Inhibition of Oral Tumorigenesis by Antitumor B
Phase: EARLY_PHASE1
Conditions: Squamous Cell Cancer of the Oral Cavity
Sponsor: Medical College of Wisconsin

PROTOCOL 
OFFICIAL TITLE OF CT.GOV RECORD:  Inhibition of Oral Tumorigenesis by Antitumor B 
CT.GOV NUMBER:  NCT04278989 
PROTOCOL DATE:  April 25, 2024 

Short Title: ATB Randomized Window Study 
 
  1                                                       Version No.: 
5.1 
IND No.: 145798 
 
Version Date: 04/25/2024 
 
 
 
 
Inhibition of Oral Tumorigenesis by Antitumor B 
 
 
 
Short Title: 
 
 
 
 
 
 
 
                                       
 
 
 
 
 
 
Stuart J. Wong, MD (Study PI) 
 
 
Current Version Number and Date 
v1.0 04/13/2020 
v.2.0 04/06/2022 
v.3.0 08/05/2022 
v. 4.0 09/26/2022 
v. 5.0 12/06/23 
v. 5.1 4/25/2024 
 
 
 
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. 
ATB 
Randomized 
Window 
Study 

Short Title: ATB Randomized Window Study 
 
  2                                                       Version No.: 
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IND No.: 145798 
 
Version Date: 04/25/2024 
 
TITLE:     Inhibition of Oral Tumorigenesis by Antitumor B 
 
MCW Protocol No.: Pending 
IRB Pro No.:   037907 
Clinical trials.gov No.:   NCT04278989 
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:   
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:   
Jennifer Bruening, MD 
Assistant Professor 
Department of Otolaryngology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave.  
Milwaukee, WI 53226 
414-805-5583 
Email: jbruening@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:  
Michael Stadler, MD 
Associate Professor 
Department of Otolaryngology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave.  
Milwaukee, WI 53226 
414-805-8548 
Email: mstadler@mcw.edu  
 
Sub-investigator:  
Ming Hu, PhD 
Professor  
Department of Pharmacological and  
Pharmaceutical Sciences 
4349 Martin Luther King Blvd 
University of Houston 
Houston, TX 77204 
832-842-8320 
Email: mhu4@Central.UH.EDU  
 
Biostatistician: 
Anjishnu Banerjee, PhD 
Associate Professor 
Division of Biostatistics 
Institute for Health & Society 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-955-8358 
Email:  abanerjee@mcw.edu  
Pathologist: 
Tamara Giorgadze, MD 
Professor 
Department of Pathology 
9200 W. Wisconsin Ave 
Milwaukee, WI 53226 
Email:  tgiogadze@mcw.edu  
 Funder: 
NCI, R01 CA205633 (Ming You, contact PI) 

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TABLE OF CONTENTS 
PROTOCOL SUMMARY ........................................................................................................... 6 
STUDY SCHEMA ...................................................................................................................... 8 
STUDY CALENDAR .................................................................................................................. 9 
LIST OF ABBREVIATIONS ......................................................................................................11 
1. BACKGROUND ....................................................................................................................13 
1.1 HEAD AND NECK CANCER ......................................................................................................13 
1.2 CHEMOPREVENTION: ANTITUMOR B (ATB) .............................................................................13 
1.3 ATB DOSE AND SCHEDULE ....................................................................................................14 
1.4 ATB SAFETY AND TOXICITY ...................................................................................................14 
1.5 PRECLINICAL STUDIES: MECHANISM OF ACTION, EFFICACY, ATB KEY ACTIVE COMPONENTS ....15 
1.6 ATB MECHANISM OF ACTION .................................................................................................16 
1.7 ATB KEY ACTIVE COMPONENTS ............................................................................................17 
1.8 WINDOW OF OPPORTUNITY STUDY DESIGN ............................................................................18 
2 HYPOTHESIS AND OBJECTIVES ........................................................................................18 
2.1 PRIMARY OBJECTIVES ...........................................................................................................19 
2.2 SECONDARY OBJECTIVES ......................................................................................................19 
2.3 PRIMARY ENDPOINT ..............................................................................................................19 
2.4 SECONDARY ENDPOINT .........................................................................................................19 
3 STUDY DESIGN ....................................................................................................................19 
3.1 GENERAL DESCRIPTION ........................................................................................................19 
3.2 ESTIMATED TIME FOR COMPLETION OF STUDY ENROLLMENT ....................................................20 
4 SUBJECT PARTICIPATION, DISCONTINUATION AND WITHDRAWAL ............................20 
4.1 SUBJECT STATUS ..................................................................................................................20 
4.2 PRESCREENING AND SCREENING LOG ....................................................................................21 
4.3 CONSENT .............................................................................................................................21 
4.4 SCREENING PROCEDURES .....................................................................................................21 
4.5 ELIGIBILITY CRITERIA ............................................................................................................22 
4.6 DISCONTINUATION OF STUDY TREATMENT, WITHDRAWAL, AND COMPLIANCE ............................25 
4.7 LOST TO FOLLOW-UP ............................................................................................................25 
4.8 ACCRUAL SUSPENSION AND CLOSURE ...................................................................................26 
4.9 END OF STUDY DEFINITION ....................................................................................................26 
4.10 STUDY DISCONTINUATION AND CLOSURE .............................................................................26 
5 TREATMENT PLAN ...............................................................................................................26 

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5.1 ATB ADMINISTRATION ...........................................................................................................26 
5.2  SUPPLY ...............................................................................................................................27 
5.3  STORAGE AND STABILITY ......................................................................................................28 
5.4  ACCOUNTABILITY..................................................................................................................28 
5.5  DRUG DESTRUCTION ............................................................................................................28 
5.6 BIOPSY SPECIMEN, OPERATIVE SPECIMEN, AND TISSUE PROCESSING ......................................28 
5.7 DOSE MODIFICATIONS ...........................................................................................................29 
5.8 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................30 
5.9 DIETARY RESTRICTIONS ........................................................................................................30 
5.10 MONITORING SUBJECT COMPLIANCE ....................................................................................30 
6 ADVERSE EVENTS: DEFINITIONS, COLLECTION AND REPORTING REQUIREMENTS ........................30 
6.1 DEFINITIONS .........................................................................................................................30 
6.1.1 Adverse Event ............................................................................................................................................ 30 
6.1.2 Serious Adverse Event (SAE) ................................................................................................................... 31 
6.1.3 Attribution of an Adverse Event ............................................................................................................... 31 
6.1.4 Expectedness of an Adverse Event ........................................................................................................... 32 
6.2 COLLECTION AND REPORTING REQUIREMENTS FOR ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS .....................................................................................................................................32 
6.2.1 Collection of Adverse Events .................................................................................................................... 32 
6.2.2 Reporting of Adverse Events and Serious Adverse Events ...................................................................... 32 
6.2.3 Reporting Instructions .............................................................................................................................. 33 
6.3 UNANTICIPATED PROBLEM INVOLVING RISK TO SUBJECT OR OTHER (UPIRSO) ........................34 
6.4 SUBJECT COMPLAINTS ..........................................................................................................34 
7 STATISTICAL CONSIDERATIONS .......................................................................................34 
7.1 STATISTICAL DESIGN .............................................................................................................34 
7.2 .............................................................................................................................................34 
7.3 MISSING DATA ......................................................................................................................35 
7.4 DATA QUALITY, ANALYSIS PLAN .............................................................................................35 
8 DATA AND SAFETY MONITORING PLAN (DSMP) ..............................................................35 
8.1  STUDY TEAM........................................................................................................................35 
8.2  QUALITY ASSURANCE ...........................................................................................................36 
8.3  CLINICAL TRIALS OFFICE ......................................................................................................36 
8.4  DSMC .................................................................................................................................36 
9.2 REGULATORY COMPLIANCE ...................................................................................................37 
9.3 PRESTUDY DOCUMENTATION .................................................................................................37 
9.4 INSTITUTIONAL REVIEW BOARD ..............................................................................................37 
9.5 SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ................................38 

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9.6 PROTECTION OF HUMAN SUBJECTS .......................................................................................39 
9.6.1 Protection from Unnecessary Harm ......................................................................................................... 39 
9.6.2 Protection of Privacy ................................................................................................................................. 39 
9.7 CHANGES IN THE PROTOCOL .................................................................................................39 
9.8 INVESTIGATOR COMPLIANCE ..................................................................................................40 
10 DATA HANDLING AND RECORD KEEPING ......................................................................40 
10.1 OVERVIEW ..........................................................................................................................40 
10.2 DATA MANAGEMENT RESPONSIBILITIES ................................................................................40 
10.2.1 Principal Investigator ............................................................................................................................. 40 
10.2.2 Research Coordinator ............................................................................................................................. 40 
10.2.3 Research Nurse/Medical Staff ................................................................................................................ 40 
10.2.4 Biostatistician .......................................................................................................................................... 40 
10.3 HANDLING AND DOCUMENTATION OF CLINICAL SUPPLIES ......................................................40 
10.4 SOURCE DOCUMENTS .........................................................................................................41 
10.5 CASE REPORT FORMS .........................................................................................................41 
10.6 STUDY RECORD RETENTION ................................................................................................42 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ...............................................................43 
APPENDIX 2. STUDY DIARY ...................................................................................................44 
APPENDIX 3: SUBJECT LOST TO FOLLOW-UP LETTER ......................................................47 
REFERENCES .........................................................................................................................48 
 

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PROTOCOL SUMMARY 
 
Title 
Inhibition of Oral Tumorigenesis by Antitumor B 
IND Sponsor 
Sponsor Investigator 
Principal Investigator  
Stuart J. Wong, MD 
Study Sites 
Froedtert & the Medical College of Wisconsin  
Clinical Trial Phase 
Phase 0 
Study Disease 
Oral cavity squamous cell cancer 
Main Eligibility 
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 protocol therapy. 
3. Clinical stage I-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. Zubrod/ECOG Performance status < 2. 
6. Age ≥ 18 years. 
Primary Objective 
To determine the antiproliferative effects of ATB versus placebo as 
determined by tumor Ki-67. 
Secondary Objectives 
1. Characterize the pharmacokinetics (PK) and pharmacodynamics 
(PD) properties 
2. Determine the biologic correlates of response including NFKB, and 
RNASeq. 
Primary Endpoint 
Determine the anti-proliferative effects of ATB as determined by tumor Ki-
67 in baseline tumor biopsy compared to resected control tumor tissue 
from untreated patients. 
Secondary Endpoints 
1. PK and PD properties from the saliva samples collected during the 
period of the study will be calculated. 
2. Measure biologic correlates of response including NFKB, and 
RNASeq from the tumor specimens collected at baseline and on 
the day of surgery. 
Study Design 
This is a window of opportunity study of ATB. 
The study has been amended from a randomized study of ATB versus placebo 
to a single arm open label trial of ATB   

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Upon initiating study treatment, patients will start taking the study drug. The 
duration of treatment will depend upon scheduling of their surgery—typically from 
the time surgery is scheduled it will be between seven to 28 days. Four (300 mg) 
pills will be taken three times per day until the evening prior to surgery.  
Number of Subjects 
Approximately *** subjects will be enrolled to achieve 14 total ATB-treated 
patients. 
Estimated Time to 
Complete Enrollment: 
Approximately two years. 

 
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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ARM 1: Anti-Tumor B: 
Daily treatment until Day-1 of  
surgery 
R
E
G
I
S
T
R
A
T
I
O
N 
Screening 
Surgery 
Baseline Biopsy 
Post Treatment Biopsy 
Primary endpoint*: Ki-67 
Secondary Endpoints*: PK, PK/PD, NfκB, RNA-Seq, Imaging 
 
*Comparison with control tissue from untreated patients  

 
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STUDY CALENDAR: 
 
Procedure 
Screening1 
ATB Administration:  
(Daily until Day -1 of Surgery) 
End of Treatment 
Study Day/Visit Day 
Day – 28 to 
Enrollment 
Day 1 
Prior to 
Surgery12, 13 
Day of 
Surgery 
Follow 
Up13 
Informed Consent 
X 
 
 
 
 
AE Reporting 
Recorded from day 1 of the study drug through 30 days after the last dose of 
study drug (Section 6). 
 
Concomitant Medications3 
Recorded from signing of the ICF through 30 days after the last dose of study 
drug. 
 
Physical Exam2 
X 
 
 
X 
X 
Medical History2 
X 
 
 
 
 
Pregnancy Test (Serum or Urine)4, 13 
X 
 
 
 
 
ECOG Performance Status5 
X 
 
 
 
 
Vital Signs per institutional standards 
X 
 
 
 
 
Complete metabolic panel6,13 
X 
 
 
X 
 
X 
CBC w/ Diff and platelet count13 
X 
 
X 
 
 
PT, INR13 
 
 
X 
 
 
Research saliva samples7 
 
See footnote 7 for research saliva sample draw 
timepoints. 
 
 
Tumor Measurement by Physical Exam 
X 
 
 
 
 
Tumor Specimen9 
X 
 
 
X8 
 
CT9, 8 
X 
 
X 
 
 
MDASI-HN (MD Anderson Symptom 
Inventory-Head and Neck Survey)13 
 
X 
X 
 
 
ATB administration 
 
Patient to take as directed from day 1-prior to 
surgery 
 
 
Patient Diary11 
 
X 
X 
 
 

 
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1. Screening procedures must occur within 28 days prior to registration. ATB administration should start within 
seven days of registration. 
2. Focused physical examination by a study investigator. 
3. Capture medications taken from signing of informed consent document until 30 days post last dose of ATB 
Medications given during the surgical hospitalization will only be collected if related to Adverse event 
treatment. 
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, , calcium, BUN, and glucose. 
7. A total of at least two patient samples (saliva) per day will be collected  (predose, before lunch, or before 
dinner dose 1, dose 2, dose 3 of study drug). Saliva samples will be collected in a 5-ml bio vial, time 
documented by the patient,  then frozen and stored by the patient until collection (see Section 3.1 for more 
details). 
8. Fresh frozen tumor specimen will be collected, see section 5.6 for processing. 
9. CT at baseline may be performed within six weeks prior to study registration. CT at day -1 of surgery can 
have a window of - 3 days. If baseline tumor is not measurable by baseline imaging (eg due to dental 
artifact) then follow-up imaging is NOT required 
10. Patient will complete study diary with all relevant information and will submit the diary to study coordinator 
on the day of surgery. 
11. The date for follow-up assessment is at the discretion of the surgeon and will correspond with the first post-
operative outpatient assessment. 
12. The indicated assessment for this timepoint will be collected only once with a window of two days:  Day -3 
to Day 0 of surgery.  
13. In special cases and with study team approval, subjects may be able to have imaging, lab work, and 
completion of surveys completed at specific community sites. This would be done instead of being required 
to perform these procedures at MCW/FH. They would have to travel to MCW/FH at times for all other 
procedures and visits. 
 
 
 

 
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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATB 
antitumor B 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
COPD 
chronic obstructive pulmonary disease 
CR 
complete response 
CRC 
clinical research coordinator 
CrCl 
creatinine clearance 
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 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
MCWCC 
Medical College of Wisconsin Cancer Center 
NCI 
National Cancer Institute 

 
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ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PD 
disease progression 
PK 
Pharmacokinetics 
PR 
partial response 
RBC 
red blood cell (count) 
SAE 
serious adverse event 
SCC 
squamous cell carcinoma 
SD 
stable disease 
SD 
standard deviation 
SOP 
standard operating procedure 
SRC 
Scientific Review Committee 
TLC 
thin layer chromatography 
ULN 
upper limit of normal 
UP 
unanticipated problem 
UPIRSO   
unanticipated problems involving risks to subjects or others 
WBC 
white blood cell (count) 
WOO 
window of opportunity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1. BACKGROUND  
 
1.1. 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. More than 90% of oral 
cancers are 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, 7). Development of effective chemopreventive 
interventions of HNSCC is, therefore, urgently needed.  
 
1.2 Chemoprevention: 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 Traditional Chinese Medicine Pharmaceutical 
Engineering Technology Research Center (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. In addition, it has been 
safe 
in 
trials 
using 
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 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 a remarkable 52.2% and 47.3%, respectively (9-11).  
 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 
Latin
Chinese
Sophora tonkinensis
Shan Dou Gen
Water Extract
18-24
Polygonum bistorta
Quan Shen
Water Extract
17-21
Prunella vulgaris
Xia Ku Cao
Water Extract
18-25
Sonchus brachyotus
Bei Bai Jiang
Water Extract
17-23
Dioscorea bulbifera
Huang Yao Zi
Water Extract
 3-6
Dictamnus dasycarpus
Bai Xian Pi
 Powder
 8-12
Herbal Name
Form
% Content
Table 1. Composition of Antitumor B (percent weight)   

 
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administered them either ATB tablets or placebo tablets orally. The treatment regimen was four 
(300 mg) tablets each time, three times per day for eight to12 months. During 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 nine 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). 
 
1.3 ATB Dose and Schedule 
ATB has been administered in 
clinical 
studies 
for 
upper 
aerodigestive 
disease 
prevention in wide ranges of 
agent doses and schedules, 
summarized in Table 2 below. 
Tablet strength in all of these 
studies was 300 mg. The dose 
range used in clinical trials 
was from 2,400 mg/d to 4,800 
mg/d. The duration of therapy 
ranged from two months to 
five years. 
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.  
 
1.4 ATB Safety and 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. Previous studies of ATB, described in the ATB Health Canada Application 
Supporting Documentation, have been performed in China for prevention of upper aerodigestive 
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. 
 
 
Table 3. Effect of ATB (ACAPHA) on blood parameters following chemoradiation 

 
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cancer prevention. These studies were placebo controlled and utilized long durations 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 durations 
of administration lasting years. In the Hebei Province study of 300 participants randomized to ATB 
(ZSP) for a duration of six months (taking eight tablets BID (4,800 mg/d)), no toxicity was 
observed, including no side effects related to 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 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 preoperative coagulation test. 
A PK run-in study of ATB in oral cancer patients is currently active at MCW. This trial has 
examined safety and tolerability of ATB in four patients and two additional patients may be needed 
to finish this trial. A companion trial in eight normal subjects at University of Houston using the 
same dose has provided PK information and examined safety/tolerability of ATB as well. Taken 
together, there were no safety or tolerability concerns remaining to be addressed before 
randomized trial of ATB.  Therefore, we believe that it is time to initiate randomized trial of ATB. 
 
1.5 Preclinical Studies: Mechanism of Action, Efficacy, ATB Key Active 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 the 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 (12), and identified the following three compounds from a 
more active fraction GS409 using oral cancer cell line SCC2095: fraxinellone, dictamnine and 
maackiain (see Fig.1 for structures, and Table 2 for activities). Trifolirhizin is also expected to be 
highly active because it is rapidly biotransformed to maackiain in vivo (13). 
 
 
 
 
 
 
Fig 1. Chemical structures of key active compounds present in ATB and active against 
lung tumor cell lines LM1 and/or oral cancer cell line SCC2095.    
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

 
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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.(13) 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.(13) 
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 2), which used a 
lower 
dose 
than 
our 
published study but was 
equally as effective. 
 
1.6 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,  (14-17) we examined the effects of ATB 
in NF-ĸB signaling pathway via NF-ĸB proteomic array in order to validate the RNA seq result 
Fig 2. Inhibition of B(a)P-induced lung 
tumorigenesis in A/J mice using 
human equivalent dose of ATB 
(4g/kg) in the diet.   
 
Figure 3 
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 twofold while inhibiting p50/105, p52/p100 and RelA/p65 
expression levels compared to that of vehicle control treated SCC15 cells. 

 
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(Fig. 4 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. 3). Growth of oral cancer 
cells, SCC9 and SCC15 was 
also 
inhibited 
to 
ATB 
treatment 
in 
a 
dose-
dependent manner (Fig. 4A).  
We also further validated the 
effects of ATB on NF-κB 
signaling in SCC9 oral 
cancer cells via Western blot 
(Fig. 4C), 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. 4B). 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. 
1.7 ATB Key Active Components 
 
The efficacy of ATB is further illustrated in preclinical 
studies that examined the key components of ATB 
and 
that, 
in 
particular, 
examined 
varying 
concentrations of the key components. We call the 
concentrated forms of the three compounds, ATB-
KACα.. For comparison purpose, the IC50 values (in 
µg/ml) were 1963 for ATB, 303 for GS409, and 90 for 
ATB-KACα (Fig. 5). Therefore, ATB-KACα (target 
IC50 of 90 µg/ml) will be at least 21-fold more active 
than ATB, and it will contain at least 50% of three 
most 
active 
compounds 
(i.e., 
fraxinellone, 
dictamnine, 
and 
maackiain, 
Fig. 
1). 
The 
Fig 4. Proposed Mechanism of ATB in the Inhibition of HNSCC Tumorigenesis A) 
ATB inhibited cell proliferation of both SCC9 and SCC15 in a dose-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.  
Fig 5. IC50 Values of ATB, GS409 and 
projected IC50 value of ATB-KACα. 

 
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concentrated forms of these three compounds is the subject of ongoing in vitro investigation which 
will lead to future clinical investigation of ATB-KACα. 
 
ATB-KACα has a well-defined chemical composition unlike a natural compound which can be 
affected by environmental factors. This approach of simplifying natural product extract to 
something that is better defined has been used repeatedly in the past for cancer prevention (15, 
16). 
1.8 Window of Opportunity Study Design 
A window of opportunity (WOO) trial design (17), 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 (17). Employing this trial design, a study participant will receive a novel agent (or placebo, 
in a double-blinded randomized study) for a short duration during the standard waiting period prior 
to their definitive anticancer 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 biologic/molecular effects, and/or PD/PK parameters. The utility of these biomarker-
based early phase trials for oral pre-malignancy, such as proposed here, has been highlighted by 
Szabo. (18) A head and neck cancer clinical trial examined erlotinib in a similarly designed trial 
with a window duration of 7 to 14 days. (19) This study demonstrated significant reduction of Ki67 
as well as alteration of multiple other biologic markers of response following a short window of 
treatment prior to surgery. This study illustrates the utility of the phase 0 or window of opportunity 
trial design in which, even with a short duration of treatment, mechanistic questions of biologic 
tumor targets can be addressed.  This study of ATB is part of a larger project in which we ultimately 
wish to examine the chemo preventive effects of ATB in oral pre-cancer lesions. Examination 
saliva PK of ATB, as we propose in this study, will establish bioavailability of the agent in direct 
exposure to oral mucosa. 
The clinical trial study design, proposed here, is shown in study schema. This single arm open 
label WOO trial of ATB 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 allow a 
portion of the standard of care (diagnostic tumor biopsy) to be used for the study, and to take 
study agents or placebo for a duration (7 to 28 days) until the time of their surgery. A second, 
post-treatment tumor biopsy is not needed because the OR-resected tumor will serve this 
purpose. Pre-and post-treatment CT scans will be performed on patients for correlation of ΔKi67 
with change in tumor size and diffusion-weighted MRI.  
 
 
2 HYPOTHESIS AND OBJECTIVES  
We hypothesize that oral administration of ATB will have desirable PK properties and biomarker 
responses oral cancer. 

 
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This hypothesis will be testing in a single-arm, open-label WOO clinical trial evaluating ATB and 
comparing control tissue bank specimens from untreated patients by blinded review.  
2.1 Primary Objectives 
To determine the antiproliferative effects of ATB as determined by tumor Ki-67. 
 
2.2 Secondary Objectives 
1. Characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties. 
2. Determine the biologic correlates of response, including NFKB, and RNASeq. 
 
2.3 Primary Endpoint 
 
Determine the antiproliferative effects of ATB as determined by tumor Ki-67 in baseline tumor 
biopsy compared to resected tumor tissue following treatment and utilizing tissue bank 
specimens as control. 
 
2.4 Secondary Endpoint 
 
To examine PK and PD properties from the saliva samples collected during the period of the 
study and biologic correlates of response including NFKB, and RNASeq from the tumor 
specimens collected at baseline and on the day of surgery.  
 
3 STUDY DESIGN 
 
3.1 General Description 
 
A window of opportunity (WOO) Clinical Trial permits examination of drug effects 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 drug. This is a single arm, open-label window of opportunity study of ATB. 
Upon initiating study treatment, patients will start taking study drug. The duration of treatment will 
depend upon scheduling of their surgery—typically, from the time surgery is scheduled, it will be 
between seven to 28 days. Four (300 mg) pills will be taken three times per day until the evening 
prior to surgery. A pill diary will be completed by the patient.   
While taking study medication, patients will be required to provide saliva samples. Patients will be 
given specimen tubes and will store collected samples in the freezer.  Saliva sample tubes will be 
prelabeled to reflect the time of collection (Dose 1- morning, Dose 2-midday and Dose 3- evening). 
The patients’ diaries will contain checkbox reminders for daily saliva collection. Approximate 1 ml 
of saliva will be collected. Participants will store collected saliva in storage container provided by 
the study coordinator in their home freezer. 
 
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. All the specimens will be collected on the day of their surgery. 
 

 
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Saliva samples (1 ml) will be collected at the following timepoints: day 1: then to the evening of 
the day prior to surgery:  A total of at least two patient samples (saliva) will be collected daily 
corresponding to agent dose timepoints (Dose 1- morning, Dose 2-midday or Dose 3- evening ). 
Saliva samples will be collected in a 5-ml bio vial, time documented by patient, and then frozen 
and stored by the patient until collection. Patients will be given supplies for saliva collection, 
storage, and for transportation at the end of the collection period. Compliance of > 90% saliva 
sample collection is deemed acceptable. Sample storage will be 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 should be shipped in dry ice to the following location: 
 
Ming Hu, PhD 
Department of Pharmacological and Pharmaceutical Sciences 
College of Pharmacy 
4349 Martin Luther King Blvd 
University of Houston 
Houston, TX 77204 
Contact Information: 832-842-8320 
 
Participants will continue taking ATB for a total of seven to 28 days, which they will record in a 
study diary. 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 Estimated time for completion of study enrollment 
 
The study will reach primary completion in approximately 24 months from the time the study opens 
to accrual. 
 
 
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. 

 
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• 
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. 
 
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 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. 

 
 
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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. 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 
 
Each subject must meet all the following inclusion criteria to be enrolled in the study: 
1. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent may be 
withdrawn by the subject at any time without prejudice to future medical care. 
2. In the event that the diagnosis of SCC is made by an outside pathologist, hence not 
verified, the patient can start study agent administration but histological confirmation of 
squamous cell cancer (SCC) of the oral cavity (or histologic variants of SCC) by an MCW 
pathologist must happen within seven days of registration in order to continue protocol 
therapy*. 
3. Clinical stage I-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 28 
calendar days of study registration. 
6. Zubrod/ECOG Performance status < 2. 
7. Age ≥ 18 years. 
8. CBC/differential obtained within 28 calendar days prior to registration, with adequate bone 
marrow function defined as follows: 
o Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;  
o Platelets ≥ 100,000 cells/mm3;  
o Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve 
Hgb ≥ 8.0 g/dl is acceptable). 
9. Adequate renal and hepatic function within 28 calendar days prior to registration, defined 
as follows: 
o Serum creatinine < 1.5 mg/dl or creatinine clearance (CCr) ≥ 50 ml/min within 14 
calendar days prior to registration, determined by 24-hour collection or estimated by 
Cockcroft-Gault formula: 
o CCr male = [(140 – age) x (wt in kg)] 
o [(Serum Cr mg/dl) x (72)] 
 
o CCr female = 0.85 x (CrCl male) 
CRC Initials: ___________                                                              Date: _________________ 
 
Investigator/Enrolling Physician Initials: ___________                    Date: _________________ 

 
 
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10. Total bilirubin < 2 x the institutional ULN; 
11. AST or ALT ≤ 3 x the institutional ULN;  
12. Calcium, glucose, potassium, and sodium within 28 calendar days prior to registration, 
with the following required parameters: 
o  
o Calcium: > 7 mg/dl or < 12.5 mg/dl; 
o Glucose: > 40 mg/dl or < 250 mg/dl; 
o Potassium: > 3 mmol/L or < 6 mmol/L; 
o Sodium: > 130 mmol/L or < 155 mmol/L. 
13. Female subjects must meet one of the following:  
• 
Postmenopausal for at least one year before enrollment,  
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), agrees to practice two acceptable methods of contraception (combination 
methods require 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 21days 
after the last dose of study agent, OR 
• 
Agrees to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable contraception methods.) 
14. Male subjects, 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 
• 
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, 
symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
15. Enrollment on an interventional postoperative study is allowed if study agents do not 
overlap.  
16. Gastric tube drug administration is permissible. 
 
* Note: patients whose confirmatory biopsy fails to demonstrate invasive carcinoma will be 
excluded from continued participation in the study and considered a screen failure. 
 
 
CRC Initials: ___________                                                              Date: _________________ 
 
Investigator/Enrolling Physician Initials: ___________                    Date: _________________ 

 
 
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Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Pregnant or lactating women are ineligible due to unforeseeable risks to embryo or fetus. 
2. Concurrent use of any medicinal botanical, natural, or other herbal compounds. 
3. Planned subtotal or debulking surgery is not permissible.  
4. Prior systemic chemotherapy for oral SCC; note that prior chemotherapy for a different 
cancer is allowable. 
5. 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. 
6. Severe active comorbidity, such as liver disease, uncontrolled cardiac disease, infection, 
and severe COPD.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
“I have reviewed all inclusion/exclusion criteria and confirm the subject is eligible.” 
 
 
CRC Name and Initials 
Date 
 
 
Enrolling Investigator Name (print) 
 
 
Enrolling Investigator 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.  
• 
Intercurrent 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. The 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 agrees 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 occur 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 of its phases, 
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.  
 
 
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 

 
 
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human oral leukoplakia trials and in esophageal cancer prevention trials. ATB may be taken 
with or without food.  
Regimen Description 
ARMS 
Study 
agent 
Premedication; 
precautions 
Dose 
Route 
Schedule 
Duration 
ARM 1 
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.  
 
• 
Patient must submit completed study dairy to the study coordinator. 
 
5.2 Supply 
 
ATB 
 
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 agents will be shipped to MCW in one batch. Study agent ordering contact information: 
 
Ming Hu, PhD 
Department of Pharmacological and Pharmaceutical Sciences 
College of Pharmacy 
4349 Martin Luther King Blvd 
University of Houston 
Houston, Texas 77204 
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); 
• 
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”); 

 
 
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• 
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. Key active ingredients of ATB will be tested 
at regular intervals (every 3-6 months) to allow shelf life extension.  Current data indicate ATB is 
stable at 90 days without decrement of active components at controlled room temperature (15°C 
– 30°C). Placebo tablets should be stored in the same way as ATB.  
 
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 
 
Baseline tumor specimens will be analyzed for Ki67 and ATB accumulation and stored for tissue 
banking for future research. For ATB accumulation studies, tumor and peritumor samples (>150 
mg each per patient) should be snaped frozen in liquid N2 and stored at -80C freezer until it is 
shipped. The samples for ATB accumulation studies should not be fixed in formalin.  
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 Dr. Tamara Giorgadze (phone 
number 414-805-8442).  Enrollment may proceed prior to receipt of outside biopsy specimen if it 
can be confirmed that there is sufficient tissue and sample will be released. 
A portion of the OR-resected tumor will serve as post treatment specimen for comparison to the 
pre-treatment biopsy. At the time of surgery, a portion of the resected tumor will be utilized for the 
study. When possible, separate the tumors from the surrounding peritumor tissue.  The specimen 
(i.e., tumor and peritumor) (minimum of 150 mg each) should be fresh frozen in liquid N2 and then 
stored in -80C freezer without formalin fixing. Any remnant tissue will be stored for further testing 
of biological correlates as mandated by the protocol. 
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, they will be delivered to the CRI Histology 
Core for Ki67 testing. The paraffin block of the resected tumor and biopsy should be delivered to 
the following location:  
Dr Tamara Giorgadze 
Wisconsin Diagnostics Laboratories 

 
 
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9200 W Wisconsin Ave 
Milwaukee, WI 53226 
 
 
Immune response biomarker assessment (such as multiplex immunofluorescent staining) will be 
performed on biospecimens. Additional immune response testing will be performed based on 
initial results. 
 
5.7 Dose Modifications 
As indicated in the study calendar, a complete metabolic panel (including LFTs) will be performed 
midway 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 14 days). 
 
If concomitant elevation of AST/ALT 3 times 
the upper limit of normal and bilirubin elevation 
two 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.  
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% will be considered 
after 
maximum 
supportive 
care 
recommendations are introduced. 
 
 
 
Dose Level 
Dose 
-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 anticancer 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. 
 
 
6 ADVERSE EVENTS: DEFINITIONS, COLLECTION AND REPORTING 
REQUIREMENTS 
 
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). 
 

 
 
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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 (exceptions eg hospitalization for surgical removal of head/neck tumor, 
planned hospitalization for elective procedures such as G-tube placement). 
• 
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. 
 
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.  
 

 
 
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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 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.  
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 following 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. 
 
 

 
 
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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, which includes 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 4 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. 
 
 
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: 
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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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. 
 
7 STATISTICAL CONSIDERATIONS 
 
7.1 Statistical Design 
The primary goal of the clinical trial is to study the antitumor effects of ATB. The trial and its 
statistical design are adapted from three published studies (19-21) and various statistical methods 
will be used as described below. Upon registration patients will receive treatment with ATB. 
Control biobanked specimens (from PRO00040992 and PRO00041026) from untreated head and 
neck cancer patients will be used as comparison.  Testing will be performed by investigators who 
are blinded to specimen origin. Testing the overall effect would be done using two sample t tests. 
Pilot estimates for the baseline distribution of ΔKi67 are obtained from the Gross et al study. (19) 
A minimum of 12 patients would have at least 80% power to detect a difference in ΔKi67 of 2.5 
or higher between treatment arm versus control, with a standard deviation of 2 or lower (implying 
an effect size of approximately 1.25) using a two-sided t-test with significance level of 0.05; 28 
patients will be targeted to allow for 5% dropout. (19, 22) 
 
Analysis of secondary outcomes:  A flexible time dependent Emax model will be used for the PK 
modeling. Appropriate plasma active compound concentrations (Cp,max, AUCp and Cp,ss) will 
be estimated. Linear models will be used to estimate the association of the arms with biologic 
correlates, NFKB, and RNASeq.  
 
7.2 Investigator Blinding, Control Specimens 

 
 
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Investigators who perform endpoint assessment will be blinded to patient identifiers on study 
specimens. Dr. Banerjee will oversee specimen blinding and will retain the key to specimen 
coding. Specimen labeling will be performed by WDL under direction of Dr. Banerjee.  Unblinding 
(method for access, conditions for unblinding, end of study comparison of study specimens versus 
control specimens from untreated patients, unblinding documentation etc.) will adhere to MCW 
CTO SOP. Radiology review will also be performed without identifiers so that imaging review will 
also be blinded. Dr. Banerjee will oversee coding of radiology files for blinded review. Unblinding 
will occur at the direction of Dr. Banerjee following completion of accrual of all patients and 
confirmation that endpoint analysis is complete.  
 
Prior to this amendment some of the patients treated on this study who were randomized to the 
control arm received placebo. Therefore in order to determine how many additional patients need 
to be enrolled, Dr. Banerjee will perform and unblinding assessment. 
 
7.3 Missing Data 
Data from patients who withdraw from the study, including AEs and any follow-up, will be included 
in the analyses of primary and secondary outcomes. Patients who are not able to complete at 
least 50% of planned therapy will be replaced. 
 
7.4 Data Quality, Analysis Plan 
Dr. Wong will perform drug quality assurance review with the goal of evaluating protocol 
compliance. Participants whose compliance with the study drug is >75% of the prescribed dose 
will be deemed within an acceptable variation for inclusion of the study analysis.  
 
8 DATA AND SAFETY MONITORING PLAN (DSMP) 
 
Data and Safety Management Overview 
The Medical College of Wisconsin (MCW) Data and 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: 
8.1 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.  
 
 
 
 

 
 
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8.2 Quality Assurance  
 
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. 
 
8.3 Clinical Trials Office 
The MCWCC Clinical Trials Office [CTO] provides administrative assistance and support to the 
DSMC.  
 
8.4 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 (review frequency may change based on study risk per DSMC 
discretion) 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. 
 
8.5 Stopping Rule  
A temporary suspension of the study will be mandated if any serious toxicity (grade >3) that occurs 
during or within 30 days of drug administration and that is definitely, probably, or possibly related 
to the study drug. Resumption of the study will be permissible following DSMC review and 
approval. 
 
 

 
 
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9 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT 
 
9.1 Ethical Standard 
 
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©(4); consistent with GCP and all applicable 
regulatory requirements. 
 
9.2 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 §312 
(Investigational New Drug Application; 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. 
9.3 Prestudy Documentation 
  
Prior to implementing this protocol at MCWCC, the protocol, informed consent form and any other 
information pertaining to participants must be approved by the MCW IRB.  
9.4 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. 
Potential subjects will be told, and a statement will be included that this study is designed to 
determine both safety and effectiveness. The consent forms will include the approved MCW IRB 
template language. 
Consent forms will be IRB approved and the subject (and legally authorized representative, if 
necessary) will be asked to read and review the document. The treating physician or the 
investigator will explain the research study to the subject and answer any questions that may 

 
 
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arise. The study coordinator may complete the consenting process. 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 who 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.  
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 
was 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. 
9.5 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. 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 
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in the case report forms contain the study identifiers, subject initials, date of birth and date of 
service.  
Personal identifiers, such as name and medical record number, will be removed from 
accompanying lab reports and test results. Any data/PHI that are not stored for the purposes of 
the study are shredded in the Clinical Trials Office. 
After all study queries and analyses are completed, the data/PHI will not be destroyed but will be 
archived in a secure long-term storage site in order to keep an accurate record of screened and 
enrolled subjects for the sponsor and potential audit purposes only specific for this study.  
9.6 Protection of Human Subjects 
9.6.1 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 
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. 
9.6.2 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.  
9.7 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. 
 
 
 

 
 
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9.8 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).  
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 
10.2.1 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.  
10.2.2 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. 
10.2.3 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. 
10.2.4 Biostatistician 
The biostatistician may assist in CRF development (content and design), dataset specifications 
(annotation of CRFs and record layout) and validation. 
10.3 Handling and Documentation of Clinical Supplies 
The MCWCC principal investigator will maintain complete records showing the receipt, 
dispensation, return, or other disposition of all investigational drugs. The date, quantity and batch 

 
 
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or code number of the drug, and the identification of patients to whom study drug has been 
dispensed by patient number and initials will be included. The sponsor-investigator will maintain 
written records of any disposition of the study drug. 
The principal investigator shall not make the investigational drug available to any individuals other 
than to qualified study patients. Furthermore, the principal investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 
10.4 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:  
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. 
 
10.5 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 safety and treatment outcomes for safety 
monitoring and data analysis. 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 

 
 
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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. 
10.6 Study Record Retention 
 
The principal investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity and use by subjects, as well as written records of the disposition of the 
drug when the study ends.  
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 on each 
individual administered the investigational drug or employed as a control in the investigation. 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. 
In accordance with FDA regulations, the investigator shall retain records for a period of two years 
following the date a marketing application is approved for the drug for the indication for which it is 
being investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until two years after the investigation is discontinued and FDA is notified. 

 
 
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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. 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.  
 
The 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 the 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. The study coordinator will provide you with specific instruction on how to complete the diary.  
 
2. Record the date and when you took ATB. Record the dose as soon as you take them; do not 
batch entries together at a later time. 
 
3. Take study medication every 8 hours until the evening prior to surgery 
 
4. Record the time of saliva sample collection. Collect the saliva sample even if you miss any 
dose. 
 
5. 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. 
 
6. 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 up 
for the missed dose. 
 
7. 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 study 
medication / 
saliva sample 
 
 
 
Saliva sample 
collection time 
Minimum 2 
times daily 
  
 
Study Medication 
Administration 
Time 
 
 
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 
 
 

 
 
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Antitumor B (ATB) Medication Diary 
Subject # (completed by study staff): __________________ 
 
 
 
 
 
 
 
APPENDIX 3: SUBJECT LOST TO FOLLOW-UP LETTER 
 
 
Day 
 
 
Date 
Administration 
of study 
medication / 
saliva sample 
 
 Saliva sample 
collection time  
Minimum 2 
times daily  
 
Study Medication 
Administration 
Time 
 
 
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 
 
 

 
 
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Date: ___________________________________ 
 
 
 
Dear ___________________________________, 
 
 
 
 
 
 
The research study team has been unable to contact you regarding the clinical trial (Inhibition of 
Oral Tumorigenesis by Antitumor B) you participated in. 
 
 
 
We would like to discuss how you are doing and if we may continue contacting you. 
 
 
 
 
 
Please contact us at  
_____________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
Sincerely, 
 
 
 
 
___________________________________ 
 
 
 
REFERENCES 
 

 
 
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1. 
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 
2010;60(5):277-300. 
2. 
Masthan KM, Babu NA, Sankari SL, Priyadharsini C. Leukoplakia: A short review on 
malignant potential. J Pharm Bioallied Sci. 2015;7(Suppl 1):S165-6. 
3. 
Dionne KR, Warnakulasuriya S, Zain RB, Cheong SC. Potentially malignant disorders of 
the oral cavity: current practice and future directions in the clinic and laboratory. Int J Cancer. 
2015;136(3):503-15. 
4. 
Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med. 
2001;345(26):1890-900. 
5. 
Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med. 
2008;359(11):1143-54. 
6. 
Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, et al. 
Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without 
cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. 
2014;32(27):2940-50. 
7. 
Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human 
papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 
2010;363(1):24-35. 
8. 
Sun Z, Guan X, Li N, Liu X, Chen X. Chemoprevention of oral cancer in animal models, 
and effect on leukoplakias in human patients with ZengShengPing, a mixture of medicinal 
herbs. Oral Oncol. 2010;46(2):105-10. 
9. 
Lin PZ, Zhang JS, Cao SG, Rong ZP, Gao RQ, Han R, et al. [Secondary prevention of 
esophageal cancer--intervention on precancerous lesions of the esophagus]. Zhonghua Zhong 
Liu Za Zhi. 1988;10(3):161-6. 
10. 
Lin P ZJ, Rong Z, Han R, Xu S, Gao R, Ding Z, Wang J, Feng H, Cao S. . Studies on 
medicamentous inhibitory therapy for esophageal precancerous lesions--3- and 5-year inhibitory 
effects of antitumor-B, retinamide and riboflavin. . Proc Chin Acad Med Sci Peking Union Med 
Coll 1990;5:121-39. 
11. 
P. L. Medicamentous inhibitory therapy of precancerous lesions of the esophagus--3 and 
5 year inhibitory effect of antitumor B, retinamide and riboflavin. Zhongguo Yi Xue Ke Xue Yuan 
Xue Bao. 1990;12:235-45. 
12. 
Yin T, Yang G, Ma Y, Xu B, Hu M, You M, et al. Developing an activity and absorption-
based quality control platform for Chinese traditional medicine: Application to Zeng-Sheng-
Ping(Antitumor B). J Ethnopharmacol. 2015;172:195-201. 
13. 
Wang Y, Yao R, Gao S, Wen W, Du Y, Szabo E, et al. Chemopreventive effect of a 
mixture of Chinese Herbs (antitumor B) on chemically induced oral carcinogenesis. Mol 
Carcinog. 2013;52(1):49-56. 
14. 
Li Z, Yang Z, Passaniti A, Lapidus RG, Liu X, Cullen KJ, et al. A positive feedback loop 
involving EGFR/Akt/mTORC1 and IKK/NF-kB regulates head and neck squamous cell 
carcinoma proliferation. Oncotarget. 2016. 
15. 
Li Z, Yang Z, Lapidus RG, Liu X, Cullen KJ, Dan HC. IKK phosphorylation of NF-kappaB 
at serine 536 contributes to acquired cisplatin resistance in head and neck squamous cell 
cancer. Am J Cancer Res. 2015;5(10):3098-110. 
16. 
Nottingham LK, Yan CH, Yang X, Si H, Coupar J, Bian Y, et al. Aberrant IKKalpha and 
IKKbeta cooperatively activate NF-kappaB and induce EGFR/AP1 signaling to promote survival 
and migration of head and neck cancer. Oncogene. 2014;33(9):1135-47. 
17. 
Kim SB, Kim JS, Lee JH, Yoon WJ, Lee DS, Ko MS, et al. NF-kappaB activation is 
required for cisplatin-induced apoptosis in head and neck squamous carcinoma cells. FEBS 
Lett. 2006;580(1):311-8. 
18. 
Szabo E. Assessing efficacy in early-phase cancer prevention trials: the case of oral 
premalignancy. Cancer Prev Res (Phila). 2008;1(5):312-5. 

 
 
Short Title: ATB Randomized Window Study 
 
  50                                                       Version No.: 
5.1 
IND No.: 145798 
 
Version Date: 04/25/2024 
19. 
Gross ND, Bauman JE, Gooding WE, Denq W, Thomas SM, Wang L, et al. Erlotinib, 
erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in 
operable head and neck cancer. Clin Cancer Res. 2014;20(12):3289-98. 
20. 
Ma T, Galimberti F, Erkmen CP, Memoli V, Chinyengetere F, Sempere L, et al. 
Comparing histone deacetylase inhibitor responses in genetically engineered mouse lung 
cancer models and a window of opportunity trial in patients with lung cancer. Mol Cancer Ther. 
2013;12(8):1545-55. 
21. 
Owonikoko TK, Ramalingam SS, Miller DL, Force SD, Sica GL, Mendel J, et al. A 
Translational, Pharmacodynamic, and Pharmacokinetic Phase IB Clinical Study of Everolimus in 
Resectable Non-Small Cell Lung Cancer. Clin Cancer Res. 2015;21(8):1859-68. 
22. 
Bland M. Estimating Mean and Standard Deviation from the Sample Size, Three 
Quartiles, Minimum, and Maximum. International Journal of Statistics in Medical Research 
2014;4 (1): 57–64. 
23. 
DA F. Statistical Models: Theory and Practice: Cambridge University Press; 2005. 
24. 
DR C. Principles of statistical inference2006. 
25. 
J. C. Statistical power analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: 
Lawrence Erlbaum. 1988.