PK Analysis of Antitumor B in Patients With Oral Cancer
Phase: EARLY_PHASE1
Conditions: Squamous Cell Carcinoma of the Oral Cavity
Sponsor: Medical College of Wisconsin

Protocol Title:  Pharmacokinetic (PK) Analysis of Antitumor B in Patients With Oral Cancer 
Clinical Trials.gov Number:  NCT03459729 
Date of Protocol:  4/16/2020 

 
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Short Title:   Antitumor-B PK Study                                                           
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PK Analysis of Antitumor B in Patients with Oral Cancer 
 
 
 
 
 
Short Title: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stuart J. Wong, MD (Study PI) 
 
 
Current Version Number and Date 
V1 11/14/2019 
V2 4/16/2020 
 
 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board approval 
and informed consent, or as required by federal and state laws. Persons to whom this 
information is disclosed should be informed that this information is privileged and confidential 
and that it should not be further disclosed.  
Antitumor-B  
PK Study 

 
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Title: PK Analysis of Antitumor B in Patients with Oral  
 Cancer 
 
MCW Protocol No.:  IIT-WONG-ATB 
IRB Pro No.: PRO00036718  
FDA IND No.: 145798 
Principal Investigator:  
Stuart J. Wong, MD  
Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave.  
Milwaukee, WI 53226 
414-805-4600 
Email:  swong@mcw.edu  
 
Sub-investigator:   
Michael Stadler, MD 
Assistant Professor 
Department of Otolaryngology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave.  
Milwaukee, WI 53226 
414-805-8548 
Email: mstadler@mcw.edu  
 
Sub-investigator:   
Bruce Campbell MD 
Professor 
Department of Otolaryngology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave.  
Milwaukee, WI 53226 
414-805-5583 
Email: bcampbell@mcw.edu  
 
Sub-investigator:  
Becky Massey MD 
Associate Professor 
Department of Otolaryngology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave.  
Milwaukee, WI 53226 
414-805-8325 
Email: blmassey@mcw.edu  
 
Sub-investigator:  
Joseph Zenga, MD 
Assistant Professor 
Department of Otolaryngology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI  53226 
414-955-0831 
Email:  jyzenga@mcw.edu 
 
 
Sub-investigator:  
Ming Hu, PhD 
Professor  
Department of Pharmacological and  
Pharmaceutical Sciences 
1441 Moursund St. 
University of Houston 
Houston, TX 77030 
832-842-8320 
Email: mhu4@Central.UH.EDU  
 
Biostatistician: 
Anjishnu Banerjee, PhD 
Assistant Professor 
Division of Biostatistics 
Institute for Health & Society 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-955-8358 
Email:  abanerjee@mcw.edu  
 
 
 

 
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PROTOCOL SUMMARY 
Title 
PK Analysis of Antitumor B in Patients with Oral Cancer 
IND Sponsor 
Sponsor Investigator 
Funding Source 
NCI, R01 CA205633 (M. You, contact PI) 
Principal Investigator  
Stuart J. Wong, MD 
Study Sites 
Froedtert & the Medical College of Wisconsin 
Clinical Trial Phase 
Phase 0 
Study Disease 
Squamous cell cancer of the oral cavity 
Main Eligibility 
Criteria 
 
Histologically confirmed squamous cell cancer of the oral 
cavity (including variants of squamous cell histologies). 
 
New diagnosis of oral cancer for which definitive surgery is 
planned 
 
Prior diagnosis and treatment of head and neck cancer is 
allowed. 
 
ECOG Performance status < 2. 
 
Age ≥ 18 years. 
 
Normal organ function  
Study Rationale 
Establishing the PK profile for Antitumor B (ATB) is a critical initial 
step before future clinical trials can be performed that examine anti-
cancer and cancer preventive effects of ATB. 
Primary Objectives 
To examine the pharmacokinetic properties of ATB.  
Study Design 
A window of opportunity clinical trial. This study design permits 
examination of effects of an oral agent on cancer patients during the 
“window” between diagnosis of their cancer and their definitive 
cancer surgery.  Similar to a phase 0 study, the trial design permits 
examination of the biologic effects of an agent; in this study 
pharmacokinetic properties will be examined. 
Study Intervention 
Description 
Study participants will take the natural botanical compound ATB 
during a short window (seven to 28 days).  Participants will provide 
blood samples, and saliva samples during ATB administration and 
a portion of the initial tumor biopsy.  
Number of Subjects 
Eight patients will be enrolled to ensure that there will be six 
analyzable patients. 
Estimated Time to 
Complete Enrollment: 
Approximately one year. 
 

 
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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
Surgery 
Screening 
 
ATB: 
Daily administration until 
Day-1 of surgery 
 
Full PK Profiles 

 
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STUDY CALENDAR  
 
 
Period/Procedure 
Screening 
ATB Administration:  
(Daily till Day -1 of Surgery) 
  End of ATB  
 administration 
Study Day/Visit Day 
-14 to 0 
Days1 
Day 1 
 
Midway during 
ATB 
administration 
Day -2 to Day -
1 of Surgery13 
Day of Surgery 
Informed Consent  
X 
 
 
 
 
Physical Examination2 
X 
 
 
 
X 
Medical History3 
X 
 
 
 
 
Vitals 
 
X 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
ATB Administration 
 
X 
 
X 
 
Pregnancy Test (Serum or Urine)4 
X 
 
 
 
 
ECOG Performance Status5 
X 
 
 
 
X 
AE Assessment 
X 
X 
 
X 
X 
Complete Blood Count (CBC) With 
Differential and Platelet Count 
X 
 
 
 
X 
PT, INR 
 
 
 
X 
 
Complete Metabolic Panel6 
X 
 
X12 
X 
X 
Research Blood7 
 
X 
 
 
 
Research Saliva Samples8 
 
See footnote 8 for research saliva sample draw 
timepoints 
 
Tumor Specimen9 
X 
 
 
 
X 
Patient Diary10 
 
X 
 
X 
 
Compliance Assessment11 
 
 
 
X 
 

 
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1. Screening procedures must occur within 14 days prior to registration. ATB administration should start within 
seven days of registration. 
2. Focused physical examination  
3. Capture medications taken within 14 days of day 1 of ATB administration 
4. For women of childbearing potential.  
5. Refer to Appendix 1. 
6. Including albumin, total protein, total bilirubin, direct bilirubin, ALT, AST, LDH, alkaline phosphatase, 
bicarbonate, sodium, potassium, chloride, creatinine, magnesium, calcium, BUN, and glucose. 
7. Day 1: Blood samples will be taken at baseline (prior to study agent administration), then at 30, 60, 120, 180, 
240, 360, 480, and 1,440 min (a total of nine points). For each blood draw 1 ml of blood will be drawn to yield 
approximately 500 µl or 0.5 ml of plasma. All blood sample collections are allowed a window of ± 10 minutes. 
There will only be ONE ATB dose on day 1. Dose on day 2 must be delayed until completion of PK 
specimen (blood and saliva) collection.  
8. Day 1: Saliva samples (1 ml) should be collected at baseline (prior to study agent administration), then at 30, 
60, 120, 180, 240, 360, 480, and 1,440 min (a total of nine points). Note: 30 min time point has + 5 min 
window, all other time points have + 10 min window.  There will only be ONE ATB dose on day 1. All saliva 
sample collections are allowed a window of ± 10 minutes. Day 2 to day -1 of surgery:  A total of at least three 
patient samples (saliva) will be collected for each time point (predose, before lunch, and before dinner).  
9. Refer to Section 5.1. 
10. Patient will complete study diary (Appendix 2) with all relevant information and will submit the diary to study 
coordinator. 
11. Study coordinator will contact patients twice weekly for compliance assessment and reminders for protocol 
procedures. 
12. Chemistry panel with AST, ALT, T. Bilirubin will be performed approximately midway during treatment. 
13. The indicated assessment for this timepoint will be collected only once with a window of 2 days:  Day -2 to 
Day -1 of surgery.  
 
 

 
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TABLE OF CONTENTS 
PROTOCOL SUMMARY ........................................................................................................... 3 
STUDY SCHEMA ...................................................................................................................... 4 
STUDY CALENDAR .................................................................................................................. 5 
LIST OF ABBREVIATIONS ....................................................................................................... 9 
1 BACKGROUND .....................................................................................................................11 
1.1 ANTITUMOR B (ATB) .........................................................................................................11 
1.2 ATB COMPONENTS ...........................................................................................................15 
1.3 WINDOW OF OPPORTUNITY STUDY DESIGN .........................................................................16 
1.4 HEAD AND NECK CANCER .................................................................................................16 
2 HYPOTHESIS AND OBJECTIVES ........................................................................................17 
2.1 PRIMARY OBJECTIVES .......................................................................................................17 
3 STUDY DESIGN ....................................................................................................................17 
3.1 GENERAL DESCRIPTION .....................................................................................................17 
3.2 NUMBER OF PATIENTS .......................................................................................................18 
3.3 STUDY DURATION..............................................................................................................18 
3.4 STUDY COMPLETION .........................................................................................................18 
4 SUBJECT PARTICIPATION, DISCONTINUATION AND WITHDRAWAL ............................18 
4.1 SUBJECT STATUS ..............................................................................................................18 
4.2 PRESCREENING AND SCREENING LOG ................................................................................19 
4.3 CONSENT ..........................................................................................................................19 
4.4 SCREENING PROCEDURES .................................................................................................19 
4.5 ELIGIBILITY CRITERIA- PART 1 (ENROLLMENT CRITERIA FOR THE DOSE ESCALATION 
COHORT) .....................................................................................................................20 
4.6 DISCONTINUATION OF STUDY TREATMENT, WITHDRAWAL, AND COMPLIANCE .......................23 
4.7 LOST TO FOLLOW-UP ........................................................................................................23 
4.8 ACCRUAL SUSPENSION AND CLOSURE ...............................................................................24 
4.9 END OF STUDY DEFINITION ................................................................................................24 
4.10 STUDY DISCONTINUATION AND CLOSURE .........................................................................24 
5 TREATMENT PLAN ..............................................................................................................25 
5.1 ATB ADMINISTRATION .......................................................................................................25 
5.2  SUPPLY ...........................................................................................................................25 
5.3  STORAGE AND STABILITY ..................................................................................................26 
5.4  ACCOUNTABILITY .............................................................................................................26 
5.5  DRUG DESTRUCTION ........................................................................................................26 
5.6 BIOPSY SPECIMEN, OPERATIVE SPECIMEN, AND TISSUE PROCESSING ..................................26 
5.7 DOSE MODIFICATIONS .......................................................................................................27 
5.8 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ........................28 
5.9 DIETARY RESTRICTIONS ....................................................................................................28 
5.10 MONITORING SUBJECT COMPLIANCE ................................................................................28 
6 ADVERSE EVENTS: DEFINITIONS, COLLECTION AND REPORTING REQUIREMENTS .29 
6.1 DEFINITIONS .....................................................................................................................29 

 
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6.1.1 Adverse Event ............................................................................................................................................ 29 
6.1.2 Serious Adverse Event (SAE) ................................................................................................................... 29 
6.1.3 Attribution of an Adverse Event ............................................................................................................... 30 
6.1.4 Expectedness of an Adverse Event ........................................................................................................... 30 
6.2 COLLECTION AND REPORTING REQUIREMENTS FOR ADVERSE EVENTS AND SERIOUS ADVERSE
 ...................................................................................................................................30 
6.2.1 Collection of Adverse Events .................................................................................................................... 30 
6.2.2 Reporting of Adverse Events and Serious Adverse Events ...................................................................... 31 
6.2.3 Reporting Instructions .............................................................................................................................. 32 
6.3 UNANTICIPATED PROBLEM INVOLVING RISK TO SUBJECT OR OTHER (UPIRSO) ...................32 
6.4 SUBJECT COMPLAINTS ......................................................................................................32 
6.5 SAFETY ASSESSMENT .......................................................................................................32 
7 STATISTICAL CONSIDERATIONS .......................................................................................33 
7.1  STATISTICAL DESIGN AND SAMPLE SIZE CALCULATIONS ....................................................33 
7.2  STUDY OBJECTIVES AND END POINTS ...............................................................................33 
7.3  STATISTICAL METHODOLOGY AND ANALYSIS PLAN ............................................................33 
8 DATA AND SAFETY MONITORING PLAN (DSMP) .............................................................33 
8.1 DATA AND SAFETY MANAGEMENT OVERVIEW .....................................................................33 
8.2 STUDY TEAM .....................................................................................................................33 
8.3 QUALITY ASSURANCE........................................................................................................33 
8.4 CLINICAL TRIALS OFFICE ...................................................................................................33 
8.5 DSMC ..............................................................................................................................34 
9 REGULATORY COMPLIANCE, ETHICS, AND STUDY ........................................................34 
9.1 REGULATORY COMPLIANCE ...............................................................................................34 
9.2 PRE-STUDY DOCUMENTATION ............................................................................................35 
9.3 INSTITUTIONAL REVIEW BOARD ..........................................................................................35 
9.4 SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ...........................36 
9.5 PROTECTION OF HUMAN SUBJECTS ...................................................................................36 
9.5.1  
Protection from Unnecessary Harm ................................................................................................ 36 
9.5.2  
Protection of Privacy ........................................................................................................................ 37 
9.5.3 
Changes in the Protocol ........................................................................................................................ 37 
9.6 INVESTIGATOR COMPLIANCE ..............................................................................................37 
10 DATA HANDLING AND RECORD KEEPING .....................................................................38 
10.1 OVERVIEW ......................................................................................................................38 
10.2 DATA MANAGEMENT RESPONSIBILITIES ...........................................................................38 
10.3 SOURCE DOCUMENTS ......................................................................................................38 
10.4 CASE REPORT FORMS .....................................................................................................39 
10.5 STUDY RECORD RETENTION ............................................................................................39 
REFERENCES .........................................................................................................................41 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ..............................................................44 
APPENDIX 2. STUDY DIARY ...................................................................................................45 

 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CR 
complete response 
CRC 
clinical research coordinator 
CRF 
case report form 
CT 
computerized tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTO 
clinical trials office 
DFS 
disease-free survival 
DLT 
dose-limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
data and safety monitoring plan 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
HCT 
hematocrit 
HNC 
head and neck cancer 
HNSCC 
head and neck squamous cell carcinoma 
HPV 
human papilloma virus 
ICF 
informed consent form 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
MCWCC 
Medical College of Wisconsin Cancer Center 
NCI 
National Cancer Institute 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PD 
disease progression 
PK 
pharmacokinetics 

 
 
 
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PR 
partial response 
RBC 
red blood cell (count) 
SAE 
serious adverse event 
SD 
stable disease 
SD 
standard deviation 
SOP 
standard operating procedure 
SRC 
Scientific Review Committee 
ULN 
upper limit of normal 
UP 
unanticipated problem 
UPIRSO   
unanticipated problems involving risks to subjects or others 
WBC 
white blood cell (count) 
ATB 
antitumor B 
SCC 
squamous cell carcinoma 
TLC 
thin layer chromatography 
WOO 
window of opportunity 
CrCl 
creatinine clearance 
COPD 
chronic obstructive pulmonary disease 
IND 
Investigational New Drug 
ICH 
International Conference on Harmonisation 
 

 
 
 
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1 BACKGROUND 
1.1 Antitumor B (ATB) 
One of the most promising chemopreventive agents to prevent head and neck cancer is Antitumor 
B (ATB), a Chinese herbal mixture. It is a botanical agent composed of six Chinese herbs: 
Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus brachyotus, Dictamnus 
dasycarpus, and Dioscorea bulbifera. ATB is formulated as 300 mg tablets (Table 1), (8) and 
manufactured in a GMP facility by National Engineering and Research Center for TCM Shanghai 
Traditional Chinese Medicine Technology Co. Ltd. (Shanghai, China). Previously, Dr. You and 
Dr. Hu were able to secure a 20-kg batch of ATB for their proposed study in a funded NIH grant 
(NIH AT003203), and as such we are confident that we will again be able to secure a large single 
batch of ATB, enough for its exclusive use in this grant. ATB appears to be very effective in the 
chemoprevention of upper aerodigestive tract tumors in humans and also safe to several 
thousand subjects over a period of more than two decades (9–11). Earlier clinical studies 
conducted in China showed that use of ATB reduced the cancerization rate of marked esophageal 
dysplasia by 50%. (9–11) In this remarkable clinical trial, more than 2,500 cases of marked 
esophageal dysplasia were randomly divided into groups for ATB and placebo, respectively. (9–
11) After three or five years of treatment, the progression of esophageal dysplasia to esophageal 
cancer was inhibited by 52.2% and 47.3%, respectively. (9–11)  
Table 1. Botanical Raw Materials of Antitumor B (mg per 300 mg extract) 
Herbal name 
Plant parts 
used 
Form 
Content (mg/300 mg) 
Latin name 
Chinese 
name 
 
 
Range 
Midpoint 
Sophora tonkinensis 
Gagnep. 
Shan Dou 
Gen 
Dried roots 
and taproot 
Water 
extract 
54-72 
63 
Polygonum bistorta L. 
Quan 
Shen 
Dried 
rhizome 
Water 
extract 
51-63 
57 
Sonchus brachyotus 
DC. 
Bei Bai 
Jiang 
Dried whole 
plant 
Water 
extract 
51-69 
60 
Prunella vulgaris L. 
Xia Ku 
Cao 
Dried flower 
stem 
Water 
extract 
54-75 
64.5 
Dioscorea bulbifera L. 
Huang 
Yao Zi 
Dried 
rhizome 
Water 
extract 
9-18 
13.5 
Dictamnus 
dasycarpus Turcz. 
Bai Xian Pi 
Dried root 
bark 
Powder 
24-36 
30 
 
Total 
 
 
 
 
243-333 
 
288 
 
A randomized study of ATB as a preventive agent in patients with oral leukoplakia. Since 
oral SCC has etiology, histopathology, and molecular mechanism similar to esophageal SCC, it 
is likely that ATB may be effective for oral cancer chemoprevention. A recent study by Sun Z et 
al. examined the chemopreventive effects of ATB in a short-term clinical trial of oral leukoplakia. 
(8). In a three-year period, they recruited 120 patients with oral leukoplakia in Beijing, China and 

 
 
 
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administered them either ATB tablets or placebo tablets orally. The treatment regimen was 4 (300 
mg) tablets each time, three times per day for eight to 12 months. In the entire trial, they conducted 
clinical evaluations at the study entry time, monthly during the intervention, and three months after 
the study period; they recorded oral leukoplakia lesions with color photos and measured sizes. 
They defined a positive response as a disappearance or reduction of size by more than 50% at 
the final checkup, stable disease as an insignificant change in the size, and progressive disease 
as an increase in the size of the lesion by >50% or the development of new lesions. In the end, 
they found that the ATB intervention reduced the size of oral leukoplakia in 40 out of 59 patients 
whereas the placebo was effective in 9 out of 53 patients.(8) The difference was significant 
(p < 0.01). Such an effect was associated with a significant decrease in the labeling indexes of 
biomarkers of cell proliferation (AgNOR and PCNA).(8) 
ATB Dose and Schedule 
ATB has been administered in clinical studies for upper aerodigestive disease prevention in wide 
ranges of agent dose and schedule, summarized in Table 2 below. Tablet strength in all of these 
studies was 300 mg. The dose range used in clinical trials was from 2400 mg/d to 4800 mg/d. 
The duration of therapy ranged from two months to five years. 
Study description 
Dose/schedule 
SATCM (State Administration 
of 
Traditional 
Chinese 
Medicine) Multicenter Trial, 
380 hospitals, 24,275 pts 
8 tabs BID (4,800 mg/d) x2 
months ON, 1 week OFF= 
one cycle 
Duration 2 years 
Oral Leukoplakia n=150 ATB; 
control =148 
8 tabs BID (4,800 mg/d) x 2 
months 
Oral Leukoplakia. n=59 ATB; 
n=53 placebo (8)   
4 tabs TID (3,600 mg/d) 
Henan province 1983  
Esoph dysplasia, ZSP 
N=744 agent; n=777 placebo 
8 tabs QD (2,400 mg/d) x 5 
years 
1984 Hebei Province 
N=300 randomized to ZSP 
and n=149 control  
8 tabs BID (4,800/d) x 6 
months  
Table 2 Summary of clinical trials illustrating dose and schedule of ATB. 
In the current trial, the dose of ATB is in the mid-range (3,600 mg/d), but significantly shorter 
duration, compared to other ATB studies.  
Toxicity 
Toxicology studies performed in China, translated and summarized in the enclosed ATB Health 
Canada Application Supporting Documentation, indicates very low acute toxicity and no obvious 
pathologic changes in organs from chronic toxicology testing, as well as no mutagenic effects 
from the Ames test. 

 
 
 
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Previous studies of ATB, described in the ATB Health Canada Application Supporting 
Documentation, have been performed in China for prevention of upper aerodigestive cancer 
prevention. These studies were placebo controlled and utilized long duration of therapy from two 
months to five years. In China, there is a general acceptance and common use of natural 
compounds to treat and prevent disease. The style of reporting of clinical trials of natural 
compounds reflects this difference compared to the West. Toxicity is qualitatively described in 
these trials as having low rates of adverse events and high compliance rates even for duration of 
administration lasting years. In the Hebei Province study of 300 participants randomized to ATB 
(ZSP) for a duration of six months eight tablets BID (4,800 mg/d), no toxicity was observed 
including no effects in blood, liver, or kidney function. In the largest trial (24,275 patients), the 
SATCM study, blood parameters were reported on a subgroup of 349 patients from the SATCM 
study, who received ATB for three months following completion of definitive chemoradiation for 
cancer treatment, Minor or non-significant changes were observed in blood parameters.  The 
authors of the SATCM study concluded that overall ATB had little associated little acute of chronic 
toxicity (“some” patients with loose stool, and a “few” with jaundice and rash). They conclude 
further that ATB was safe for long-term administration. The SATCM study included patient-
reported questionnaires that surveyed a large array of upper intestinal symptoms associated with 
esophagitis and GERD pre- and during therapy.  The study showed improvement of symptoms in 
the ATB group compared to control. Although previous clinical trials did not specifically examine 
the effects of ATB on surgical risk, past studies had included biopsies without report of bleeding 
or healing complications.  As a safeguard, however, we have included in our amended protocol, 
a pre-operative coagulation test. 
 Preclinical Efficacy 
 
Table 3. Effect of ATB (ACAPHA) on blood parameters following chemoradiation 

 
 
 
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Chemopreventive Efficacy of ATB in 4NQO-Induced Oral Carcinogenesis. We evaluated the 
chemopreventive efficacy of ATB on the development of 4-nitroquinoline-1-oxide (4NQO)-induced 
oral SCC in A/J mice.(12) A progression protocol was used in this study by which administration 
of ATB was initiated in the diet (at 3:7 ratio in AIN76A powder diet) for eight weeks following the 
first dose of 4NQO. The ATB-containing food was the sole food supply for mice eight weeks after 
the first dose of 4NQO and continued for 24 consecutive weeks. The details of the experiment 
are described in our recent paper.(12) In the paper, we showed that ATB inhibited 4NQO-induced 
oral cancer development by ~60%. In addition, we did not observe 
any body weight changes in ATB-treated mice. To investigate the 
effects of ATB on cell proliferation, we quantified Ki-67 stained 
cells in normal, 
dysplastic, 
and 
SCC 
oral 
epithelium 
and 
found that ATB 
inhibited Ki-67 in 
both 
dysplasias 
and 
SCCs.(12) 
Recently, 
we 
have shown ATB 
exhibited 
a 
significant 
inhibitory 
effect 
on benz(a)pyrene 
[B(a)P]-induced 
lung 
tumorigenesis in 
A/J mice using 
the 
human 
equivalent 
dose 
of ATB (4 g/kg 
which equals to 
12 mg/mouse by 
oral gavage) in 
the diet (p < 0.05; 
Fig 1), which use 
a lower dose than 
our 
published 
study 
but 
was 
equally 
as 
effective. 
ATB Mechanism 
of Action 
ATB Inhibits Oral Cancer Cell Tumorigenesis via Inhibition of NF-kB Signaling Pathway. 
As the NF-ĸB signaling pathway is known to play a major role in oral cancer tumorigenesis,  (13–
16) we examined the effects of ATB in NF-ĸB signaling pathway via NF-ĸB proteomic array in 
Fig 1. Inhibition of B(a)P-induced 
lung tumorigenesis in A/J mice 
using human equivalent dose of 
ATB (4g/kg) in the diet.   
 
Figure 2 
A) Heatmap showing the suppression of NF-κB direct binding biomarkers by ATB in mouse lung 
tumors; color scheme: red  –  high expression, blue – low expression, white – middle-level 
expression; B) 11 NF-ĸB induced human oncogenic signature genes (from MSigDB) were 
significantly inhibited by ATB in mouse lung tumors, indicating the suppression of NF-ĸB signaling; C) 
NF-Kb proteomic array indicated that ATB inhibited NF-ĸB signaling activating proteins (both 
p50/105,p52/p100 and RelA/p65) while upregulated NF-ĸB  signaling inhibitory proteins ( IkBα and 
SOCS6). D) Quantification of NF-kB proteomic array results in C. Notably, ATB treatment in SCC15 
cells induced IkBα expression levels more than two folds while inhibited p50/105, p52/p100 and 
RelA/p65 expression levels compared to that of vehicle control treated SCC15 cells. 

 
 
 
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order to validate the RNA seq 
result (Fig 2 C, D). As 
predicted from the RNA seq, 
ATB 
inhibited 
NF-ĸB 
signaling pathway as NF-κB 
inhibitory proteins IkBα and 
SOCS6 were upregulated 
while 
NF-κB 
activating 
proteins (both p50/p105 and 
p52/p10) and RelA  were 
downregulated 
in 
ATB 
treated SCC15 oral cancer 
cells compared to that of 
vehicle control treated cells 
(Fig. 2). Growth of oral 
cancer 
cells, 
SCC9 
and 
SCC15 was also inhibited to 
ATB treatment in a dose-
dependent manner (Fig. 3A). 
We also further validated the 
effects of ATB on NF-κB 
signaling 
in 
SCC9 
oral 
cancer cells via Western blot 
(Fig. 3C), which confirmed 
that 
ATB 
treatment 
downregulated key components of NF-ĸB signaling pathways in SCC9 oral cancer cells. The 
functional role of the NF-κB signaling pathway in ATB efficacy was further validated with H1299 
lung cancer cells expressing dominant negative IkBα. Growth rate was significantly inhibited in 
H1299 cells expressing IkBα dominant negative compared to that of control and they were 
resistant to ATB treatment whereas control H1299 cells were sensitive to ATB treatment in terms 
of cell proliferation (Fig. 3B). It has been reported that expression of dominant negative IkBα 
suppressed oral cancer proliferation, survival and tumor growth both in vitro and in vivo, (17) 
which indicate the important role of NF-kB signaling pathway in oral cancer tumorigenesis. We 
are performing the same experiments with SCC9 and SCC15 oral cancer cell lines expressing 
dominant negative IkBα and a similar result is expected. Therefore, we propose that NF-ĸB 
pathway plays a key role in mediating the efficacy of ATB in oral cancer. 
Although our preclinical data are compelling regarding the efficacy of ATB as a cancer preventive 
agent, it is necessary for us to first examine pharmacokinetic properties of ATB to test the 
hypothesis that oral administration of ATB will have the desirable PK properties in 
humans. 
1.2 ATB Components 
There are six plants in ATB, described above, and the presence of each of the plants can be 
verified using a standard thin layer chromatography (TLC) method based on official Compendium 
of Chinese Pharmacopeia. However, the only compound used in the product’s current quality 
control criteria was matrine, which was only moderately active against lung cancer cell line LM1. 
To identify additional compounds useful for QA and QC purposes, we performed activity guided 
fractionation of ATB,(18) and identified the following three compounds from a more active fraction 
GS409 using oral cancer cell line SCC2095: fraxinellone, dictamnine and maackiain (see Fig. 4 
Fig 3. Proposed Mechanism of ATB in the Inhibition of HNSCC Tumorigenesis 
A) ATB inhibited cell proliferation of both SCC9 and SCC15 in doses dependent 
manner. B) Induction of I IkBα dominant negative in H1299 lung cancer cells 
abrogated anti-proliferative effects of ATB compared to that of control H1299 cells. C) 
SCC9 oral cancer cells treated with ATB and NF-ĸB pathway were examined by 
western blot. ATB inhibited NF-ĸB pathway in SCC9 oral cancer cells compared to 
that of cells treated with vehicle control. D) Proposed mechanism of ATB in the 
inhibition of HNSCC tumorigenesis based on the preliminary data.  

 
 
 
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for structures). Trifolirhizin is also expected to be highly active because it is rapidly bio transformed 
to maackiain in vivo. (19) 
 
 
 
1.3 Window of Opportunity Study Design 
Window of opportunity (WOO) trial design,(23) similar in concept as a phase 0 trial design, is well 
established and is typically used in the early development of novel targeted anti-cancer agents. 
(23) Employing this trial design, a study participant will receive administration of a natural 
compound for a short duration during the standard waiting period prior to their definitive anti-
cancer treatment, which is nearly always surgery in the case of oral cancer. Traditional clinical 
endpoints (such as objective response) are typically not the primary objective in WOO or phase 
0 trials. 
Most commonly, the primary objective is to determine whether an agent achieves its desired or 
predicted PD/PK parameters (as proposed here). The utility of these biomarker-based early phase 
trials for oral premalignancy, such as proposed here, has been highlighted by Szabo. (24)  
The clinical trial study design, proposed here, is shown in study schema. This study will enroll 
patients with resectable stage I-IVB squamous cell cancer of the oral cavity who are candidates 
for surgical tumor resection. Participants will agree to take the study agent for seven to 28 days, 
allowing collection of specimens for pharmacokinetic testing (blood, saliva, and tumor tissue).   
1.4 Head and Neck Cancer 
Head and neck cancer refer to a group of biologically similar cancers originating from the upper 
aerodigestive tract, including the lips, oral cavity, nasal cavity, paranasal sinuses, pharynx, and 
larynx. Most head and neck cancers are SCC originating from the flattened epithelium of these 
regions. Head and neck cancer accounts for about 3–5% of all malignancies in Western countries 
with cancer of the oral cavity accounting for 30% of all head and neck cancers. Oral cancer is the 
sixth most frequent cancer in the world and approximately 36,500 new cases are diagnosed and 
8,000 patients die annually in the United States from this disease. (1) Squamous cell carcinomas 
(SCC) are the most common malignant neoplasm of the oral cavity. Surgical resection is the 
primary treatment for SCC of the oral cavity.  More than 90% of oral cancer is SCC, of which most 
have premalignant epithelial lesion stages, such as oral leukoplakia and erythroplakia. (2, 3) The 
survival rate of patients with HPV negative and oral cavity SCC of the head and neck (HNSCC) 
remains poor. (4, 5) Despite significant advancements in chemotherapy and radiation therapy, 
five-year survival rates for these patients have not changed markedly in the past two decades (6, 
O
O
O
O
HO
H
H
O
O
O
Fraxinellone
Maackiain
O
O
O
O
O
O
OH
HO
HO
HO
H
H
Trifolirhizin
Dictamnine
N
O
OCH3
Fig 4.  Chemical structures of key active compounds present in ATB and active against lung tumor  
           cell lines LM1 and/or oral cancer cell line SCC2095.    

 
 
 
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7). Development of effective chemopreventive interventions of HNSCC is, therefore, urgently 
needed. ATB may have efficacy in treating or preventing HNSCC, however establishing 
pharmacokinetic properties is an essential first step. 
2 HYPOTHESIS AND OBJECTIVES 
We hypothesize that oral administration of ATB will have the desirable PK properties in humans. 
We propose to examine pharmacokinetic properties of ATB. 
2.1 Primary Objectives 
To examine pharmacokinetic properties of ATB for short course duration of seven to 28 days. 
3 STUDY DESIGN 
3.1 General Description 
A window of opportunity (WOO) clinical trial permits examination of effects of study agent on 
cancer patients during the “window” between diagnosis of their cancer and their definitive cancer 
surgery.  Similar to the phase 0 study design, the WOO trial design permits examination of the 
biologic effects of a study agent; in this trial we will examine PK properties of ATB.  
Blood samples will be taken at the following time points Day 1: Blood samples will be taken at 
baseline (prior to study agent administration), then at 30, 60, 120, 180, 240, 360, 480, and 1,440 
min (a total of nine points). For each blood draw 1 ml of blood will be drawn to yield approximately 
500 µl or 0.5 ml of plasma. All blood sample collections are allowed a window of ± 10 minutes. A 
blood sample for liver function test will be performed following completion of ATB on day -1 or day 
of surgery. 
 
Saliva samples (2-4 ml) will be collected at the following time points: Day 1: Predose, then at 30, 
60, 120, 180, 240, 360, 480, and 1440 min (a total of 9 points). A + 5 minute window is allowed 
for the 30 min time point. All other time points will have a + 10 min window. However every effort 
should be made to obtain samples at the precise time. Day 2 to day -1 of surgery:  A total of at 
least three patient samples (saliva) will be collected for each time point (predose, before lunch, 
or before dinner). Participants have no limitation on eating or drinking prior to saliva sample 
collection. Saliva samples will be collected in a 5 ml bio vial and then frozen and stored in an 
airtight container at 0 to -20o C until batch shipment to Dr. Hu’s laboratory at the University of 
Houston. The blood, saliva, and tumor tissue specimen will be used for PK analysis and should 
be shipped in dry ice to the following location: 
 
 
Ming Hu, PhD 
Department of Pharmacological and Pharmaceutical Sciences 
College of Pharmacy 
1441 Moursund St. 
University of Houston 
Houston, Texas 77030 
Contact Information: 832-842-8320 
 

 
 
 
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Participants will continue ATB administration for a total of seven to 28 days, which they will 
record in a study diary (Appendix 2).  ATB administration must not exceed more than 28 days. 
The study diary will be collected at the completion of the study.  
 
At the end of the course, patients will be asked to return the storage specimens to the study 
coordinator. Patients will be given a Styrofoam transportation container with freeze packs for this 
purpose. All the specimens will be collected on the day of their surgery. 
 
 
3.2 Number of Patients 
The study team will enroll eight patients in the study. 
3.3 Study Duration 
Based upon the duration of funding and a conservative estimate of accrual the duration of the 
clinical trial will be approximately one year. 
 
3.4 Study Completion 
The study will reach completion after the last evaluable patient completes protocol therapy. 
 
4 SUBJECT PARTICIPATION, DISCONTINUATION AND WITHDRAWAL 
MCW personnel must follow all MCW IRB requirements and policies regarding subject 
participation, found here: 
 
https://www.mcw.edu/HRPP/Policies-Procedures.htm 
 
4.1 Subject Status 
Subject statuses throughout the trial are defined as follows:   
• 
Prescreening: pre-consent (subject considering trial or study staff considering patient for 
the trial per institutional recruitment methods). 
• 
Screening: period after consent, but prior to eligibility confirmation. 
• 
Consented: consented, prior to eligibility confirmation. 
• 
Eligible: the local investigator confirms all eligibly criteria apply. 
• 
On study/enrolled: date eligibility is confirmed. 
• 
On arm: date of enrollment. 
• 
On treatment: first day treatment was given to the last day treatment was given. 
• 
Off treatment: the last day treatment was given. 
• 
On follow up: from last day of treatment to the end of follow-up period. 
• 
Off study: follow-up period completed, with no additional data gathered. 
• 
Withdrawn: subject fully withdraws consent (i.e., refuses ALL follow-up, even survival) or 
is taken off study by the local PI. 
 

 
 
 
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4.2 Prescreening and Screening Log 
The MCW study PI regularly reviews screen failure reasons to understand barriers to accrual and 
consider amending eligibility criteria. Screen failures are defined as participants who were 
considered for the trial to participate in the clinical trial with or without consent but are not 
subsequently assigned to the study intervention or enrolled in the study. MCWCC CTO will follow 
its SOPs regarding prescreening and screening tracking. 
 
4.3 Consent  
Investigators or their appropriate designees will identify potentially eligible subjects from their 
clinics, subject self-referrals, referrals from other clinicians and/or other IRB-approved recruitment 
methods. No study conduct, including subject prescreening, can occur until after IRB approval. 
 
A written, signed informed consent form (ICF) must be obtained before any study-specific 
assessments are initiated. A signed ICF copy will be given to the subject and a copy will be filed 
in the medical record (per local IRB policies and SOPs). The original will be kept on file with the 
study records.  
 
After consent, an OnCore® new subject entry occurs must occur within 24 hours of consent. 
 
4.4 Screening Procedures 
Refer to the study calendar of events. 
 
Visit procedures that were performed as standard of care prior to consent (without the specific 
intent to make the subject eligible for the trial), may count toward screening tests and eligibility if 
they are within the screening window. 

Subject Initials: _________   Subject Study ID: ______________    Enrolling Physician___________ 
 
 
 
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4.5 Eligibility Criteria 
Study staff must adhere to MCWCC CTO SOPs regarding eligibility review/confirmation.  
 
No waivers of protocol eligibility will be granted, but when clinical factors relating to an eligibility 
item are unclear or questionable, the study PI (Stuart Wong, swong@mcw.edu) can only provide 
guidance or clarification on eligibility.  
 
Inclusion Criteria 
 
1. Clinical diagnosis of oral cavity squamous cell cancer.  
2. Patient can start study agent administration but histological confirmation of squamous cell 
cancer (SCC) of the oral cavity (or histologic variants of SCC) by the pathologist must happen 
within seven days of registration in order to continue study agent administration. 
3. Clinical stage II-IVA (as defined by the AJCC, 8th Edition) and amenable to surgical resection 
4. New diagnosis of oral SCC, new second primary, or recurrent oral SCC following a minimum 
remission of six months following previous definite surgery. 
5. History and physical examination by an otolaryngologist and medical oncologist within 14 
calendar days of study registration. 
6. Study agent administration should start within seven days of registration. 
7. Patient must receive administration of study agent for a minimum of seven days. 
8. ECOG Performance status < 2. 
9. Age ≥ 18 years. 
10. CBC/differential obtained within 14 calendar days prior to registration, with adequate bone 
marrow function defined as follows: 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;  
Platelets ≥ 100,000 cells/mm3;  
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 
8.0 g/dl is acceptable.); 
11. Adequate renal and hepatic function within 14 calendar days prior to registration, defined as 
follows: 
Serum creatinine < 1.5 mg/dl or creatinine clearance (CrCl) ≥ 50 ml/min within 14 calendar 
days prior to registration, determined by 24-hour collection or estimated by Cockcroft-Gault 
formula: 
CrCl male = [(140 – age) x (wt. in kg)], [(Serum Cr mg/dl) x (72)] 
 
CrCl female = 0.85 x (CrCl male) 
   
  CRC Initials: ___________                                                              Date: _______________ 
  Investigator/Enrolling Physician Initials: ___________                    Date: _________________ 
 
 
 

Subject Initials: _________   Subject Study ID: ______________    Enrolling Physician___________ 
 
 
 
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12. Total bilirubin < 2 x the institutional ULN within 14 calendar days prior to registration. 
13. AST or ALT ≤ 3 x the institutional ULN within 14 calendar days prior to registration. 
14. Magnesium, calcium, glucose, potassium, and sodium within 14 calendar days prior to 
registration, with the following required parameters: 
Magnesium: > 0.9 mg/dl or < 3 mg/dl; 
Calcium: > 7 mg/dl or < 12.5 mg/dl; 
Glucose: > 40 mg/dl or < 250 mg/dl; 
Potassium: > 3 mmol/L or < 6 mmol/L; 
Sodium: > 130 mmol/L or < 155 mmol/L. 
 
15. Female patients must meet one of the following:  
• 
Postmenopausal for at least one year before the screening visit, or  
• 
Surgically sterile (i.e., undergone a hysterectomy or bilateral oophorectomy), or  
• 
If subject is of childbearing potential (defined as not satisfying either of the above two 
criteria), agree to practice two acceptable methods of contraception (combination 
methods requires use of two of the following: diaphragm with spermicide, cervical 
cap with spermicide, contraceptive sponge, male or female condom, hormonal 
contraceptive) from the time of signing of the informed consent form through 90 days 
after the last dose of study agent, AND 
o Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptom-thermal, post ovulation methods] and withdrawal are not acceptable 
contraception methods.) 
 
16. Male patients, even if surgically sterilized (i.e., status postvasectomy), must agree to one of 
the following: 
• 
Practice effective barrier contraception during the entire study period and through 60 
calendar days after the last dose of study agent, OR 
• 
Must also adhere to the guidelines of any study-specific pregnancy prevention 
program, if applicable, OR 
• 
Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptom-
thermal, post ovulation methods] and withdrawal are not acceptable methods of 
contraception.) 
 
17. Patients must be deemed able to comply with the study plan. 
18. Gastric tube study agent administration is permissible. 
19.  Patients must provide study-specific informed consent prior to study entry. 
 
CRC Initials: ___________                                                              Date: _______________ 
 
  Investigator/Enrolling Physician Initials: ___________                    Date: _________________ 
 
 
 
 

Subject Initials: _________   Subject Study ID: ______________    Enrolling Physician___________ 
 
 
 
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Exclusion Criteria 
 
1. History of active liver disease.  
2. Pregnant or lactating women are ineligible due to unforeseeable risks to embryo or fetus. 
3. Concurrent use of any medicinal botanical, natural, or other herbal compound/s that the study 
PI believes could potentially have an impact on the results/objectives of this study.  
4. Planned subtotal or debulking surgery, as determined by enrolling physician determination, is 
not permissible.  
5. Prior systemic chemotherapy for oral SCC; note that prior chemotherapy for a different cancer 
is allowable. 
6. Prior radiotherapy for oral SCC is permissible if disease free for one year since prior oral 
cancer treatment and free of significant late radiation effects. 
7. Severe active comorbidity, such as uncontrolled cardiac disease, infection, severe COPD.  
 
 
 
 
 
 
I have reviewed all inclusion and exclusion criteria and confirm the subject is eligible. 
 
_______________________________________         
 
_______________ 
                   (CRC Signature)                                                       
        (Date) 
 
 
_____________________________________         
 
_______________ 
   (Investigator/Enrolling Physician Signature)                                        (Date) 

 
 
 
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4.6 Discontinuation of Study Treatment, Withdrawal, and Compliance 
 
Discontinuation from the study treatment does not mean discontinuation from the study. Subject 
will be considered in follow-up, study procedures should still be completed as indicated by the 
study protocol, and AEs/SAEs will continue to be reported according to this protocol. 
 
In the absence of treatment delays due to adverse events, study treatment/intervention may 
continue until:  
 
• 
Disease progression.  
• 
General or specific changes in the subject’s condition renders the subject 
unacceptable for further treatment in the investigator’s judgment.  
• 
Inter-current illness that prevents further treatment administration.  
• 
Subject decides to withdraw from the study.  
• 
The subject has significant noncompliance with the protocol (see below).   
• 
Unacceptable adverse event(s) and/or dose level reduction beyond requirements as 
detailed in this protocol.  
• 
Study stopping rules are met. 
 
Subjects who sign the informed consent form, enroll and receive the study intervention, but 
subsequently withdraw, or are withdrawn or discontinued from the study will not be replaced.  
 
Consent Withdrawal 
 
A subject may decide to withdraw from the study at any time. MCWCC CTO will follow its IRB of 
record’s SOPs regarding consent withdrawal.  
 
If a subject intends on withdrawing consent, staff should confirm which of the following options 
the subject chooses and document the discussion: 
 
• 
Full consent withdrawal, with no study follow-up. 
• 
Selective consent withdrawal from interventional portion of the study but agree to continued 
follow-up of associated clinical outcome information. 
Investigator-Initiated Withdrawal 
The investigator will withdraw a subject whenever continued participation is no longer in the 
subject’s best interests. Reasons for withdrawing a subject include, but are not limited to, disease 
progression, the occurrence of an adverse event or a concurrent illness, a subject’s request to 
end participation, a subject’s noncompliance or simply significant uncertainty on the part of the 
investigator that continued participation is prudent. The reason for study withdrawal and the date 
the subject was removed from the study must be documented. 
4.7 Lost to Follow-Up 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit and/or is unable to be reached for follow-up: 
 

 
 
 
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• 
The investigator or designee must make every effort to regain contact and/or reschedule a 
missed visit with the participant. 
• 
A participant is deemed lost to follow-up if his/her status cannot be obtained after all of the 
following occurs at two consecutive scheduled protocol calendar timepoints: 
 
o Three telephone calls (at least one day apart) from the study team are unanswered,  
AND  
o A letter to the participant’s last known mailing address goes unanswered, AND 
o These contact attempts must be documented in the participant’s medical record or 
study file.  
 
• 
Update OnCore® (Follow-up tab and eCRF) when a participant is officially considered lost to 
follow-up. 
• 
If a subject is considered lost to follow-up, but subsequently contacts the study team, the 
subject should be considered in follow-up again. 
 
4.8 Accrual Suspension and Closure 
 
The MCW PI facilitates the suspension and closing of accrual in the following manner: 
 
• 
OnCore® tracks accrual throughout the study. 
• 
If the study must be suspended, OnCore® is updated to a ‘suspended’ status. 
• 
When the accrual number is reached, OnCore® notifies staff of study closure. 
 
4.9 End of Study Definition 
A participant is considered to have completed the study if he or she completed all phases of the 
study, including the last visit or the last scheduled procedure shown in the calendar of events or 
has been discontinued. 
 
4.10 Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause (as determined by the MCW study PI, DSMC, sponsor, and/or IRB). Written 
notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study participants, investigator, funding agency, the 
Investigational New Drug (IND) sponsor and regulatory authorities. If the study is prematurely 
terminated or suspended, the MCW principal investigator (PI) will promptly inform the MCW 
Institutional Review Board (IRB), and the sponsor and will provide the reason(s) for the 
termination or suspension. Study participants will be contacted, as applicable, and be informed of 
changes. 
 

 
 
 
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5 TREATMENT PLAN 
5.1 ATB Administration 
ATB will be administered on an outpatient basis. ATB will be administered at a dose of 1,200 
mg three times per day (roughly spaced every eight hours) as has been studied for ATB in 
human oral leukoplakia trials and in esophageal cancer prevention trials. ATB may be taken 
with or without food.  
Regimen Description 
Study 
agent 
Premedication; 
precautions 
Dose 
Route 
Schedule 
Duration 
ATB  
None 
1,200 mg, 
Three 
times a day 
Oral 
Daily 
7-28 daysa 
a. Total duration depends upon scheduling of surgery. ATB administration must not 
exceed 28 days.  
 
• 
There will only be ONE ATB dose on day 1. Dose on Day 2 must be delayed until 
completion of PK specimen (blood and saliva) collection.  
• 
Patient must submit completed study dairy to the study coordinator. 
 
5.2  Supply 
 
ATB will be produced by National Traditional Chinese Medicine Pharmaceutical Engineering 
Technology Research Center and shipped to MCW in the form of a tablet.  ATB will be stored at 
room temperature in a cool place, free from excessive moisture and should be stable for two 
years. Analysis of pharmacokinetic properties is necessary before future efficacy trials can be 
initiated. We will examine an oral ATB dose of 1,200 mg, three times per day.  
 
Study agent will be shipped to MCW in one batch. Study agent ordering contact information: 
 
Ming Hu, Ph.D. 
Department of Pharmacological and Pharmaceutical Sciences 
College of Pharmacy 
1441 Moursund St. 
University of Houston 
Houston, Texas 77030 
Contact Information:  832-842-8320 
 
Each patient-specific bottle will be labeled by IDS pharmacy with the following: 
 
• 
The study number; 
• 
The bottle number (i.e., Bottle 1 of 2 and Bottle 2 of 2); 

 
 
 
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• 
The number of tablets; 
• 
The patient ID number (e.g. ATB-YYY, where the study number and sequence number 
represent the unique patient identifier assigned at registration); 
• 
The patient’s initials (i.e., first, middle, last); 
• 
A blank line for the site pharmacist to enter the patient’s name; 
• 
Administration instructions (i.e., “Take xx tablets every day for xx days”); 
• 
Storage instructions (i.e., “Store at controlled room temperature, xx degrees”); 
• 
Emergency contact instructions. 
 
5.3  Storage and stability 
 
The intact bottles should be stored at controlled room temperature (15°C – 30°C). Shelf life 
surveillance studies of the intact bottle are ongoing. Current data indicate ATB is stable at 90 
days without decrement of active components at controlled room temperature (15°C – 30°C). 
5.4  Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents. It is the responsibility of the investigator to 
ensure that the agents are only dispensed to study patients.  
 
5.5  Drug Destruction  
 
Opened bottles of ATB must be disposed of by incineration at the site as chemotherapy or 
biohazardous waste. At the completion of the study, all unused ATB also must be incinerated at 
the site. It is the responsibility of the investigator to ensure that a current record of agent 
disposition is maintained at each study site where agents are inventoried and disposed, including 
dates and quantities.  
 
5.6 Biopsy specimen, Operative Specimen, and Tissue Processing 
Tumor specimens will be analyzed for ATB accumulation and stored for tissue banking for future 
research. Submission of a block is preferred and is highly encouraged. If a block is not available, 
please provide at least five unstained slides. The block (or unstained slides) should be hand 
delivered to the CRI Histology Core (address below): The contact person is Christine Duris (phone 
number 414-955-8624).   
Second post-ATB administration tumor biopsy is not needed because the OR-resected tumor will 
serve this purpose. At the time of surgery, a portion of the resected tumor will be utilized for the 
study.  
The resected tumor will be received and processed by the MCW tissue bank staff. The tissue will 
be fixed in 10% buffered formalin as soon as resected, grossed into cassettes and processed into 
paraffin blocks.  Once the blocks are in paraffin – the blocks will be delivered to the CRI Histology 
Core for further testing. The paraffin block of the resected tumor and biopsy should be delivered 
to the following location:  
 
Children’s Research Institute – Histology Core Laboratory 
Medical College of Wisconsin 

 
 
 
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TBRC-CRI Room C4305 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
 
The biopsy specimen and tumor specimen will be used for PK analysis. 
5.7 Dose Modifications 
As indicated in the study calendar, a complete metabolic panel (including LFTs) will be performed 
mid-way during the course of ATB. Adverse events will be graded according to CTCAE v.5. 
Adverse Event (CTCAE, v. 5) 
Action 
Non-hematological, grade 1 or 2 
 
Continue ATB therapy at full dose prescribed.  
Apply 
maximum 
supportive 
care 
recommendations. If persistent duration of 
grade 2 adverse event is affecting quality of 
life, a one-time decrease of 25%. 
Non-hematological, grade 3 or 4 
 
Apply 
maximum 
supportive 
care 
recommendations.  Hold ATB therapy until 
recovery to grade ≤ 1 (up to 7 days). 
 
If concomitant elevation of AST/ALT 3 times 
the upper limit of normal and bilirubin elevation 
2 times the upper limit of normal (Hy’s Law 
criteria) the patient must be removed from 
study treatment, ATB must be permanently 
discontinued. 
 
If recurrence of adverse event after drug hold 
and/or interruptions is observed and maximum 
supportive care measures applied, a dose 
reduction by 25% is recommended. ATB 
should not be used at doses below 50% 
Non-hematological, grade 3 or 4 and adverse 
events NOT resolved to grade ≤ 2 within a 
maximum of 14 calendar days from last 
planned administration  
Dose reductions by 25% (up to 2 reductions) 
will be considered after maximum supportive 
care recommendations are introduced. 
 
Dose Level 
Dose 
-2 
600 mg TID 
-1 
900 mg TID 
0 
1200 mg TID  
 

 
 
 
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5.8 General Concomitant Medication and Supportive Care Guidelines 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
source documents as concomitant medication. 
Concurrent or concomitant use of medication is not restricted during protocol therapy. However, 
patients are not permitted to take any anti-cancer medications or supplements during study 
duration. 
Few side effects of ATB have been reported. ATB has shown to improve many baseline 
gastrointestinal symptoms particularly those associated with GERD. However, diarrhea has been 
rarely reported in relation to ATB administration and should be managed using the following 
guidelines. 
• 
Loperamide (Imodium) 
All patients should be instructed to begin taking loperamide at the earliest signs of diarrhea 
and/or abdominal cramping that occur more than eight hours after receiving ATB.  Patients 
will be instructed to begin taking loperamide at the earliest signs of (1) a poorly formed or 
loose stool, (2) the occurrence of one to two more bowel movements than usual in one day, 
or (3) unusually high volume of stool. Loperamide should be taken in the following manner: 
4 mg at the first onset of diarrhea, then 2 mg every two hours around the clock until 
diarrhea-free for at least 12 hours. Patients may take 4 mg of loperamide every four hours 
during the night. Additional antidiarrheal measures may be used at the discretion of the 
treating physician. 
 
5.9 Dietary Restrictions 
 
No food interactions are known to occur with ATB, thus, no dietary restrictions will be placed 
upon participants 
 
5.10 Monitoring Subject Compliance  
ATB will be administered or dispensed only to eligible patients under the supervision of the 
investigator or trained study staff or identified sub investigator(s). The appropriate study personnel 
will maintain records of study agent receipt and dispensing. Comprehensive instructions will be 
provided to the patient to ensure compliance with dosing procedures. 

 
 
 
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6 ADVERSE EVENTS: DEFINITIONS, COLLECTION, REPORTING 
REQUIREMENTS AND SAFETY ASSESSMENT 
6.1 Definitions 
 
6.1.1 Adverse Event 
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. (International Conference on Harmonisation [ICH], E2A, E6). 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0, located on the CTEP web site: 
 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic procedures. 
 
6.1.2 Serious Adverse Event (SAE)  
Serious Adverse Event (SAE) means any untoward medical occurrence that results in any of the 
following outcomes: 
• 
Death. Results in death. 
• 
Life threatening. Is life threatening (refers to an AE in which the patient was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
• 
Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization (see clarification in the paragraph below on planned hospitalizations). 
• 
Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions). 
• 
Pregnancy. 
• 
Medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse; any organism, 
virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent. 
 

 
 
 
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6.1.3 Attribution of an Adverse Event 
An assessment of the relationship between the adverse event and the medical intervention, using 
the following categories:  
 
Definitely Related: The AE is clearly related to the intervention. There is clear evidence to 
suggest a causal relationship, and other possible contributing factors can be ruled out.  
 
Probably Related: The AE is likely related to the intervention. There is evidence to suggest a 
causal relationship, and the influence of other factors is unlikely.  
 
Possibly Related: The AE may be related to the intervention. There is some evidence to suggest 
a causal relationship (e.g., the event occurred within a reasonable time after administration of the 
trial medication). However, the influence of other factors may have contributed to the event (e.g., 
the subject’s clinical condition, other concomitant events).  
 
Unlikely: The AE is doubtfully related to the intervention. A clinical event, including an abnormal 
laboratory test result, whose temporal relationship to drug administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after administration 
of the trial medication) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the subject’s clinical condition, other concomitant treatments).  
 
Unrelated: The AE is clearly NOT related to the intervention. The AE is completely independent 
of study drug administration, and/or evidence exists that the event is definitely related to another 
etiology.  
 
6.1.4 Expectedness of an Adverse Event 
 
Study investigator or treating physician will be responsible for determining whether an AE is 
expected or unexpected as indicated in the protocol, informed consent form and/or drug 
information brochure. An AE will be considered unexpected if the nature, severity, or frequency 
of the event is NOT consistent with the risk information previously described for the study 
intervention. 
 
6.2 Collection and Reporting Requirements for Adverse Events and Serious Adverse   
      Events 
 
6.2.1 Collection of Adverse Events 
 
All (or specify if only certain grade AE needed) adverse events (including SAEs) must be recorded 
in OnCore® and/or an adverse event log. All AEs required to be collected must be graded 
according to the CTCAE v5. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event. Investigator’s or treating physician’s 
assessment of AE attributions must also be documented.  
 
AEs will be collected from the time the subject signs the consent form through 30 days post last 
dose of study drug(s). AEs will be tracked and followed until resolution, subject withdraws 
consent, or is lost to follow-up (including subjects who discontinue early). All adverse events 
collected per the protocol will be followed with appropriate medical management until they are 
resolved, if they are related to the study treatment, or until the investigator deems the event to be 
chronic.  

 
 
 
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Please see section 6.2.2 and table 4 to identify the adverse events that need to be reported.  
 
 
6.2.2 Reporting of Adverse Events and Serious Adverse Events 
 
Please refer to table 4 below to identify adverse events that meet reporting requirements.  
 
All serious adverse events (SAEs) that occur after the subject has signed the consent form 
through 30 days post last dose of study drug(s) will be reported. All SAEs will be followed until 
satisfactory resolution, or until the investigator deems the event to be chronic. 
 
All serious adverse events (SAEs) must also be documented in OnCore®. 
 
Table 4 
 
1. Guidance on adverse event reporting to the IRB is available online at MCW IRB Policies and 
Procedures.  
2. For expedited DSMC reporting, study coordinator/research nurse must notify the DSMC via 
email including the subject ID, date of event, grade, relatedness, expectedness, and a short 
narrative. DSMC will review data entered into OnCore®.  
3. For routine reporting, the events will be reported to IRB as part of the annual continuing 
progress report and the DSMC will review data entered into OnCore® at the time of scheduled 
monitoring. 
4. Fatal or life-threatening SAEs meeting the criteria indicated in the above table will be reported 
to FDA no later than seven calendar days after study staff’s initial awareness of the event. If 
the SAE is not fatal or life-threatening and meets the above criteria, the timeline for submitting 
an IND safety report to FDA is no later than 15 calendar days after study staff’s initial 
awareness of the event. See section 6.2.3 for detailed reporting instructions. 
 
 
 
Attribution 
SAE 
AE 
Grade 1, 2 & 3 
Grade 4 and 5 
Grade 3 
Grade 4  
Expected 
Unexpected 
Expected 
Unexpected 
Unexpected 
Expected 
Unexpected 
Unrelated 
Unlikely 
IRB1 and 
DSMC2- 
Routine 
Review3 
 
 
 
IRB1 and 
DSMC2- 
Routine 
Review3 
 
 
IRB1- 
Routine 
Review3 
 
DSMC2-
Within 5 
calendar 
days 
 
 
 
IRB1- 
Routine 
Review3 
 
DSMC2-
Within 5 
calendar 
days 
DSMC2- 
Routine 
Review3 
 
DSMC2- 
Within 5 
calendar 
days 
DSMC2- 
Within 5 
calendar 
days 
 
Possible 
Probable 
Definite 
IRB1 and 
DSMC2- 
Within 5 
calendar 
days 
 
FDA4 
 
IRB1 and 
DSMC2- 
Within 5 
calendar 
days 
 
FDA4 
 

 
 
 
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6.2.3 Reporting Instructions  
 
An IND safety report will be submitted for any adverse event that meets all three definitions: 
possibly related to the study drug, unexpected, and serious. If the adverse event does not meet 
one of the above definitions, it should not be submitted as an expedited IND safety report.  
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information 
is available (21 CFR 312.32(d)(2)).  
Suggested Reporting Form: 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm  
 
6.3 Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to unanticipated problems involving risks to subjects or others. This information may be found on 
the Human Research Protection Program website.  
6.4 Subject Complaints 
 
If a complaint is received by anyone on the study staff, it will be discussed with the study staff and 
will be addressed on a case-by-case basis. The PI will be notified of any complaints. Complaints 
will be reported to the IRB if indicated.  
 
If the subject has questions about his or her rights as a study subject, wants to report any 
problems or complaints, obtain information about the study or offer input, the subject can call the 
Medical College of Wisconsin/Froedtert Hospital research subject advocate at 414-955-8844. 
This information is provided to the subject in their consent.  
 
A product complaint is a verbal, written or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality or stability of a drug product. Individuals who identify 
a potential product complaint situation should immediately contact the drug manufacturer and 
report the event. Whenever possible, the associated product should be maintained in accordance 
with the label instructions pending further guidance from a drug manufacturer representative. 
Product complaints in and of themselves are not reportable events. If a product complaint results 
in an SAE, an SAE form should be completed. 
 
6.5 Safety Assessment 
 
Dose-limiting toxicity (DLT) is defined as the occurrence of any grade > 3 adverse event (AE) that 
is definitely or probably related to ATB and occurs during the study. 
 
An early safety assessment will be performed after the first four patients complete protocol 
therapy and reported to the DSMC. In the event of 0-1 DLT events, the experimental therapy is 
considered safe and the study will proceed to the second cohort of four patients. In the event of 
> 2 DLTs in the first four patients, the study chairs and DSMC will recommend proceeding with 
the second cohort at dose level -1 or dose level -2. 

 
 
 
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7 STATISTICAL CONSIDERATIONS 
7.1  Statistical Design and Sample Size Calculations  
Rationale: Assuming the SD of the PK parameters are approximately 50% of the mean of the PK 
parameters, which implies an effect size of two, a sample size of six analyzable patients will 
provide 95% confidence intervals with a margin of error, based on a t distribution with five degrees 
of freedom, of approximately +/- 52.5% of the mean. These are typical for PK estimation studies. 
 
7.2  Study Objectives and End Points 
The endpoint of the study is the successful evaluation of a PK profile, with estimation of PK 
parameters such as plasma and saliva AUC and Cmax. The study shall be deemed complete 
when the 6th evaluable patient has completed therapy and the samples sent for PK analysis. 
 
7.3  Statistical Methodology and Analysis Plan 
Statistical methodology: PK parameters for drug concentration in both saliva and plasma samples 
will be calculated. These PK parameters include area under the concentration curves to last 
collection time (AUCt), maximum measured concentration (Cmax) and time to maximum 
concentration (Tmax). 
 
8 DATA AND SAFETY MONITORING PLAN (DSMP) 
8.1 Data and Safety Management Overview 
The Medical College of Wisconsin (MCW) Data Safety Monitoring Committee (DSMC) and the 
MCW Institutional Review Board (IRB) will approve protocol-specific DSM plans. A local, 
investigator-initiated trial will be required to be continuously monitored by the principal investigator 
of the study with safety and progress reports submitted to the DSMC.  
The DSMP for this study will involve the following entities: 
8.2 Study Team 
The study team minimally consists of the principal investigator, the clinical research coordinator, 
regulatory specialist, and the study biostatistician. While subjects are on study, the principal 
investigator will meet regularly with the research coordinator and the study biostatistician to review 
study status. This review will include but not be limited to reportable SAEs and UPIRSOs and an 
update of the ongoing study summary that describes study progress in terms of the study schema. 
The appropriateness of further subject enrollment and the specific intervention for a next subject 
enrollment is addressed. All meetings including attendance are documented.  
8.3 Quality Assurance  
The MCWCC Clinical Trials Office provides ongoing quality assurance audits. This protocol was 
classified as high risk and will be reviewed internally by the MCW Cancer Center Clinical Trials 
Office Quality Assurance Staff according to the MCWCC Data and Safety Monitoring Plan and 
current version SOP, 6.5.2 Internal Quality Assurance Reviews.8.4 Clinical Trials Office 
The MCWCC Clinical Trials Office (CTO) provides administrative assistance and support to the 
DSMC.  

 
 
 
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8.5 DSMC 
The Medical College of Wisconsin Cancer Center places the highest priority on ensuring the 
safety of patients participating in clinical trials. Every cancer interventional trial conducted at MCW 
includes a plan for safety and data monitoring. 
More information can be found related to the MCWCC Data and Safety Monitoring Plan at the 
MCWCC website (Data and Safety Monitoring Plan).  
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC activities are as 
follows:  
 
Review the clinical trial for data integrity and safety  
 
Review all DSM reports 
 
Submit a summary of any recommendations related to study conduct  
 
Terminate the study if deemed unsafe for patients  
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be maintained 
in the study research file and updated as membership changes. The committee will review reports 
from the study PI twice annually (or more frequently if needed) and provide recommendations on 
trial continuation, suspension, or termination as necessary.  
Any available DSMC letters will be submitted to the IRB of record as required. 
9 REGULATORY COMPLIANCE, ETHICS, AND STUDY    
     MANAGEMENT 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
9.1 Regulatory Compliance 
This study will be conducted in compliance with: 
 
The protocol 
 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and 45 CFR 46 
Subparts A (Common Rule), B (Pregnant Women, Human Fetuses and Neonates), C 
(Prisoners), and D (Children), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 

 
 
 
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9.2 Prestudy Documentation  
Prior to implementing this protocol at MCWCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the MCW 
IRB.  
The clinical investigation will not begin until the Investigator has received a letter from FDA stating 
that the study is exempt from IND requirements.  
9.3 Institutional Review Board 
The protocol, the proposed informed consent form and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) will be reviewed and approved by 
the MCW Institutional Review Board. Prior to obtaining MCW approval, the protocol must be 
approved by the Medical College of Wisconsin Cancer Center Scientific Review Committee. The 
initial protocol and all protocol amendments must be approved by the IRB prior to implementation.  
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 
Consent forms describing in detail the study interventions/products, study procedures and risks 
are given to the subject and written documentation of informed consent is required prior to starting 
intervention/administering study product. 
Consent forms will be IRB-approved and the subject (and Legally Authorized Representative, if 
necessary) will be asked to read and review the document. Upon reviewing the document, the 
investigator will explain the research study to the subject and answer any questions that may 
arise. In accordance with 46 CR 46.111, the subject will sign and date the informed consent 
document prior to any procedures being done specifically for the study.  
A witness should only sign when required, per FH/MCW IRB policy. If a witness signs the 
document when not required, the study staff should document in the legal medical record (or note 
to file) the relationship to the patient and why a witness signed. (i.e., “Although not required, the 
subject’s spouse was present during the consenting process and signed as the witness.” Or 
“Although not required, hospital staff was present for consenting process and signed as a 
witness.”) 
The subjects will have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The subjects may withdraw consent at any time throughout the 
course of the trial.  
A copy of the informed consent document will be given to the subjects for their records. The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. If there are 
changes to the consent form, all revisions will be reviewed with study subject at the next 
appropriate opportunity. Patients that require reconsenting will be defined in the IRB approved 
amendment submission. The process for obtaining informed consent will again be performed. 
Study subjects will not be reconsented for continuing reviews. The MCWCC CTO will follow the 
MCW/FH IRB’s policy for subjects who demonstrate limited English proficiency or limited literacy.  

 
 
 
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After the subject’s visit in which the consent is signed, it is documented in the clinic chart that the 
consent has been signed and that all questions have been answered to the subject’s satisfaction 
after adequate time for review of the consent. It is also documented that a copy of the consent is 
given to the subject. The original consent is kept with the subject’s study file, and a copy of the 
consent is sent to the OCRICC office, which will then submit to HIM a copy of the signed consent 
to be scanned into EPIC, the legal medical record. 
9.4 Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating 
investigators, and any staff, [and the sponsor(s) and their agents] (include bracketed portion if 
applicable). This confidentiality includes the clinical information relating to participating subjects, 
as well as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized 
third party without prior written approval of the principal investigator. 
The conditions for maintaining confidentiality of the subjects’ records are required for the life of 
the data. These rules apply equally to any and all MCWCC projects.  
One risk of taking part in a research study is that more people will handle the personal health 
information collected for this study. The study team will make every effort to protect the information 
and keep it confidential, but it is possible that an unauthorized person might see it. Depending on 
the kind of information being collected, it might be used in a way that could embarrass the subject 
or affect his/her ability to get insurance. 
While data are being collected and after all data have been collected but are still in the process 
of being analyzed, the subject’s data/PHI are stored in the locked Clinical Research office in the 
Clinical Trials Office. Databases in which the study subject information is stored and accessed 
are password protected, allowing for limited access by authorized personnel only. Data/PHI kept 
in the Case Report Forms contain the study identifiers, subject initials, date of birth and date of 
service.  
The principal investigator will allow access to all source data and documents for the purposes of 
monitoring, audits, IRB review, and regulatory inspections.  
The study monitor/s or other authorized representatives of the principal investigator may inspect 
all documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this study. 
The clinical study site will permit access to such records. 
9.5 Protection of Human Subjects 
9.5.1  Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. This 
is accomplished through the IRB mechanism and the informed consent process. The IRB reviews 
all proposed studies involving human experimentation and ensures that the subject’s rights and 
welfare are protected and that the potential benefits and/or the importance of the knowledge to 
be gained outweigh the risks to the individual. The IRB also reviews the informed consent 

 
 
 
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document associated with each study in order to ensure that the consent document accurately 
and clearly communicates the nature of the research to be done and its associated risks and 
benefits. 
9.5.2  Protection of Privacy 
As noted, patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they will 
be asked to sign informed consent documents. The original signed document will become part of 
the patient’s medical records, and each patient will receive a copy of the signed document.  
9.5.3 Changes in the Protocol 
Once the protocol has been approved by the MCW IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the investigator 
and approved by IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
Investigator must then notify the IRB in writing within five working days after implementation.  
The IRB may provide, if applicable regulatory authority(ies) permit, expedited review, and 
approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB. The investigator will submit all protocol modifications to the sponsor 
and the regulatory authority(ies) in accordance with the governing regulations. 
Changes to the protocol may require approval from the sponsor. 
Any departures from the protocol must be fully documented in the source documents. 
9.6 Investigator Compliance  
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies).  
Onsite Audits 
Auditing is essential to ensure that research conducted at the Medical College of Wisconsin 
(MCW) Cancer Center is of the highest quality and meets MCW and regulatory agency standards.  
Regulatory authorities, the IRB and/or sponsor may request access to all source documents, data 
capture records and other study documentation for on-site audit or inspection. Direct access to 
these documents must be guaranteed by the investigator, who must provide support at all times 
for these activities. 
 
 

 
 
 
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10 DATA HANDLING AND RECORD KEEPING 
 
10.1 Overview 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed 
before the research begins. Investigators focus on the following to ensure data integrity:  well-
trained data collectors/recorders to ensure consistency and quality, well-designed data collection 
protocols and ongoing monitoring. In this way, study rigor and validity are maintained. Data is 
protected from physical damage as well as from tampering, loss, or theft. This project’s data 
management is a multidisciplinary activity that includes investigators, research coordinators and 
nurses, data mangers, support personnel, biostatisticians, and database programmers. Quality 
control will be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly.  
10.2 Data Management Responsibilities 
Principal Investigator 
The principal investigator oversees the management of patient records/case report forms and 
ensures that a) complete and accurate data will be obtained and provided to the sponsor; b) 
patient records are maintained to include history, prescribed medication, and investigational 
product(s), measurements, exams, evaluations, and adverse events; c) corrections are applied 
to clinical research data according to principles of good research practice (i.e., single-line delete, 
date and initial). He or she will ensure that there is correlation between the case report forms and 
the source documents.  
Research Coordinator  
A research coordinator creates, collects, and organizes clinical trial documentation. He or she 
ensures that source documentation and data abstraction and entry are being done at protocol 
specified time points. 
 
Research Nurse/Medical Staff 
The research nurse and medical staff documents protocol-required care or assessment of the 
subject’s outcomes, adverse events, and compliance to study procedures. 
Biostatistician 
The biostatistician may assist in CRF development (content and design), dataset specifications 
(annotation of CRFs and record layout) and validation. 
10.3 Source Documents 
Source documents for clinical information (patient history, diagnosis, clinical and diagnostic test 
reports, etc.) are maintained in the patient’s clinical file.  
All source documents will be written following ALCOA standards:  
 
 

 
 
 
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ALCOA Attribute 
Definition 
Attributable 
Clear who has documented the data. 
Legible 
Readable and signatures identifiable. 
Contemporaneous 
Documented in the correct time frame along with the flow of events. 
If a clinical observation cannot be entered when made, chronology 
should be recorded. Acceptable amount of delay should be defined 
and justified. 
Original  
Original, if not original should be exact copy; the first record made 
by the appropriate person. The investigator should have the 
original source document. 
Accurate 
Accurate, consistent and real representation of facts. 
Enduring 
Long-lasting and durable. 
Available and 
accessible 
Easily available for review by treating physicians and during 
audits/inspections. The documents should be retrievable in 
reasonable time. 
Complete 
Complete until that point in time. 
Consistent 
Demonstrate the required attributes consistently. 
Credible 
Based on real and reliable facts. 
Corroborated 
Data should be backed up by evidence. 
 
10.4 Case Report Forms  
The principal investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study-
specific Case Report Forms (CRFs) will document outcomes. All study data will be entered into 
OnCore® via standardized CRFs, in accordance with the study calendar, using single data entry 
with a secure access account. The clinical research coordinator will complete the CRFs as soon 
as possible upon completion of the study visit; the investigator will review and approve the 
completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by 
MCWCC personnel. All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The principal investigator will 
approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate.  
All source documentation and data will be available for review/monitoring by the MCWCC DSMC 
and regulatory agencies. 
10.5 Study Record Retention 
The principal investigator is required to maintain adequate records. 
The principal investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation. 

 
 
 
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Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
sponsor-investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 

 
 
 
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carcinoma proliferation. Oncotarget. 2016. 

 
 
 
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27. Ma T, Galimberti F, Erkmen CP, Memoli V, Chinyengetere F, Sempere L, et al. Comparing 
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2005. 

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

 
 
 
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APPENDIX 2. STUDY DIARY 
 
Participants will complete study diary to track compliance, saliva specimen collection, and daily 
symptom documentation. A paper study diary will be provided to each subject at screening to 
record the following information: 
 
1. Study Agent administration date and time  
2. Time of saliva sample collection  
3. Side effects and/or any new symptoms 
 
Patients will be trained on use of the diary. The diary will be provided in paper format and remain 
with the patient for the duration of the study. The study coordinator will review the diary for 
completeness and request missing information periodically and in a timely manner. Side 
effects/symptoms recorded in the diary will be reported as AEs according to the investigator’s 
discretion and clinical judgment. The subject diary will serve as a source record and remain at the 
study site after the subject completes the study.  
 
Study coordinator will contact patients twice weekly for compliance assessment and reminders 
for protocol procedures. At the end of the course of therapy patients will be asked to return the 
storage specimens to the study coordinator. Patients will be given a Styrofoam transportation 
container with freeze packs for this purpose. Patient will complete study diary with all relevant 
information and will submit the diary to study coordinator on the day of surgery. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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STUDY DIARY PATIENT INSTRUCTIONS: 
 
 
1. Study coordinator will provide you specific instruction on how to complete the diary  
 
2. Record the date, when you took ATB, and when you took them. Record dose as soon as you 
take them; do not batch entries together at a later time. 
 
3. Record the time of saliva sample collection. Collect saliva sample even if you miss any dose. 
 
4. If you have any comments or notice any side effects, please record them in the Comments/ 
Symptoms. If you make a mistake while you write, please cross it out with one line, put your 
initials next to it, and then write the corrected information next to your initials 
 
5. If you miss a dose of ATB, you should take it as soon as possible, as long as it is on the same 
day. Do not take an extra dose of ATB on the next day or any subsequent days to make it up 
for the missed dose. 
 
6. Please return this diary to the study coordinator after study completion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Antitumor B (ATB) Medication Diary 
 
 
 
Subject # (completed by study staff): __________________ 
Cycle # (completed by study staff): ____________    
Assigned pill strength # (completed by study staff): ____________    
 
 
 
 
 
Day 
 
 
Date 
Administration 
of ATB 
 
 
Administration 
Time 
 
Time of saliva sample 
collection (e.g. Pre-
dose, before lunch or 
before dinner) 
 
 
Comments/ 
Symptoms 
Day1 
 
Dose 1 
 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 

 
 
 
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Short Title:   Antitumor-B PK Study                                                           
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Antitumor B (ATB) Medication Diary 
Subject # (completed by study staff): __________________ 
Cycle # (completed by study staff): ____________    
Assigned pill strength # (completed by study staff): ____________    
 
 
 
 
Day 
 
 
Date 
Administration 
of ATB 
 
 
Administration 
Time 
 
Time of saliva sample 
collection (e.g. Pre-
dose, before lunch or 
before dinner) 
 
 
Comments/ 
Symptoms 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3 
 
 
 
 
Dose 1 
 
 
 
Dose 2 
 
 
Dose 3