Clinical trial NCT04883645
Conditions: Oral Squamous Cell Carcinoma
Sponsor: Medical University of South Carolina
Start date: 2022-04-28; Completion date: 2024-07-31
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research study is to find out what effects, good and/or bad, topical application of the drug Aldara will have on patients and on their oral cancer. Aldara is a drug that activates toll-like receptor (TLR) in oral cancer cells causing self-destruction of tumor cells. It also activates immune cells to attack and eliminate cancer cells. Aldara is currently approved by the Food and Drug Administration (FDA) for treatment of skin cancer and melanoma. Its use in this study is 'off-label' (use of a drug approved by FDA for skin cancer to treat oral cancer in this study).

The preliminary efficacy of topical imiquimod in a neoadjuvant setting in patients with early-stage oral squamous cell carcinoma will be determined by a reduction in tumor cellularity in post-treatment tissue compared to pre-treatment tissue. Safety and tolerability will be evaluated by CTCAE v5 criteria. The effect of imiquimod on the tumor immune microenvironment will be assessed by performing quantitative multiplex immunofluorescence.

Detailed description:
The researchers propose an exploratory clinical trial to evaluate the efficacy of topical imiquimod, a TLR-7 agonist, in patients with early-stage oral squamous cell carcinoma. The analysis of pre- and post-treatment tumor specimen collected from patients treated on this study will be used for quantitative immunoflourescence analysis to assess the immunomodulatory activity of imiquimod in human tumor samples. The researchers hypothesize that TLR-7 stimulation will reduce the size of the tumor in patients with early-stage oral squamous cell carcinoma. The researchers anticipate that activation of immune cells will correlate with response to therapy.

Arms: arm 1: All patients receive the same treatment (there is no "placebo" arm). Treatment will be self-administered by the patients on an outpatient basis. All patients with untreated and biopsy confirmed oral squamous cell carcinoma (OSCC) who meet the inclusion criteria.
Interventions: intervention 1: Imiquimod 5% Cream
Intervention descriptions: intervention 1: Imiquimod as a 5% cream is being used to treat several skin cancers, including malignant melanoma, basal cell carcinoma (BCC) and SCC. With respect to SCC treatment, it has been demonstrated that imiquimod stimulates tumor destruction by recruiting T cells (cells in the immune system) from blood and by inhibiting tonic anti-inflammatory signals within the tumor. The patient will be instructed to apply imiquimod cream, 7 nights a week for 4 weeks to the oral tumor at bedtime.

Protocol documents:
Prot_SAP_001.pdf: 
 
Neoadjuvant Imiquimod for Oral Cancer 
 
Protocol Number: 103625 
National Clinical Trial (NCT) Identified Number:  04883645 
Principal Investigator: Angela Yoon, DDS 
Sponsor: Investigator-sponsored  
Funded by: NIH/NCI 
Version Number:  9.3 
Date: 15 NOV 2023 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
All 
Organization change 
Dr. Yoon relocated from Columbia 
University to MUSC.  
3, 9 
Addition of tumor cell quantification using 
immunofluorescence in the primary endpoint 
assessment 
Additional statistical analyses as required  
Expansion of laboratory techniques to 
evaluate primary endpoint 


  
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Table of Contents 
Table of Contents .................................................................................................................................................... ii 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY.................................................................................................................................... 2 
1.1 Synopsis ........................................................................................................................................................... 2 
1.2 Schema ............................................................................................................................................................ 3 
1.3 SCHEDULE OF ACTIVITIES (SoA) ............................................................................................................. 5 
2 
INTRODUCTION ................................................................................................................................................. 6 
2.1 Study Rationale ............................................................................................................................................... 6 
2.2 Background ...................................................................................................................................................... 7 
2.3 Risk/Benefit Assessment ............................................................................................................................... 7 
2.3.1 Known Potential Risks ............................................................................................................................ 7 
2.3.2 Known Potential Benefits ....................................................................................................................... 9 
2.3.3 Assessment of Potential Risks and Benefits ....................................................................................... 9 
3 
OBJECTIVES AND ENDPOINTS ..................................................................................................................... 9 
4 
STUDY DESIGN ............................................................................................................................................... 10 
4.1 Overall Design ............................................................................................................................................... 10 
4.2 Scientific Rationale for Study Design ......................................................................................................... 11 
4.3 Justification for Dose .................................................................................................................................... 11 
4.4 End of Study Definition ................................................................................................................................. 11 
5 
STUDY POPULATION ..................................................................................................................................... 11 
5.1 Inclusion Criteria ........................................................................................................................................... 11 
5.2 Exclusion Criteria .......................................................................................................................................... 11 
5.3 Lifestyle Considerations ............................................................................................................................... 12 
5.4 Screen Failures ............................................................................................................................................. 12 
5.5 Strategies for Recruitment and Retention ................................................................................................. 12 
6 
STUDY INTERVENTION ................................................................................................................................. 13 
6.1 Study Intervention(s) Administration .......................................................................................................... 13 
6.1.1 Study Intervention Description ............................................................................................................ 13 
6.1.2 Dosing and Administration ................................................................................................................... 14 
6.2 Preparation/Handling/Storage/Accountability ........................................................................................... 14 
6.2.1 Acquisition and accountability ............................................................................................................. 14 
6.2.2 Formulation, Appearance, Packaging, and Labeling ....................................................................... 14 
6.2.3 Product Storage and Stability .............................................................................................................. 15 
6.2.4 Preparation 15 
6.3 Measures to Minimize Bias: Randomization and Blinding ...................................................................... 15 
6.4 Study Intervention Compliance ................................................................................................................... 15 
6.5 Concomitant Therapy ................................................................................................................................... 15 
6.5.1 Rescue Medicine 
15 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 16 
7.1 Discontinuation of Study Intervention ........................................................................................................ 16 
7.2 Participant Discontinuation/Withdrawal from the Study .......................................................................... 16 
7.3 Lost to Follow-Up .......................................................................................................................................... 17 
8 
STUDY ASSESSMENTS AND PROCEDURES .......................................................................................... 17 
8.1 Efficacy Assessments .................................................................................................................................. 17 
8.2 Safety and Other Assessments .................................................................................................................. 18 


  
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8.3 Adverse Events and Serious Adverse Events .......................................................................................... 18 
8.3.1 Definition of Adverse Events (AE) ...................................................................................................... 18 
8.3.2 Definition of Serious Adverse Events (SAE) ..................................................................................... 19 
8.3.3 Classification of an Adverse Event ..................................................................................................... 19 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up .............................................. 20 
8.3.5 Adverse Event Reporting ..................................................................................................................... 20 
8.3.6 Serious Adverse Event Reporting ....................................................................................................... 21 
8.3.7 Reporting Events to Participants ......................................................................................................... 21 
8.3.8 Events of Special Interest .................................................................................................................... 21 
8.3.9 Reporting of Pregnancy ........................................................................................................................ 21 
8.4 Unanticipated Problems ............................................................................................................................... 21 
8.4.1 Definition of Unanticipated Problems (UP) ........................................................................................ 21 
8.4.2 Unanticipated Problem Reporting ....................................................................................................... 22 
8.4.3 Reporting Unanticipated Problems to Participants ........................................................................... 22 
9 
STATISTICAL CONSIDERATIONS ............................................................................................................... 22 
9.1 Statistical Hypotheses .................................................................................................................................. 23 
9.2 Sample Size Determination ......................................................................................................................... 23 
9.3 Populations for Analyses ............................................................................................................................. 23 
9.4 Statistical Analyses ....................................................................................................................................... 23 
9.4.1 General Approach 
23 
9.4.2 Analysis of the Primary Efficacy Endpoint ......................................................................................... 24 
9.4.3 Analysis of the Secondary Endpoint / safety endpoint .................................................................... 24 
9.4.4 Baseline Descriptive Statistics ............................................................................................................ 24 
9.4.5 Planned Interim Analyses .................................................................................................................... 24 
9.4.6 Sub-Group Analyses 24 
9.4.7 Tabulation of Individual participant Data ............................................................................................ 24 
9.4.8 Exploratory Analyses 24 
9.4.9 SURVIVAL Analyses 25 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ................................... 25 
10.1 Regulatory, Ethical, and Study Oversight Considerations ...................................................................... 25 
10.1.1 
Informed Consent Process .............................................................................................................. 25 
10.1.2 
Study Discontinuation and Closure ................................................................................................ 26 
10.1.3 
Confidentiality and Privacy .............................................................................................................. 26 
10.1.4 
Future Use of Stored Specimens and Data .................................................................................. 27 
10.1.5 
Key Roles and Study Governance ................................................................................................. 27 
10.1.6 
Safety Oversight 
28 
10.1.7 
Clinical Monitoring 28 
10.1.8 
Quality Assurance and Quality Control .......................................................................................... 28 
10.1.9 
Data Handling and Record Keeping ............................................................................................... 29 
10.1.10 Protocol Deviations 30 
10.1.11 Publication and Data Sharing Policy .............................................................................................. 30 
10.1.12 Conflict of Interest Policy ................................................................................................................. 31 
10.2 Additional Considerations ............................................................................................................................ 31 
10.3 Abbreviations ................................................................................................................................................. 32 
10.4 Protocol Amendment History....................................................................................................................... 34 
11 REFERENCES .................................................................................................................................................. 36 
Appendix A: ECOG Performance Status Criteria. ............................................................................................ 40 


  
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Appendix B: Daily Diary ....................................................................................................................................... 41 
 


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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
 
Exploratory clinical trial of topical Imiquimod 5% cream as window-of-
opportunity monotherapy for early-stage oral cancer 
 
Study Description: 
 
Our aim is to conduct an exploratory clinical trial to assess the efficacy of 
neoadjuvant imiquimod immunomodulatory topical therapy in reducing 
the size of primary oral cancer and evaluate its safety and toxicity in early-
stage oral cancer patients.  
 
Objectives: 
 
Primary Objective: To assess the preliminary efficacy of topical imiquimod 
in neoadjuvant setting in patients with early-stage oral squamous cell 
carcinoma as determined by a minimum of 50% reduction in tumor assessed 
first by pathologic review and then confirmed with tumor cell count using 
quantitative immunofluorescence. 
Secondary Objective: To assess local and systemic safety and 
tolerability by CTCAE v5 criteria. 
Exploratory Objective: To explore the effect of imiquimod on the tumor 
immune microenvironment (immune profile) by performing quantitative 
multiplex immunofluorescence. 
Endpoints: 
Primary Endpoint: The primary endpoint is the overall clinical and 
histological response rate as defined as the precent reduction in tumor 
size obtained by measuring the longest perpendicular bidirectional size of 
the clinically visible lesion, and the percent change in tumor cell count 
assessed first by pathologic review and then confirmed with tumor cell 
count using quantitative immunofluorescence , confirmed at 4 weeks of 
the start of study therapy. 
Secondary Endpoints: The secondary endpoint is defined as safety and 
toxicity assessed using CTCAE v5.0 criteria. 
Study Population: 
A total of 15 subjects will be accrued. We will accrue oral squamous cell 
carcinoma (OSCC) patient ≥18 years old, with biopsy confirmed OSCC, 
assigned to clinical stage I or II, awaiting surgical excision and who have an 
ECOG performance status of ≤2 at MUSC, South Carolina. 
 
Phase: 
 
0 (Exploratory) 
 
Description of 
Sites/Facilities Enrolling  
Participants: 
 
This is an open-label, single-center clinical trial that will be conducted in 
Hollings Cancer Center at MUSC.   
 
 


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Description of Study 
Intervention: 
Off-label use of imiquimod 5% topical cream:  The patient will be 
instructed to apply imiquimod cream, 7 nights a week for 28 days to the 
oral tumor at bedtime. Instructions will also include application of cream 
in the surrounding area extending at least 2 cm beyond the outlined tumor 
margins to cover potentially cancerized field. 
 
Study Duration: 
 
2-years 
 
Participant Duration: 
 
1 month 
 
1.2 
SCHEMA 
 
 


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Screening Visit
Days -14 to -1
•Phone call (PI): Reach out to patients with histologic confirmation of OSCC, ensure patient is not 
immunocompromised or on immunosuppressive medication, otherwise in good health or have conditions well 
managed by medication; if eligible, ask the patient to come in for a screening visit, email informed consent
•Screening visit: Review and obtain informed consent, complete demographic/medical history form, prior/active 
medication form; oral examination (no other tumor should be present), take cinical photo, measure tumor size; 
provide instruction for imiquimod application & daily diary form. *This is to be completed prior to initiation of 
the study drug on Day 1.
•(SOC) Head & Neck initial consultation: Schedule for the surgery ~4 weeks from Day 1
•Blood draw (CBC): SOC as a part of H&N consult. Obtain and keep record of baseline CBC for comparison with 
that at the endpoint (immiediately prior to surgery); if the patient is a women of child bearing potential, 
pregnancy test is to be performed to meet the eligibility criteria (cost covered by the study)
•Request research pharmacy to dispense imiquimod 5% cream (28 packets)
Baseline (Day 1) Televisit
Day 1
•Ask the patient to start medication and contact PI if there are any side effects
Day 14 (+/- 5 days)
•Oral examination, tumor measurements, and take photo
•Check adverse events
Midpoint (Day 14) Cinic Visit
Day 29 (+/- 5 days)
•Oral examination, tumor measurements, and take photo
•Adverse events form
•Concomitant medication form
•Collect Daily Diary form
•Compliance form
•Collect remaining medication and send to the research pharmacy
One-Month Follow-up phone call
Day 60 (+/- 7 days)
•Check for ongoing adverse events
•Concomitant medication
Endpoint (Day 29) Televisit


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
*Days -14 to -1: Excludes weekends (Saturday, Sunday) and holidays 
*+/-5 days for Day 14 and Day 29: Excludes weekends (Saturday, Sunday) and holidays 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure 
Days  -14 to -1* 
Day 1 
(Televisit)  
Day 14 
(+/-5)* 
Day 29 
(+/-5)* 
Day 30 
(+/-14) 
Day 60 
(+/-7) 
 
Screening Visit 
Histology confirmation of 
OSCC in the biopsy 
specimen (SOC) 
 
 
x 
 
 
 
 
 
Inclusion/Exclusion Criteria  
x 
 
 
 
 
 
Informed Consent  
x 
 
 
 
 
 
Demographics/Medical 
History 
x 
 
 
 
 
 
Prior/Active Medication 
Review 
x 
 
 
 
 
 
Blood draw (CBC); Serum 
pregnancy test if women of 
childbearing potential) 
X (SOC for CBC) 
 
 
 
x (SOC) 
 
H&N Surgical Consult 
x (SOC) 
 
 
 
 
 
Baseline Symptoms Form 
x 
 
 
 
 
 
Physical Symptoms Form 
x 
 
 
 
 
 
Oral Examination/Tumor 
measurements/Photography 
x 
 
x 
x 
 
 
 
Treatment Administration 
 
Topical Imiquimod 5% cream application  
(Days 1-28) 
(Apply one single-use packet daily before 
bed) 
 
 
Adverse Events Form 
 
 
x 
x 
 
x 
Daily Diary Form 
 
 
 
x 
 
 
Concomitant Medication 
Form 
 
 
 
x 
 
x 
Compliance Form 
 
 
 
x 
 
 
 
Surgical Resection 
 
 
 
 
 
 
x (SOC) 
 


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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Our overall goal is to discover the most efficacious treatment regimen for patients with early-stage 
(TNM Stages I/II) oral squamous cell carcinoma (OSCC). Since 80% of oral cancer patients are in early 
stage at the time of diagnosis2, there exists a window of opportunity in which accurate prognostication 
and subsequent decisions for appropriate treatment will dramatically improve the 5-year survival of 
patients with this deadly disease.  
For early-stage oral cancer patients, the five-year survival rate is estimated to be 60%7. We are currently 
developing a microRNA-based prognostic model to distinguish the 40% who will die of the disease from 
the 60% who will most likely survive15. However, treatment modalities for those at a high risk for cancer-
specific mortality remains unexplored. It is imperative to discover effective therapy for the early-stage 
oral cancer patients who have a poor prognosis and are at a high cancer-specific mortality risk following 
standard surgical treatment. 
To address these critical gaps, we propose to assess the efficacy of a topical imiquimod 5% cream in an 
exploratory clinical trial as a ‘window-of-opportunity’ monotherapy, administered between the biopsy 
confirmation of OSCC and the initial tumor surgery. Imiquimod is an FDA-approved Toll-like receptor 
agonist (TLR)16-25. We have previously reported that intra-oral application of topical imiquimod resulted 
in complete resolution of malignant melanoma with minimal adverse events and the patient had a 
recurrence-free 5-year survival22. Imiquimod can induce tumor cell apoptosis and necrosis, and activate 
anti-tumoral immune response16-25.  
A topically applicable therapeutic agent has the advantage in that there is minimal systemic absorption, 
hence, it is well tolerated with negligible systemic adverse events28. It can also be applied directly on the 
oral tumor and adjacent tissue to control the cancerized field, thereby decreasing the rate of local 
recurrence, the primary culprit of oral cancer-related death following initial surgery. To this end, 
imiquimod has demonstrated efficacy and safety in cancerized field treatment, showing promise for 
reducing the incidence of recurrences, thereby increasing overall survival43. 
We  propose  an  exploratory  clinical  trial  to  evaluate  the  efficacy  of topical imiquimod,  a TLR-7 
agonist,  in  patients  with early-stage oral squamous cell carcinoma.  The  analysis  of  pre-  and  post-
treatment  tumor  specimen  collected from  patients  treated  on  this  study  will  be  used  for  
quantitative immunofluorescence analysis  to  assess  the immunomodulatory activity of imiquimod in 
human tumor samples. We hypothesize that TLR-7 stimulation will reduce the size of the tumor in 
patients with  early-stage oral squamous cell carcinoma. We anticipate that activation of CD4+ T-cell and 
macrophage will correlate with response to therapy. 
 
 
 
 


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2.2 
BACKGROUND  
 
Topical imiquimod 5% cream is a FDA-approved TLR (Toll-like receptor) agonist. Imiquimod immune-
modulatory therapy has aroused considerable cancer clinical research interest and showed promising 
results in clinical trials. Imiquimod induces apoptosis and necrosis of tumor cells. Imiquimod‐induced 
necrosis of OSCC cells leads to release of high mobility group box 1 (HMGB1) protein, which in turn acts 
as a chemokine and induces a pro-inflammatory response16-24. Given that a wide variety of genetic and 
epigenetic defects can suppress apoptosis in most cancers, therapeutic agents with the ability to induce 
tumor necrosis are advantageous16. Imiquimod also initiates tumor cell apoptosis by shifting the pro- 
and anti-apoptotic Bcl factors toward the pro-apoptotic Bax protein, and by stimulating the release of 
mitochondrial cytochrome c into the cytosol, activating caspase-9 and caspase-321-23. Indeed, a study 
showed that imiquimod increased both apoptosis and necrosis of OSCC cells (32.03% and 15.23%, 
respectively)24. 
 
Moreover, imiquimod is an immune response modifier, activating macrophages and other cells via TLR7. 
Imiquimod provokes Th1 cell-mediated immune response by inducing the secretion of proinflammatory 
cytokines such as interferon-α (IFN-α), tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12)23-25. 
Currently, imiquimod as a 5% cream is being used to treat several skin cancers, including malignant 
melanoma, basal cell carcinoma (BCC) and SCC26-28. With respect to SCC treatment, it has been 
demonstrated that imiquimod stimulates tumor destruction by recruiting cutaneous effector T cells 
from blood and by inhibiting tonic anti-inflammatory signals within the tumor29. Other evidence shows 
that topical imiquimod treatment attenuates the de novo growth of UV-induced SCC through activation 
of Th17/Th1 cells and cytotoxic T lymphocytes30. While surgical excision is the first line treatment, 
imiquimod has been shown to be an efficacious, non-invasive topical treatment modality, especially 
when utilized in the neoadjuvant setting prior to initial surgery.  Taken together, imiquimod is a 
promising agent in the treatment of squamous cell carcinoma involving oral mucosa. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Application site reactions: 
• 
Redness, itching, burning, or bleeding of the treated area (33%) 
• 
flaking, scaling, dryness, or thickening of the skin (33%) 
• 
swelling, stinging, or pain in the treated area (33%) 
• 
blisters, scabs, or bumps on the skin (33%) 
• 
inflammation or swelling of the tissue lining the sinuses (7%) 
• 
headache (11%) 
• 
diarrhea (3%) 
• 
red and itchy skin reaction (2%) 
• 
back pain (1%) 
• 
tiredness (1%) 
• 
irregular and rapid heat rate (1%) 


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• 
virus infection (1%) 
• 
dizziness (1%) 
• 
vomiting (1%) 
• 
infection of any part of urinary system (1%) 
• 
fever (1%) 
• 
tremor caused by a chill (1%) 
Systemic side effects:  
• 
Flu-like symptoms such as nausea, fever, chills, tiredness, and muscle weakness or pain 
(15%) 
Women of child-bearing potential: Pregnancy Category C: There are no adequate and well-controlled 
studies in pregnant women. Imiquimod cream should be used during pregnancy only if the potential 
benefit justifies the potential risk to the fetus. 
Breast-feeding: Women using imiquimod should not breast-feed as it is not known whether topically 
applied imiquimod is excreted in breast milk. 
Overdosage: Persistent topical overdosing of imiquimod could result in an increased incidence of severe 
local skin reactions and may increase the risk for systemic reactions. The most clinically serious adverse 
event reported following multiple oral imiquimod doses of >200 mg (equivalent to imiquimod content of 
>16 packets) was hypotension, which resolved following oral or intravenous fluid administration. 
Alternative Procedures: Patients  may  continue  imiquimod  for  Grade  1  or  tolerable  Grade  2  toxicity  
without  a  dose reduction (graded according to NCI CTCAE v5.0).  For  intolerable  Grade  2,  Grade  3  or  
Grade  4  toxicity,  imiquimod  must  be  withheld until the toxicity has resolve to Grade 1 or tolerable 
Grade 2. At the discretion of the treating clinician,  imiquimod  may  then  be  resumed  as  per  following  
guidelines  (Table  1).  If an adverse event is not covered in the table, doses may be reduced or held at 
the discretion of the investigator for the subject’s safety (eg, once every other day). The tables are 
intended to serve as guidance and cases in which  the  management  is  unclear  should  be  discussed  
with  the  principal  investigator  or  study medical monitor as appropriate. 
Subjects with adverse events that are manageable with supportive therapy may not require dose 
reductions (e.g., local site irritation may be treated with non-medicating moisturizing gel rather than by 
dose reduction). 
Subjects will be withdrawn from the study treatment if they fail to recover to Grade 0, Grade 1 or 
tolerable grade 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from  a  
treatment-related  adverse  event  within  21  days  unless  the  principal  investigator  agrees that the 
subject should remain on the study because of evidence that the patient is/may continue deriving 
benefit from continuing study treatment. 
Doses should not be increased during the 4 weeks of therapy. 


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Table 1. Dose Modifications 
 
 
 
 
 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Topical application of imiquimod 5% cream may reduce the size of the tumor, so that less tissue will 
have to be removed at the time of surgery. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
While surgical excision is the first line treatment, imiquimod has been shown to be an efficacious, non-
invasive topical treatment modality, especially when utilized in the neoadjuvant setting prior to initial 
surgery31-34. A topically applicable therapeutic agent has the advantage in that there is minimal systemic 
absorption, hence, it is well tolerated with negligible systemic adverse events28. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
Type 
Name 
Time Frame 
Brief Description 
Primary 
Clinical reduction in size of 
tumor, confirmed by 
reduction in tumor cell 
count  
4-weeks compared 
to baseline 
Change in tumor size measured at the endpoint 
compared to that of the baseline, histologically 
assessed by the change in proportion of tumor 
islands in the surgical tissue specimen, which is 
quantitatively confirmed by assessing tumor cell 
count using quantitative immunofluorescence, 
compared to that of the biopsy 
Secondary 
Safety and tolerability of 
topical imiquimod 5% 
cream 
Continuously during 
the study and for 4-
weeks  after the last 
dose of treatment 
Safety and toxicity will be assessed using CTCAE 
v5.0 criteria 
Exploratory 
Explore anti-tumoral and 
immunomodulatory effect 
of imiquimod 
4-weeks compared 
to baseline 
To evaluate the anti-tumoral and 
immunomodulatory effect of imiquimod using 
quantitative multiplex immunofluorescence 
 
 
 
 
 
 
Dose Level 
Dose 
0 
Apply once every day 
-1 
Apply once in two days  
-2 
Apply once in three days 


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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
We hypothesize that Imiquimod 5% topical cream applied daily on tumor for 28 days will 
significantly decrease the clinical tumor size with confirmation by histology. Minimal local and 
systemic adverse events are anticipated. 
 
This is a single-arm, phase 0 exploratory study evaluating the efficacy of imiquimod 5% cream in 
early-stage oral cancer patients. 
 
Study Intervention: All subjects will apply imiquimod 5% cream on the oral tumor and adjacent area, 
once a day before bedtime, for 28-days. 
 
Schedule of Evaluations: Formal tumor measurements (length of longest dimension in cm) with 
photography will be performed and the baseline blood test result recorded. Safety assessment 
(documentation of side effects experienced by the participant) and tumor measurement will be 
performed at the midpoint visit. The safety assessment, including routine blood work and intra-oral 
clinical examinations, will be performed and the tumor size measured at the endpoint visit. 
 
Response to treatment will be determined by formal tumor measurements with photography: 
Decrease in tumor size measured at the endpoint compared to that of the baseline, histologically 
assessed by the change in the proportion of tumor islands in the surgical tissue specimen, which is 
quantitatively confirmed by assessing tumor cell count using quantitative immunofluorescence  in 
the surgical tissue specimen compared to that of the biopsy. Toxicity evaluation will utilize CTCAE 
v5.0 criteria. 
 
Duration of Treatment: Subjects will continue treatment for a total of 28-days, until confirmed 
disease progression (defined as doubling of tumor size compared to baseline) or intolerable toxicity 
or side effects. Subjects will be withdrawn from the study and proceed with scheduled surgical 
excision. 
 
Duration of Follow-Up: Toxicity will be graded using the NCI CTCAE v5.0 scoring system. Adverse 
events will be assessed continuously during the study and for 1 month after the last dose of 
treatment. Subjects will be followed for at least 1 month post-study, or until all treatment related 
adverse events have recovered to baseline or are deemed irreversible by the investigator. Subjects 
who are removed from study for reasons other than progression of disease will be followed every 3 
months to evaluate disease status and survival analysis while the study remains open. 
 
The current study is limited to assessing the endpoint response at the week 4 mark. However, lack 
of rapid tumor regression might not mean that the treatment was ineffective, and rapid early 
regression may be associated with no long-term benefits. Moreover, immune therapies often take 
longer than 4 weeks to work; therefore, clinical response may be underestimated with this duration. 
We will continue to follow the current cohort via periodic review of the electronic medical record 
beyond the R21 project term, and collect the recurrence and survival data to gain insight into the 
long-term effect of imiquimod. 


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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
This is an exploratory single-arm study. 
 
4.3 
JUSTIFICATION FOR DOSE 
 
The dosing schedule and treatment duration are not standardized49. The recommended schedule in the 
US and Europe is 5 times a week for 6 weeks with a success rate of 73–77%32,50 – this is a total of 30 days 
of treatment, which is equivalent to 7 times a week for 4 weeks (a total of 28 days). Topical imiquimod 
was applied daily for 14 consecutive days intraorally without significant side effect, resulting in a 
complete resolution of recurrent OSCC36. Hence, a once a day for 4 weeks regimen of topical imiquimod 
closely follows the recommended schedule, with minimal adverse events and potentially optimal clinical 
response, without delay in surgical treatment. 
 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed baseline, midpoint 
and endpoint visits, as well as the Day 60 follow-up phone call.   
 
5 
STUDY POPULATION 
 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Provision of signed and dated informed consent form 
 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
 
3. Biopsy confirmed primary oral squamous cell carcinoma (OSCC) 
 
4. Clinical (TNM) stage I or II  
 
5. Age >= 18 years 
 
6. ECOG =< 2. 
 
 
5.2 
EXCLUSION CRITERIA 


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An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1.  Patients currently on systemic or intraoral immunosuppressive therapy 
2.  Treatment with any other investigational agents for OSCC 
3.  HIV positive patients on combination antiretroviral therapy 
4.  Pregnant women are excluded from this study because imiquimod may have adverse effect on 
the fetus (FDA pregnancy risk category C). Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with imiquimod, 
breastfeeding should be discontinued if the mother is receiving study treatment 
5.  Male patients unwilling or unable to comply with pregnancy prevention measures 
6.  Subjects not receiving initial surgical treatment at MUSC. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
During this study, participants are asked to: 
• 
Abstain from eating or drinking for at least 30 minutes after application of topical imiquimod 
cream.  
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, and eligibility criteria. 
 
Individuals who do not meet the criteria for participation in this trial (screen failure), tests with results 
that fail eligibility requirements may be repeated during the screening phase if the investigator believes 
the results to be in error. Additionally, a subject who fails screening may repeat the screening process 1 
time if the investigator believes there has been a change in eligibility status (eg, after recovery from an 
infection). 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
A total of 15 patients will be enrolled to the study. Four patients already completed the study. The 
remaining 11 patients will be recruited at MUSC. 
We will plan to accrue 3-5 patients per month. We anticipate that the last patient will be enrolled 
approximately 3-5 months after the study initiation at MUSC.  


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The MUSC Oral Biopsy Laboratory receives ~7000 specimens from the tristate area annually. 
Approximately 150-200 cases are of OSCC (oral squamous cell carcinoma). As these are biopsy 
specimens from the private dental practices, most of these OSCC are of early clinical stages. Once the 
histologic diagnosis of OSCC is rendered, the submitting clinician will be contacted by the PI, who is the 
case pathologist, for permission to directly speak with the patient. The patient will be informed of the 
clinical trial and referred to the MUSC Head and Neck Surgery for the initial consultation, at which time 
the medical history is reviewed and treatment option (surgery alone vs surgery with elective neck 
dissection) is discussed. If eligible, the patient will be approached to obtain consent. The surgeon will be 
informed of the patient’s involvement in the clinical trial and the surgery will be scheduled for 4 week 
following the initiation of topical imiquimod therapy. Subjects will be limited to those who will receive 
surgical treatment at MUSC.  
The protocol investigators will be available to all patients for further questions and information through 
a contact number provided on the consent form. During the initial conversation between the 
investigator/research staff and the patient, the patient may be asked to provide certain health 
information that is necessary to the recruitment and enrollment process. The investigator/research staff 
may also review portions of their medical records in order to further assess eligibility. They will use the 
information provided by the patient and/or medical record to confirm that the patient is eligible and to 
contact the patient regarding study enrollment. If the patient turns out to be ineligible for the research 
study, the research staff will destroy all information collected on the patients during the initial 
conversation and medical records review, except for any information that must be maintained for 
screening log purposes. Given considerable number of oral cancer cases received by the biopsy service, 
we do not anticipate difficulty in subject recruitment. 
 
 
6 
STUDY INTERVENTION 
 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Topical imiquimod 5% cream is a TLR (Toll-like receptor) agonist. Imiquimod 5% cream is FDA approved 
for the topical treatment of the following. 
• 
Clinically typical, non-hyperkeratotic, non-hypertrophic actinic keratosis (AK) on the face and 
scalp in immunocompetent adults (1.1)  
• 
Biopsy confirmed, primary superficial basal cell carcinoma (sBCC) in immunocompetent adults; 
maximum tumor diameter of 2.0 cm on trunk, neck, or extremities (excluding hands and feet), 
only when surgical methods are medically less appropriate and patient follow-up can be 
reasonably assured (1.2).  


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• 
External genital and perianal warts/condyloma acuminate in patients 12 years old or older (1.3). 
Because there is no FDA approved indication for the use in the OSCC patients, we will submit 
Investigatrional New Drug (IND) application for intra-oral use of drug in OSCC patients to the FDA. 
Each gram of the 5% cream contains 50 mg of imiquimod in an off-white oil-in-water vanishing cream 
base consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, 
sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben, and 
propylparaben. Chemically, imiquimod is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. 
Imiquimod has a molecular formula of C14H16N4 and a molecular weight of 240.3.  
6.1.2 DOSING AND ADMINISTRATION 
 
Imiquimod is a topically-administered cream. Patients with adequate immune function will be started on 
a dose of 5mg once daily. Dosing will be adjusted for safety as delineated in Table 1. Treatment will 
consist of 28-day cycle. Treatment will continue for a maximum of 28-days or severe toxicity requiring 
cessation occurs. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Twenty-eight packets (single-use packets) of imiquimod Cream, 5%, will be procured by the clinical 
research pharmacy and dispensed to the patient upon request by the PI/study team.  The medication 
will either be overnighted via Fedex/UPS a day before Day 1 or delivered by career service to the 
patient’s home address.  Although imiquimod 5% topical cream has the ‘external use only’ label, it will 
be explained to the patients that it has been safely used in the vulvar, vaginal and cervical mucosa34,55, 
as well as in the oral mucosa36,54. Patients are to return all unused medication to the investigator at the 
endpoint visit, which will then be returned to the research pharmacy for proper destruction and 
disposal. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Imiquimod cream (5%) are manufactured, packaged, and pre-labeled, which will be procured and 
dispensed by the clinical research pharmacy. 
 


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6.2.3 PRODUCT STORAGE AND STABILITY 
 
The study drug will be stored in the research pharmacy in room-temperature. 
 
 
6.2.4 PREPARATION 
 
Not applicable. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Not applicable. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Subject compliance will be monitored with the aid of a “Patient Daily Diary” (Appendix B) which will be 
reviewed by the study team at each visit. Subjects who are non-compliant with protocol schedule or 
filling out the daily diary will be removed from the study at the discretion of the study investigator. 
 
6.5 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. 
 
 
6.5.1 RESCUE MEDICINE 
 
Because there is a potential immunosupressive effect of concomitantly administered topical/systemic 
corticosteroids, the case report form must capture the concurrent use of all other drugs, over-the-
counter medications, or alternative therapies.  The Principal Investigator should be alerted if the patient 
is using all types of corticosteroids. The topical therapies permitted will be non-medicating moisturizing 
gel and oral antihistamines for itching. 


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The use of rescue medications is allowable at any time during the study. The date and time of rescue 
medication administration as well as the name and dosage regimen of the rescue medication must be 
recorded. 
   
 
 
 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from topical imiquimod 5% cream does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol.  If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). Patients who discontinue 
early (missing 14 or more days of daily treatment regimen) should return within 30 days of the last 
application of the study drugs for a follow up evaluation. Assessments including clinical oral examination 
and blood test may be performed at that time. 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Reason for study treatment discontinuation 
• 
Protocol specified endpoint assessment (clinical size of lesion, concomitant medication, daily 
diary form 
• 
AE follow-up information: follow-up until resolution or determined by the investigator that the 
event has become stable or irreversible 
• 
Survival data. 
 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE) or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
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The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are enrolled in the study but do 
not receive the study intervention may be replaced.  Subjects who sign the informed consent form, and 
receive the study intervention, and subsequently withdraw, or are withdrawn or discontinued from the 
study, will be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for the scheduled visits and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit 5 business days 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
 
8.1 
EFFICACY ASSESSMENTS  
  
Clinical size of tumor: For the purposes of this study, patients will be evaluated for response on Day 1, 
Day 14 and Day 29.  Changes in OSCC size will be measured as the percent change from baseline 
compared to endpoint in the longest diameters will be reported for each patient. 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 5 days before the beginning of the treatment. 
Histologic response: Pre- and post-treatment tumor tissue samples will be obtained from all 15 subjects 
as a part of standard of care. Pre-treatment tissue samples will be obtained from the diagnostic biopsy 
tissue. Post-treatment tissue samples will be obtained from the surgical resection tissue.  
Timing of Biopsy Samples: The formalin-fixed, paraffin-embedded tissue samples will be obtained from 
the MUSC Oral Pathology & Pathology Department archived at the following time-points: 
• 
Prior to treatment (anytime during the screening period) (mandatory) 


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• 
Post-treatment (immediately following the surgical resection) (mandatory) 
Collection & Processing Instructions: Collection and processing of the tissue samples will be a part of 
standard of care. For the study, representative H&E slides of the biopsy and surgical specimen will be 
examined for correlation with clinical change in tumor size. The HCC Pathology Core laboratory will be 
notified by email (yoona@musc.edu) for retrieval of FFPE tissue blocks and generation of H&E slides and 
immunoblank slides. The email will contain the following information:  
• 
Subject ID number  
• 
Time point (e.g. baseline vs end of treatment) 
 
The formalin-fixed, paraffin-embedded slides will first be stained with H&E for review and the 
representative tumor section slides will be selected by the board-certified pathologist (PI). The most 
representative area of the selected slides (one for biopsy and one for surgical tissue) will be 
macrodissected for further multispectral imaging (quantitative immunofluorescence). The slides will be 
stained with pan-cytokeratin using Lunaphore Comet automated stainers, and the pan-cytokeratin 
positive tumor cells for quantification of tumor cells present.  
 
In addition, the percent change in the tumor cell proliferation marker (PCNA) and immune suppression 
marker on tumor cells (PD-L1) will be assessed using quantitative immunofluorescence. 
 
 
Immunologic response:  Immunoblanks will be delivered to HIMC in person for quantitative multiplex 
immunofluorescence study. The HIMC will also be notified by email on the day of immunoblank slide 
submission.  The email will contain the following information: 
•  Subject ID 
•  Time point (e.g. baseline vs end of treatment) 
•  Contents of samples (number of immunoblank slides for each case) 
 
The result will be reported as % change in the immune cell profiles. 
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Adverse events will be monitored from the time of the first dose of imiquimod. Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs throughout 
the study. All AEs (serious and non-serious) must be recorded on the source documents and eCRFs 
regardless of the assumption of a causal relationship with the study drug. All AEs of unknown etiology 
associated with imiquimod exposure should be evaluated to determine if it is possibly an irAE. Therapy-
related AEs and the grade will be reported using the CTCAE v.5.0.To assess potential systemic AEs, Blood 
test to assess complete blood count (CBC) will be conducted prior to Day 1, and compared to that of the 
endpoint. The endpoint blood test result will be obtained from the patient’s medical chart, which is 
performed as part of SOC prior to surgery.  
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 


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Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 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. 
 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 


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• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The PI and study investigators will be responsible for determining whether an adverse event (AE) is 
expected or unexpected.  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. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The study team will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
 
8.3.5 ADVERSE EVENT REPORTING  
 
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 recorded in the source document, though should be grouped under one diagnosis. 


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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 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. 
 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the Data Coordinating Center (DCC)/study sponsor and should be 
provided as soon as possible. 
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Not applicable 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable 
 
8.3.9 REPORTING OF PREGNANCY  
 
Not applicable 
 
8.4 
UNANTICIPATED PROBLEMS 
 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 


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The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 5-days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 5-days of the 
investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials as required by an institution’s 
written reporting procedures, the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 5-days of the IRB’s receipt of the report of the 
problem from the investigator. 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Not applicable 
 
9 
STATISTICAL CONSIDERATIONS  


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9.1 
STATISTICAL HYPOTHESES 
 
 
• 
Primary Efficacy Endpoint: Imiquimod 5% topical cream applied daily on tumor for 28-days will 
decrease the clinical tumor size at least by 50% with confirmation by tumor cell count. Minimal 
local and systemic adverse events are anticipated. 
 
• 
Secondary Efficacy Endpoint: Imiquimod will increase apoptosis and necrosis of the tumor cells 
and activate anti-tumoral immune cells. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
In the only study available, which has one patient with recurrent oral squamous cell carcinoma (OSCC), 
imiquimod achieved a complete (100%) response with 14 days of daily treatment43. To be conservative, 
we will estimate the response rate (reduction in tumor size) to be at least 0.5 with 28 days of daily 
imiquimod treatment. In this proof-of-concept clinical trial, we can accrue and evaluate 15 subjects 
during the allotted 2-year study period. With 15 subjects and the estimate response rate of 0.5, we will 
achieve the 95% confidence interval (CI) of 0.239 to 0.761, using a two-sided exact binomial test with a 
type I error of 0.05. Because the trial is conducted between the diagnostic biopsy and the initial surgery, 
minimal loss to follow-up is anticipated. If the participants opts out of the trial during the 4-week period, 
we will accrual additional patients until we have 15 evaluable participants. Secondary toxicity analyses 
will include all patients who received the therapy. 
 
 
9.3 
POPULATIONS FOR ANALYSES 
 
All patients treated in the study must be assessed for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible. Patients who initiate therapy but ultimately 
deemed unevaluable for response will be replaced with an additional patient to ensure that the required 
number of evaluable patients are accrued. 
 
9.4 
STATISTICAL ANALYSES 
 
 
9.4.1 GENERAL APPROACH 
 
We will estimate response rate of OSCC to topical imiquimod treatment and provide the exact 95% CI 
based on binomial distribution. Descriptive statistics will be used to quantify secondary end points of 
toxicity and tolerability. Statistical analyses will also be conducted using SAS version 9.4 (SAS Institute 
Inc, Cary, NC) and R (www.r-project.org), and p<0.05 (two sided) will be considered as statistically 
significant. 
 


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9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
 
Clinical changes in tumor size will be measured as the percent change from baseline compared to 
endpoint in the longest diameters will be reported for each patient. 
The pan-cytokeratin positive tumor cells will be quantified and the percent change will be calculated.  
The concordance between the percent change in clinical size and the tumor count will be assessed using 
Cohen κ. 
All of the patients who meet the eligibility criteria (with the possible exception of those who received no 
study medication) will be included in the main analysis of the response rate. Patients in response 
categories 4-9 will be considered to have a treatment failure (disease progression). Precise definitions 
for categories 4-9 will be protocol specific. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT / SAFETY ENDPOINT 
 
Descriptive statistics will be used to quantify the secondary endpoints of toxicity and tolerability.  
Summary of therapy-related adverse events and the grade will be reported using the CTCAE v.5.0. 
 
 
9.4.4 BASELINE DESCRIPTIVE STATISTICS 
 
Not applicable 
 
9.4.5 PLANNED INTERIM ANALYSES  
 
Not applicable 
 
9.4.6 SUB-GROUP ANALYSES 
 
All conclusions will be based on all eligible patients. Subanalyses may then be performed on the basis of 
a subset of patients, excluding those for whom major protocol deviations have been identified (e.g., 
early death due to other reasons, early discontinuation of treatment, major protocol violations, etc.). 
However, these subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly reported. The 95% 
confidence intervals will also be provided. 
 
9.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be summarized and presented as the baseline characteristics.  
 
 
9.4.8 EXPLORATORY ANALYSES 
 


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The precent change in immune profile following the imiquimod treatment (endpoint; surgical tissue) for 
each of 15 subjects will be compared to that of the baseline (biopsy tissue).  
 
Paired t-test will be performed to assess the significance of the change in the marker expression levels. 
Statistical analyses will be conducted using SAS 9.4 (SAS Institute Inc.) and p<0.05 will be considered 
statistically significant. 
 
 
In addition, the percent change in the tumor cell proliferation marker (PCNA) and immune suppression 
marker on tumor cells (PD-L1) will be assessed using quantitative immunofluorescence. 
 
 
9.4.9 SURVIVAL ANALYSES 
 
Using the time of data cutoff as Sep 30, 2023, the time from surgery (initial treatment) to the time to 
cancer recurrence (relapse-free survival) and death will be assessed. 
 
The data will be shown as the  
1. mean follow-up time in months  
2. one year recurrence-free survival rate.   
 
For the recurrence-free survival rate, the time-to-event efficacy will be estimated using two-sided 
corresponding 95% CIs.   
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol: ECOG performance status criteria, Daily diary form. 
 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 


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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. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants 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. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to funding agency, the Investigational New Drug (IND) 
and regulatory authorities.  If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and 
sponsor and will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
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strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the HCC CTO Data Coordinating Center. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research data 
will be identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by HCC CTO Data Coordinating Center research staff will be secured 
and password protected. At the end of the study, all study databases will be de-identified and archived 
at the HCC CTO Data Coordinating Center. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the HCC Data Coordinating Center. After the 
study is completed, the de-identified, archived data will be transmitted to and stored at the HCC Data 
Repository, for use by other researchers including those outside of the study. Permission to transmit 
data to the HCC Data Repository will be included in the informed consent.  
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at the HCC Biosample Repository with the same goal as the 
sharing of data with the HCC Data Repository. These samples could be used to research the causes of 
oral cancer, its complications and other conditions for which individuals with oral cancer are at 
increased risk, and to improve treatment. The HCC will also be provided with a code-link that will allow 
linking the biological specimens with the phenotypic data from each participant, maintaining the 
blinding of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
When the study is completed, access to study data and/or samples will be provided through the HCC. 
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 


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Principal Investigator 
Medical Monitor 
Angela Yoon, DDS 
Name, degree, title 
MUSC  
Institution Name  
173 Ashley Ave, BSB 344 MSC 507 
Address 
843-792-4495 
Phone Number 
yoona@mucs.edu 
Email 
 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise in oncology, research pharmacy, research nursing, and data 
management. Members of the DSMB should be independent from the study conduct and free of conflict 
of interest, or measures should be in place to minimize perceived conflict of interest.  The DSMB will 
meet at least semiannually to assess safety and efficacy data on each arm of the study. The DMSB will 
operate under the rules of an approved charter that will be written and reviewed at the organizational 
meeting of the DSMB. At this time, each data element that the DSMB needs to assess will be clearly 
defined. The DSMB will provide its input to the PI National Institutes of Health staff. 
 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
Monitoring for this study will be performed by the HCC CTO’s DSMC.  
• 
On-site monitoring will be provided throughout the study with random review of certain data 
(less than 100% data verification or targeted data verification of endpoint, safety and other key 
data variables). 
• 
CTO will be provided copies of monitoring reports within 10 days of visit. 
• 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP 
describes in detail who will conduct the monitoring, at what frequency monitoring will be done, 
at what level of detail monitoring will be performed, and the distribution of monitoring reports. 
• 
Independent audits will be conducted by CTO’s DSMC to ensure monitoring practices are 
performed consistently across all participating sites and that monitors are following the CMP. 
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 


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Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will be 
developed to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into RedCap, a 21 CFR Part 11-compliant data capture 
system provided by the CTO. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 
 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
[Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
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or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 7 working days of 
the scheduled protocol-required activity.  All deviations must be addressed in study source documents, 
reported to NCI Program Official and CTO.  Protocol deviations must be sent to the reviewing 
Institutional Review Board (IRB) per their policies. The site investigator is responsible for knowing and 
adhering to the reviewing IRB requirements. Further details about the handling of protocol deviations 
will be included in the MOP. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers x years after the 
completion of the primary endpoint by contacting <specify person or awardee institution, or name of 
data repository>.  
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
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data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single 
nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the NCI has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
No additional considerations. 
 
 
 


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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CRF 
Case Report Form 
CTO 
Clinical Trials Office 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HCC 
Hollings Cancer Center 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
MUSC 
Medical University of South Carolina 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
OSCC 
Oral Squamous Cell Carcinoma 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 


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SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change 
Brief Rationale 
8 
1/21/2022 
Change of Institution 
 
9 
8/30/2023 
Addition of tumor cell count 
quantification using 
immunofluorescence in the primary 
endpoint assessment 
 
Additional statistical analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11 REFERENCES  
 
1. Sasahira T, Kirita T. Hallmarks of cancer-related newly prognostic factors of oral squamous cell 
carcinoma. Int J Mol Sci 2018;19:2413. 
2. Kademani D. Oral cancer. Mayo Clin Proc 2007;82:878-887. 
3. Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology of Human Papillomavirus-
positive head and neck squamous cell carcinoma. J Clin Oncol 2015;33:3235-3242. 
4. Neville BW, Day TA. Oral cancer and precancerous lesions. CA Cancer J Clin 2002;52:195-215. 
5. Markopoulos AK. Current aspects on oral squamous cell carcinoma. Open Dent J 2012;6:126-
130. 
6. Omura K. Current status of oral cancer treatment strategies: surgical treatments for oral 
squamous cell carcinoma. Int J Clin Oncol 2014;19:423-430. 
7. Cramer JD, Reddy A, Ferris RL, Duvvuri U, Samant S. Comparison of the seventh and eighth 
edition American Joint Committee on cancer oral cavity staging systems. Laryngoscope 
2018;128:2351-2360. 
8. Huang SH, O’Sullivan B. Overview of the 8th edition TNM classification for head and neck cancer. 
Curr Treat Options in Oncol 2017;18:40. 
9. Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers-major changes in the American 
Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67:122-
137. 
10. Moeckelmann N, Ebrahimi A, Tou YK, et al. Prognostic implications of the 8th edition American 
Joint Committee on Cancer (AJCC) staging system in oral cavity squamous cell carcinoma. Oral 
Oncol 2018;85:82-86. 
11. Tirelli G, Gatto A, Nata FB, et al. Prognosis of oral cancer: a comparison of the staging systems 
given in the 7th and 8th editions of the American Joint Committee on cancer staging manual. Br 
J Oral Maxillofac Surg 2018;56:8-13. 
12. Faisal M, Bakar MA, Sarwar A, et al. Depth of invasion (DOI) as a predictor of cervical nodal 
metastasis and local recurrence in early stage squamous cell carcinoma of oral tongue (ESSCOT). 
PLoS ONE 2018;13:e0202632. 
13. Almangush A, Makitie AA, Makinen LK, et al. Small oral tongue cancers (<4cm in diameter) with 
clinically negative neck: from the 7th to the 8th edition of the American Joint Committee on 
cancer. Virchows Archiv 2018;473:481-487. 
14. Baykul T, Yilmaz HH, Aydin U, Aydin MA, Aksoy MC, Yildirim D. Early diagnosis of oral cancer. J 
Int Med Res 2010;38:737-749. 
15. Yoon AJ, Wang S, Wang T, Kutler DI, LaRoche D, Philipone E, Peters SM, Hernandez B, McDowell 
BD, Stewart CR, Momen-Heravi F, Santella RM. MicroRNA-based risk scoring system to identify 
early-stage oral squamous cell carcinoma patients at high-risk for cancer-specific mortality. Head 
Neck 2020. doi.org/10.1002/hed.26089. 
16. Amaravadi RK, Thompson CB. The roles of therapy-induced autophagy and necrosis in cancer 
treatment. Clin Cancer Res 2007;13:7271-7279. 


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17. Katayama M, Kawaguchi T, Berger MS, Pieper RO. DNA damaging agent-induced autophagy 
produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death 
Differ 2007;14:548–558. 
18. Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A. Autophagy delays apoptotic death 
in breast cancer cells following DNA damage. Cell Death Differ 2007;14:500–510. 
19. Crighton D, Wilkinson S, O'Prey J, et al. DRAM, a p53-induced modulator of autophagy, is critical 
for apoptosis. Cell 2006;126:121–134. 
20. Rose TL, Bonneau L, Der C, Marty-Mazars D, Marty F. Starvation-induced expression of 
autophagy-related genes in Arabidopsis. Biol Cell 2006;98:53–67. 
21. Ahn MY, Kwon SM, Cheong HH, Park JH, Lee J, Min SK, Ahn SG, Yoon JH. Toll-like receptor 7 
agonist, Imiquimod, inhibits oral squamous carcinoma cells through apoptosis and necrosis. J 
Oral Pathol Med 2012;41:540-546. 
22. Smyth EC, Flavin M, Pulitzer MP, Gardner GJ, Costantino PD, Chi DS, Bogatch K, Chapman PB, 
Wolchok JD, Schwartz GK, Carvajal RD. Treatment of locally recurrent mucosal melanoma with 
topical imiquimod. J Clin Oncol 2011;29:e809-e811. 
23. Schon MP, Schon M. Imiquimod: mode of action. British J Dermatol 2007;157:8-13. 
24. Sohn KC, Li ZJ, Choi DK, Zhang T, Lim JW, Chang IK, Hur GM, Im M, Lee Y, Seo YJ, Lee JH, Kim CD. 
Imiquimod induces apoptosis of squamous cell carcinoma (SCC) cells via regulation of A20. 
2014;9:e95337. 
25. Stanley MA. Imiquimod and the imidazoquinolones: mechanism of action and therapeutic 
potential. Clin Exp Dermatol 2002;27:571-577. 
26. Geisse JK, Rich P, Pandya A, Gross K, Andres K, et al. Imiquimod 5% cream for the treatment of 
superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study. J Am Acad 
Dermatol 2002;47:390-398. 
27. Stary G, Bangert C, Tauber M, Strohal R, Kopp T, et al. Tumoricidal activity of TLR7/8-activated 
inflammatory dendritic cells. J Exp Med 2007;204:1441-1451. 
28. Bong AB, Bonnekoh B, Franke I, Schön M, Ulrich J, et al. Imiquimod, a topical immune response 
modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology 
2002;205:135-138. 
29. Huang SJ, Hijnen D, Murphy GF, Kupper TS, Calarese AW, et al. Imiquimod enhances IFN-gamma 
production and effector function of T cells infiltrating human squamous cell carcinomas of the 
skin. J Invest Dermatol 2009;129:2676-2685. 
30. Yokogawa M, Takaishi M, Nakajima K, Kamijima R, Digiovanni J, et al. Imiquimod attenuates the 
growth of UVB-Induced SCC in mice through Th1/Th17 cells. Mol Carcinog 2013;52:760-769. 
31. Rich AM, Hussaini HM, Parachuru V, Seymour GJ. Toll-like receptors and cancer, particularly oral 
squamous cell carcinoma. Front Immunol 2014;5:464. 
32. Schulze HJ, Cribier B, Requena L, et al. Imiquimod 5% cream for the treatment of superficial 
basal cell carcinoma: Results from a randomized vehicle-controlled phase III study in Europe. Br J 
Dermatol 2005;152:939-947. 
33. Love WE, Bernhard JD, Bordeaux JS. Topical imiquimod or fluorouracil therapy for basal and 
squamous cell carcinoma: A systematic review. Arch Dermatol 2009;145:1431-1438. 


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34. Iavazzo C, Pitsouni E, Athanasiou S, et al. Imiquimod for treatment of vulvar and vaginal 
intraepithelial neoplasia. Int J Gynaecol Obstet 2008;101:3-10. 
35. Gkoulioni V, Eleftheriadou A, Yiotakis I, Ferekidou E, Chrisovergis A, Lazaris AC, et al. The efficacy 
of imiquimod on dysplastic lesions of the oral mucosa: an experimental model. Anticancer Res 
2010;30:2891-2896. 
36. Wester A, Eyler JT, Swan JW. Topical imiquimod for the palliative treatment of recurrent oral 
squamous cell carcinoma. JAAD Case Reports 2017;3:329-331. 
37. Schmitz A, Duhoux F, Machiels JP. Window of opportunity studies: Do they fulfil our 
expectations? Cancer Treat Rev 2016;43:50-57. 
38. Marous M, Bieche I, Paoletti X, Alt M, Razak AR, Stathis A. et al. Designs of preoperative 
biomarkers trials in oncology: a systemic review of the literature. Ann Oncol 2015;26:2419-2428. 
39. Torezan LA, Festa-Neto C. Cutaneous field cancerization: clinical, histopathological and 
therapeutic aspects. An Bras Dermatol 2013;88:775-786. 
40. Christensen SR. Recent advances in field cancerization and management of multiple cutaneous 
squamous cell carcinomas. 2018;7: doi: 10.12688/f1000research.12837.1. 
41. Wang B, Zhang S, Yue K, Wang XD. The recurrence and survival of oral squamous cell carcinoma: 
a report of 275 cases. Chin J Cancer 2013;32:614-618. 
42. Gombos K, Horvath R, Szele E, et al. miRNA expression profiles of oral squamous cell 
carcinomas. Anticancer Res 2013;33:1511-1517. 
43. Troiano G, Mastrangelo F, Caponio VCA, et al. Predictive prognostic value of tissue-based 
microRNA expression in oral squamous cell carcinoma: a systemic review and meta-analysis. J 
Dent Res 2018;97:759-766. 
44. Sarode GS, Sarode SC, Maniyar N, Anand R, Patil S. Oral cancer database: a comprehensive 
review. J Oral Pathol Med 2018;47:547-556. 
45. Kumarasamy C, Madjav MR, Sabarimurugan S, et al. Prognostic value of miRNAs in head and 
neck cancers: a comprehensive systemic and meta-analysis. Cells 2019;8. doi: 
10.3390/cells8080772. 
46. Megill C, Wilkin T. Topical therapies for the treatment of anal high-grade squamous 
intraepithelial lesions. Semin colon Rectal Surg. 2017;28:86-90. 
47. Daayana S, Elkord E, Winters U, Pawita M, Roden R, Stern PL, Kitchener HC. Phase II trial of 
imiquimod and HPV therapeutic vaccination in patients with vulvar intraepithelial neoplasia. Br J 
Cancer 2010;102:1129-1136. 
48. Tristram A, Hurt CN, Madden T, et al. Activity, safety, and feasibility of cidofovir and imiquimod 
for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicenter, open-label, randomized, 
phase 2 trial. Lancet Oncol 2014;15:1361-1368. 
49. Singal A, Daulatabad D, Pandhi D, Arora VK. Facial basal cell carcinoma treated with topical 5% 
imiquimod cream with dermoscopic evaluation. J Cutan Aesthet Surg 2016;9:122-125. 
50. Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the 
treatment of superficial basal cell carcinoma: Results from two phase III, randomized, vehicle-
controlled studies. J Am Acad Dermatol 2004;50:722-33. 


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51. Gartrell RD, Marks DK, Hart TD, Li G, Davari DR, Wu A, Blake Z, Lu Y, Askin KN, et al. Quantitative 
analysis of immune infiltrates in primary melanoma. Cancer Immunol Res 2018;6:481-493. 
52. Parra ER, Uraoka N, Jiang M, Cook P, Gibbons D, Forget MA, et al. Validation of multiplex 
immunofluorescence panels using multispectral microscopy for immune-profiling of formalin-
fixed and paraffin-embedded human tumor tissues. Sci Rep 2017;17:13380. 
53.  Koyama T, Chen H. “Proper Inference from Simon’s Two-Stage Designs.” Statistics in Medicine 
2008;27(16), 3145–3154.  
54. Mane S, Patilsoman B, Bhate P, Das D, Malusare P, Tomar N. To evaluate the efficacy and 
tolerability of topical 5% imiquimod in cases of oral leukoplakia: a pilot study. J Indian Acad Oral 
Med Rad 2021;33:27-31. https://www.jiaomr.in/text.asp?2021/33/1/27/312195 
55. Pachman DR, Barton DL, Clayton AH, et al. Randomized clinical trial of imiquimod: an adjunct to 
treating cervical dysplasia. Am J Obstet Gynecol 2012;206:e1-42. doi: 
10.1016/j.ajog.2011.06.105 
 
 
 


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40 
APPENDIX A: ECOG PERFORMANCE STATUS CRITERIA. 
 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 


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APPENDIX B: DAILY DIARY 
 
Exploratory clinical trial of topical Imiquimod 5% cream as window-of-opportunity monotherapy for 
early-stage oral cancer 
 
Patient Name: _____________________ Study ID: ______________ MRN:_________________ 
(To be Completed by RN) 
Total Daily Dose of Imiquimod: 5mg 
 
PLEASE FILL OUT AND BRING THIS SHEET AT YOUR NEXT VISIT. 
SPECIAL INSTRUCTIONS 
 
1. Imiquimod 5% cream should be applied once a day at bedtime.  
2. Missed doses should be skipped and not taken as a double dose at the next dosing time. 
 
3. Imiquimod 5% cream should be stored at room temperature. 
 
 
 
 
Day 
Medication 
Date 
Time 
Comments 
Example 
Imiquimod 
5/1/2021 
9:00PM 
 
1 
Imiquimod 
 
 
 
2 
Imiquimod 
 
 
 
3 
Imiquimod 
 
 
 
4 
Imiquimod 
 
 
 
5 
Imiquimod 
 
 
 
6 
Imiquimod 
 
 
 
7 
Imiquimod 
 
 
 
8 
Imiquimod 
 
 
 
9 
Imiquimod 
 
 
 
10 
Imiquimod 
 
 
 
11 
Imiquimod 
 
 
 
12 
Imiquimod 
 
 
 
13 
Imiquimod 
 
 
 
14 
Imiquimod 
 
 
 
15 
Imiquimod 
 
 
 
16 
Imiquimod 
 
 
 
17 
Imiquimod 
 
 
 
18 
Imiquimod 
 
 
 


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19 
Imiquimod 
 
 
 
20 
Imiquimod 
 
 
 
21 
Imiquimod 
 
 
 
22 
Imiquimod 
 
 
 
23 
Imiquimod 
 
 
 
24 
Imiquimod 
 
 
 
25 
Imiquimod 
 
 
 
26 
Imiquimod 
 
 
 
27 
Imiquimod 
 
 
 
28 
Imiquimod 
 
 
 
 
 
Patient Signature: ___________________________________________ Date: _____________ 
Consenting Professional/Research RN Signature: ____________________ Date: ______________ 
Consenting Professional/Research RN Comments: 
_________________________________________________________________________________ 
_________________________________________________________________________________ 
_________________________________________________________________________________ 
 
 

ICF_000.pdf: 
Page 1 of 12 
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Medical University of South Carolina 
CONSENT TO BE A RESEARCH SUBJECT 
 
 
 
TITLE OF RESEARCH: Exploratory clinical trial of topical Imiquimod 5% cream as window-
of-opportunity monotherapy for early-stage oral cancer  
 
MUSC CTO # 103625 
Principal Investigator:  Angela Yoon, DDS 
 
 
 
You are being asked to participate in a research study. This document will explain what the 
study is about, what you will be asked to do, and the risks and benefits of participating in the 
study so that you can make a decision whether or not you want to participate. Your 
participation is voluntary, which means you can decide whether or not you want to 
participate. If you decide not to participate, your care at Medical University of South Carolina 
will not be affected and your doctor will discuss your treatment options. You will be given a 
copy of this form to take home and discuss with your family, friends, or your doctor. If you 
have any questions, you should ask the study team. If you decide to participate, you will be 
asked to sign a copy of this form. 
 
• 
We are asking for your consent to voluntarily participate in this study.   
• 
The purpose of this research study is to find out what effects, good and/or bad, topical 
application of the study drug Imiquimod will have on you and your oral cancer. 
• 
You will need to come to see your study doctor to see if you are eligible for the study, 
and if you are, you will have a Day 1 tele-visit (by phone), and Day 14 and Day 29 clinic 
visits.  At the clinic visits, report any side-effects you have experienced to your study 
doctor. You will have oral exams and pictures taken of the growths, inside your mouth.  
You will be in this study for about 8 weeks. 
• 
You will receive Imiquimod for a maximum of 28 days until your scheduled surgery. If 
you stop using Imiquimod cream due to unacceptable side effects or cancer growth, your 
study doctor will continue to watch you for side effects and follow your condition for at 
least 30 days or until the side effect has resolved. Your surgery will proceed as initially 
scheduled but the doctor will follow your progress. 
• 
The most likely side effect of the study drug is the irritation of the treatment site, such as 
redness, itching or burning.  
• 
You may not directly benefit from the study drug, but there is a possibility that the 
treatment you receive may prove to be effective in shrinking the size of tumor before the 
surgery, although this cannot be guaranteed. 
• 
The alternative is to receive clinical care, which may include surgery, without 
participating in this study. 
 


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In summary, you will receive Imiquimod for 28 days until your scheduled surgery if you are 
tolerating the study drug and your cancer is not growing while receiving the study drug. If 
you stop using Imiquimod cream due to unacceptable side effects or cancer growth, your 
study doctor will continue to watch you for side effects and follow your condition for at least 
30 days or until the side effect has resolved.  
 
A. PURPOSE OF THE RESEARCH 
 
The purpose of this research study is to find out what effects, good and/or bad, topical 
application of the study drug Imiquimod will have on you and your oral cancer. Imiquimod is 
a drug that activates toll-like receptor (TLR) in oral cancer cells causing self-destruction of 
tumor cells. It also activates immune cells to attack and eliminate cancer cells. Imiquimod is 
currently approved by the Food and Drug Administration (FDA) for treatment of skin 
precancer and cancer, as well as genital and perianal (around the anus) warts. There is only 
limited information on whether imiquimod can be used in mouth cancers. Its use in this study 
is not approved by the FDA and is considered investigational for the purposes of this study.   
 
In this exploratory study, we want to find out if we can give Imiquimod topical cream for four 
weeks before your scheduled surgery. Specifically, we want to find out if there is 
considerable shrinkage of oral cancer with 28 days of Imiquimod application. A grant from 
the National Institutes of Health (NIH) will sponsor this study. Portions of Dr. Yoon and his 
research team’s salaries will be paid by this grant. 
 
Please read this consent form carefully and take your time making your decision. As your 
study doctor or study staff discusses this consent form with you, please ask him/her to 
explain any words or information that you do not clearly understand.  You are being asked to 
participate in this study because you are/have oral cancer. The investigator in charge of this 
study at MUSC is Dr. Yoon. The study is being done at MUSC only. Approximately 15 
people will take part in this study. 
 
B. PROCEDURES 
You will have your first consultation with the head and neck surgeon to go over your current 
condition and treatment options. He/she will conduct physical examination and may order 
scan of your body (PET scan; an imaging test that allows your doctor to check for disease in 
your body) as standard of care. He/she will also schedule the surgery date in 4 weeks after 
the first day of Imiquimod treatment. 
 
Most of the exams, tests, and procedures you will have are part of the usual approach for 
your condition. However, there are three extra oral exams that you will need to have if you 
take part in this study. 
 
 


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If you agree to be in this study, the following will happen: 
1. 
We will request the following during the screening visit to find out if you can be in the 
study.   
• Previous biopsy result showing evidence of oral cancer 
• Oral examination to measure size of tumor and take picture 
• A complete list of your current medications including vitamins and supplements to 
your study doctor as some medications may interact with Imiquimod and your 
study doctor will need to be aware of what drugs, vitamins and supplements you 
are currently taking 
• Blood pregnancy test in women of child-bearing potential.  Approximately one 
teaspoon of blood will be collected for a blood pregnancy test. 
 
o If you are a woman of childbearing potential and /or a man capable of fathering 
a child before, during, and/or after, participation precaution should be taken. 
Examples of acceptable methods of birth control for participants involved in the 
study includes birth control pills, patch, IUD, condom, sponge, diaphragm with 
spermicide, or avoiding sexual activity that could cause you to become 
pregnant. 
3.  
If the oral and physical examination show that you are eligible for the study, you will 
be asked to take blood test (a measure of your health by a full blood count) in which 
approximately one teaspoon of blood will be drawn.  You will also be given instruction 
as to how to apply the medicine and a daily diary form. 
4. 
You may pick up your study medication in person, or it can be mailed to you, if that is 
preferred and the study doctor will call asking you to start applying the medicine. You 
will be asked to keep a daily diary to track the use of study drug once a day.  The 
drug can be applied using your finger or Q-tip.  Remember to wash your hands after 
drug application. 
**Please abstain from eating or drinking for at least 30 minutes after application of 
topical imiquimod cream** 
5. 
Fourteen (14) days after the first use of the study drug, you will be asked to come in 
for an oral exam.  At this time, we will measure the tumor size to see if there is any 
change and take a picture.  We will also ask if you had any side effects using the 
medicine. This procedure will take about 30 minutes. 
6. 
Twenty-nine (29) days after the first use of the study drug, you will be asked to return 
for a final oral exam. Again, we will measure the tumor size to see if there is any 
change and take a picture.  We will also ask if you had any side effects using the 
medicine. You will be asked to provide the list of any other new medicine used since 
the study start time. The daily diary form you completed, and any unused study drugs 
should be returned to your study doctor on this visit. This procedure will take about 40 
minutes. 
7. 
We will collect results or your pre-surgery blood tests from your medical record to use 
as a comparison to your blood work obtained at the beginning of the study.   


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8. 
Sixty (60) days after enrollment, we will contact you to see how you are doing. 
9.  
Your medical record will continue to be reviewed until you complete the study 
(approximately 8 weeks after consent). 
 
C. DURATION 
 
Participation in the study will take about 3 visits over the period of 4 weeks. You will remain 
in the study, to include the follow up period, for a total of 8 weeks.  
 
D. RISKS AND DISCOMFORTS 
 
Common adverse events (side effects) are:  
 
• Redness, itching, burning, or bleeding of the treated area (33%) 
• Flaking, scaling, dryness, or thickening of the skin (33%) 
• Swelling, stinging, or pain in the treated area (33%) 
• Blisters, scabs, or bumps on the skin (33%) 
Less common adverse events (side effects) are: 
 
• Headache (11%) 
• Inflammation or swelling of the tissue lining the sinuses (7%) 
• Diarrhea (3%) 
• Red and itchy skin reaction (2%) 
• Back pain (1%) 
• Tiredness (1%) 
• Irregular and rapid heat rate (1%) 
• Virus infection (1%) 
• Dizziness (1%) 
• Vomiting (1%) 
• Infection of any part of urinary system (1%) 
• Fever (1%) 
• Tremor caused by a chill (1%) 
Some side effects can be serious. If you experience any of these symptoms, call your study 
doctor immediately:  
 
• Flu-like symptoms such as nausea, fever, chills, tiredness, and muscle weakness or pain 
(15%) 
 


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LOSS OF CONFIDENTIALITY 
There is a risk of loss of confidentiality since medical records will be reviewed during this 
study. MUSC and its study team members will take every effort to ensure that your 
information is kept confidential during this study. 
 
PREGNANCY RISKS 
It is not know what effects, if any, Imiquimod cream would have on pregnancy or a fetus.  
Therefore, women should avoid becoming pregnant during the course of the study. 
 
E. MEDICAL RECORDS AND CERTIFICATE OF CONFIDENTIALITY 
 
If you are an MUSC patient you have an MUSC medical record:  If you have never been an 
MUSC patient, a MUSC medical record will be created for the purposes of this study. 
Results of research tests or procedures will be included in your MUSC medical record. All 
information within your medical record can be viewed by individuals authorized to access 
the record We will make every effort to keep confidential all research information in the 
medical record that identify you to the extent allowed by law. 
 
This research is covered by a Certificate of Confidentiality from the Federal government. 
This means that the researchers may not disclose information or biospecimens that may 
identify you, even by a court subpoena, in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings, nor can the information or biospecimens be 
used as evidence, unless you have consented to this disclosure. Information or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except if you have consented to the disclosure, including for 
your medical treatment; or if it is used for other scientific research, as allowed by federal 
regulations protecting research subjects. 
A Certificate of Confidentiality does not prevent you from voluntarily releasing information 
about yourself or your involvement in this research. If you are an MUSC patient you have an 
MUSC medical record. If you have never been an MUSC patient, a MUSC medical record 
will be created for the purposes of this study. Results of research tests or procedures will be 
included in your MUSC medical record. All information within your medical record can be 
viewed by individuals authorized to access the record. We will make every effort to keep 
confidential all research information in the medical record that identify you to the extent 
allowed by law; however, there is the possibility that your research information will be 
disclosed. 
 
 


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The Certificate of Confidentiality will not be used to prevent disclosure as required by 
federal, state, or local law. Examples of required disclosure include: child abuse and 
neglect, or harm to self or others 
Finally, a Certificate may not be used to withhold information from the Federal government 
needed for auditing or evaluating Federally funded projects or information needed by the 
FDA. 
 
F. BENEFITS 
 
The potential benefit to you is that the treatment you receive may prove to be effective in 
shrinking the size of tumor before the surgery, although this cannot be guaranteed. 
 
G. COSTS 
 
There will be no additional costs to you because of being in this study.  However, routine 
medical care for your condition (care you would have received even if you were not in this 
study) will be charged to you or your insurance company.  You may wish to contact your 
insurance company to discuss this further. It is possible that your insurance company will 
refuse to pay for the costs associated with study participation, in which case you will be held 
financially responsible. Please ask Dr. Yoon if you would like to know more about which 
tests and studies are being done solely for research purposes. 
H. PAYMENT TO PARTICIPANTS 
 
You will not be paid for participating in this study. 
 
I. ALTERNATIVES 
The alternative is to receive clinical care, which may include surgery, without participating in 
this study. 
J. DATA SHARING 
Information about you (including your identifiable private information and/or any identifiable 
biospecimens) may have all of your identifiers removed and used for future research studies 
or distributed to other researchers for future research without additional informed consent 
from you or your legally authorized representative. 
 
 
 
 


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K. DISCLOSURE OF RESULTS 
 
Clinically important results, such as tumor becoming larger or smaller, will be disclosed to 
you. 
 
L. AUTHORIZATION TO USE AND DISCLOSE (RELEASE) MEDICAL INFORMATION 
 
As part of this research study, your study doctor and her research team will keep records of 
your participation in this study. 
 
The health information MUSC may use or disclose (release) for this research study includes 
information in your medical record, results of physical exams, medical history, lab tests or 
certain health information indicating or relating to your condition.  
 
Your study doctor and her research team will use and disclose (release) your health 
information to conduct this study. The health information listed above may be used by 
and/or disclosed (released) to the following, as applicable: 
 
• The sponsor of the study including its agents such as data repositories or contract 
research organizations monitoring the study. 
• Other institutions and investigators participating in the study. 
• Data Safety Monitoring Boards. 
• Accrediting agencies. 
• Clinical staff not involved in the study whom may become involved if it is relevant; 
• Parents of minor children if less than 16 years old. Parents of children 16 years old or 
older require authorization from the child; or 
• Health insurer or payer in order to secure payment for covered treatment. 
• Federal and state agencies and MUSC committees having authority over the study 
such as: 
o The Institutional Review Board (IRB) overseeing this study; Committees with 
quality improvement responsibilities; Office of Human Research Protections; Food 
and Drug Administration; National Institutes of Health or Other governmental 
offices, such as a public health agency or as required by law. 
o The United States Food and Drug Administration ('FDA') and/or the Office of 
Human Research Protections ('OHRP') 
o National Institute of Health (NIH), an institution that will be able to inspect and 
collect your clinical data and/or samples. 
 
In addition to this study, you have the option of participating in future storage of your tumor 
tissue specimens, for possible genetic study. Your protected health information may be used 
or shared with others outside of MUSC for this research as well. Please initial below if we 
may use/disclose your protected health information for the optional research portion/s of this 
study. 
 
  


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_________Yes, you may use my protected health information for the optional research 
portions of this study. 
  
_________No, you may not use my protected health information for the optional research 
portions of this study. 
 
 
Those persons who receive your health information may not be required by Federal privacy 
laws (such as the Privacy Rule) to protect it and may share your information with others 
without your permission, if permitted by laws governing them. You do not have to sign this 
consent form.  If you choose not to sign, it will not affect your treatment, payment or 
enrollment in any health plan or affect your eligibility for benefits.  However, you will not be 
allowed to be a participant in this research study. 
 
You will be given a copy of this consent form.  Your authorization will expire at the 
conclusion of this study or, if you are participating in a study designed for the development 
of a drug or device, your authorization will remain in effect until the drug or device is 
approved by the FDA or until the company’s application to study the drug/device is 
withdrawn. You have the right to withdraw your agreement at any time.  You can do this by 
giving written notice to your study doctor.  If you withdraw your agreement, you will not be 
allowed to continue participation in this research study.  However, the information that has 
already been collected will still be used and released as described above.  You have the 
right to review your health information that is created during your participation in this study.  
After the study is completed, you may request this information. 
 
Your health information will be used or disclosed when required by law.  Your health 
information may be shared with a public health authority that is authorized by law to collect 
or receive such information for the purpose of preventing or controlling disease, injury or 
disability and for conducting public health surveillance, investigations or interventions.  No 
publication or public presentation about the research study will reveal your identity without 
another signed authorization from you.   
 
If you have questions or concerns about this Authorization or your privacy rights, please 
contact MUSC’s Privacy Officer at (843) 792-8740.   
 
M. SIGNIFICANT NEW FINDINGS 
 
If there are significant new findings during the course of the study, you will be notified.  
 
N. CLINICAL TRIALS.GOV  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 


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most, the Web site will include a summary of the results. You can search this Web site at 
any time. 
 
O. COLLECTION OF SPECIMENS  
 
As part of this study, we would like to store tumor tissue specimens collected from you for 
future research on oral cancer. This future research may be conducted by Dr. Yoon or by 
other researchers who obtain IRB approval for their research. This research may involve 
genetic studies.  Part of the tissue collected will go to Dr. Yoon for a related study that will 
evaluate the effect the study drug has on immune cells.  
 
There are several things you should know before allowing your tissues to be studied or to be 
stored. 
 
1. The tumor tissue specimens will be labeled with a code that only study personnel can link 
back to you. Researchers outside of this study will not be given a link between the code 
number and your name or any other identifying information. While we hope this will 
prevent any potential loss of privacy or confidentiality, we cannot make any guarantees. 
2. In addition to your name, other information about you might be connected to your sample. 
For instance, information about race, ethnicity, sex, your medical history, and so forth 
might be available to investigators studying your specimen. Such information might be 
important for research or public health. It is possible that this information (including 
genetic information) might come to be associated with your racial or ethnic group. 
3. The specimens obtained from you in this research may help in the development of a 
future commercial product. There are no plans to provide financial compensation to you 
should this occur. 
4. Investigators in this study may try to re-contact you in the future to find out about your 
health. If you are contacted and want to know what the investigators have learned about 
your samples, you should understand that the following are the kinds of things the 
investigators or your health team might tell you: 
a. Information is too preliminary to give you details, but you will receive a 
newsletter informing you about the results of the project. 
b. For any future research, we may contact you with a new consent form giving 
you additional information. 
c. You carry a gene for a particular disease that can be treated. 
d. You carry a gene for a particular disease for which there is no current 
treatment. This news might cause severe anxiety or other psychological 
distress, depending on the severity of the disease. 
e. You carry a gene for a disease and might consider informing relatives that 
they, too, might carry the gene. It can be very difficult to decide whether to 
share such information with relatives. Genetic counselors can help sort out the 
various options in such a case. 


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You may request at any time that your research samples be removed from storage and not 
be used for future research. If you decide you want your samples removed, you may contact 
Dr. Yoon via written communication at the following address: 39 Sabin St., Walton Research 
Bldg. 7th Floor, Charleston SC 29425. Once the request is received, and if your samples 
have not already been used for other research, they will be destroyed. If you do not make 
such a request, your specimens will be stored indefinitely or until completely used. 
 
 
Initial your choice below: 
 
____________Yes, I agree to allow my samples to be kept and used for future unknown 
research, and I also allow Dr. Yoon to use part of the sample to study immune cells. 
 
 
 
____________No, I do NOT agree to allow my samples to be kept and used for future 
unknown research, and I also do NOT agree to allow Dr. Yoon to use part of the sample to 
study immune cells. 
 
 
P. FUTURE CONTACT 
The researcher in charge of this study might like to contact you in the future about other 
research opportunities. Please initial by your choice below:  
____________Yes, I agree to be contacted 
 
____________No, I do NOT agree to be contacted 
 
Results of this research will be used for the purposes described in this study. This information 
may be published, but you will not be identified. Information that is obtained concerning this 
research that can be identified with you will remain confidential to the extent possible within 
State and Federal law. The sponsor and the Food and Drug Administration (FDA) will receive 
copies of the research records. The investigators associated with this study, employees of the 
sponsor, the FDA, and the MUSC Institutional Review Board for Human Research will have 
access to identifying information. All records in South Carolina are subject to subpoena by a 
court of law. 
 
In the event of a study related injury, you should immediately go to the emergency room of 
the Medical University Hospital, or in case of an emergency go to the nearest hospital, and 


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tell the physician on call that you are in a research study. They will call your study doctor who 
will make arrangements for your treatment. If the study sponsor does not pay for your 
treatment, the Medical University Hospital and the physicians who render treatment to you 
will bill your insurance company. If your insurance company denies coverage or insurance 
is not available, you will be responsible for payment for all services rendered to you. 
 
Your participation in this study is voluntary. You may refuse to take part in or stop taking part 
in this study at any time. You should call the investigator in charge of this study if you decide 
to do this. The data collected on you to this point remains part of the study database and may 
not be removed. Your decision not to take part in the study will not affect your current or future 
medical care or any benefits to which you are entitled. 
 
The investigators and/or the sponsor may stop your participation in this study at any time if 
they decide it is in your best interest. They may also do this if you do not follow the 
investigator’s instructions. 
 
 
 


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Volunteers Statement 
 
I have been given a chance to ask questions about this research study. These questions have 
been answered to my satisfaction. If I have any more questions about my participation in this 
study or study related injury, I may contact Dr. Yoon at 843-792-4271. I may contact the 
Medical University of SC Patient and Family Care Liaison (843) 792-5555 concerning medical 
treatment. 
 
If I have any questions, problems, or concerns, desire further information or wish to offer input, 
I may contact the Medical University of SC Institutional Review Board for Human Research 
IRB Manager or the Office of Research Integrity Director at (843) 792-4148. This includes any 
questions about my rights as a research subject in this study. 
 
I agree to participate in this study. I have been given a copy of this form for my own records. 
 
 
 
 
 
________________________________ 
Signature of Person Obtaining Consent Date *Name of Participant 
 
 
 
                                                                                      
Signature of Participant                              Date