Pilot Clinical Trial of Neoadjuvant Toll-like Receptor 7 Agonist (Imiquimod) Immunotherapy in Early-Stage Oral Squamous Cell Carcinoma
Phase: EARLY_PHASE1
Conditions: Oral Squamous Cell Carcinoma
Sponsor: Medical University of South Carolina

 
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 
 

Neoadjuvant Imiquimod for Oral Cancer 
Version 9.3 
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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Neoadjuvant Imiquimod for Oral Cancer 
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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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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: 
_________________________________________________________________________________ 
_________________________________________________________________________________ 
_________________________________________________________________________________