Predictability of Carcinomatous Invasion of the Maxilla or Mandible: An Assessment of Radiologic Modalities With Histologic Correlation
Conditions: Oral Cavity Squamous Cell Carcinoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University

THOMAS JEFFERSON UNIVERSITY 
Kimmel Cancer Center 
Predictability of Carcinomatous Invasion of the Maxilla or Mandible: An Assessment of 
Radiologic Modalities with Histologic Correlation 
Principal 
Investigators: 
Lionel Gold, DDS, Professor, Dept. of Oral and Maxillofacial 
Surgery and Pathology  
David Cognetti, MD, Assistant Professor, Dept. of Otolarygology-
Head and Neck Surgery, Co-Director, Jefferson Center for Head and 
Neck Surgery 
Co-Investigator(s): 
Robert Diecidue, DMD, MD, Professor and Chairman, Dept. of Oral 
and Maxillofacial Surgery 
Madalina Tuluc, MD, PhD, Assistant Professor, Dept. Of Pathology 
James Gates, DMD, Chief Resident, Dept. of Oral and Maxillofacial 
Surgery 
Steven Finden, MD, DDS, Assistant Professor, Dept. of Radiology-
Neurologic & Ear, Nose and Throat 
William Keane, MD, Professor and Chairman, Dept. of 
Otolaryngology-Head and Neck Surgery, Co-Director, Jefferson 
Center for Head and Neck Surgery 
Daniel Taub, DDS, MD, Assistant Professor, Program Director, Dept. 
of Oral and Maxillofacial Surgery 
Joseph Curry, MD, Assistant Professor Dept. of Otolaryngology-
Head and Neck Surgery 
Adam Luginbuhl, MD, Assistant Professor Dept. of Otolaryngology-
Head and Neck Surgery 
Funding Sponsor: 
Departmental 
Regulatory Sponsor: 
N/A 
IND Number: 
N/A 
Study Product: 
N/A 
Protocol Number: 
Version: 
Date: 
15D.468

2 
CONFIDENTIAL 
This document is confidential and the property of THOMAS JEFFERSON 
UNIVERSITY.  No part of it may be transmitted, reproduced, published, or used by 
other persons without prior written authorization from the study sponsor. 
1.0
03/23/2016

 
 
 
 
 
3 
Table of Contents 
STUDY SUMMARY ................................................................................................................................................... 6 
1 
INTRODUCTION .............................................................................................................................................. 8 
1.1 
SPECIFIC AIMS AND HYPOTHESIS ................................................................................................................ 8 
1.2 
BACKGROUND ............................................................................................................................................. 8 
1.3 
STUDY THERAPY ......................................................................................................................................... 8 
1.4 
PRECLINICAL DATA ..................................................................................................................................... 9 
1.5 
CLINICAL DATA TO DATE............................................................................................................................ 9 
1.6 
DOSE RATIONALE AND RISK/BENEFITS ............................................... ERROR! BOOKMARK NOT DEFINED. 
2 
STUDY OBJECTIVES ...................................................................................................................................... 9 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................... 8 
2.2 
SECONDARY OBJECTIVE(S) ......................................................................................................................... 8 
3 
STUDY DESIGN .............................................................................................................................................. 10 
3.1 
GENERAL DESIGN...................................................................................................................................... 10 
3.2 
PRIMARY STUDY ENDPOINTS .................................................................................................................... 10 
3.3 
SECONDARY STUDY ENDPOINTS ............................................................................................................... 10 
3.4 
PRIMARY SAFETY ENDPOINTS ................................................................................................................... 10 
4 
SUBJECT SELECTION AND WITHDRAWAL.......................................................................................... 10 
4.1 
INCLUSION CRITERIA ................................................................................................................................. 10 
4.2 
EXCLUSION CRITERIA ............................................................................................................................... 10 
4.3 
GENDER/MINORITY/PEDIATRIC INCLUSION FOR RESEARCH ...................................................................... 10 
4.4 
SUBJECT RECRUITMENT AND SCREENING ................................................................................................. 10 
4.5 
EARLY WITHDRAWAL OF SUBJECTS .......................................................................................................... 11 
4.5.1 
When and How to Withdraw Subjects .................................................................................................. 11 
4.5.2 
Data Collection and Follow-up for Withdrawn Subjects ..................................................................... 11 
5 
STUDY: RADIOLOGY ................................................................................................................................... 11 
5.1 
DESCRIPTION ............................................................................................................................................. 11 
5.2 
TREATMENT REGIMEN .............................................................................................................................. 11 
5.3 
RISKS ........................................................................................................................................................ 11 
5.4 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS .................................................................. 11 
5.5 
PREPARATION AND ADMINISTRATION OF STUDY RADIOLOGIC MODALITIES ....... ERROR! BOOKMARK NOT 
DEFINED. 
5.6 
SUBJECT COMPLIANCE MONITORING ........................................................................................................ 12 
5.7 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................ 12 
5.8 
PACKAGING ......................................................................................... ERROR! BOOKMARK NOT DEFINED. 
5.9 
BLINDING OF STUDY DRUG ................................................................. ERROR! BOOKMARK NOT DEFINED. 
5.10 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................... ERROR! BOOKMARK NOT DEFINED. 
5.10.1 
Receipt of Drug Supplies ....................................................................... Error! Bookmark not defined. 
5.10.2 
Storage ................................................................................................... Error! Bookmark not defined. 
5.10.3 
Dispensing of Study Drug ...................................................................... Error! Bookmark not defined. 
5.10.4 
Return or Destruction of Study Drug ..................................................... Error! Bookmark not defined. 
6 
STUDY PROCEDURES .................................................................................................................................. 12 
6.1 
STUDY VISIT SCHEDULE ............................................................................................................................ 13 
6.2 
DEFINITION OF DOSE LIMITING TOXICITIES .............................................................................................. 13 
6.3 
DOSE DELAYS AND DOSE MODIFICATIONS. ........................................ ERROR! BOOKMARK NOT DEFINED. 
7 
STATISTICAL PLAN ..................................................................................................................................... 13 

 
 
 
 
 
4 
7.1 
SAMPLE SIZE DETERMINATION ................................................................................................................. 13 
7.2 
STATISTICAL METHODS............................................................................................................................. 13 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS .................................................................................................. 13 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 14 
8.1 
DEFINITIONS .............................................................................................................................................. 14 
8.2 
RECORDING OF ADVERSE EVENTS............................................................................................................. 16 
8.3 
UNBLINDING PROCEDURES........................................................................................................................ 17 
8.4 
STOPPING RULES ....................................................................................................................................... 17 
8.5 
DATA AND SAFETY MONITORING PLAN .................................................................................................... 17 
8.5.1 
Medical Monitoring and AE/SAE Reporting ....................................................................................... 18 
8.5.2 
Data and Safety Monitoring Committee .............................................................................................. 19 
9 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 19 
9.1 
CONFIDENTIALITY ..................................................................................................................................... 19 
9.2 
SOURCE DOCUMENTS ................................................................................................................................ 20 
9.3 
CASE REPORT FORMS ................................................................................................................................ 20 
9.4 
RECORDS RETENTION ................................................................................................................................ 20 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ....................................................................... 20 
10.1 
STUDY MONITORING PLAN ....................................................................................................................... 20 
10.2 
AUDITING AND INSPECTING ....................................................................................................................... 21 
10.2.1 
Independent External and Internal Audits ........................................................................................... 24 
11 
ETHICAL CONSIDERATIONS .................................................................................................................... 21 
12 
STUDY FINANCES ......................................................................................................................................... 22 
12.1 
FUNDING SOURCE ..................................................................................................................................... 22 
12.2 
CONFLICT OF INTEREST ............................................................................................................................. 22 
12.3 
SUBJECT STIPENDS OR PAYMENTS ...................................................... ERROR! BOOKMARK NOT DEFINED. 
13 
PUBLICATION PLAN .................................................................................................................................... 23 
14 
REFERENCES ................................................................................................................................................. 23 
15 
APPENDICES .................................................................................................................................................. 27 
 

 
 
 
 
 
5 
List of Abbreviations 
 
OMFS or OMS: Oral and Maxillofacial Surgery 
JHNS: Jefferson Head and Neck Surgery 
SCC: Squamous Cell Carcinoma 
CBCT: Cone Beam Computed Tomography 
 
 
 
 
 

 
 
 
 
 
6 
Study Summary 
Title 
Predictability of Carcinomatous Invasion of the Maxilla or 
Mandible: An Assessment of Radiologic Modalities with 
Histologic Correlation 
Short Title 
Prediction of Bone Invasion by Squamous Cell Carcinoma 
Protocol Number 
The standard protocol number used to identify this study 
(e.g. CCRRC # and IRB #)   
Phase 
N/A, This is not a clinical trial, it is one of imaging modalities 
Methodology/Study 
Design 
Prospective, non-randomized, double blind study 
Study Duration 
2 years 
Study Center(s) 
Single-center 
Objectives 
In this study, we aim to explore which imaging modality or 
combination of imaging methods, in conjunction with clinical 
and histological examination, will most accurately predict 
the presence or absence of invasion of the mandible or 
maxilla by intraoral squamous cell carcinoma (SCC) 
Number of 
Subjects 
20 
Diagnosis and 
Main Inclusion 
Criteria 
Inclusion: SCC of the oral cavity 
Exclusion: 
prior 
mandibular 
surgery, 
primary 
intraosseous carcinoma, prior    history of 
radiation to the mandible, obvious finding of 
clinical invasion of the mandible, age under 18 
years old 
 
Study Therapy, 
Dose, Route, 
Regimen 
N/A 
Duration of 
administration and 
follow-up 
N/A 
Reference therapy 
N/A 
Statistical 
Methodology 
Sensitivity and specificity of mandibular or maxillary 
invasion will be determined, in addition to true and false 
positive as well as true and false negative.  Finally the 
positive and negative predictive values for each of the 
imaging modalities will be calculated based upon the 
previously mentioned statistical analysis.  
Schema 
See attached schema in the appendix section at the end 

 
 
 
 
 
7 
 

 
 
 
 
 
8 
1.0 INTRODUCTION 
 
This document is a protocol for a human research study. This study is to be 
conducted according to US and international standards of Good Clinical Practice 
(FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies 
and procedures.  
1.1 Specific Aims and Hypothesis 
 
There are newer imaging modalities that have not been studied sufficiently 
to determine whether intraoral SCC has or has not infiltrated a segment of the 
mandible or maxilla, necessitating partial or complete resection of the jaw.  One 
such modality is cone beam CT (CBCT), which delivers approximately 1/6 the 
amount of radiation and is about 1/10 the cost of a multi-slice, helical CT1.  A 
previously published imaging protocol by Van Cann et al2 used MRI, CT and 
bone SPECT to image the mandible.  In contrast to the prior algorithm, this study 
aims to test newer modalities such as the CBCT, PET/CT and helical CT against 
more traditional imaging techniques, to attempt to detect neoplastic infiltration of 
the mandible and maxilla.  We hypothesize that CBCT or a combination of the 
aforementioned modalities can be used in order to more accurately predict 
invasion of the maxilla or mandible by intraoral SCC.   
 
The accurate prediction of the presence or absence of malignant invasion 
of the jaws greatly influences the surgical treatment plan.  This is important for 
several reasons.  First, it may change the staging of the disease, necessitating a 
more or less involved resection and reconstruction.  Second, this knowledge will 
greatly benefit the surgeon, since the reconstruction of an extensive surgical 
defect will be more complex and require greater planning.  In addition, occult 
infiltration of the jaws may be a source of locoregional regrowth and recurrence 
that may be detectable by such imaging, leading to a wider, more appropriate 
and oncologically sound resection.  Third, if absence of mandibular or maxillary 
invasion can be proven statistically, it will permit “sparing” of complete or partial 
resection.  Thus, the mandible and maxilla, which are critical to facial form and 
function, will be preserved in some form and improve the overall quality of life of 
the cancer patient.   
 
1.2 Background and Rationale 
 
In 2008, Van Cann et al2 published a protocol of assessment of 
mandibular invasion by intraoral SCC.  This algorithm involved using a 
combination of MRI, bone SPECT and helical CT.  In 2010, Hendrikx et al3 
examined CBCT to determine its ability to predict invasion of the mandible by 
carcinoma.  They found that CBCT has the potential to obviate unnecessary 
mandibular resection and that it warranted further evaluation as such a tool.  
Review of CBCT literature shows two other studies that examined CBCT for the 

 
 
 
 
 
9 
detection of mandibular invasion by SCC1,4.  These studies have been 
retrospective in nature and none of them have examined the maxilla for possible 
invasion by SCC.  Thus, this study will compare CBCT, PET/CT, and helical CT 
of the maxilla and mandible in a prospective manner with a larger study cohort 
than previous studies.   
 
The accurate prediction of the presence or absence of mandibular or 
maxillary infiltration by SCC will allow use of 3-D surgical planning models for the 
immediate reconstruction of the defect and preclude prolonged loss of function 
that patients may experience post-resection. 
1.3 Study Therapy 
This is a study comparing radiologic modalities already in use as the standard of 
care in order to determine bone invasion by oral squamous cell carcinoma.   
 
1.4 Preclinical Data 
Summarize the available non-clinical data (published or available unpublished 
data) that could have clinical significance. 
 
Refer to section 1.2 “Background and Rationale” 
1.5 Clinical Data to Date 
Summarize the available clinical study data (published or available unpublished 
data) with relevance to the protocol under construction. 
 
Refer to section 1.2 “Background and Rationale” 
 
2.0 STUDY OBJECTIVES 
 
2.1 Primary Objective: 
To determine which imaging modality or combination of imaging methods, in 
conjunction with clinical and histological examination, will most accurately predict 
the presence or absence of invasion of the mandible or maxilla by intraoral 
squamous cell carcinoma (SCC). 
 
2.2 Secondary Objective: 
To compare the histopathologic findings to the radiologic findings 

 
 
 
 
 
10 
3.0 STUDY DESIGN 
3.1 General Design 
Prospective, non-randomized, double blinded study 
3.2 Primary Study Endpoints 
The primary endpoint is to determine if any one or combination of imaging 
modalities can accurately predict the presence or absence of bone invasion by 
oral squamous cell carcinoma 
3.3 Secondary Study Endpoints 
 
The secondary endpoint would be to more accurately plan the resection of 
mandibular or maxillary bone if invasion is predicted.  If invasion is not predicted 
based upon the imaging modalities, then the secondary endpoint would be to 
spare resection of uninvolved bone 
3.4 Primary Safety Endpoints 
 
As this study compares radiologic modalities of diagnosis that are currently used 
for standard of care practice, there is no safety risk. 
4.0 SUBJECT SELECTION AND WITHDRAWAL 
 
4.1 Inclusion Criteria 
• Age 18-90 
• Diagnosis of squamous cell carcinoma of the oral cavity 
• Able to read and sign and informed consent  
4.2 Exclusion Criteria 
• prior mandibular surgery,  
• primary intraosseous carcinoma,  
• prior   history of radiation to the mandible,  
• obvious finding of clinical invasion of the mandible 
 
4.3 Gender/Minority/Pediatric Inclusion for Research 
All ethnicities will be included in this study of both male and female gender.  The 
patients will be adults, 18 years of age or older and have a biopsy proven 
squamous cell carcinoma of the oral cavity. 
 
While men have an increased incidence of oral SCC by 2:1 as compared to 
women, there will be no preference for one gender or another.  Also, the ratio of 
men: women in the study will be monitored and all patients that meet the 
inclusion criteria will be added regardless of gender 

 
 
 
 
 
11 
 
4.4 Subject Recruitment and Screening 
All patients will be from the Dept of OMS or JHNS practice.  The patients will 
have a Cone Beam CT which will be used in the detection of mandibular or 
maxillary invasion by the oral squamous cell carcinoma as well as the evaluation 
of the dentition prior to possible radiation therapy. 
 
4.5 Early Withdrawal of Subjects 
4.5.1 When and How to Withdraw Subjects 
Early withdrawal from the study is not foreseen as this study does not use any 
therapies of treatment, only radiologic tools for diagnosis 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
Not applicable 
5.0 STUDY DRUG/THERAPY  
N/A 
5.1 Description 
Cone beam CT scan 
5.2 Treatment Regimen 
 
This study will compare helical, medical grade CT, PET/CT and CBCT for the 
ability to predict invasion of the maxilla or mandible.  Currently, helical CT and 
PET/CT are routinely used.  Currently, panoramic radiographs are taken for 
patients with oral SCC necessitating therapeutic radiation.  These radiographs on 
average emit 24 Micro Sieverts of absorbed radiation to the patient.  The CBCT 
which provides three dimensional imaging of the teeth and jaws yield 
approximately 85 Micro Sieverts, which is only a small increase of 60 Micro 
Sieverts, with the benefit being the ability to more accurately predict invasion or 
absence of extension of the carcinoma with the hope of more accurate surgical 
margins and the sparing of uninvolved tissue when invasion is absent.   
5.3 Risks 
Formerly, patients received a panoramic radiograph in the OMFS 
Department  for evaluation of dentition prior to radiation.  The experimental 
procedure will now include CBCT in place of a panoramic x-ray which will more 
accurately predict invasion of the maxilla or mandible, and give better resolution 
concerning the risk of osteoradionecrosis of the jaw, should radiation therapy be 
used in the future.  Although CBCT has slightly more radiation as compared to 

 
 
 
 
 
12 
the panoramic radiograph (87 Micro Sieverts vs 24 Micro Sieverts), it has the 
ability to yield more information relevant to patient diagnostic benefit and as such 
these benefits outweigh the approximate 60 Micro Sievert increase in absorbed 
radiation dose.  
Risk will be minimized by using the smallest field of view necessary to 
provide diagnostic benefit of the CBCT.  In addition, patients will be adequately 
shielded using a lead apron and thyroid collar. 
 
The relative increase in absorbed radiation dose between the panoramic 
radiograph and the CBCT is small in comparison to the potential improvement in 
quality of life for these patients if they can avoid locoregional reccurence, 
tracheotomy, feeding tubes, cosmetic deformity and loss of masticatory function 
and speech function.   In addition, the increase of approximately 40 micro 
sieverts from the panoramic radiograph to the CBCT gives the image greater 
resolution and contrast as well as 3-dimensional representation of the image, 
greatly increasing the accuracy of the image.  
 
5.4 Method for Assigning Subjects to Treatment Groups 
This study will not be randomized.  All patients will received a helical CT, PET/CT 
and CBCT 
5.6 Subject Compliance Monitoring 
In this study, compliance is minimized in that once the imaging is completed and 
the surgical treatment carried out, the patient will have little commitment to the 
study. 
5.7 Prior and Concomitant Therapy 
In this section, describe: 
• What prior and/or concomitant medical therapy will be collected (if 
applicable):  
•  
None 
• Which concomitant medicines/therapies (including rescue therapies) are 
permitted during the study:  
•  
Any that are prescribed by the medical oncologist, given that the 
imaging is unrelated 
• Which concomitant medicines/therapies are not permitted during the study 
(if applicable): 
•  
Radiation to the mandible or maxilla 
 
6.0 STUDY PROCEDURES 
 
6.1 Study Visit Schedule 

 
 
 
 
 
13 
Screening: Once patients are referred to the OMFS or JHNS departments 
with oral SCC, they will be evaluated to see if they meet the inclusion 
criteria and do not satisfy the exclusion criteria.  Once they are deemed a 
candidate for the study by one of the involved doctors, they will have an 
appointment setup for a CBCT 
Visit 1: CBCT in OMFS Office 
Visit 2: Surgical planning in JHNS office, blinded to the result of the CBCT 
 
Definitive Surgical Treatment 
 
Follow-up:  The patient will follow up in the JHNS department for necessary 
adjuvant therapies and post-surgical care when surgical treatment is 
carried out. 
 
Please see the appendix for an outline of the study and also a card that will 
be posted in both JHNS and OMFS office to be used when evaluating 
patients for inclusion 
Procedures, situations, or materials that may be hazardous to personnel and the 
relevant precautions, should also be outlined here.  
 
7.0 STATISTICAL PLAN 
7.1 Sample Size Determination 
Sample size was based upon the average number of cases per year that meet 
inclusion for the study based upon previous diagnostic and surgical logs 
7.2 Statistical Methods 
Sensitivity and specificity of the clinical exam, CBCT, helical CT, PET/CT, 
MRI and any other imaging modality used in detection of bone invasion will be 
calculated, as compared to the histological examination of the specimens. 
 
Sensitivity: [ TP / (TP + FN)  ] x 100 
Specificity: [ TN / (FP + TN)  ] x 100 
 
Also, the confidence interval will be determined for the sensitivity and 
specificity. 
 
 
 
True positive (TP): pts with histologic and radiographic evidence of 
invasion 
True negative (TN): pts without histologic or radiographic evidence of 

 
 
 
 
 
14 
invasion 
False Positive (FP): pts with positive radiologic evidence of invasion 
without histologic evidence  
False Negative (FN): Those without radiographic evidence of invasion, but 
with histologic invasion present 
 
In addition, the positive and negative predictive value will be calculated for 
each modality using the true positive and negatives as well as false 
positive and negative values. 
 
7.3 Subject Population(s) for Analysis 
This section should be very specific in defining the subject populations whose 
data will be subjected to the study analysis – both for the primary analysis and 
any applicable secondary analyses.   
 
The data from all of the subjects that are enrolled and have consented to be a 
part of the study will be analyzed.  
 
8.0 SAFETY AND ADVERSE EVENTS 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that 
develops or worsens in severity during the course of the study.  Intercurrent 
illnesses or injuries should be regarded as adverse events.  Abnormal 
results of diagnostic procedures are considered to be adverse events if the 
abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.   
 
A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 

 
 
 
 
 
15 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life 
threatening, but are clearly of major clinical significance. They may 
jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or 
abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be 
considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be 
regarded as non-serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally 
defined as the period from the initiation of any study procedures to the end 
of the study treatment follow-up.  For this study, the study treatment follow-
up is defined as 30 days following the last administration of study treatment.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A 
preexisting condition should be recorded as an adverse event if the 
frequency, intensity, or the character of the condition worsens during the 
study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also 
be recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until 
the events are resolved, the subject is lost to follow-up, or the adverse event 
is otherwise explained.  At the last scheduled visit, the investigator should 
instruct each subject to report any subsequent event(s) that the subject, or 
the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the study sponsor 
of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be 
related to this study.  The sponsor should also be notified if the investigator 
should become aware of the development of cancer or of a congenital 
anomaly in a subsequently conceived offspring of a subject that has 
participated in this study.  
Abnormal Laboratory Values 

 
 
 
 
 
16 
A clinical laboratory abnormality should be documented as an adverse 
event if any one of the following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test 
to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. 
change of dose, discontinuation of the drug, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization 
should be documented and reported as a serious adverse event unless 
specifically instructed otherwise in this protocol.  Any condition responsible 
for surgery should be documented as an adverse event if the condition 
meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery 
are reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery should not 
be reported as an outcome of an adverse event if the purpose of the 
surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target 
disease of the study, unless it is a worsening or increase in 
frequency of hospital admissions as judged by the clinical 
investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on 
adverse events by specific questioning and, as appropriate, by examination.  
Information on all adverse events should be recorded immediately in the source 
document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should be recorded in the source document, though should be 
grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded   
 
The clinical course of each event should be followed until resolution, stabilization, 
or until it has been determined that the study treatment or participation is not the 
cause.  Serious adverse events that are still ongoing at the end of the study 
period must be followed up to determine the final outcome.  Any serious adverse 

 
 
 
 
 
17 
event that occurs after the study period and is considered to be possibly related 
to the study treatment or study participation should be recorded and reported 
immediately. 
8.3 Unblinding Procedures 
If it is found that any one or combination of imaging studies is able to accurately 
predict the presence or absence of bone invasion, this information will be 
unblinded to the oncologic surgeon, thereby allowing them to use the information 
in planning their surgical resection 
 
8.4 Stopping Rules  
If it is determined that this study is unsafe or of little clinical efficacy, then it will be 
stopped.  As there are no drugs or other therapies being tested, stopping 
the study should not be necessary. 
8.5 Data and Safety Monitoring Plan 
It is the responsibility of the Principal Investigator to oversee the safety of the 
study at his/her site.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the 
compliance and implementation of the KCC data and safety-monitoring plan.  
Medical monitoring will include a regular assessment of the number and type of 
serious adverse events by both the assigned Medical Monitor and the KCC 
DSMC. 
 
8.5.1 Medical Monitoring and AE/SAE Reporting 
A Medical Monitor is assigned to this study at the Thomas Jefferson University.  This is 
a physician/pharmacist who is not directly involved in the trial, and is not currently 
collaborating with the sponsor/investigator on any other trial.  The role of the Medical 
Monitor is to review all reportable AEs/SAEs (in real-time) including grading, toxicity 
assignments, non-reportable AEs (quarterly), protocol violations/deviations, as well as 
all other safety data and activity data observed in the ongoing clinical trial occurring at 
Thomas Jefferson University. The Medical Monitor may recommend reporting of 
adverse events and relevant safety data, and may also recommend suspension or 
termination of the study to the DSMC and TJU IRB.   
 
Every KCC investigator initiated protocol includes requirements for reporting of 
adverse events based on CTC 4.0. All events are reported to the IRB and Medical 
Monitor using a password protected web-site. In addition all unexpected and serious 
adverse events (SAEs) are reported to the TJU IRB and to the Food and Drug 
Administration (FDA) if applicable. The investigator is required to submit all 
unexpected and serious adverse events to the TJU IRB and the Medical Monitor 
within the timeframes outlined in the below table. All AE/SAEs will be reported to the 
DSMC at the quarterly DSMC review meetings; however, if the Medical Monitor 
determines corrective action is necessary, an “ad hoc” DSMC meeting will be called. 

 
 
 
 
 
18 
Fatal adverse events related to treatment which are unexpected must be 
reported within 24 hours to the TJU IRB and the DSMC. Fatalities not related to 
the study drug/device must be reported within 5 days. A summary of the 
reporting requirements for KCC investigator initiated Phase I and Phase II studies 
are presented below.  
 
 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 4 
and 5 
 
Unexpected 
and 
Expected 
Unexpected 
Expected 
Unexpected 
with 
Hospitalization 
Unexpected 
without 
Hospitalization 
Expected with 
Hospitalization 
Expected 
without 
Hospitalization 
Unexpected 
and 
Expected 
Unrelated 
Unlikely 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
5 Working 
Days 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
5 Working 
Days 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Phase 1 -     
48 Hours   
(Death: 24 
Hours) 
 
Phase 2 -     
5 Working 
Days        
Possible 
Probable 
Definite 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
5 working 
days 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
48 Hours    
(Death: 24 
Hours) 
Phase 1 -        
48 Hours   
 
Phase 2 -        
5 Working 
Days 
48 Hours    
(Death: 24 
Hours) 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Phase 1 and 
Phase 2 -     
48 Hours     
(Death: 24 
Hours) 
 
 
**NOTE: This table is based on the NCI AE/SAE reporting Guidelines and the TJU IRB Policy and 
Procedures. Please follow the individual protocol AE/SAE reporting guidelines if more stringent 
reporting procedures are specified. 
 
8.5.2 Data and Safety Monitoring Committee 
Data and Safety Monitoring Committee (DSMC) is the Data and Safety Monitoring 
Board (DSMB) for the KCC. The DSMC is a multidisciplinary committee charged 
with overseeing the monitoring of safety of participants in clinical trials, and the 
conduct, progress, validity, and integrity of the data for all clinical trials at the 
Thomas Jefferson University KCC. The committee meets quarterly to review the 
progress and safety of all active research protocols that are not monitored by 
another safety and data monitoring committee or board. 
• The DSMC meets quarterly. Additional DSMC meetings are scheduled 
based on the nature and number of trials being monitored over a 
specified time period. The DSMC meets (by conference call) within 24 

 
 
 
 
 
19 
hours following the notification of an unexpected adverse event felt to 
be related to the study drug.  
• Prior to each DSMC meeting, each board member, is provided a 
printout of all reported AEs and SAEs occurring during the reporting 
period for this clinical trial. The principal investigator provides a detailed 
and comprehensive narrative assessment of current adverse events to 
date, indicating their possible significance and whether these toxicities 
have affected the conduct of the trial. DSMC members are provided 
with the principal investigator’s assessment, a written report 
summarizing adverse events, safety data, and activity data observed 
during the specified time period described in each protocol, as well as 
recommendations from the Medical Monitor. A review of outcome 
results (response, toxicity and adverse events) and factors external to 
the study (such as scientific or therapeutic developments) is discussed, 
and the Committee votes on the status of each study.  
• A summary of the board’s action is sent to each investigator, the 
CCRRC and TJU IRBs. The DSMC actions may include 
recommendations/requirements that will lead to improved patient safety 
and/or efficacy, significant benefits or risks that have developed, or 
other changes determined to be necessary. The DSMC may also take 
note of slow accrual or lack of scientific progress, and refer such issues 
to the CCRRC. The DSMC provides the investigator with the rationale 
for any decision made.  
 
9.0 DATA HANDLING AND RECORD KEEPING 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according 
to the requirements of the Health Insurance Portability and Accountability Act of 
1996 (HIPAA).  Those regulations require a signed subject authorization 
informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in 
this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of 
their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period. 

 
 
 
 
 
20 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation 
of the trial.  Source data are contained in source documents   Examples of these 
original documents, and data records include: hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies 
or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must 
be explained.  If a space on the CRF is left blank because the procedure was not 
done or the question was not asked, write “N/D”.  If the item is not applicable to 
the individual case, write “N/A”.  All entries should be printed legibly in black ink.  
If any entry error has been made, to correct such an error, draw a single straight 
line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT 
ERRORS.  For clarification of illegible or uncertain entries, print the clarification 
above the item, then initial and date it. 
 
9.4 Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at 
least 2 years after the last approval of a marketing application in their country 
and until there are no pending or contemplated marketing applications in their 
country or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents should be 
retained for a longer period if required by an agreement with the sponsor.  In 
such an instance, it is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be 
retained.  
 
10.0 STUDY MONITORING, AUDITING, AND INSPECTING 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for monitoring activities.  The 
Investigator will also ensure that the medical monitor or other compliance or 
quality assurance reviewer is given access to all the above noted study-related 

 
 
 
 
 
21 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by 
the IRB, the funding sponsor, government regulatory bodies, and University 
compliance and quality assurance groups of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable 
study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential 
inspection by government regulatory authorities and applicable University 
compliance and quality assurance offices. 
 
10.2.1 Independent External and Internal Audits  
In addition to review by the DSMC, all studies initiated by KCC investigators are 
audited by an independent auditor once they have achieved 10% of target accrual. 
However, a study can be audited at any time based on recommendations by the 
IRB, DSMC, CCRRC and/or the Director of Clinical Investigations, KCC. Studies are 
re-audited once they have achieved 50% of target accrual. Special audits may be 
recommended by the IRB, DSMC or CCRRC based on prior findings, allegations of 
scientific misconduct and where significant irregularities are found through quality 
control procedures. Any irregularities identified as part of this process would result in 
a full audit of that study.  
 
In addition to the audits at 10 and 50%, the CRMO randomly audits at least 10 
percent of all patients entered into therapeutic KCC trials and other trials as 
necessary, on at least a bi-annual basis, to verify that there is a signed and dated 
patient consent form, the patient has met the eligibility criteria, and that SAEs are 
documented and reported to the TJU IRB.  
 
All audit reports are submitted to the DSMC for review and action (when 
appropriate). A copy of this report and recommended DSMC action is sent to the 
CCRRC and TJU IRB. The committee regards the scientific review process as 
dynamic and constructive rather than punitive. The review process is designed to 
assist Principal Investigators in ensuring the safety of study subjects and the 
adequacy and accuracy of any data generated. The TJU IRB may, based on the 
DSMC and auditor’s recommendation, suspend or terminate the trial.  
11.0 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of 
Good Clinical Practice (FDA Title 21 part 312 and International Conference on 

 
 
 
 
 
22 
Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator 
before commencement of this study.   
 
All subjects for this study will be provided a consent form that is compliant with 
local and federal regulations, describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in 
this study.  See Attachment for a copy of the Subject Informed Consent Form.  
This consent form will be submitted with the protocol for review and approval by 
the IRB for the study.  The formal consent of a subject, using the IRB-approved 
consent form, must be obtained before that subject is submitted to any study 
procedure.  This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional 
obtaining the consent.  
 
12.0 STUDY FINANCES: 
12.1 Funding Source 
Departmentally funded. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, 
etc.) must have the conflict reviewed by a properly constituted Conflict of Interest 
Committee with a Committee-sanctioned conflict management plan that has 
been reviewed and approved by the study sponsor prior to participation in this 
study.  All Jefferson University Investigators will follow the TJU Conflicts of 
Interest Policy for Employees (107.03). 

 
 
 
 
 
23 
13.0 PUBLICATION PLAN 
 
Once imaging and histologic data have been collected from the target sample 
size, the information will be compiled for publication.  This information will not be 
published in any manner prior to official publication 
14.0 REFERENCES 
1 Closmann, James J., and Schmidt, Brian L.. "The use of cone beam computed 
tomography as an aid in evaluating and treatment planning for mandibular 
cancer." Journal of Oral and Maxillofacial Surgery 65.4 (2007): 766-771. 
2 Van Cann, E. M., et al. "Assessment of mandibular invasion of squamous cell 
carcinoma 
by 
various 
modes 
of 
imaging: 
constructing 
a 
diagnostic 
algorithm."International journal of oral and maxillofacial surgery 37.6 (2008): 535-
541. 
3 Hendrikx, A. W. F., et al. "Cone-beam CT in the assessment of mandibular 
invasion by oral squamous cell carcinoma: results of the preliminary 
study."International Journal of Oral and Maxillofacial Surgery 39.5 (2010): 436-
439. 
4 Momin, Mohammad A., et al. "Diagnostic accuracy of cone-beam CT in the 
assessment of mandibular invasion of lower gingival carcinoma: comparison with 
conventional panoramic radiography." European journal of radiology 72.1 (2009): 
75-81. 
5 Smith, Jonathan C., et al. "Quality of life, functional outcome, and costs of early 
glottic cancer." The Laryngoscope 113.1 (2003): 68-76. 
 
    
 
 

 
 
 
 
 
24 
15.0 APPENDICES 
 
To be posted in OMFS and JHNS office: 
 
 
Prediction of Bone Invasion by Squamous Cell Carcinoma: 
 
Inclusion: SCC of the oral cavity 
 
Exclusion:  
1. prior mandibular surgery 
2. primary intraosseous carcinoma 
3. prior history of radiation to the mandible 
4. obvious finding of clinical invasion of the mandible,  
5. age under 18 years old 
 
Visit I: Screening visit 
 
Visit II: Referral to OMS department for CBCT  
 
Visit III: Definitive Surgical Treatment Plan 
 
Goal: 
 
To determine if any imaging modalities or combination of studies can 
accurately predict the presence or absence of maxillary or mandibular 
invasion by oral SCC.  The diagnostic imaging will be compared to the 
histologic investigation of the resected specimens in order to determine 
their accuracy.  
 
 
 

 
 
 
 
 
25 
 
Patient Cohort 
(N=10) 
Finden: review CBCT 
1. Invasion: Y/N 
2. Risk of ORN 
3. Extractions: Y/N
Referred to 
OMFS 
Referred to 
JHNS 
Initial consultation: 
Records, previous biopsy 
Clincal exam 
Diecidue completes 
exam and CBCT 
JHNS completes 
exam, orders imaging, 
refers for CBCT
For CBCT 
Patient Returns 
Finden: reports 
to JHNS 
(CT, MRI, PET) 
Resection of 
Carcinoma 
-blinded images to 
Finden for interpretation  
-JHNS blinded to CBCT 
report/images 
Specimen to 
Lab: 
-imaging, photos 
of specimen 
-gross exam 
Gross 
Study 
Histologic 
Study 
Comprehensive review of all 
parameters by investigators