated associate. 
Examples of adequate contraception may include but are not limited to a 
combination of any two of the following: 
• Use of oral, injected or implanted hormonal methods of contraception 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
• Total abstinence 
• 
Male/female sterilization 
9. All subjects must have radiographically assessable disease per RECIST v1.1 
obtained by imaging within 28 days prior to registration. 
10. Must be able to swallow and retain oral medication.  
11. Subject must be deemed a suitable candidate for regorafenib as per their treating 
physician 
Exclusion Criteria 
1. Subject should not be receiving any agent for fatigue including steroids or 
megace.  
NOTE: Subjects who have a contrast-induced allergy are allowed to receive 
steroids for their scans. 
2. Radiotherapy within 2 weeks prior to randomization. Subjects must have 
recovered from all therapy-related toxicities.  
3. Prior treatment with regorafenib. 
4. Previous assignment to treatment during this study. Subjects permanently 
withdrawn from study participation will not be allowed to re-enter study. 
5. Congestive heart failure > New York Heart Association (NYHA) class 2. 
i. Unstable angina (angina symptoms at rest), new-onset angina (begun within 
the last 3 months). Myocardial infarction less than 6 months before start of 
study medication. 
ii. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or 
digoxin are permitted). 
iii. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic 
pressure > 90 mmHg despite optimal medical management). 

 
 
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6. Evidence or history of bleeding diathesis or coagulopathy. 
7. Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior 
to start of study medication.  
8. Subjects with thrombotic, embolic, venous, or arterial events, such as 
cerebrovascular accident (including transient ischemic attacks) deep vein 
thrombosis or pulmonary embolism within 6 months of start of study treatment or 
within 6 months of informed consent. 
9. Previous or concurrent cancer that is distinct in primary site or histology from 
colorectal cancer within 3 years prior to randomization EXCEPT for curatively 
treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder 
tumors [Ta (Non-invasive tumor), Tis (Carcinoma in situ) and T1 (Tumor invades 
lamina propria)]. 
10. Subjects with pheochromocytoma. 
11. Known history of human immunodeficiency virus (HIV) infection or current 
chronic or active hepatitis B or C infection requiring treatment with antiviral 
therapy. 
12. Ongoing infection > Grade 2 NCI-CTCAE v4.0. 
13. Metastatic brain or meningeal tumors (symptomatic or asymptomatic). 
14. Major surgical procedure or significant traumatic injury within 28 days before 
start of study medication 
15. Renal failure requiring hemo- or peritoneal dialysis. 
16. Dehydration Grade > 1 NCI CTCAE v4.0. 
17. Subjects with seizure disorder requiring medication. 
18. Persistent proteinuria ≥ Grade 3 NCI CTCAE v4.0 (> 3.5 g/24 hours, measured 
by urine protein: creatinine ratio on a random urine sample). 
19. Interstitial lung disease with ongoing signs and symptoms at the time of informed 
consent.  
20. Pleural effusion or ascites that causes respiratory compromise (≥ NCI CTCAE 
version 4.0 Grade 2 dyspnea). 
21. History of organ allograft (including corneal transplant). 
22. Known or suspected allergy or hypersensitivity to any of the study drugs, study 
drug classes, or excipients of the formulations given during the course of this 
trial. 
23. Any malabsorption condition. 
24. Women who are pregnant or breast-feeding. 
25. Any condition, which, in the site investigator’s opinion, makes the subject 
unsuitable for trial participation. 
26. Substance abuse, medical, psychological, or social conditions that may interfere 
with the subject’s participation in the study or evaluation of the study results. 
27. Treatment with any investigational agent within 28 days prior to registration. 
STATISTICAL 
CONSIDERATIONS 
 
Ninety (90) subjects will be enrolled and randomized using a 2:1 allocation with 60 
subjects enrolled in the Regorafenib + Ginseng group and 30 enrolled in the 
Regorafenib + placebo No Ginseng group. Expected standard deviations for the 
outcome of interest are 27.0 for the Ginseng group and 26.1 for the no ginseng group. 
Using a two group Satterthwaite t-test with a 0.050 two-sided significance level, 
there is 80% power to detect a difference between groups if the change in the No 

 
 
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Ginseng group is 10 and the change in the Ginseng group is 27 (or greater). A two-
sided 95.0% confidence interval for the difference of the two means (change in 
fatigue score for Ginseng group vs change in fatigue score for no ginseng group) will 
extend 11.833 from the observed difference in means, assuming that the common 
standard deviation is 27.0 (conservatively choosing the standard deviation from the 
Ginseng group since it is larger than the no ginseng standard deviation) when the 
sample sizes are 60 and 30 respectively (a total sample size of 90) and the confidence 
interval is based on the large sample z statistic.  
ESTIMATED 
ENROLLMENT 
PERIOD 
12 months 
ESTIMATED STUDY 
DURATION  
18 months 
 
 

 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... 8 
SCHEMA ..................................................................................................................................... 11 
1. 
BACKGROUND AND RATIONALE ............................................................................... 12 
2. 
STUDY OBJECTIVES ....................................................................................................... 13 
3. 
ELIGIBILITY CRITERIA ................................................................................................. 13 
4. 
SUBJECT REGISTRATION ............................................................................................. 17 
5. 
TREATMENT PLAN.......................................................................................................... 17 
6. 
TREATMENT DISCONTINUATION .............................................................................. 25 
7. 
STUDY SCHEDULE OF EVENTS ................................................................................... 27 
8 
CRITERIA FOR DISEASE EVALUATION.................................................................... 31 
9 
STUDY DRUG INFORMATION ...................................................................................... 34 
10 DEFINITIONS OF ADVERSE EVENTS ...... ERROR! BOOKMARK NOT DEFINED. 
11 STATISTICAL CONSIDERATIONS ............................................................................... 40 
12 TRIAL MANAGEMENT ................................................................................................... 42 
13 DATA HANDLING AND RECORD KEEPING ............................................................. 43 
14 ETHICS ................................................................................................................................ 45 
15 REFERENCES .................................................................................................................... 46 
 
 

 
 
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LIST OF ABBREVIATIONS 
 
ADL 
Activities of Daily Living  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
Ang 
Angiopoietin 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BCRP 
Breast Cancer Resistance Protein 
BID 
bis in die, twice daily 
BP 
Blood pressure 
B-Raf 
B isoform of Rapidly Accelerated Fibrosarcoma protein 
BUN 
Blood Urea Nitrogen 
CBC 
Complete blood count 
CCCWFU 
Comprehensive Cancer Center of Wake Forest University 
CFR 
Code of Federal Regulations 
c-KIT 
Stem Cell Factor Receptor Tyrosine Kinase 
CR 
Complete Response 
C-RAF 
C isoform of Rapidly Accelerated Fibrosarcoma protein 
CRC 
Colorectal cancer 
CRF 
Cancer-related fatigue 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program  
CYP2C19 
Cytochrome P450 2C19 
CYP2D6 
Cytochrome P450 2D6 
CYP3A4 
Cytochrome P450 3A4 
DCE 
Dynamic Contrast Enhanced 
DMSO 
Dimethyl sulfoxide 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EOT 
End of treatment 
ERK 
Extracellular Signal-regulated Kinases 
FACT-F 
Functional Assessment of Cancer Therapy: Fatigue 
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 
HCRN 
Hoosier Cancer Research Network 
HFSR 
Hand-foot-skin reaction 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 

 
 
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HPA 
Hypothalamic-pituitary-adrenal 
IB 
Investigator’s Brochure 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug 
IL-1β 
Interleukin 1 beta 
IL-2 
Interleukin 2 
IL-6 
Interleukin 6 
IL-8 
Interleukin 8 
INR 
International normalized ratio 
IR 
Immediate Release 
IRB 
Institutional Review Board 
MAPK 
Mitogen Activated Protein Kinase 
MEK 
MAP Kinase / ERK Kinase 1 
MFSI-SF 
Multidimensional Fatigue Symptom Inventory-Short Form 
mL 
Milliliter 
NCI 
National Cancer Institute 
NM 
Nanomolar 
NYHA 
New York Heart Association 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive Disease 
PDGFR-β 
Platelet Derived Growth Factor Receptor-beta 
PFS 
Progression free survival 
po 
per oris, oral 
PR 
Partial Response 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PS 
Performance Status 
PTT 
Partial thromboplastin time 
QC 
Quality control 
QOL 
Quality of life 
RAF 
Rapidly Accelerated Fibrosarcoma 
RAS 
Rat sarcoma 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria for Solid Tumors 
RET 
Rearranged during transfection 
rpm 
Revolutions per minute 
RPMI-1640 
Roswell Park Memorial Institute medium 1640 
RTK 
Receptor Tyrosine Kinase 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SPM 
Study Procedures Manual 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TIE2 
Tyrosine kinase with Immunoglobulin and Epidermal Growth Factor 
(EGF) homology domain 2 
TK 
Tyrosine Kinase 

 
 
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TK 
Tyrosine Kinase 
TNF-α 
Tumor necrosis factor alpha 
TTP 
Time to Progression 
UGT1A1 
UDP-glucuronosyltransferase 1-1 
UGT1A9 
UDP-glucuronosyltransferase 1-9 
ULN 
Upper limit of normal 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
WBC 
White blood cell 
 
 

 
 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (2:1 in favor of ginseng arm) 
Regorafenib + Ginseng 
for 8 weeks 
Regorafenib+ No Ginseng  
for 8 weeks 
Subjects with stage IV adenocarcinoma of the colon who are 
candidates for regorafenib treatment 
Fatigue and Disease 
evaluation  
after 8 weeks 

 
 
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1. BACKGROUND AND RATIONALE 
Safe, effective interventions to improve cancer-related fatigue (CRF) are needed because it 
remains a limiting factor for quality of life as well as a prevalent, distressing, and activity-
limiting symptom. In addition, patients impacted by low levels of fatigue are not candidates for 
active anticancer therapies. Furthermore, patients have difficulty remaining on active anticancer 
therapies because of declines in performance status. Fatigue is a major component of declining 
performance and many times, it is difficult to estimate if it is drug related or cancer related. The 
prevalence of fatigue in patients undergoing chemotherapy is reported to be between 59% and 
96% and, in patients receiving radiation therapy, between 65% and 100%. Therefore, improving 
energy level could increase adherence and eligibility to active anticancer therapies. A phase III 
trial was developed to evaluate the efficacy of American ginseng (Panax quinquefolius) on 
cancer related fatigue and reported that 2,000mg daily of American Ginseng significantly 
decreased the level of fatigue in the treatment group  [1].  
 
Regorafenib is a recently approved active treatment for good performance status patients with 
colorectal cancer (CRC) as a third line. 47% of the patients in the regorafenib group had fatigue 
of any grade compared with 28% in the placebo group. 9% of patients in the regorafenib group 
had grade 3 fatigue versus 5% in the placebo group. Most adverse events occurred early in the 
course of treatment (during cycles 1–2) [2] .Fatigue can be significant and debilitating in the first 
few cycles, and symptoms, which are most prominent toward the end of dosing in each cycle, 
can begin early (e.g., hoarseness within the first 3–4 days) [3]. 
 
We hypothesize that Ginseng will decrease fatigue and increase adherence to chemotherapy for 
patients receiving regorafenib for colon cancer.  
 
We propose a randomized phase II study of Ginseng in colorectal cancer patients treated with 
Regorafenib to determine if Ginseng will reduce fatigue in this patient population and improve 
adherence to Regorafenib.  
 
Specific Hypothesis: Regorafenib is a recently approved active, third line treatment for good 
performance status patients with CRC. One of the potential treatment-limiting toxicities is 
fatigue, observed in approximately 50% of the patients. We hypothesize that Ginseng will 
decrease fatigue and increase adherence to chemotherapy for patients receiving regorafenib for 
colon cancer. The fatigue level will be evaluated with 2 different scales: MFSI-SF 
(multidimensional fatigue symptom inventory-short form) and PROMIS (Patient-Reported 
Outcomes Measurement Information System) Short Form v1.0 – Fatigue 8a [4] . The Patient-
Reported Outcomes Measurement Information System (PROMIS) initiative is an example of an 
effort to develop a standard battery of valid and reliable measures that can be used in symptom 
management and QOL research [5].We will use the MFSI-SF tool that was used in the original 
ginseng study by Barton et.al and compare its results with the PROMIS scale which represents 
the NCI recommended tool to evaluate symptoms in oncology clinical trials [6].  
 
 

 
 
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2. STUDY OBJECTIVES AND ENDPOINTS 
 
2.1. 
Primary Objective  
Assess the difference in fatigue scores using the Multidimensional Fatigue Symptom Inventory-
Short Form (MFSI-SF) and Patient-Reported Outcomes Measurement Information System 
(PROMIS Short Form v1.0 – Fatigue 8a) for each group (Regorafenib+ No Ginseng vs. 
Regorafenib + Ginseng) to determine if 2000 mg of American Ginseng for 8 weeks has an 
impact on the fatigue score. 
 
2.2. 
Secondary Objectives 
1) Assess the difference in adherence to regorafenib between the two groups. Pill counts will be 
used to assess adherence. The hypothesis is that Ginseng may increase adherence by 
decreasing fatigue. 
 
2) Assess the difference in toxicities between the two arms. 
 
3) Assess the difference in retention between the two arms.  Retention is the proportion of 
subjects who complete the study.  Note that they may not completely adhere to the study 
medication, but as long as they come in for the last measurements, they are considered 
retained.  
 
4) Assess response rate and overall survival  
 
2.3 
Endpoints 
Fatigue score, adherence, toxicity and retention  
 
3. ELIGIBILITY CRITERIA 
 
3.1. 
Inclusion Criteria 
 
1. Subjects must be able to understand and be willing to sign the written informed consent and 
HIPAA authorization for release of personal health information. A signed informed consent 
form must be appropriately obtained prior to the conduct of any trial-specific procedure. 
NOTE:  HIPAA authorization may be included in the informed consent or obtained 
separately. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. Life expectancy of at least 12 weeks (3 months) as determined by the treating physician. 
 
4. ECOG Performance Status of 0 or 1 within 28 days prior to registration. 
 
5. Histological or pathologically confirmed stage IV adenocarcinoma of the colon.  
 
 

 
 
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6. Adequate bone marrow, liver and renal function as assessed by the following laboratory 
values obtained within 7 days prior to registration for protocol therapy. 
• Absolute neutrophil count (ANC) count > 1,500/mm3 
• Hemoglobin (Hgb) > 9g/dL 
• Platelet count > 100,000/mm3 
• Total bilirubin ≤ 1.5 × the upper limit of normal (ULN).  
• Alanine aminotransferase (ALT) and aspartate amino-transferase (AST)  ≤ 2.5 x ULN 
(≤ 5 × ULN for subjects with liver involvement of their cancer) 
• Alkaline phosphatase limit ≤ 2.5 × ULN (≤ 5 × ULN for subjects with liver 
involvement of their cancer) 
• Serum creatinine ≤ 1.5 × the ULN 
• International normalized ratio (INR)/Partial thromboplastin time (PTT) < 1.5 × ULN. 
NOTE: Subjects who are prophylactically treated with an agent such as warfarin or 
heparin will be allowed to participate if no prior evidence of underlying abnormality 
in coagulation parameters exists. Close monitoring of at least weekly evaluations will 
be performed until INR/PTT is stable based on a measurement that is pre-dose as 
defined by the local standard of care.  Warfarin dose should not exceed 1 mg 
 
7. 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.  
 
8. Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least2 months after the last dose of 
study drug. The definition of adequate contraception will be based on the judgment of the 
treating physician or a designated associate. 
NOTE: Examples of adequate contraception may include but are not limited to a 
combination of any two of the following: 
• Use of oral, injected or implanted hormonal methods of contraception 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
• Total abstinence 
• Male/female sterilization 
 
9. All subjects must have radiographically assessable disease per RECIST v1.1 obtained by 
imaging within 28 days prior to registration. 
 
10. Must be able to swallow and retain oral medication.  
 
11. Subject must be deemed a suitable candidate for regorafenib as per their treating physician 
 
 

 
 
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3.2. 
Exclusion Criteria 
 
1. Subject should not be receiving any agent for fatigue including steroids or megace.  
NOTE: Subjects who have a contrast-induced allergy are allowed to receive steroids for their 
scans.  
 
2. Radiotherapy within 2 weeks prior to study registration. Subjects must have recovered from 
all therapy-related toxicities.  
 
3. Prior treatment with regorafenib. 
 
4. Previous assignment to treatment during this study. Subjects permanently withdrawn from 
study participation will not be allowed to re-enter study. 
 
5. Congestive heart failure > New York Heart Association (NYHA) class 2. 
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 
months). Myocardial infarction less than 6 months before study registration. 
• Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are 
permitted). 
• Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure 
> 90 mmHg despite optimal medical management). 
 
6. Evidence or history of bleeding diathesis or coagulopathy. 
 
7. Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to study 
registration.  
 
8. Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular 
accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism 
within 6 months of study registration. 
 
9. Previous or concurrent cancer that is distinct in primary site or histology from colorectal 
cancer within 3 years prior to randomization EXCEPT for curatively treated cervical cancer 
in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (Non-invasive tumor), 
Tis (Carcinoma in situ) and T1 (Tumor invades lamina propria)]. 
 
10. Subjects with pheochromocytoma. 
 
11. Known history of human immunodeficiency virus (HIV) infection or current chronic or 
active hepatitis B or C infection requiring treatment with antiviral therapy. 
 
12. Ongoing infection > Grade 2 NCI-CTCAE v4.0. 
 
13. Metastatic brain or meningeal tumors (symptomatic or asymptomatic). 
 

 
 
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14. Major surgical procedure or significant traumatic injury, as defined by the site investigator, 
within 28 days before study registration. 
 
15. Renal failure requiring hemo- or peritoneal dialysis. 
 
16. Dehydration Grade > 2 NCI CTCAE v4 within 7 days prior to registration. 
 
17. Subjects with seizure disorder currently requiring medication. 
 
18. Persistent proteinuria ≥ Grade 3 NCI CTCAE v4.0 as defined as > 3.5 g/24 hours, measured 
by urine protein: creatinine ratio on a random urine sample. 
 
19. Interstitial lung disease with ongoing signs and symptoms at the time of study registration.  
 
20. Pleural effusion or ascites that causes respiratory compromise (≥ NCI CTCAE version 4.0 
Grade 2 dyspnea). 
 
21. History of organ allograft (including corneal transplant). 
 
22. Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or 
excipients of the formulations given during the course of this trial. 
 
23. Any malabsorption condition which, in the opinion of the treating physician, will affect the 
absorption of any of the agents used in this study. 
 
24. Women who are pregnant or breast-feeding. 
 
25. Any condition, which, in the site investigator’s opinion, makes the subject unsuitable for trial 
participation. 
 
26. Substance abuse, medical, psychological, or social conditions that may interfere with the 
subject’s participation in the study or evaluation of the study results. 
 
27. Treatment with any investigational agent within 28 days prior to registration. 
 
3.3. 
Excluded therapies and medications, previous and concomitant 
 
1. Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, 
biologic therapy, or tumor embolization) other than study treatment (regorafenib, other 
agents being investigated in combination with regorafenib) 
NOTE: Steroids for contrast related allergy or pain management are allowed. 
 
 

 
 
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2. Subjects on therapeutic anticoagulation will be excluded form study.  
NOTE: 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. 
• Low dose aspirin ( 100 mg daily). 
• Prophylactic doses of heparin. 40 mg daily  
 
3. Subjects with prior history of a bleeding disorder will be excluded from study. 
 
4. Concurrent use of any herbal remedy or preparation other than ginseng (e.g. St. John’s wort 
[Hypericum perforatum]) 
 
3.4. 
Inclusion of Women and Minorities 
Men and women of all races and ethnicities who meet the above-described eligibility criteria are 
eligible for participation in this study. 
 
4. SUBJECT REGISTRATION 
All subjects must be registered and randomized through the Hoosier Cancer Research Network 
(HCRN) electronic data capture (EDC) system. 
  
Subjects must be registered and randomized prior to starting protocol therapy. Subjects must 
begin therapy within 5 business days of randomization.  
 
5. TREATMENT PLAN 
Regorafenib will be administered 160 mg once daily for the first 21 days of each 28-day cycle.  
Subjects that randomize to receive Ginseng will take 2,000 mg orally once daily every day for 8 
weeks (2 cycles). Subjects that randomize to NOT receive Ginseng will not be given Ginseng.  
Subjects will be instructed to take regorafenib with a low-fat meal. 
 
Subjects will undergo the fatigue assessments, using the MFSI-SF instrument and PROMIS 
according to the study calendar. Subjects will have a pill count C2D1 and at the end of treatment 
visit. Subjects will have the re-staging scan (CT of chest/abdomen/pelvis) at the end of Cycle 2/ 
week 8 (±5). See Study Procedures Manual for questionnaire administration and pill count 
instructions. 
  
 
 

 
 
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5.1. 
Study Drug Administration 
 
Table 1: Study Drug Administration; One cycle is 28 days.  
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Regorafenib 
160 mg 
Days 1-21 of each  
28-day cycle 
Orally 
2 
Ginseng  
1,000 mg 
Twice a day (total of 
2,000 mg per day) for 
4 weeks (28 days) 
Orally 
2 
 
5.1.1 Treatment Schedules 
 
5.1.1.1 Regorafenib 
Regorafenib 160 mg PO once daily will be taken for 3 weeks on/1 week off for 2 cycles. Four 
40-mg regorafenib tablets should be taken once a day with approximately 8 fluid ounces (240 
mL) of water after a low-fat (<30% fat) meal. Some examples of a low-fat meal are: 
• Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of 
jelly and 8 ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g of fat). 
• One cup of cereal (i.e. Special K), 8 ounces (240 mL) of skim milk, one piece of toast 
with jam (no butter or marmalade), apple juice, and one cup of coffee or tea (2 g fat, 17 g 
protein, 93 g of carbohydrate, 520 calories. 
 
5.1.1.2 Ginseng  
Ginseng 2,000 mg per day will be taken for 4 weeks on for 2 cycles. Dosing will be 1,000 mg 
PO twice a day. The (4) 500 mg capsules consist of pure ground root of Wisconsin ginseng and 
should be swallowed whole. Do not chew, crush or break. May be taken with or without food. 
For subjects that randomize to ginseng, if regorafenib is held due to toxicity the ginseng may 
continue per protocol schedule. 
 
5.1.2 Missed Doses 
Missed doses can be within 4 hours of the time that the dose was scheduled. If the timing is 
beyond 4 hours, the subject will skip the dose and take the next dose as scheduled. Under no 
circumstances should a subject take two doses on the same day to make up for a missed dose 
from the previous day. 
 
5.1.3 Pre-medications 
Premedication is not required, but can be implemented per site investigator discretion. 
 
5.1.4 Concurrent 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 site 
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 

 
 
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that is metabolized by the cytochrome enzymes CYP2C8, CYP2B6, and CYP2C9. Such 
concomitant medication should be avoided, if possible. 
 
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of 
regorafenib decreased the mean exposure of regorafenib, increased the mean exposure of the 
active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite 
M-2. Avoid concomitant use of regorafenib with strong CYP3A4 inducers (e.g. rifampin, 
phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) 
 
Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160mg dose of 
regorafenib increased the mean exposure of regorafenib and decreased the mean exposure of the 
active metabolites M-2 and M-5. Avoid concomitant use of regorafenib with strong inhibitors of 
CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, 
posaconazole, telithromycin, and voriconazole). 
 
Permitted concomitant therapy includes: 
• Standard therapies for concurrent medical conditions. 
• Supportive care for any underlying illness. 
• 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 site 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 if they do not interfere with the study endpoints, in the opinion 
of the site investigator. 
• Bisphosphonates 
 
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 (other than testosterone supplements used to treat 
erectile dysfunction). 
• Bone marrow transplant or stem cell rescue 
• Subjects taking narrow therapeutic index medications should be monitored proactively 
(e.g. warfarin, phenytoin, quinidine, carbamazepine, Phenobarbital, cyclosporine, and 
digoxin). Warfarin is metabolized by the cytochrome enzyme CYP2C9 and its levels may 
be especially affected by regorafenib 
• Use of any herbal remedy or preparation other than ginseng (e.g. St. John’s wort 
[Hypericum perforatum]) 
 
5.2. 
Dose Modifications 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be used 
to grade adverse events. 
 

 
 
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Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Section 7. 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation at each study visit for the duration of 
their participation in the study. 
 
A treatment-limiting adverse event is any adverse event related to study drug experienced during 
the study resulting in treatment termination. 
 
5.2.1 Dose Modifications for Ginseng 
For subjects randomized to receive ginseng there are no dose delays or reductions. If regorafenib 
is held due to toxicity, the ginseng may continue if the toxicity is attributed to regorafenib only.  
 
5.2.2 Dose Modifications for Regorafenib 
 
5.2.2.1 
Dose Reduction Levels 
The starting dose of regorafenib is 160 mg once daily. Study medication will be administered on 
a 3 weeks on/1 week off schedule [3 weeks out of every 4]. 
 
Doses will be delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to protocol therapy according to the guidelines shown in the Dose 
Delays/Dose Modifications table that follows. Dose modifications will follow predefined dose 
levels. Dose adjustments for hematologic toxicity are based on the blood counts obtained in 
preparation for the day of treatment. 
 
The modifications of regorafenib will follow the following predefined dose levels: 
Dose level 0 (standard starting dose) 
160 mg orally 
every day 
Four 40-mg tablets of regorafenib 
Dose level - 1 
120 mg orally 
every day  
Three 40-mg tablets of regorafenib 
Dose level - 2 
80 mg orally 
every day  
Two 40-mg tablets of regorafenib 
 
If a subject experiences more than one toxicity, dose reduction should be according to the 
toxicity with the highest grade. 
  
In the case of two or more toxicities of the same grade, the site 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 160 mg daily dose) at the discretion of the 
treating physician, provided that the toxicity(ies) has resolved to baseline. 
 
The following tables outline dose adjustments for toxicities related to study drug except hand-
foot skin reaction, hypertension, and liver function test abnormalities.  

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

 
 
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(NCI-CTCAE v4.0) 
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 site investigator. 
b. If toxicity returns to Grade 0-1 after dose reduction, dose re-escalation is permitted at the discretion of the site 
investigator if subject has completed one cycle at reduced dose without recurrence of event. 
c. If there is no recovery after a 4-week delay, treatment with regorafenib will be discontinued permanently. 
d. Subjects requiring > 2 dose reductions should go off protocol therapy. 
e. The maximum daily dose is 160 mg. 
 
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. 
 
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. 
 

 
 
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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 Epsom salts 
 
Hypertension 
Hypertension is a known AE associated with regorafenib treatment. Subject will have their blood 
pressure measured at every clinic visit or more frequently if clinically indicated. 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 site 
investigator. Every effort should be made to control blood pressure by medical means other than 
study drug dose modification. If necessary, the table below outlines suggested dose reductions. 
 
Management of Treatment-Emergent Hypertension 
Grade   
(CTCAE v4.0) 
Antihypertensive Therapy 
Regorafenib Dosing 
1 
 
Prehypertension (systolic BP 120 - 
139 mmHg or diastolic BP 80 - 89 
mmHg) 
None 
• Continue regorafenib 
• Consider increasing blood pressure (BP) 
monitoring 
2 
 
Systolic BP 140 - 159 mmHg or 
diastolic BP 90 – 99 mmHg, 
OR 
Symptomatic increase by > 20 
mmHg (diastolic) if previously 
within normal limits 
• Treat with the aim to 
achieve diastolic BP ≤ 90 
mm Hg: 
• If BP previously within 
normal limits, start anti-
hypertensive monotherapy 
• If subject already on anti-
hypertensive medication, 
titrate up the dose. 
• Continue regorafenib 
 
• If symptomatic, hold regorafenib until 
symptoms resolve AND diastolic BP ≤ 
90 mm Hga. When regorafenib is 
restarted, continue at the same dose 
level. 
 

 
 
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3 
 
Systolic BP ≥ 160 mmHg or 
diastolic BP ≥ 100 mmHg 
OR 
More than one drug or more 
intensive therapy than previously 
used indicated 
Treat with the aim to 
achieve diastolic BP ≤ 90 
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. Subjects requiring a delay of >4 weeks should go off protocol therapy 
b. If BP remains controlled for at least one cycle, dose re-escalation permitted per site investigator’s discretion. 
c. Subjects requiring >2 dose reductions should go off protocol therapy. 
 
Liver Function Abnormalities 
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. 
 
For subjects with observed worsening of serum liver tests considered related to regorafenib (i.e. 
where no alternative cause is evident, such as post-hepatic cholestasis or disease progression), 
the dose modification and monitoring advice in the table below should be followed. 
 
Regorafenib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur 
in subjects with Gilbert’s syndrome. 
 
 

 
 
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Dose Modification/interruption for alanine aminotransferase and/or aspartate aminotransferase 
increases related to study drug 
 
5.2.3 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., antidiarrheals and optimized hydration 
status). 
 
Anti-diarrhea medications may be introduced if symptoms occur. Previous trials have shown that 
the diarrhea could be managed with loperamide. The recommended dose of loperamide is 4 mg 
at first onset, followed by 2 mg every 2 to 4 hours until diarrhea-free for 12 hours. 
 
6 
TREATMENT DISCONTINUATION 
 
6.2 
Reasons for Discontinuing Study Drug 
In the absence of treatment delays due to adverse events, treatment may continue for up to 2 
cycles or until one of the following criteria applies: 
• Disease progression 
• Intercurrent illness that prevents further administration of study drug 
• Unacceptable adverse event(s) 
• Subject decides to withdraw from the study 
• General or specific changes in the subject’s condition render the subject unacceptable for 
further treatment in the judgment of the site investigator 
 
 
Increases in 
AST/ALT (per 
NCI CTCAE v 
4) 
1st Occurrence 
Restart 
Recurrence 
AST and/or ALT 
< 5 X ULN 
(<Grade 3) 
Continue dosing, with weekly monitoring 
of liver function until transaminases return 
to < 3 X ULN (< Grade 1) or baseline. 
 
 
ALT and/or AST 
> 5 X ULN (> 
Grade 3) 
Interrupt dosing, with weekly monitoring 
until transaminases return to < 3 X ULN 
or baseline. 
If the potential benefit of 
reinitiating regorafenib is 
considered to outweigh the risk 
of hepatotoxicity: reduce 1 dose 
level and measure serum 
transaminases weekly for at 
least 4 weeks. 
Discontinue 
ALT and/or AST 
> 20 X ULN (> 
Grade 4) 
Discontinue 
 
 
ALT and/or AST 
> 3 X ULN (> 
Grade 2) with 
concurrent 
bilirubin > 2 X 
ULN 
Discontinue treatment and measure serum 
transaminases weekly until resolution. 
Exception: subjects with Gilbert's 
syndrome who develop elevated 
transaminases should be managed as per 
the recommendations outlined above for 
ALT/AST elevations. 
 
 

 
 
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6.3 
Reasons for Withdrawal from Study 
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 site investigator’s opinion, continuation of the trial would be harmful to the 
subject’s well-being. 
• Subject is lost to follow-up. 
• Death. 
 
Subjects may be withdrawn from the study for the following reasons: 
• The subject is non-compliant with study drug, trial procedures, or both; including the use of 
anti-cancer therapy not prescribed by the study protocol. 
• Severe allergic reaction to regorafenib (such as exfoliative erythroderma or Grade 3 or 4 
hypersensitivity reaction) or ginseng. 
• The development of a second cancer.  
• Development of an intercurrent illness or situation which would, in the judgment of the site 
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 site 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 eCRF and in the subject’s medical 
records.

 
 
 
 
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7 
STUDY SCHEDULE OF EVENTS  
Cycle = 28 days 
Examination 
Screening 
Cycle 1  
 
Cycle 2 
 
After  
completion of 
Cycle 2  
End of 
Treatment  
Visit 7 
Follow up8 
-28 days 
-7 days 
Day 1 
 
Day 15 
(±3) 
Day 1 
(±3) 
Day 15 
(±3) 
(±5) 
30 days (± 7) 
after last dose 
of Cycle 2 
(±7) 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
X 
X 
X 
X 
 
X 
 
Vital signs including BP, weight 
and ECOG performance status 
X 
X9 
X 
X 
X 
X 
 
X 
 
CBC w/ differential 
 
X 
 
X 
X 
X 
 
X 
 
Complete Metabolic Profile1 
 
X 
 
X 
X 
X 
 
X 
 
PT/INR and aPTT 2 
 
X 
[D5] 
 
[X] 
 
 
X 
 
Pregnancy test3 
 
X 
 
 
 
 
 
 
 
Urinalysis10 
 
X 
X 
 
X 
 
 
 
 
AEs & concomitant medications 
X 
 
X 
X 
X 
X 
 
X 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
 
 
Pathology Review 
X 
 
 
 
 
 
 
 
 
CT chest/abdomen/pelvis4 
X 
 
 
 
 
 
X4 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
Regorafenib5 
 
X 
X 
X 
X 
 
 
 
Ginseng5 
 
X 
X 
X 
X 
 
 
 
OTHER 
 
 
 
 
 
 
 
 
MFSI-SF, PROMIS6 
 
X 
 
X6 
 
 
X 
 
Pill count6 
 
 
 
X 
 
 
X 
 
FOLLOW-UP 
 
 
 
 
 
 
 
 
For progression, start of 
additional cancer treatment, and 
survival 
 
 
 
 
 
 
 
X 
 
 
 

 
 
 
 
 
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Footnotes: 
CBC=complete blood count; CT=computed tomography; D=days; ECOG=Eastern Cooperative Oncology Group; ICS = informed consent; MFSI-SF= 
Multidimensional Fatigue Symptom Inventory-Short Form 
 
1.  Serum chemistries (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total bilirubin, alkaline phosphatase, 
and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium) 
2. All subjects will have PT/INR/aPTT at screening and End of Treatment Visit. ONLY subjects who are prophylactically treated with an agent such as warfarin 
or heparin must have close monitoring on Cycle 1 Day 5 and Day 1 of each cycle. If either of these values is above the therapeutic range, subjects should have 
at least weekly evaluations until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care. 
3. Complete only for women of childbearing potential 
4. Baseline CTs must be completed within 28 days prior to registration. CTs for re-staging will be performed after Cycle 2 (8 weeks) is complete and may be 
performed ± 5 days of scheduled clinic visit. Regardless of randomization, all subjects will follow up with their physician to discuss results. 
5. Regorafenib 160 mg PO once daily will be administered for 3 weeks on/1 week off. If subject randomizes to receive Ginseng: 2,000 mg PO per day (1,000 mg 
BID), every day of each 28-day cycle. For subjects that randomize to ginseng, if regorafenib is held due to toxicity the ginseng may continue per protocol 
schedule. 
6. See Study Procedures Manual for MFSI-SF and PROMIS questionnaires and additional information. The research nurse will provide the questionnaires to the 
subject as well as instructions on completion of the questionnaires. These instructions should include the importance of the subject completing the surveys 
without family assistance. The first set of surveys will be administered by the research nurse in the clinic via interview. The remainder of the surveys will be 
self-administered by the subject in clinic. If the subject has a question regarding the surveys the research nurse or physician will be available to respond. For 
pill count, please ask the subject to bring their pill bottle to verify number of doses taken at the time of clinic visit. 
7. The End of Treatment visit should occur 30 days after completion of Cycle 2 (± 7 days). Subjects who stop treatment prior to completion of Cycle 2 should 
have the EOT 30 days after discontinuation of treatment. Subjects who have an ongoing ≥ grade 2 or serious AE (SAE) at this visit will continue to be 
followed until the AE resolves to ≤ Grade 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, whichever is earlier.  
8. Follow up will occur in all subjects after completion of Cycle 2 every 3 months for 18 months. Follow up may be accomplished via clinic visit, phone call, or 
other avenues as appropriate. 
9 
Day -7 only ECOG performance status need be obtained. 
10 Urinalysis should be done if proteinuria is suspected as per site investigator’s discretion. 
 
 
 
 
 
 

 
 
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7.1 Screening 
 
Within 28 days of study registration 
• Informed consent statement 
• Complete medical history  
• Complete physical examination 
• Vital signs including blood pressure (BP), height, weight and ECOG performance status  
• Adverse event and concomitant medication assessment 
• Local pathology review for confirmation of adenocarcinoma 
• CT scans of the chest, abdomen, and pelvis to assess all measurable or non-measurable sites 
of disease  
 
Within 7 days of study registration 
• ECOG performance status 
• Laboratory testing: 
o Complete Blood Count (CBC) with differential and platelet count 
o Complete metabolic profile (CMP) including: serum chemistries (creatinine, glucose, 
total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total 
bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and alanine 
transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium) 
o PT/INR and aPTT  
o Urine pregnancy test or serum HCG (only for women of child bearing potential) 
o Urinalysis should be done if proteinuria is suspected as per site investigator’s discretion. 
 
7.2 On Treatment  
 
7.2.1 Cycle 1 Day 1 
 
NOTE: Cycle 1 Day 1 testing need not be repeated if completed within 7 days of starting 
protocol therapy. 
• Complete physical examination  
• Vital signs including BP, weight and ECOG performance status 
• Adverse event and concomitant medication assessment 
• MFSI-SF and PROMIS questionnaires 
• Drug administration as outlined in Section 5 and Study Calendar  
 
7.2.2 Cycle 1 Day 15 (± 3 days) 
• Complete physical examination  
• Vital signs including BP, weight and ECOG performance status 
• Laboratory testing: 
o Complete Blood Count (CBC) with differential and platelet count 
o Complete metabolic profile (CMP) 
• Adverse event and concomitant medication assessment 
• Drug administration as outlined in Section 5 and Study Calendar 
• Administer MFSI-SF and PROMIS questionnaires 

 
 
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7.2.3 Cycle 2 Day 1 (± 3 days) 
• Complete physical examination  
• Vital signs including BP, weight and ECOG performance status 
• Laboratory testing: 
o Complete Blood Count (CBC) with differential and platelet count 
o Complete metabolic profile (CMP) 
o PT/INR and aPTT 
o Urinalysis should be done if proteinuria is suspected as per site investigator’s discretion. 
• Adverse event and concomitant medication assessment 
• Drug administration as outlined in Section 5 and Study Calendar 
• Administer MFSI-SF and PROMIS questionnaires 
• Pill Count 
 
7.2.4 Cycle 2 Day 15 (± 3 days) 
• Complete physical examination  
• Vital signs including BP, weight and ECOG performance status 
• Complete metabolic profile (CMP) 
• Adverse event and concomitant medication assessment 
• Drug administration as outlined in Section 5 and Study Calendar 
• Administer MFSI-SF and PROMIS questionnaires 
 
7.2.5 After completion of Cycle 2/ 8 weeks (± 5 days) 
• CT scans of the chest, abdomen, and pelvis to assess all measurable or non-measurable sites 
of disease. Regardless of randomization, all subjects will follow up with their physician to 
discuss results. 
 
7.3 
End of Treatment: At least 30 days (±7) after the last dose of Cycle 2 
• Complete physical examination  
• Vital signs including BP, weight and ECOG performance status 
• Laboratory testing: 
o Complete Blood Count (CBC) with differential and platelet count?? 
o Complete metabolic profile (CMP) 
o PT/INR and aPTT 
• Adverse event and concomitant medication assessment 
• Administer MFSI-SF and PROMIS questionnaires 
• Pill count 
 
7.4 
Follow-Up (±7) 
Subjects will be followed every 3 months for 18 months after completion of Cycle 2:  
• Disease progression 
• Type and start date of additional cancer treatment 
• Survival status 
 
 
 

 
 
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8 
CRITERIA FOR EVALUATION 
 
8.1 
Definitions Associated with Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 
 
8.1.1 Measurable disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
8.1.2 Measurable lesions  
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥20 chest x-ray, as ≥10 mm with CT scan, or >10 
mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
8.1.3 Non-measurable lesions  
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, lymphangitis 
cutis/pulmonis, inflammatory breast disease, cystic lesions, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
 
8.1.4 Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
 
8.1.5 Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions, recorded, and 
measured at baseline. Target lesions should be selected based on their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion, which can be measured reproducibly, should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
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reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
8.1.6 Non-target lesions  
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
8.1.7 Response Criteria 
 
8.1.7.1 Evaluation of target lesions 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
Partial 
Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note:  the 
appearance of one or more new lesions is also considered progressions). 
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study 
 
8.1.7.2 Evaluation of non-target lesions 
Complete 
Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (<10 mm short 
axis) 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a subject to be considered in complete clinical response. 
Non-CR/Non-
PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits 
Progressive 
Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status 
change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed later by the sponsor-investigator. 
 
 

 
 
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8.1.7.3 Evaluation of best overall response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not evaluated 
No 
PR 
SD 
Non-CR/ Non-PD/not evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
8.2 
Definitions for Response Evaluation – RECIST version 1.1 
 
8.2.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
8.2.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response 
are first met. 
 
8.2.3 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started). 
 
8.2.4 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 
 
8.2.5 Objective response rate  
The objective response rate is the proportion of all subject with confirmed PR or CR according to 
RECIST v.1.1, from the start of treatment until disease progression/recurrence (taking as 

 
 
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reference for progressive disease the smallest measurements recorded since the start of 
treatment). 
 
8.2.6 Time to Progression  
A measurement from the date of randomization until the criteria for disease progression is met as 
defined by RECIST 1.1. Subjects who have not progressed or have died due to any cause will be 
right-censored at the date of the last disease evaluation or date of death. 
 
8.2.7 Progression Free Survival 
A measurement from the date of randomization until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be right-censored 
at the date of the last disease evaluation.  
 
8.2.8 Overall Survival  
Overall survival is defined by the date of randomization to date of death from any cause. 
 
8.3 
Measurement of Fatigue 
 
8.3.1 Multidimensional fatigue symptom inventory-short form (MFSI-SF) 
The MFSI-SF tool that was used in the original ginseng study by Barton et.al will be used in this 
clinical trial.  Please see document entitled “Information about the Fatigue Symptom Inventory 
(FSI) and the Multidimensional Fatigue Symptom inventory (MFSI)” in the SPM for detailed 
information. 
 
8.3.2 Patient –Reported Outcomes Measurement Information System (PROMIS) 
The Patient-Reported Outcomes Measurement Information System (PROMIS) initiative is an 
example of an effort to develop a standard battery of valid and reliable measures that can be used 
in symptom management and QOL research [5].  Please see the document entitled “PROMIS 
Fatigue Scoring Manual” in the SPM for detailed information. 
 
9 
DRUG INFORMATION 
The two drugs used in this trial are Regorafenib and Ginseng.  
 
9.1 
American Ginseng (Panax quinquefolius) 
Ginseng’s proposed mechanism based on preclinical and clinical data is by down regulating 
inflammatory pathways , decrease inflammation and modulate cortisol and the impact of chronic 
stress on the hypothalamic pituitary adrenal axis  [7-12] . 
 
Formulation 
Because ginseng is not regulated by the FDA and is a plant that is subject to all of the variables 
relevant to any agricultural crop, this study will use American Ginseng manufactured in 
Wisconsin, which was also used in the phase 3 clinical trial (Barton et al 2013) (Ginseng Board 
of Wisconsin, and Wausau, WI), and which is manufactured using good manufacturing practices 
by Beehive Botanicals (Hayward, WI).  
 
 

 
 
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Administration 
Subjects will take four 500-mg opaque capsules consisting of pure ground root of Wisconsin 
ginseng. Dosing will be twice a day at 1000 mg (around meal and at lunch or noon). Total dose 
is 2,000 mg per day. 
 
Precautions 
Ginseng is known to interfere with blood coagulation and some components of ginseng can 
elevate plasma insulin levels, causing hypoglycemia. Treating physicians should closely monitor 
persons with hypoglycemia or those on anticoagulants per local standard of care. 
 
Side Effects 
May cause insomnia, nervousness, restlessness, increased heart rate, increased blood pressure or 
nausea.   
 
9.2 
Regorafenib 
Regorafenib tablets will be packaged in high-density polyethylene bottles with a white child 
resistant closure and induction seal. Each bottle includes 30 tablets and a 3-gram desiccant. The 
bottles will have a label affixed containing study identification, product identification, and 
quantity of tablets. Once the drug has been received, it must be kept in a secure, dry location. 
Study drug must be stored in its original bottle at a temperature not above 25°C (77°F). 
 
The study drug must be exclusively used for the investigation specified in this protocol and it 
will only be accessible to authorized staff. 
 
Drug Logistics and Accountability 
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practices (GMP) requirements and the instructions 
given by the clinical supplies department of the Institution and will be inaccessible to 
unauthorized personnel. 
 
Storage and Handling 
Store all study drugs at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F) [See 
USP Controlled Room Temperature].  
 
Store study drugs in the original bottle.  
 
Do not remove the desiccant from the original bottle. Keep the bottle tightly closed after first 
opening. Discard any unused tablets 28 days after opening the bottle.  
 
Accountability 
The site investigator, or a responsible party designated by the site investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of charge) 
using the NCI Drug Accountability Record or another comparable drug accountability form. (See 
the CTEP website at http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines 
for Accountability and Storage of Investigational Agents” or to obtain a copy of the drug 
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Destruction and Return 
At the end of the study, unused supplies of regorafenib and ginseng should be destroyed 
according to institutional policies. Destruction will be documented on the Drug Accountability 
Record Form. A certificate of destruction should be sent to HCRN (or designee). 
 
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 site investigator, a subject may be discontinued from the trial for non-compliance with 
follow-up visits or study drug. 
 
Adverse Events 
Site investigators should refer to the Safety Information section of the current IB or prescribing 
information 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. 
 
10 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v4 will be utilized for AE 
assessment. A copy of the CTCAE v4 can be downloaded from the CTEP website at 
http://ctep.cancer.gov. All forms for AE/SAE recording and reporting can be found in the Study 
Procedure Manual or in OnCore (Documents and Information Tab). 
 
10.1 
Definitions 
 
10.1.1 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 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.  
An adverse event may include the following: an adverse event occurring in the course of the use 
of a drug in professional practice; an adverse event occurring from drug overdose whether 
accidental or intentional; an adverse event occurring from drug withdrawal and any failure of 
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10.1.2 Serious Adverse Event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria: 
• Results in death, other than death related to disease progression 
• Is life-threatening. 
o The term ‘life-threatening’ in the definition refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
o A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met: 
o The admission results in a hospital stay of less than 24 hours. 
o The admission is pre-planned.  
(i.e. elective or scheduled surgery arranged prior to the start of the study) 
o The admission is not associated with an AE (e.g. social hospitalization for purposes 
of respite care). 
o 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. 
• Results in persistent or significant disability/incapacity. 
o Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
• Is a congenital anomaly/birth defect. 
• Is another medically important serious event. 
o An event may be considered an important medical event when, based upon 
appropriate medical judgment, it may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in the definitions above. 
 
10.1.3 Adverse Drug Reaction 
Adverse reaction means any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ 
means there is evidence to suggest a causal relationship between the drug and the adverse event. 
A suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug. 
 
10.1.4 Serious Adverse Drug Reaction 
A serious adverse drug reaction is an event that meets any of the criteria for seriousness as 
previously defined and has a possible causal relationship to the study drugs. 
 
10.2 
Adverse Event Reporting 
 
10.2.1 Site Requirements for Recording Adverse Events 
Adverse events (AEs) will be recorded from the time of consent and for 30 days after the last 
dose of study drugs, regardless of whether or not the event(s) are considered related to the study 
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Criteria for Adverse Events (CTCAE) v4 will be utilized for AE reporting. A copy of the 
CTCAE v4 can be downloaded from the CTEP website at http://ctep.cancer.gov. 
 
All AEs considered related to study drug will be followed until resolution, return to baseline, or 
deemed clinically insignificant, even if this occurs post-trial. 
 
10.2.2 Site Requirements for Reporting Serious Adverse Events to HCRN 
Site investigators and other site personnel must report any SAEs occurring from the time of 
informed consent to 30 days after the last dose of study drugs.  This includes events both related 
and unrelated to the study drugs.   
 
The definition of “related” being that there is a reasonable possibility the drug caused the adverse 
experience. 
 
Unrelated 
The Adverse Event is clearly not related to the study drug(s) 
Unlikely 
The Adverse Event is doubtfully related to the study drug (s) 
Possible 
The Adverse Event may be related to the study drug (s) 
Probable 
The Adverse Event is likely related to the study drug (s) 
Definite 
The Adverse Event is clearly related to the study drug (s) 
 
The completed SAE Submission Form (see SPM) must be sent to HCRN within 24 hours of 
discovery of the event.  The form may be sent to HCRN either electronically to 
safety@hoosiercancer.org or by fax to 317-921-2053. The site investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 
 
The original copy of the SAE Submission Form and the fax confirmation sheet/email must be kept 
within the site study file. 
 
Follow-up information should be submitted to HCRN either electronically to 
safety@hoosiercancer.org or by fax to 317-921-2053, using a SAE Submission Form stating that 
this is a follow-up to the previously reported SAE and providing the follow-up number if 
appropriate.  Each re-occurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was treated, and 
whether the subject continued or withdrew from study participation. 
 
10.2.3 HCRN Requirements for Reporting Serious Adverse Events to Bayer 
HCRN will report all SAEs to Bayer within 24 hours of receipt of the SAE Submission Form 
from the site and to regulatory authorities (FDA) per federal guidelines.   
 
HCRN will report SAEs using a MedWatch form available at http://www.fda.gov/medwatch/ for 
SAEs reportable to FDA; all other SAEs will be reported using the HCRN SAE Submission 
Form.  All SAE reports must include the following minimum information:  
 
1.  The name and contact information of the reporter 
2.  The name of the study drug(s) 
3.  A description of the reported SAE 

 
 
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4.  A subject identified by one or more of the following:  
a.  Subject initials 
b.  Subject number  
c.  Knowledge that a subject who experienced the adverse event exists 
d.  Age 
e.  Sex 
5.  An investigator assessment of study drug causality.  For studies with combination therapy, a 
separate causality assessment should be provided for each study drug. 
 
Additional data which would aid the review and causality assessment of the case include but are 
not limited to:   
The date of onset 
The severity 
The time from administration of study drug(s) to start of the event 
The duration and outcome of the event 
Any possible etiology for the event 
The final diagnosis or syndrome, if known 
Action(s) taken, if any 
 
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  
 
P.O. Box 915  
 
Whippany, NJ 07981-0915  
 
Address:   
100 Bayer Boulevard, Whippany, NJ 07981  
FDX or UPS only 
67 Whippany Road, Whippany NJ 07981 for UPS 
 
Reports for all Bayer products can also be phoned in via our Medical Communications 
Department 
 
Phone:                  
1-888-842-2937 
 
10.2.4 Expedited Reporting of Other Safety Information: 
Sites will report to HCRN within 24 hours of discovery of event and HCRN shall report to 
Bayer within 24 hours of receipt of report:   
• An adverse event related to study specific procedures which the site investigator 
reasonably believes impacts subject safety (For Non-SAEs: site investigator decision 
whether to file to Bayer and other regulatory authorities). 
• Any new and important event related to treatment with the study drug(s) which the site 
investigator reasonably believes impacts subject safety (this is up to the site investigator 
to determine what is new and important and related to the study drug.  Site investigator 
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• Any pregnancy during which a female patient was exposed to the study drug(s). 
Any pregnancy in the partner of a male subject, where the male subject was exposed to 
study drug at the time of conception or conception occurred within two weeks of the last 
dose of study drug(s). 
 
Any communication, other than communication provided by Bayer, concerning safety related 
information to regulatory authorities or ethics committees including but not limited to: 
Development Safety Update Reports (DSUR) / relevant parts of IND reports for study drugs.  
Any other safety related reports, issues and queries that are either raised by or communicated to 
regulatory authorities or ethics committees. 
 
10.2.5 HCRN Reporting to the Food and Drug Administration (FDA) 
HCRN will manage the Investigational New Drug Application (IND) associated with this 
protocol on behalf of the sponsor-investigator. HCRN will cross-reference this submission to the 
IND (73,088) sponsored by Charles L Loprinzi MD at Mayo Clinic.  
 
For protocols conducted under an IND, HCRN will be responsible for all communication with 
the FDA in accordance with 21CFR312 including but not limited to the 7 and 15 Day Reports, as 
well as an Annual Progress Report.  
 
10.2.6 IND Safety Reports Unrelated to this Trial 
IND safety reports not occurring on this trial but involving the trial treatment (outside SAEs) 
received from Bayer will be forwarded to participating sites for submission to their Institutional 
Review Boards per their guidelines.  IND safety reports will also be available in HCRN 
electronic data capture system. 
 
11 
STATISTICAL CONSIDERATIONS 
 
Power/Sample Size:   
The pilot study will enroll 90 total subjects and randomize them using a 2:1 allocation with 60 
subjects enrolled in the Regorafenib + Ginseng group and 30 enrolled in the regorafenib + no 
ginseng group.  The sample size is calculated based on the MFSI-SF fatigue endpoint.  Based on 
the data published in Barton et al (2013), the expected standard deviations for the outcome of 
interest are 27.0 for the Ginseng group and 26.1 for the no ginseng group. Using a two group 
Satterthwaite t-test with a 0.050 two-sided significance level, there is 80% power to detect a 
difference between groups if the change in the no ginseng group is 10 and the change in the 
Ginseng group is 27 (or greater) (a group difference of 17 units). In addition, with this sample 
size, a two-sided 95.0% confidence interval for the difference of the two means (change in 
fatigue score for Ginseng group vs. change in fatigue score for no ginseng group) will extend 
11.833 from the observed difference in means, assuming that the common standard deviation is 
27.0 (conservatively choosing the standard deviation from the Ginseng group since it is larger 
than the no ginseng standard deviation) when the sample sizes are 60 and 30 respectively (a total 
sample size of 90) and the confidence interval is based on the large sample z statistic.   
 
Based on previous published data [1] we believe that the Ginseng mean change in fatigue score 
will likely be closer to 20 (rather than 27); thus, we do not anticipate that this trial will reach 

 
 
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statistical significance. However, we will be able to refine our estimate of the standard deviation 
for the fatigue score in this subject population and provide a 95% confidence interval to estimate 
the likely boundaries for the true effect size. This information, along with estimates of retention 
and adherence, can be used to determine the sample size for further evaluation. 
 
Furthermore, if the observed difference between groups is 12 or larger then this trial will provide 
both statistically significant and clinically meaningful evidence that Ginseng can help reduce 
fatigue in subjects taking regorafenib and a follow-up trial would not be needed. If the observed 
difference between groups at the end of the trial is 8-12 (expected difference based on previous 
study of Ginseng’s impact on fatigue), then this study will have provided strong support for the 
potential efficacy of Ginseng and the follow-up trial designed to detect an effect of that 
magnitude would be justified. If at the end of this trial the observed difference between groups is 
close to zero then this would provide evidence to suggest that the potential beneficial effects of 
Ginseng may be less than expected and would warrant further discussion about whether a future 
trial should be performed. 
 
Analyses: 
The primary objective is to assess the effect of Ginseng on fatigue using the multidimensional 
Fatigue Symptom Inventory–Short Form (MFSI-SF) and PROMIS Short Form v1.0 – Fatigue 
8a. Subjects will have fatigue assessed at baseline and at weeks 2, 4, and 8. Repeated measures 
analysis of covariance will be used to assess the effect of Ginseng on fatigue. An unstructured 
covariance matrix will be used initially to account for the within subject correlation in fatigue 
over time. Additional covariance structures (exchangeable, autoregressive, Toeplitz, etc.) will be 
considered to reduce the number of fitted parameters, and the final structure will be chosen based 
on likelihood ratio tests for nested structures and the AIC statistic for non-nested structures. The 
primary hypothesis will be assessed using a linear contrast at the end of cycle 1. Additional 
contrasts will be used to assess the difference in fatigue at each time as well as the average 
difference in fatigue over time. 
 
The secondary objectives are as follows:  
(1) To assess the difference in adherence to regorafenib between the 2 groups. We will assess 
regorafenib adherence at three times, at the end of the 3rd week of each cycle. Since the 
recommended dose is once daily for 21 days, a measure of adherence would be the number of 
pills (out of 21) that each subject takes during each cycle. Using this measure for each subject, 
we will first compare groups using a 2-sample t-test for cycle 1, cycle 2 and then overall. Next, 
we will define subjects as being adherent based on having taken their pills on 17 (or more) days 
out of 21 (i.e. over 80% adherence). Using this definition of adherence, we will fit a 2x2 table 
comparing adherence rates between groups using a 1 degree of freedom Chi-square test. In 
addition, the statistician will compare mean daily doses using a t test and median daily doses by 
using Mann-Whitney test. Our hypothesis for these analyses is that Ginseng will reduce fatigue 
and thus lead to greater adherence to regorafenib in subjects who are in the Ginseng arm when 
compared to the no ginseng arm  
 
(2) To assess the difference in toxicities between the two arms. Fisher exact tests will be used to 
assess the difference in toxicities between the two groups as well as the proportion of subjects 

 
 
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who experience grade 3 or higher toxicities of any kind according to the data safety monitoring 
plan described below.   
 
(3) To assess the difference in retention between the two arms. As subjects can drop out of the 
study at various times, we will use Kaplan-Meier methods to estimate the retention distributions 
in each group and a log-rank test to assess the difference in distributions between the two groups. 
 
(4) Response rate and overall survival are secondary objectives for the trial. Overall survival 
(OS) as an endpoint is defined in section 8.2.8 of the protocol. OS will be estimated using the 
Kaplan-Meier method13 and 90% confidence intervals derived as described in Brookmeyer and 
Crowley14. The median will be provided along with the corresponding 95% CI. Additionally, the 
25% and 75% percentiles for these endpoints will also be provided.  
 
Response rate (RR) as an endpoint is defined in section 8.2.5 of the protocol. Objective response 
(complete response + partial response) rate defined as the proportion of patients who achieve an 
objective response out of all patients treated on that arm will be estimated along with a 95% 
confidence interval.   
 
12 
TRIAL MANAGEMENT 
 
12.1 
Data and Safety Monitoring Plan 
The study will be conducted in accord with the Comprehensive Cancer Center of Wake Forest 
University’s Data and Safety Monitoring Plan.  
 
HCRN oversight activities include: 
• Review all adverse events requiring expedited reporting as defined in the protocol 
• Notify participating sites of adverse events requiring expedited reporting  
• Provide trial accrual progress and safety information to the sponsor-investigator  
• Provide data summary reports to the sponsor-investigator  
• Submit data summary reports to the lead institution Data Safety Monitoring Committee 
for review as per their DSMP. 
 
12.2 
DSMP Reporting Guidelines 
HCRN will compile data summary reports for this trial and submit these reports monthly to the 
sponsor-investigator. HCRN will submit data summary reports at a minimum twice a year to a 
Data and Safety Monitoring Committee (DSMC) associated with this protocol for review.  
 
12.3 
On-Site Monitoring 
Monitoring visits to the trial sites will be made periodically during the trial, to ensure all aspects 
of the protocol are followed. Source documents will be reviewed for verification of agreement 
with data as submitted via the data collection system. The site investigator/Institution guarantee 
access to source documents by HCRN or its designee and appropriate regulatory agencies.  The 
trial site may also be subject to quality assurance audit by Bayer Pharmaceutical or its designee 
as well as inspection by appropriate regulatory agencies. 
 

 
 
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It is important for the site investigator and their relevant personnel to be available during the 
monitoring visits and possible audits and for sufficient time to be devoted to the process. 
 
13 
DATA HANDLING AND RECORD KEEPING 
 
13.1 
Case Report Forms and Submission 
This study will utilize electronic case report form (eCRF) in the Hoosier Cancer Research 
Network (HCRN) electronic data capture (EDC) system. The EDC system is a comprehensive 
database used by HCRN. Access to the data through EDC system is restricted by user accounts 
and assigned roles. Once logged into the EDC system with a user ID and password, the EDC 
system defines roles for each user, which limits access to appropriate data. User information and 
passwords can be obtained by contacting HCRN at (317) 921-2050.  
 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in the EDC system or other secure database. If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 
The completed dataset is housed at HCRN and is the sole property of the sponsor-investigator’s 
institution. It should not be made available in any form to third parties, except for authorized 
representatives of appropriate Health/Regulatory Authorities, without written permission from 
the sponsor-investigator and HCRN.  
 
13.2 
Record Retention 
It is the expectation that all data has source documentation available at the site. The site must 
implement processes to ensure this happens. 
 
Inspections by regulatory health authority representatives (i.e. FDA and IRB[s]) are possible. 
The site investigator should notify Bayer immediately of any such inspection. 
 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all participating subject (sufficient information to link 
records; e.g., hospital records), all original signed informed consent forms, copies of all source 
documents, and detailed records of drug disposition. To comply with international regulations, 
the records should be retained by the site investigator in compliance with regulations. 
 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. Subject (hospital) files will be archived according 
to local regulations and in accordance with the maximum period permitted by the hospital, 
institution, or private practice. 
 
During data entry, range and missing data checks will be performed on-line. The checks to be 
performed will be documented in the Data Monitoring Plan for the study. A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRFs 

 
 
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will be generated for each site and transmitted to the site and the site monitor. Corrections will be 
made by the study site personnel. This will be done on an ongoing basis. 
 
13.3 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. 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.   
 
Information collected will be maintained on secure, password protected electronic systems. 
Paper files that contain personal information will be kept in locked and secure locations only 
accessible to the study team. Samples that are collected will be identified by a subject study 
number assigned at the time of registration to the trial. Any material issued to collaborating 
researchers will be anonymized and only identified by the subject study number. 
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Bayer, IRB, or government agencies, like the FDA, may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
13.4 
Changes to the Protocol 
Study procedures will not be changed without the mutual agreement of the sponsor-investigator, 
HCRN, and Bayer Pharmaceuticals.  
 
If it is necessary for the study protocol to be amended, the amendment or a new version of the 
study protocol (amended protocol) will be generated by the HCRN and must be approved by 
each IRB, Bayer Pharmaceuticals, and if applicable, also the local regulatory authority. Local 
requirements must be followed. 
 
If a protocol amendment requires a change to the Written Informed Consent Form, then the IRB 
must be notified. Approval of the revised Written Informed Consent Form by the IRB is required 
before the revised form is used.  
 
The site investigator is responsible for the distribution of these documents to his or her IRB, and 
to the staff at his or her center. The distribution of these documents to the regulatory authority 
will be handled according to local practice. 
 
Bayer Pharmaceuticals’ willingness to supply study drug is predicated upon the review of the 
protocol. HCRN agrees to provide written notice to Bayer Pharmaceuticals of any modifications 
to the protocol or informed consent. 
 
 

 
 
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14 ETHICS 
 
14.1 
Ethics Review 
The final study protocol, including the final version of the Written Informed Consent Form, must 
be approved in writing by an IRB. The site investigator must submit written approval to the 
HCRN office before he or she can enroll any subject into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subject for the study. The protocol must be re-approved by the IRB annually, as local 
regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be provided 
to the IRB according to local regulations and guidelines. 
The site investigator is also responsible for providing the IRB with reports of any serious adverse 
drug reactions from any other study conducted with the investigational product. Bayer 
Pharmaceuticals will provide this information to the sponsor-investigator. These reports will be 
reviewed by the sponsor-investigator and those considered unexpected and possibly related to 
protocol therapy and all deaths within 30 days of discontinuing treatment will be forwarded to 
participating sites for submission to their Institutional Review Boards per their guidelines. All 
other events will be held and submitted to the sites for continuing review. 
 
14.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements. 
 
14.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subject must also 
be notified they are free to discontinue from the study at any time. The subject should be given 
the opportunity to ask questions and allowed time to consider the information provided. The 
subject’s signed and dated informed consent must be obtained before conducting any procedure 
specifically for the study. The site investigator must store the original, signed Written Informed 
Consent Form. A copy of the signed Written Informed Consent Form must be given to the 
subject. 
 
 

 
 
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15 REFERENCES 
 
1. 
Barton DL, Liu H, Dakhil SR, Linquist B, Sloan JA, Nichols CR, McGinn TW, Stella PJ, 
Seeger GR, Sood A et al: Wisconsin Ginseng (Panax quinquefolius) to improve cancer-
related fatigue: a randomized, double-blind trial, N07C2. Journal of the National Cancer 
Institute 2013, 105(16):1230-1238. 
2. 
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, 
Bouche O, Mineur L, Barone C et al: Regorafenib monotherapy for previously treated 
metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, 
placebo-controlled, phase 3 trial. Lancet 2013, 381(9863):303-312. 
3. 
Grothey A, George S, van Cutsem E, Blay JY, Sobrero A, Demetri GD: Optimizing 
treatment outcomes with regorafenib: personalized dosing and other strategies to support 
patient care. The oncologist 2014, 19(6):669-680. 
4. 
Stein KD, Jacobsen PB, Blanchard CM, Thors C: Further validation of the 
multidimensional fatigue symptom inventory-short form. Journal of pain and symptom 
management 2004, 27(1):14-23. 
5. 
Yost KJ, Eton DT, Garcia SF, Cella D: Minimally important differences were estimated 
for six Patient-Reported Outcomes Measurement Information System-Cancer scales in 
advanced-stage cancer patients. Journal of clinical epidemiology 2011, 64(5):507-516. 
6. 
Garcia SF, Cella D, Clauser SB, Flynn KE, Lad T, Lai JS, Reeve BB, Smith AW, Stone 
AA, Weinfurt K: Standardizing patient-reported outcomes assessment in cancer clinical 
trials: a patient-reported outcomes measurement information system initiative. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2007, 
25(32):5106-5112. 
7. 
Jin Y, Hofseth AB, Cui X, Windust AJ, Poudyal D, Chumanevich AA, Matesic LE, 
Singh NP, Nagarkatti M, Nagarkatti PS et al: American ginseng suppresses colitis 
through p53-mediated apoptosis of inflammatory cells. Cancer prevention research 2010, 
3(3):339-347. 
8. 
Bower JE, Ganz PA, Aziz N, Fahey JL: Fatigue and proinflammatory cytokine activity in 
breast cancer survivors. Psychosomatic medicine 2002, 64(4):604-611. 
9. 
Bower JE, Ganz PA, Tao ML, Hu W, Belin TR, Sepah S, Cole S, Aziz N: Inflammatory 
biomarkers and fatigue during radiation therapy for breast and prostate cancer. Clinical 
cancer research : an official journal of the American Association for Cancer Research 
2009, 15(17):5534-5540. 
10. 
Yang CS, Ko SR, Cho BG, Shin DM, Yuk JM, Li S, Kim JM, Evans RM, Jung JS, Song 
DK et al: The ginsenoside metabolite compound K, a novel agonist of glucocorticoid 
receptor, induces tolerance to endotoxin-induced lethal shock. Journal of cellular and 
molecular medicine 2008, 12(5A):1739-1753. 
11. 
Kang A, Hao H, Zheng X, Liang Y, Xie Y, Xie T, Dai C, Zhao Q, Wu X, Xie L et al: 
Peripheral anti-inflammatory effects explain the ginsenosides paradox between poor 
brain distribution and anti-depression efficacy. Journal of neuroinflammation 2011, 
8:100. 
12. 
King ML, Murphy LL: American ginseng (Panax quinquefolius L.) extract alters 
mitogen-activated protein kinase cell signaling and inhibits proliferation of MCF-7 cells. 
Journal of experimental therapeutics & oncology 2007, 6(2):147-155. 

 
 
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13. 
Kaplan, E. L.; Meier, Paul (1958), "Nonparametric estimation from incomplete 
observations", Journal of the American Statistical Association 53 (282): 457–481 
14. 
Brookmeyer R, Crowley J (1982) A confidence interval for the median survival time. 
Biometrics 38: 29–41 
 

 
 
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Appendix 1 
 
List of medications to be used with caution during study drug treatment 
 
Category 
Drug Name 
Moderate CYP3A4/5 inhibitors 
Amprenavir, atazanavir, casopitant, 
cimetidine, darunavir, diltiazem, 
fosamprenavir, lomitapide, netupitant, 
tofisopam, verapamil 
Moderate CYP3A4/5 inducers 
Bosentan, efavirenz, etravirine, genistein, 
lersivirine, modafinil, nafcillin, 
talviraline 
Sensitive CYP3A4/5 substrates1 
Alpha-dihydroergocryptine, almorexant, 
alpaviroc, apixaban (doses <2.5 mg only), 
atazanavir, atorvastatin, avanafil, bosutinib, 
brecanavir, brotizolam, budesonide, 
buspirone, capravirine, casopitant, 
darifenacin, darunavir, ebastine, eletriptan, 
eplerenone, felodipine, fluticasone, 
ivacaftor, lomitapide, lumefantrine, 
lurasidone, maraviroc, midazolam, 
perospirone, quetiapine, ridaforolimus, 
sildenafil, ticagrelor, tilidine, tolvaptan, 
triazolam, vardenafil, vicriviroc, 
voclosporin 
Strong BSEP inhibitors 
Bosentan, fusidate, glibenclamide, sulindac, 
troglitazone (TGZ-sulfate)  
Medications that carry a possible risk for 
QT prolongation2 
Alfuzosin, apomorphine, aripiprazole, 
atazanavir, atomoxetine, bedaquiline, 
clozapine, dexmedetomidine, dolasetron, 
eribulin, famotidine, felbamate, fingolimod, 
foscarnet, gatifloxacin, gemifloxacin, 
granisetron, iloperidone, isradipine, lithium, 
mirabegron, mirtazapine, moexipril, 
norfloxacin, ofloxacin, olanzapine, 
ondansetron (4 mg or 8 mg), oxytocin, 
paliperidone, pasireotide, pipamperone, 
promethazine, quetiapine, ranolazine, 
rilpivirine, risperidone, roxithromycin, 
sertindole, telavancin, tetrabenazine, 
tizanidine, tolterodine, vardenafil, 
ziprasidone 
MATE1 and OCT2 substrates3 
Acyclovir, amantadine, amiloride, 
cephalexin, cephradine, cimetidine, 
famotidine, fexofenadine, memantine, 
metformin (also a substrate for OCT1, 

 
 
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MATE1, and MATE2K), pindolol, 
procainamide, ranitidine, and varencicline 
BCRP substrates 
Rosuvastatin, sulfasalazine 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-
fold or higher when co-administered with a potent inhibitor.  
2 Source: www.qtdrugs.org (as of Apr 7, 2015)  
3 Source: FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, 
Data Analysis, and implications for Dosing and Labeling (February 2012) and Yonezawa 
and Inui (2011) Importance of the multidrug and toxin extrusion MATE/SLC47A family 
to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br J 
Pharmacology 164:1817-25 
 
 

 
 
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Appendix 2 
 
List of prohibited medications during study drug treatment 
Category 
Drug Name 
Strong CYP3A4/5 inhibitors 
Voriconazole, boceprevir, clarithromycin, 
cobicistat, conivaptan, danoprevir/ritonavir, 
eltegravir/ritonavir, grapefruit juice, 
indinavir/ritonavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, 
telithromycin, tipranavir/ritonavir, 
troleandomycin, voriconazole 
Strong CYP3A4/5 inducers 
Avasimibe, carbamazepine, mitotane, 
phenobarbital, phenytoin, rifabutin, 
rifampin, St. John's wort (hypericum 
perforatum) 
CYP3A4/5 substrates with NTI 
Terfenadine, alfentanil, apixaban, aprepitant, 
astemizole, cisapride, cyclosporine, 
diergotamine, dihydroergotamine, 
ergotamine, fentanyl, lovastatin, nicardipine, 
nisoldipine, pimozide, quinidine, 
rivaroxaban, simvastatin, sirolimus, 
tacrolimus, terfenadine, thioridazine 
Medications with a known risk for QT 
prolongation 
Vandetanib, amiodarone, anagrelide, arsenic 
trioxide, astemizole, azithromycin, bepridil, 
chloroquine, chlorpromazine, cilostazol, 
ciprofloxacin, cisapride, citalopram, 
clarithromycin, disopyramide, dofetilide, 
domperidone, donepezil, dronedarone, 
droperidol, erythromycin, escitalopram, 
flecainide, fluconazole, halofantrine, 
haloperidol, ibutilide, levofloxacin, 
levomethadyl, mesoridazine, methadone, 
moxifloxacin, ondansetron (i.v. only), 
pentamidine, pimozide, probucol, 
procainamide, propofol, quinidine, 
sevoflurane, sotalol, sparfloxacin, sulpiride, 
terfenadine, thioridazine, vandetanib, 
venlafaxine 
NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in 
their exposure levels by the concomitant use of potent inhibitors may lead to serious safety 
concerns (e.g., Torsades de Pointes). 
Source: www.qtdrugs.org (as of Apt 7, 2015)