Conditions: Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8 Clinical Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8 Nasal Cavity and Paranasal Sinus Carcinoma Oral Cavity Carcinoma Pathologic Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8 Pathologic Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8 Recurrent Hypopharyngeal Carcinoma Recurrent Laryngeal Carcinoma Recurrent Nasal Cavity and Paranasal Sinus Carcinoma Recurrent Oral Cavity Carcinoma Recurrent Oropharyngeal Carcinoma Stage III Hypopharyngeal Carcinoma AJCC v8 Stage III Laryngeal Cancer AJCC v8 Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8 Stage IV Hypopharyngeal Carcinoma AJCC v8 Stage IV Laryngeal Cancer AJCC v8 Stage IV Oropharyngeal (p16-Negative) Carcinoma AJCC v8 Stage IVA Hypopharyngeal Carcinoma AJCC v8 Stage IVA Laryngeal Cancer AJCC v8 Stage IVA Oropharyngeal (p16-Negative) Carcinoma AJCC v8 Stage IVB Hypopharyngeal Carcinoma AJCC v8 Stage IVB Laryngeal Cancer AJCC v8 Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8 Stage IVC Hypopharyngeal Carcinoma AJCC v8 Stage IVC Laryngeal Cancer AJCC v8 Stage IVC Oropharyngeal (p16-Negative) Carcinoma AJCC v8
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 13
Healthy volunteers: no

Brief summary:
This phase II trial studies how well celecoxib works through surgery and radiation therapy in treating patients with head and neck cancer that has spread to other places in the body (advanced). Celecoxib is Food and Drug Administration approved to treat arthritis, acute pain, and painful menstrual periods. Adding celecoxib to standard of care treatment may help to decrease the amount of time between surgery and radiation therapy.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess the number of days from surgery to initiation of radiation with the addition of celecoxib compared to placebo.

SECONDARY OBJECTIVES:

I. To assess overall pain control and management for patients on celecoxib compared to placebo.

* Subjective pain scores on the visual analog scale of pain intensity averaged over a week at rest, with a swallow, and with a cough.
* Patient satisfaction with pain control questionnaire.
* Narcotic consumption in daily total morphine equivalents averaged over a week. II. To assess functional outcomes for patients on celecoxib compared to placebo.

III. To assess the effect of celecoxib therapy on Quality of Life (QoL) compared to placebo.

IV. To assess the average number of treatment days missed during adjuvant radiation for patients on celecoxib compared to placebo.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive celecoxib orally (PO) or via feeding tube twice daily (BID) starting 5 days prior to surgery and continues until the completion of radiation therapy (up to 6 months in total) in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO or via feeding tube BID starting 5 days prior to surgery and continues until the completion of radiation therapy (up to 6 months in total) in the absence of disease progression or unacceptable toxicity.

Arms:
arm 1: Patients receive celecoxib PO or via feeding tube BID starting 1 to 7 days prior to surgery and continues until the completion of radiation therapy (up to 6 months in total) in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive placebo PO or via feeding tube BID starting 1 to 7 days prior to surgery and continues until the completion of radiation therapy (up to 6 months in total) in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Celecoxib intervention 2: Placebo intervention 3: Quality-of-Life Assessment intervention 4: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO or via feeding tube intervention 2: Given PO or via feeding tube intervention 3: Ancillary studies intervention 4: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
Short Title: RESILIENCE 
Version Date: 18APR2023 
Principal Investigator: Richard Cannon, MD 
 
RESILIENCE: Effect of Comprehensive Celecoxib through Treatment for Advanced-Stage 
Head and Neck Cancer: A Randomized, Double-Blinded, Placebo-Controlled Trial 
HCI identifier 124211 
Principal Investigator 
Richard Cannon, MD  
Huntsman Cancer Institute - University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Email: Richard.Cannon@hsc.utah.edu 
Statistician 
Kenneth Boucher, PhD 
Huntsman Cancer Institute - University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Phone: 801-213-3774 
Email: Kenneth.boucher@hci.utah.edu 
Medical Monitor 
Anna Beck, MD 
Commercial agent 
Celecoxib  
IND Number 
IND Exempt 
NCT Number (CT.gov) 
NCT04162873 
Historical Protocol Version Dates 
Version 1: 14AUG2019 
Version 2: 31OCT2019 
Version 3: 07JUL2020 
Version 4: 14MAY2021 
Version 5: 14APR2022 
Version 6: 18APR2023 
 
 


Short Title: RESILIENCE 
Version Date: 18APR2023 
 
Page 2 of 56 
TABLE OF CONTENTS 
Page 
TABLE OF CONTENTS ................................................................................................................ 2 
LIST OF ABBREVIATIONS ......................................................................................................... 5 
PROTOCOL SIGNATURE ............................................................................................................ 9 
STUDY SUMMARY.................................................................................................................... 10 
SCHEMA ...................................................................................................................................... 12 
1 
OBJECTIVES ....................................................................................................................... 13 
1.1 
Primary Objective ....................................................................................................... 13 
1.2 
Secondary Objective ................................................................................................... 13 
2 
BACKGROUND .................................................................................................................. 13 
2.1 
Hypothesis .................................................................................................................. 13 
2.2 
Head and Neck Cancers .............................................................................................. 14 
2.3 
The Effect of Pain Control on Overall Survival and Study Objective Rational ......... 14 
2.4 
Disease group rationale .............................................................................................. 15 
2.5 
Drug selection rationale .............................................................................................. 15 
2.6 
Clinical experience ..................................................................................................... 15 
3 
DRUG INFORMATION ...................................................................................................... 15 
3.1 
Celecoxib .................................................................................................................... 15 
4 
STUDY DESIGN.................................................................................................................. 17 
4.1 
Description.................................................................................................................. 17 
4.2 
Randomization and Blinding ...................................................................................... 17 
4.3 
Number of Patients ..................................................................................................... 18 
4.4 
Number of Study Centers ........................................................................................... 18 
4.5 
Study Duration ............................................................................................................ 18 
5 
ELIGIBILITY CRITERIA.................................................................................................... 19 
5.1 
Inclusion Criteria ........................................................................................................ 19 
5.2 
Exclusion Criteria ....................................................................................................... 20 
5.3 
Recruitment Strategies ................................................................................................ 23 
6 
STRATIFICATION FACTORS ........................................................................................... 23 
7 
TREATMENT PLAN ........................................................................................................... 23 


Short Title: RESILIENCE 
Version Date: 18APR2023 
 
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7.1 
Administration Schedule ............................................................................................ 23 
7.2 
Celecoxib/ Placebo ..................................................................................................... 23 
7.3 
Concomitant Medications and Therapies ................................................................... 24 
8 
TOXICITIES AND DOSE MODIFICATION ..................................................................... 26 
8.1 
Dose Modifications..................................................................................................... 26 
8.2 
Dose Interruptions ...................................................................................................... 26 
8.3 
Dose Reductions ......................................................................................................... 26 
8.4 
Adverse Event Management ....................................................................................... 27 
8.5 
Supportive Care .......................................................................................................... 28 
8.6 
Contraception.............................................................................................................. 29 
9 
SCHEDULE OF EVENTS ................................................................................................... 29 
10 STUDY PROCEDURES ...................................................................................................... 32 
10.1 
Screening .................................................................................................................... 32 
10.2 
Treatment Period ........................................................................................................ 32 
10.3 
End of Treatment ........................................................................................................ 32 
11 STUDY ASSESSMENTS .................................................................................................... 32 
11.1 
Physical Examinations and Vital Signs ...................................................................... 33 
11.2 
Adverse Events ........................................................................................................... 33 
11.3 
Laboratory Assessments ............................................................................................. 33 
11.4 
Analgesic Use Record ................................................................................................ 34 
12 CRITERIA FOR EVALUATION AND ENDPOINT .......................................................... 34 
12.1 
Primary Objective ....................................................................................................... 34 
12.2 
Secondary Objectives ................................................................................................. 35 
12.3 
Stopping Rules ............................................................................................................ 35 
13 STATISTICAL CONSIDERATIONS.................................................................................. 36 
13.1 
Statistical hypothesis .................................................................................................. 36 
13.2 
Sample size determination .......................................................................................... 36 
13.3 
Population for analyses ............................................................................................... 36 
13.4 
Statistical Analyses ..................................................................................................... 37 
14 REGISTRATION GUIDELINES ......................................................................................... 37 
15 DATA SUBMISSION SCHEDULE .................................................................................... 38 
16 ETHICAL AND REGULATORY CONSIDERATIONS .................................................... 38 


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Version Date: 18APR2023 
 
Page 4 of 56 
16.1 
Human Subject Protections ........................................................................................ 38 
16.2 
Institutional Review .................................................................................................... 38 
16.3 
Data and Safety Monitoring Plan ............................................................................... 38 
16.4 
Adverse Events and Serious Adverse Events ............................................................. 39 
16.5 
Reporting of Pregnancy .............................................................................................. 42 
16.6 
Protocol Amendments ................................................................................................ 43 
16.7 
Protocol Deviations .................................................................................................... 43 
16.8 
FDA Annual Reporting .............................................................................................. 43 
16.9 
Clinical Trials Data Bank ........................................................................................... 43 
16.10 
Record Keeping .......................................................................................................... 44 
17 BIBLIOGRAPHY ................................................................................................................. 45 
 
List of Tables 
Table 1: Adverse events in ≥ 2% of osteoarthritis and rheumatoid arthritis patients ................... 16 
Table 2: Dose Level Reduction..................................................................................................... 27 
Table 3: Adverse Event Management Guidelines ........................................................................ 27 
Table 4: Schedule of Events ......................................................................................................... 30 
Table 5: Functional Oral Intake Scale .......................................................................................... 33 
Table 6: Laboratory Assessments ................................................................................................. 34 
 
List of Appendices  
Appendix 1: Patient Dosing Diary ................................................................................................ 46 
Appendix 2: Pain Management Diary........................................................................................... 47 
Appendix 3: MDASI Head and Neck Cancer ............................................................................... 48 
Appendix 4: EORTC Q LQ-H&N43 ............................................................................................ 50 
Appendix 5: Pain Satisfaction Questionnaire ............................................................................... 52 
Appendix 6: Pre-treatment Questionnaire .................................................................................... 53 
Appendix 7: Visual Analog Scale for Pain ................................................................................... 54 
Appendix 8: Treating Investigator Patient Assessment Guidance ................................................ 55 
 


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LIST OF ABBREVIATIONS 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 


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Abbreviation or Term1 
Definition/Explanation 
D/C 
Discontinue 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
Eg 
Exempli Gratia (for example) 
FACS 
Fluorescence-Activated Cell Sorting  
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltransferase 
GLP 
Good laboratory practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 
HNC 
Head and Neck Cancer 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
IU 
International unit 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 


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Abbreviation or Term1 
Definition/Explanation 
LLQ 
The lower limit of quantitation 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MME 
Morphine Milligram Equivalent 
MRI 
Magnetic resonance imaging 
MRSD 
The maximum recommended starting dose 
MTD 
Maximum tolerated dose  
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect-level 
PD 
Pharmacodynamic(s) 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QC 
Quality control 
RBC 
Red blood cell 
QD 
Once-daily 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Fredericia equation 
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
T1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
Tmax 
Time of maximum observed concentration 
TID 
Three times daily 
TSH 
Thyroid-stimulating hormone 
ULN 
The upper limit of normal 
ULQ 
The upper limit of quantitation 


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Abbreviation or Term1 
Definition/Explanation 
UV 
Ultraviolet 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of nonchildbearing potential 
1 All of these abbreviations may or may not be used in the protocol.  
 


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Version Date: 18APR2023 
 
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PROTOCOL SIGNATURE 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of the 
federal government. I will promptly submit the protocol to the IRB for review and approval. Once 
the protocol has been approved by the IRB, I understand that any modifications made during the 
course of the study must first be approved by the IRB prior to implementation except when such 
modification is made to remove an immediate hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study treatment, the conduct of the study, and the obligations of 
confidentiality. 
Note: This document is signed electronically through submission and approval by the Principal 
Investigator in the University of Utah IRB Electronic Research Integrity and Compliance 
Administration (ERICA) system. 


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Version Date: 18APR2023 
 
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STUDY SUMMARY 
Title 
Effect of Comprehensive Celecoxib Through Treatment for 
Advanced-Stage Head and Neck Cancer: A Randomized, Double-
Blinded, Placebo-Controlled Trial 
Short Title 
RESILENCE 
Protocol Identifiers 
(IRB – internal) 
IRB # 124211 
IND number 
IND Exempt 
Phase 
Pilot 
Design 
Randomized, double-blinded, placebo-controlled 
Study Duration 
2 years 
Study Center 
Single Site: Huntsman Cancer Institute 
Objectives 
Primary Objective: 
To assess the number of days from surgery to the initiation of radiation 
with the addition of celecoxib compared to placebo. 
 
Secondary Objectives: 
- 
To assess overall pain control and management for patients on 
celecoxib compared to placebo. 
- 
To assess functional outcomes for patients on celecoxib compared 
to placebo. 
- 
To assess the effect of celecoxib therapy on Quality of Life (QoL) 
compared to placebo. 
- 
To assess the average number of treatment days missed during 
adjuvant radiation for patients on celecoxib compared to placebo. 
Number of Subjects 
60 
Diagnosis and Main 
Eligibility Criteria 
Inclusion Criteria: 
- 
Advanced-stage (overall stage III and IV) head and neck cancers 
(sinonasal, oral cavity, oropharynx, larynx, and hypopharynx) 
undergoing surgical resection and then adjuvant radiation. 
- 
Karnofsky Performance Status of ≥ 70 
- 
Adequate organ function. 
Exclusion Criteria 
- 
Metastatic disease 
- 
Exclude patients with chronic kidney disease (stage 4 and 5), prior 
CVA or acute MI, chronic heart failure, prior episode of GI bleed 
or stomach or intestinal ulcer, and liver failure. 


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Version Date: 18APR2023 
 
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- 
Uncontrolled hypertension 
- 
Established in a pain management clinic or has taken opioids 
regularly for ≥ 6 months. 
Study Product, Dose, 
Route, Regimen 
Celecoxib/placebo 200mg BID oral or via a feeding tube 
Duration of 
administration 
Celecoxib/placebo will be taken 1 to 7 days prior to surgery until the 
completion of adjuvant radiation, approximately 4 months total, 
maximum allowable time on the study is limited to 6 months. 
Reference therapy 
Placebo 
Statistical 
Methodology 
A mixed-effects regression model that accounts for clustering (patients 
nested within providers) to compare the average number of days from 
surgery to the initiation of radiation between treatment and control 
groups 
 


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SCHEMA 
 
 
 


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1 
OBJECTIVES 
1.1 
Primary Objective 
Recent population-level evidence demonstrates that the number of days from surgery to 
initiation of adjuvant radiation for advanced-stage head and neck cancer has a strong impact 
on survival outcomes. Therefore, we seek to assess the number of days from surgery to 
initiation of radiation with the addition of celecoxib compared to placebo. 
Primary Endpoint: The number of days from surgery to the initiation of radiation. 
1.2 
Secondary Objective 
• To assess overall pain control and management for patients on celecoxib compared to 
placebo.  
Secondary Endpoints:  
o Subjective pain scores on the visual analog scale of pain intensity averaged over a 
week at rest, with a swallow, and with a cough. 
o Patient satisfaction with pain control questionnaire.  
o Narcotic consumption in daily total morphine equivalents averaged over a week. 
• To assess functional outcomes for patients on celecoxib compared to placebo 
Secondary Endpoints: Current activity level and swallowing capabilities, including food 
and liquid variety and assessment of G tube utilization. 
• To assess the effect of celecoxib therapy on Quality of Life (QoL) compared to placebo.  
Secondary Endpoint: completion of quality of life questionnaires EORTC QLQ-H&N43 
and MDASI-HN as per the schedule of events. 
• To assess the average number of treatment days missed during adjuvant radiation for 
patients on celecoxib compared to placebo.   
Secondary Endpoint: the number of treatment days missed or delayed during adjuvant 
radiation.  
2 
BACKGROUND 
2.1 
Hypothesis 
Using celecoxib comprehensively throughout treatment starting 1 to 7 days prior to surgery 
to the end of adjuvant radiation, will improve pain control, reduce opioid use, and improve 
QOL and functional status, leading to improved compliance with adjuvant radiation which is 
known to correlate with improved survival outcomes.  


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2.2 
Head and Neck Cancers 
Head and neck cancers (HNC) are defined as squamous cell carcinomas originating in the 
mucosal surfaces of the upper aerodigestive tract: the oral cavity, pharynx, larynx, nasal 
cavity, paranasal sinuses, and salivary glands.10 In the United States, an estimated 51,540 new 
cases were diagnosed in 2018 with a five-year survival rate of 64.8%.9 Successful treatment 
requires a multidisciplinary approach often combining surgery, radiation therapy, and 
chemotherapy. 30-40% of patients present with early-stage (stage I or II) disease and can 
undergo successful surgery and/or external beam or brachytherapy radiation therapy and 
experience a 70-90% overall five-year survival rate. However, patients with locoregionally 
advanced disease (stage III/IV) require a combined modality approach often incorporating 
surgery and postoperative radiation therapy with or without chemotherapy, with reduced 
overall five-year survival rates of 40-60%. 
2.3 
The Effect of Pain Control on Overall Survival and Study Objective Rational 
Currently, pain control throughout therapy is a major issue for patients with advanced-stage 
head and neck cancers (sinonasal, oral cavity, oropharynx, larynx, and hypopharynx) 
undergoing primary surgical resection and then adjuvant therapy. In order to maximize 
survival outcomes, patients treated with surgery and then adjuvant therapy (ie: radiation or 
chemoradiation) need to start adjuvant therapy within 8 weeks or approximately 60 days after 
surgery and need to minimize delays or gaps in adjuvant treatments. A recent NCDB study in 
this patient population demonstrated 5-year OS differences of 67% versus 52% in these 2 
cohorts (initiation of adjuvant therapy <50 days versus >50 days).1 This has been confirmed 
in a systematic review and other evaluations of large aggregated national datasets.2-5 Based 
on our experience and retrospective examination, we have identified that the leading culprit 
in these cases is pain management and functional issues. These issues contribute to increased 
narcotic utilization and reduced recovery after surgery with weight loss, poor oral intake, and 
reduced overall strength, resulting in delays in initiating adjuvant therapy. This post-surgical 
condition of the patient is also a significant contributor to missed treatments once adjuvant 
therapy has begun. Based on retrospective examination, it is estimated a significant percentage 
of patients do not achieve the recommended rate of compliance.   
We recently demonstrated with the addition of celecoxib (a selective COX-2 inhibitor 
NSAID) in our immediate post-operative pain management pathway that we achieved a 
statistically significant and clinically meaningful decrease in the amount of opioids utilized 
while as an inpatient.8 The primary outcome of compliance will be analyzed by the average 
number of days from surgery to the initiation of radiation and adjuvant therapy. In our 
historical cohort of over 100 recent patients, the mean was 72.8 days (Standard Deviation 16.2 
days). Our goal with this intervention is to reduce the days from surgery to radiation to 
57.2days or less because recent population-level data reaffirmed this milestone as significantly 
improving survival outcomes. Secondary outcomes are subjective pain scores, narcotic use, 
functional outcomes, and patient QOL and satisfaction with pain control throughout treatment, 
as well as the average number of days missed during adjuvant therapy. We will study these 
issues prospectively with monitoring progression through treatment, standardized pain 
questionnaires, pain score monitoring at each phase through treatment, patient satisfaction 
with pain, monitoring opioid use, and QOL and functional assessments. We strongly feel that 


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we can achieve a significant improvement in compliance with adjuvant radiation after surgery 
and will investigate this medication to achieve that end, which we hope will translate into 
improved disease-specific and overall survival for our cancer patients. 
2.4 
Disease group rationale 
Patients with advanced-stage head and neck cancers have significant challenges with pain 
control, opioid utilization, and achieving completion of treatment in a timely fashion. A recent 
examination of the national cancer database of this population demonstrated that 42% of 
patients do not start adjuvant radiation within the recommended timeframe (<50 after surgery) 
and examination of our historical cohorts showed similar findings. Therefore this disease 
group is an ideal cohort to seek to optimize these parameters, improve pain and quality of life, 
improve timely cancer care, and improve survival outcomes for our patients.   
2.5 
Drug selection rationale 
Celecoxib has been shown in randomized controlled trials and meta-analysis to improve pain 
control, decrease opioid use, and improve functional status in patients with chronic 
inflammatory conditions, such as osteoarthritis and rheumatoid arthritis, thus is a good 
candidate for our patients.6 Decreasing opioid utilization after surgery is clinically significant, 
as the CDC has shown that dosages of opioids at 50 MME (morphine milligram equivalents) 
or more per day doubles the risk of overdose and other opioid-related complications.7 
2.6 
Clinical experience 
A retrospective matched cohort study of 147 patients who had undergone head and neck 
cancer surgery with free tissue reconstruction were separated into groups based on celecoxib 
use in the postoperative setting. Groups were matched by stage and cancer site resulting in 
102 patients included, 51 celecoxib and 51 control. Postoperative use of opioids was recorded 
per patient per day and group mean morphine milligram equivalent was compared. Use of 
celecoxib was associated with a mean decrease in oral opioid use of 9.9 mg per day (95% CI, 
-1.2-21.1), an IV mean difference of 3.9 mg per day (95% CI, 1.0-6.8), and a total mean 
difference of 14 mg per day. The 51 patients who received celecoxib after surgery had a 
significant decrease in opioid requirements compared to the control group. This is a clinically 
meaningful difference in decreasing opioid utilization after surgery because the CDC has 
shown that dosages of opioids at 50 MME (morphine milligram equivalents) or more per day 
doubles the risk of overdose and other opioid-related complications.7 
3 
DRUG INFORMATION 
3.1 
Celecoxib  
3.1.1 Pharmacology 
Celecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, 
analgesic, and antipyretic activities in animal models. The mechanism of action is 
believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of 


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cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, celecoxib does 
not inhibit the cyclooxygenase-1 (COX-1) isoenzyme.  
3.1.2 Physical and Chemical Properties 
Celecoxib is chemically designated as 4-[5-(4 methylphenyl)- 3-(trifluoromethyl)-1H-
pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The empirical 
formula is C17H14F3N3O2S, and the molecular weight is 381.38. 
Peak plasma levels are reached 3 hours after fasted oral celecoxib dosing with a half-life 
of 11 hours. Under fasting conditions, both peak plasma levels (Cmax) and area under 
the curve (AUC) are roughly dose-proportional up to 200 mg BID; at higher doses there 
are less than proportional increases in Cmax and AUC. With multiple dosing, steady-state 
conditions are reached by day five with extensive distribution into tissues and about 97% 
of the drug protein bound.  
Celecoxib metabolism is primarily mediated via CYP2C9 ultimately leading to hepatic 
elimination. Three metabolites, a primary alcohol, the corresponding carboxylic acid, and 
its glucuronide conjugate, have been identified in human plasma. These metabolites are 
inactive as COX-1 or COX-2 inhibitors. 
3.1.3 Pharmaceutical Properties and Formulation  
Celecoxib will be compounded by Investigational Drug Services at Huntsman Cancer 
Institute into an oral suspension containing either 100 mg or 200 mg of celecoxib, 
together with inactive ingredients including croscarmellose sodium, edible inks, gelatin, 
lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate.  
Placebo will be identical in appearance to match active counterparts. 
3.1.4 Clinical Safety 
Celecoxib has been shown to be safe and efficacious in many patient populations and has 
demonstrated acceptable tolerance. Celecoxib use is contraindicated in patients with renal 
and hepatic impairment. Celecoxib use can increase the risk of serious gastrointestinal 
adverse events including bleeding, ulceration, and perforation of the stomach or intestines 
and older patients with a history of peptic ulcer disease and/or GI bleeding are at higher 
risk for developing serious GI events. Adverse reactions occurring in ≥ 2% of patients 
receiving celecoxib from 12 controlled studies in patients with osteoarthritis and 
rheumatoid arthritis are included in Table 1.  
Table 1: Adverse events in ≥ 2% of osteoarthritis and rheumatoid arthritis patients 
Adverse Event 
Frequency 
Gastrointestinal: 
Abdominal Pain 
Diarrhea 
Dyspepsia 
 
4.1%  
5.6%  
8.8%  


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Flatulence 
Nausea 
2.2% 
3.5% 
Body as a whole:  
Back Pain  
Peripheral Edema  
Injury-Accidental 
 
2.8%  
2.1%  
2.9% 
Central, Peripheral Nervous system: 
Dizziness  
Headache 
 
2.0%  
15.8% 
Psychiatric: 
Insomnia 
 
2.3% 
Respiratory: 
Pharyngitis  
Rhinitis  
Sinusitis  
Upper Respiratory Infection 
 
2.3%  
2.0%  
5.0%  
8.1% 
Skin:  
Rash 
 
2.2% 
 
4 
STUDY DESIGN 
4.1 
Description 
This study is a randomized, double-blind, placebo-controlled, pilot study in which patients 
will be randomized to receive comprehensive treatment with placebo or celecoxib 200mg 
twice daily. 
4.2 
Randomization and Blinding 
Patients who meet all criteria for enrollment will be randomly assigned to receive celecoxib 
(Arm 1) or placebo (Arm 2). Patients will be randomized through the OnCore system in a 1:1 
ratio between Arm 1 and Arm 2 and stratified by treating provider. 
To preserve the blind, only the Investigational Drug Services Pharmacy personnel at 
Huntsman Cancer Institute will know treatment assignments. Access to unblinded 
data/documents will be controlled by the pharmacy to ensure the blind is maintained. Every 
effort will be made to blind both the patient and the investigator to the treatment assignment, 
but the inadvertent unblinding of a patient may occur. If an investigator, site personnel, or 
patient is inadvertently unblinded, the unblinding will not be sufficient cause for the patient 
to be discontinued from study treatment or excluded from study analyses. 


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In the case of an emergency, the investigator has the sole responsibility for determining if the 
unblinding of a patient’s treatment assignment is warranted. Patient safety must always be the 
first consideration in making such a determination. If the treating investigator decides that 
unblinding is warranted, the investigator should contact the investigational pharmacy for 
treatment assignment. 
4.3 
Number of Patients 
A total of 40 evaluable patients will be enrolled in this study with 20 patients randomized to 
each arm: 20 patients will receive celecoxib and 20 patients will receive placebo. It is expected 
that 25% of patients who start study therapy and undergo surgery will not start adjuvant 
radiation. Patients who do not start adjuvant radiation will be replaced. Taking this into 
account, it is estimated that 53 patients will be randomized to result in 40 evaluable patients.  
4.4 
Number of Study Centers 
This will be a single-center trial run at the Huntsman Cancer Institute at the University of 
Utah. 
4.5 
Study Duration  
Based on current volumes, it is proposed that this study can be completed within 2 years of 
initiation.  
 
 


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5 
ELIGIBILITY CRITERIA 
This eligibility checklist is used to determine patient eligibility and filed with the enrolling 
investigator’s signature in the patient research chart.  
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
5.1 
Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
5.1.1 _____ Male or female subject aged ≥ 18 years. 
5.1.2 _____ Advanced-stage (overall stage III and IV) head and neck cancers (sinonasal 
oral cavity, oropharynx, larynx, and hypopharynx) undergoing surgical resection 
and then adjuvant radiation. Primary and recurrence cases are acceptable. 
5.1.3 _____ Karnofsky Performance Status of ≥ 70. 
5.1.4 _____ Adequate organ function demonstrated on labs drawn during the screening 
window and defined as:  
• Hematologic:  
o Hemoglobin ≥ 10 g/dL 
• Hepatic:   
o Total Bilirubin ≤ 2 mg/dL 
o AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN 
o Albumin > 3.5 g/dL 
• Renal:  
o eGFR ≥ 30 mL/min/1.73m2 or creatinine clearance ≥ 30 mL/min by Cockcroft-
Gault:  
 Males: 
(140−𝑎𝑎𝑎𝑎𝑎𝑎)×𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡[𝑘𝑘𝑘𝑘]
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 ቂ𝑚𝑚𝑚𝑚
𝑑𝑑𝑑𝑑ቃ×72 
 Females: ቆ
(140−𝑎𝑎𝑎𝑎𝑎𝑎)×𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡[𝑘𝑘𝑘𝑘]
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 ቂ𝑚𝑚𝑚𝑚
𝑑𝑑𝑑𝑑ቃ×72ቇ× 0.85  
o Serum potassium within normal limits.  


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5.1.5 _____ Negative serum or urine pregnancy test at screening for women of 
childbearing potential. 
5.1.6 _____ Highly effective contraception for female subjects throughout the study 
and for at least 5 days after the last dose of study therapy if the risk of conception 
exists (see section 8.6). 
5.1.7 _____ Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to 
any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on 
supportive therapy. 
5.1.8 _____ Willing to maintain a diary of all opioids used during the trial for the 
treatment of pain. 
5.1.9 _____ Able to provide informed consent and willing to sign an approved consent 
form that conforms to federal and institutional guidelines. 
5.1.10 _____ Subject has verbally confirmed they are willing to complete adjuvant 
radiation therapy if recommended after surgery per protocol. 
5.1.11 _____ Adjuvant radiation has been recommended by the institutional treatment 
planning conference with the best available data, but will be confirmed based on 
final surgical pathology.  
 
5.2 
Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 


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5.2.1 _____ Known distant metastatic disease or the tumor is deemed not surgically 
resectable. 
5.2.2 _____ Established in a pain management clinic or has taken opioids regularly for 
≥ 6 months. 
5.2.3 _____ Known or suspected to be poor CYP2C9 metabolizers based on previous 
history/experience with other CYP2C9 substrates (such as warfarin, phenytoin). 
5.2.4 _____ Known hypersensitivity to celecoxib, aspirin, other NSAIDs, or 
sulfonamides. 
5.2.5 _____ Uncontrolled hypertension defined as blood pressure (BP) > 150 mmHg 
systolic or > 90 mmHg diastolic on three consecutive reads, taken in one sitting, 
despite optimal antihypertensive treatment. 
5.2.6 _____ Patients with a known history of the following: 
- 
Cerebrovascular accident (CVA), stroke, or cardiovascular thrombotic 
events (e.g. acute myocardial infarction). 
- 
Chronic heart failure. 
- 
Gastrointestinal bleeding, ulceration, peptic ulcer disease, or perforation of 
the stomach or intestines. 
- 
Aspirin-sensitive asthma. 
- 
Chronic kidney disease, stage 4 or 5.  
5.2.7 _____ Patients with a prior or concurrent malignancy whose natural history or 
treatment has the potential to interfere with the safety or efficacy assessment of 
the investigational regimen  
5.2.8 _____ The subject has an uncontrolled, significant intercurrent or recent illness 
requiring systemic therapy, would preclude safe study participation, or is deemed 
clinically significant by the investigator. 
5.2.9 _____ Known HIV infection with a detectable viral load within 6 months of the 
anticipated start of treatment. 
Note: Patients on effective antiretroviral therapy with an undetectable viral load 
within 6 months of the anticipated start of treatment are eligible for this trial. 
5.2.10 _____ Known chronic hepatitis B virus (HBV) or hepatitis C virus infection with 
a detectable viral load.  
Note: Patients with an undetectable HBV viral load on appropriate suppressive 
therapy are eligible. Patients with an undetectable HCV viral load on appropriate 
treatment are eligible. 


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5.2.11 ______ Subjects taking prohibited medications as described in Section 7.3.2. A 
washout period of prohibited medications for a period of at least 5 half-lives or as 
clinically indicated should occur prior to the start of treatment. 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto this 
study.  
______________________________ 
 
_________ 
_______ 
Investigator Signature  
 
 
 
Date  
Time 
 
 
 


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5.3 
Recruitment Strategies 
Potential patients will be identified by Head and Neck Investigators in the setting of their 
outpatient clinics. 
6 
STRATIFICATION FACTORS 
At the time of randomization, patients will be stratified by the treating provider. 
7 
TREATMENT PLAN 
7.1 
Administration Schedule 
Celecoxib 200 mg/20 mL or placebo will be taken orally or by feeding tube twice daily (every 
12 hours ± 2 hours) without regard to food. Patients will complete 1 to 7 day(s) of study 
therapy prior to surgery and continue regular dosing until the completion of radiation therapy. 
7.2 
Celecoxib/ Placebo 
7.2.1 How Supplied, Stored, Packaged and Labeled 
Celecoxib/placebo will be compounded by Investigational Drug Services at Huntsman 
Cancer Institute into an oral suspension. The content of celecoxib will be suspended with 
Ora-Blend, a suspending and flavoring agent, as described by Donnelly et al to a final 
concentration of 10 mg/mL. 11 The suspension will be stored and dispensed in amber PVC 
bottles. 
Placebo will be provided as assigned and will be identical in appearance to match their 
active counterparts. 
Celecoxib/placebo will be kept at the Huntsman Cancer Institute Investigational 
Pharmacy in accordance with Good Clinical Practice (GCP) and GMP requirements and 
will be inaccessible to unauthorized personnel. Celecoxib/placebo suspension is stable 
for 93 days when refrigerated or stored at room temperature. The suspension should be 
stored in a well-ventilated area at 5-25°C. Investigators or designated personnel should 
check the temperature of the storage room daily and ensure that temperature monitoring 
devices are working correctly. 
7.2.2 Preparation and Administration 
Subjects will be provided enough celecoxib to  last until their next scheduled visit. 
Celecoxib 200 mg/20mL should be administered orally or by feeding tube without regard 
to food twice daily (every 12 hours ± 2 hours). It should not be coadministered with 
aluminum or magnesium-containing antacids. Subjects should not take extra medication 
for any reason nor should they re-administer in the case of vomiting after administration. 
If a dose is missed outside of the dosing window, it should not be made up. 


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7.2.3 Accountability and Compliance 
Drug compliance will be recorded by patients on the drug diary (see Appendix 2). A member 
of the study team will review patient drug compliance at the end of treatment for each cycle 
and provide patient re-education as required. At the discretion of the principal investigator, 
a subject may be discontinued from the trial for non-compliance with study visits or study 
drug. 
Excess or unused study drug should be returned to the investigative site, for accounting and 
destroyed in accordance with GCP after drug accountability has been performed. 
7.3 
Concomitant Medications and Therapies 
7.3.1 Allowed Therapy 
Any medication which is considered necessary for a subject’s welfare is permitted and 
may be given at the discretion of the investigator. Medications for the treatment of 
underlying disease and symptomatic treatment of adverse events are permitted. 
Exceptions are listed in the section below. 
7.3.2 Prohibited Therapy 
Prohibited therapies that are necessary for patient health and wellbeing may be allowed 
only after discussion with and approval from the principal investigator and the medical 
monitor (and the DSMC when applicable). 
Celecoxib is primarily metabolized by CYP2C9 in the liver. Co-administration of 
celecoxib with drugs that are known to inhibit CYP2C9 should be done with caution. 
Significant interactions may occur when celecoxib is administered together with drugs 
that inhibit CYP2C9. In vitro studies also indicate that celecoxib is an inhibitor of 
CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that 
are metabolized by CYP2D6. 
In addition to cautionary use of CYP2C9 inhibitory drugs and those metabolized by 
CYP2D6, the following medications are prohibited while on study therapy unless prior 
approval is obtained: 
• Other NSAIDs (e.g. ibuprofen, naproxen, etc.) 
o Aspirin may be administered post-surgery but should be administered with 
caution.  
• Anticoagulants (e.g., warfarin) 
• Known inhibitors of CYP2C9 (e.g., fluconazole) 
• Warfarin 
• Lithium 
• Thiazides, loop diuretics, ACE-inhibitors, or angiotensin II antagonists 


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Celecoxib should not be coadministered with aluminum- or magnesium-containing antacids, 
but such antacids may be taken two hours after celecoxib dosing. 
7.3.3 Duration of Therapy 
Subjects will receive twice-daily dosing of 200 mg celecoxib three to seven days prior to 
surgery and continue twice-daily dosing until the completion of adjuvant radiation. The total 
duration of treatment should be approximately four to six months.  
Subjects will receive celecoxib treatment until intolerable toxicity, completion of adjuvant 
radiation, or six months. 
7.3.4 Criteria for discontinuation of study treatment  
Patients may withdraw from treatment or the study overall at any time at their own 
request, or they may be withdrawn at the discretion of the Investigator or Sponsor for 
safety, behavioral reasons, or the inability of the patient to comply with the protocol-
required schedule of study visits or procedures. In addition to the drug-specific 
discontinuation criteria listed in Dose Modification Section and the Dose Limiting 
Toxicity Section, the following will result in treatment discontinuation: 
• Disease progression 
• Unacceptable Toxicity 
• Subject withdraws consent from the study treatment and/or study procedures.   
• Non-compliance as defined as having missed > 40% of required celecoxib doses. 
• Dose hold ≥ 14 days unless resuming treatment is judged by the Investigator to 
be in the best interest of the patient. 
• Does not require adjuvant radiation. 
• Pregnancy 
• Significant protocol violation 
• The patient refused further treatment 
• Study terminated by investigator sponsor 
• Lost to follow-up 
• Death 
7.3.5 Criteria for withdrawal from the study 
Subjects will be taken off study for the following: 
• Completed study follow-up period 
• Disease progression as assessed by the treating investigator. 
• The necessity for prohibited treatment (as defined in section 6.4) of sufficient dose 
and duration to confound the study results as assessed by the treating investigator. 


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• If, in the investigator's opinion, the continuation of the trial would be harmful to 
the subject's well-being. 
• Development of intercurrent illness or situation which would, in the judgment of 
the investigator, significantly affect assessments of clinical status and trial 
endpoints. 
• Participant requests to be withdrawn from the study 
• Death 
• Screen failure 
8 
TOXICITIES AND DOSE MODIFICATION 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for adverse event and serious adverse event reporting. 
8.1 
Dose Modifications 
Every effort should be made to administer each investigational product at the planned dose 
and schedule. In the event of study treatment toxicity, dosing may be interrupted, delayed 
and/or reduced, only as described in the dose modifications section. In the event of multiple 
toxicities, treatment/dose modifications should be based on the worst toxicity observed 
(CTCAE v5.0) and/or the most conservative recommendation for any given toxicity. Patients 
are to be instructed to notify Investigators at the first occurrence of any adverse symptom.  
All dose modifications must be clearly documented in the patient's medical chart and in the 
CRF. Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the Investigator. 
8.2 
Dose Interruptions 
Dose interruptions for study treatment-related AEs are allowed as per the recommendations 
provided in Section 8.4. Doses of celecoxib/placebo that were not administered due to toxicity 
will not be replaced. In addition to dose interruption, the need for a dose reduction at the time 
of treatment resumption should also be considered based on recommendations provided in 
Section 8.4. 
Dose interruptions of more than 14 days will result in permanent discontinuation unless 
resuming treatment is judged by the Investigator to be in the best interest of the patient. 
8.3 
Dose Reductions 
Following dosing interruption due to toxicity, the celecoxib dose may need to be resumed at 
a reduced dose as per the recommendations provided in Section 8.4. Dose reduction should 
proceed by decreasing the administered dose by one dose level per table 2. 
Once the study treatment has been reduced for a given patient, all subsequent cycles should 
be administered at that dose level. Intra-patient dose re-escalation is not allowed. 


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Table 2: Dose Level Reduction  
Agent 
Initial Dose 
Level -1 
Celecoxib/placebo 200 mg twice daily 
100 mg twice daily 
8.4 
Adverse Event Management 
General treatment modifications for study therapy are provided in table 3 for adverse events 
that are deemed definitely, probably or possibly related to study therapy. Study therapy should 
be discontinued upon the second occurrence of an adverse event requiring a dose hold and 
reduction.   
Table 3: Adverse Event Management Guidelines 
Adverse Event 
Grade 
First Occurrence 
Hematology 
Hemoglobin  
Grade ≥ 3 
Hold study therapy until recovery to grade 1 and 
reinitiate at a dose level reduction. 
Hepato-Biliary 
AST or ALT increase or 
bilirubin increase 
Grade ≥ 3 
Hold study therapy until recovery to grade 1 and 
reinitiate at a dose level reduction. 
Renal 
Serum creatinine   
Grade ≥ 2 
Hold study therapy until recovery to grade 1 and 
reinitiate at a dose level reduction. 
Hyperkalemia 
Grade ≥ 2  Hold study therapy until recovery to grade 1 and 
reinitiate at a dose level reduction. 
Skin Reactions 
Rash  
Grade ≥ 2 
Hold study therapy until recovery to grade 1 and 
reinitiate at a dose level reduction. 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
Any 
Discontinue study therapy 


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Gastro-intestinal 
Nausea or vomiting 
lasting ≥ 7 days despite 
optimal anti-emetic 
therapy  
Grade ≥ 2 
Hold study therapy until recovery to grade 1 and 
reinitiate at a dose level reduction. 
Diarrhea  
Grade ≤ 2 
Continue study therapy at the current dose level and 
initiate 
appropriate 
antidiarrheal 
treatment, 
hydration, and attention to diet. Maintain close 
monitoring. 
Grade ≥ 3 
Hold study therapy until recovery to grade 1 and 
reinitiate at a dose level reduction. 
GI Ulceration, Bleeding or 
Perforation 
Any 
Discontinue study therapy 
Cardiovascular 
Hypertension 
Grade ≥ 3 
Hold 
until 
resolution 
and 
start 
appropriate 
antihypertensive therapy. Once hypertension has 
resolved to baseline or grade ≤ 1, reinitiate celecoxib 
at one dose reduction. 
Cardiovascular thrombotic 
event (e.g. myocardial 
infarction with elevated 
troponin or stroke) 
Any 
Discontinue study therapy 
Other 
Clinically significant, 
non-hematological 
adverse events attributed 
to the study drug. 
Grade ≥ 3 
Hold study therapy until recovery to grade 1 and 
reinitiate at a dose level reduction. 
 
8.5 
Supportive Care 
All supportive measures consistent with optimal patient care may be given throughout the 
study. 


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8.6 
Contraception 
Women of childbearing potential are required to use one method of appropriate contraception 
during trial participation and 5 days after the last dose of study therapy. Childbearing potential 
is defined as those who have not been surgically sterilized or have not been free from menses 
for at least 1 year. Appropriate methods of birth controls for women include oral or implanted 
contraceptives, intrauterine device (IUD), diaphragm with spermicide, cervical cap, 
abstinence, use of a condom by the sexual partner or sterile sexual partner and also based on 
the judgment of the investigator.  
Acceptable methods of contraception are: 
• Single method (one of the following is acceptable): 
o intrauterine device (IUD) 
o contraceptive rod implanted into the skin 
• Combination method (requires the use of two of the following): 
o diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
o cervical cap with spermicide (nulliparous women only)   
o contraceptive sponge (nulliparous women only)  
o male condom or female condom (cannot be used together) 
o hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
9 
SCHEDULE OF EVENTS 
The Schedule of Events table provides an overview of the protocol visits and procedures. Refer to 
the Study Procedures section of the protocol for detailed information on each assessment required 
for compliance with the protocol. The Investigator may schedule visits (unplanned visits) in 
addition to those listed in the Schedule of Events table in order to conduct evaluations or 
assessments required to protect the wellbeing of the patient. This Schedule of Events will be 
followed for the entire study.


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Table 4: Schedule of Events 
Examination 
Screening1 
Pre-Operation2 
Surgery3 
Post-
Operation4 
5 Weeks Post-
Operation 
Mid Radiation5 
End of 
Treatment6 
Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Eligibility Criteria  
X 
 
 
 
 
 
 
Vital Signs 
X 
 
 
X 
 
X 
X 
Physical Exam7 
X 
 
 
X 
 
X 
X 
Karnofsky 
Performance Status8 
X 
X 
 
X 
 
X 
X 
Functional Oral Intake 
Score 
X 
X 
 
X 
 
X 
X 
Hematology9 
X 
 
 
X 
 
X 
X 
Chemistry10 
X 
 
 
X 
 
X 
X 
Pregnancy Test11 
 
X 
 
 
 
 
 
HIV and Hepatitis 
Serologies12  
X 
 
 
 
 
 
 
Radiation Oncology 
Consultation 
X13 
 
 
 
 
 
 
Surgery 
 
 
X14 
 
 
 
 
Celecoxib/placebo15 
 
X 
 
Questionnaires16 
 
X 
 
X 
 
X 
X 
Pre-treatment 
Questionnaire17 
 
X 
 
 
 
 
 
Analgesic Use 
Record18 
 
X 
 
X 
 
X 
X 
Adverse Events 
 
X 
Concomitant 
Medications 
X 
X 
 
X 
 
X 
X 
Telephone Call or 
Email19 
 
 
 
 
X 
 
 


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1 All screening procedures must be completed ≤ 28 days prior to surgery.  
2 This visit may be combined with Screening if all Pre-Operation visit procedures occur ≤ 14 days prior to surgery. All pre-operation activities must be completed 
prior to starting study therapy. 
3 All procedures must be completed prior to surgery. 
4 Post-operation visit will occur 5 to 30 days after surgery.  
5 Mid-radiation visit will occur 5-35 days after initiation of radiation therapy. 
6 End of treatment visit will occur 1 to 30days after the last treatment of radiation.  
7 Appendix 8: Treating Investigator Patient Assessment Guidance to be filled out by the treating investigator at the time of physical exam. 
8 See Appendix 8: Treating Investigator Patient Assessment Guidance 
9 Hematology to include CBC with platelets and differential.  
10 Chemistry to include a complete metabolic panel (CMP). 
11 All women of child-bearing potential must have a negative pregnancy test 7 days prior to surgery.  
12 Only required if there is a known history of HIV, hepatitis B, or hepatitis C to confirm eligibility. 
13 The radiation oncology consultation should be completed prior to registration if possible.  This will include a discussion of the indications for adjuvant radiation 
treatment, a typical treatment course, and the anticipated/possible side effects so the subjects know what to expect if enrolled on trial.  
14 Prior to surgery, the surgical team (physicians, nursing staff, pharmacy, etc.) will be notified about the patients involvement in the trial to ensure standard of care 
celecoxib and other prohibited therapies are not inadvertently administered.  
15 Patients will complete 1 to 7 days of study therapy prior to surgery and continue twice daily dosing until the last radiation session.  
16 Appendix 3: MDASI Head and Neck Cancer, Appendix 4: EORTC QLQ-H&N43, Appendix 5: Pain Satisfaction Questionnaire, and Appendix 7: Visual Analog 
Scale for Pain to be completed within 1 month of the scheduled time-points. 
17 Appendix 6: Pre-treatment Questionnaire to be completed at the pre-operation visit. 
18 Patients will be required to record all opioids taken for pain management on Appendix 4: Pain Management Diary while at home. Diary does not need to be 
maintained during admission post-surgery but should be started when study therapy is started and continue until completion of study therapy. 
19 5 weeks (±7 days) post-operation the study team will contact the patient to review their medication diary, adverse events, and analgesic use record. If not returning 
to the study site at this time point, patients will be asked to fax or scan and email their Patient Dosing Diary and Pain Management Diary use records for the study 
team for review to ensure timely review of study drug compliance.  
 
                                                 


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10 STUDY PROCEDURES 
10.1 
Screening 
For screening procedures see the Schedule of Events and the Assessments Section. Screening 
activities may only begin after a subject has signed consent. All screening activities must take 
place within 28 days prior to surgery unless otherwise noted. 
10.2 
Treatment Period 
Once a subject has completed screening, has been found to be eligible, and has been registered, 
treatment procedures may begin. At the pre-operation visit baseline, questionnaires will be 
completed and study medication will be dispensed. Patients will be instructed not be begin 
study medication until 6 days prior to the date of surgery to ensure 5 full days of twice-daily 
dosing. All pre-operation visit procedures must take place within 14 days prior to surgery 
unless otherwise noted. 
Upon completion of 1 to 7 days of study therapy dosing, patients will undergo head and neck 
surgery as deemed appropriate by the treating investigator. 14 days (± 7 days) after surgery 
patients will return to the clinic and begin arrangements for adjuvant radiation therapy.  
Five to thirty days post-operation every effort should be made to contact the patient to assess 
study drug compliance and adverse events. For patients not returning to the study site during 
this time frame, this contact may occur by phone or email. During this contact the study team 
will check the patient’s Dosing Diary, Pain Management Diary, and adverse events. The 
patient will be asked to scan and email or fax their Dosing Diary and Pain Management Diary 
for assessment of adherence to the study regimen. However, if the patient does not have access 
to equipment to do this or is unwilling, failure to obtain the diaries will not be considered a 
deviation. 
During adjuvant radiation, patients will return to clinic for evaluation (Mid-Radiation visit) 5 
to 30 days after initiating radiation therapy. Patients will be instructed to continue study 
therapy twice-daily dosing until completion of their last radiation treatment. 
See the Schedule of Events and the Assessments Section for treatment period procedures. 
10.3 
End of Treatment 
Upon discontinuation of study treatment, an End of Treatment visit will occur. The end of 
treatment visit will occur 1 to 30 days after the last radiation treatment or after patient 
discontinues treatment. For End of Treatment procedures see the Schedule of Events and the 
Assessments Section. 
11 
STUDY ASSESSMENTS 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator that may make it unfeasible to perform 
the test. In these cases, the Investigator will take all steps necessary to ensure the safety and well-


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being of the patient. When a protocol-required test cannot be performed, the Investigator will 
document the reason for this and any corrective and preventive actions that he or she has taken to 
ensure that normal processes are adhered to as soon as possible. 
11.1 
Physical Examinations and Vital Signs 
Patients will have physical examinations to include major body systems, vital signs, 
assessment of Karnofsky performance status (see Appendix 8), Functional Oral Intake Score 
(Table 5), weight and height (height will be measured at screening only) at the time points 
described in the Schedule of Events. If necessary to facilitate scheduling, physical exam may 
occur one day prior to study treatment. Appendix 8: Treating Investigator Patient Assessment 
Guidance is to be filled out by the treating investigator at every physical exam. 
Vital signs, to include blood pressure, pulse rate, and temperature will be also recorded at the 
time points described in the Schedule of Events.  
Table 5: Functional Oral Intake Scale 
Score 
Performance 
Implication 
Deficit 
1 
Aspirates saliva Nothing by mouth 
Profound 
2 
Tube dependent Nothing by mouth/minimal trials 
Profound 
3 
Tube dependent Full trials by mouth 
Severe 
4 
Total Oral 
Single texture trials 
Moderate 
5 
Total Oral 
Multiple texture trials 
Mild  
6 
Total Oral 
By mouth/ restrictions 
Minimal  
7 
Regular diet 
By mouth/ no restrictions 
Normal 
11.2 
Adverse Events 
Adverse events experienced during trial participation will be collected per the Schedule of 
Events and Adverse Events Section. Each study participant will be questioned about the 
occurrence of adverse events in a non-leading manner. Should the treating investigator feel 
that the adverse event is attributed to study therapy, then dose modification guidelines in the 
Dose Modification Section will be followed.  
11.3 
Laboratory Assessments 
Samples for all laboratory assessments will be drawn at the time points indicated in the 
Schedule of Events and when clinically indicated. Laboratory tests may be performed up to 3 
days prior to the scheduled clinic visit. All safety laboratory analyses will be performed by 
the local laboratory for each study center. All safety laboratory assessments must be reviewed 


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by the treating investigator. When applicable, results from the pregnancy test must also be 
available for review prior to dosing.  
Table 6: Laboratory Assessments 
Laboratory Assessments 
CBC with Platelet Count and Differential 
• 
White Blood Cell Count 
• 
Hemoglobin 
• 
Platelets 
• 
Absolute Neutrophil Count 
• 
Absolute Lymphocytes 
Complete Metabolic Panel (Chemistry) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Carbon Dioxide 
• 
Alkaline Phosphatase 
• 
Aspartate Aminotransferase 
• 
Alanine Aminotransferase 
• 
Urea Nitrogen 
• 
Glucose 
• 
Creatinine 
• 
Calcium 
• 
Protein 
• 
Albumin 
• 
Bilirubin 
Pregnancy 
• 
Beta-hCG Qualitative Urine or Serum 
11.4 
Analgesic Use Record 
All patients will be required to keep a diary of all opioids used for pain management during 
the trial. Patients should be instructed to record all opioid use from the start of study therapy 
to the end of study therapy. This information will be converted to Oral Morphine Equivalents 
(OME) and recorded in the eCRF. 
12 CRITERIA FOR EVALUATION AND ENDPOINT 
12.1 
Primary Objective 
The number of days from surgery to the initiation of adjuvant radiation will be retrospectively 
collected and compared between Arm 1 and Arm 2. The day of surgery will be considered 
day 0 and the number of days will be counted until the first dose of adjuvant radiation.  


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12.2 
Secondary Objectives 
12.2.1 Safety 
Routine safety will be evaluated from the results of reported signs and symptoms during 
study visits. Safety will be evaluated from scheduled physical examinations, vital sign 
measurements, and clinical laboratory test results collected at the participant’s visits  
Physical Examination 
Complete and symptom-directed physical examinations will be performed by a licensed 
physician (or physician’s assistant or nurse practitioner). 
Vital Signs 
Vital signs will include blood pressure, respiratory rate, pulse rate, and temperature.  
Safety Laboratory Determinations 
Laboratory evaluations will be performed as noted in the Schedule of Events. 
12.2.2 Pain Control and Management 
Pain control and management will be compared between Arm 1 and Arm 2 and will be 
gauged through: 
o Patient-reported subjective pain scores will be recorded on the visual analog scale 
of pain intensity averaged over a week at rest, with a swallow, and with a cough.  
o Questionnaires focused on patient satisfaction with pain control.  
o Narcotic consumption in daily total morphine equivalents averaged over a week 
collected from patient recorded opioid use throughout study therapy. 
12.2.3 Functional Outcome 
Functional outcomes will be compared between Arm 1 and Arm 2. Activity level will be 
assessed utilizing Karnofsky Performance Status and the use of G tube (yes or no) will 
be noted at every study visit. Patient-reported quality of life will be assessed by QLQ-
H&N43 as indicated in the Schedule of Events. Swallowing capabilities, including food 
and liquid variety, will be captured through the use of a 7-point, Functional Oral Intake 
Scale as assessed by the treating investigator.  
The number of days of adjuvant radiation missed or delayed will be retrospectively 
collected and compared between Arm 1 and Arm 2. Every day that treatment is delayed 
will be counted until the resumption of therapy. 
12.3 
Stopping Rules 
While an interim analysis is not planned for this trial, continual safety monitoring will be 
provided by the DSMC. The study will be stopped if at any time the following combination 
of conditions occurs, which is: at least 2 patients undergoing study therapy experience grade 


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≥ 3 toxicities related to study drug resulting in discontinuation, and the proportion of patients 
experiencing these toxicities exceeds 15%. With this rule, if the true proportion of patients 
experiencing these toxicities is 2%, which is considered acceptable, the probability of stopping 
accrual is 0.03. If the true proportion of patients experiencing these toxicities is 20%, which 
is considered unacceptable, the probability of stopping accrual is 0.88.   
13 STATISTICAL CONSIDERATIONS 
13.1 
Statistical hypothesis 
We will use a mixed-effects regression model that accounts for clustering (patients nested 
within providers) to compare the average number of days from surgery to the initiation of 
radiation between treatment and control groups. We hypothesize that utilization of study 
therapy will significantly reduce the average number of days to initiation of adjuvant radiation. 
13.2 
Sample size determination 
The sample size calculation was based on the current average number of days to adjuvant 
radiation in our patients with advanced-stage head and neck cancer, 72.8 days (Standard 
Deviation 16.2 days) based on the most recent 100 patients that fit criteria. Our goal is to 
reduce the current average number of days to adjuvant radiation down to 57.2days since this 
has been shown to improve survival. 
Assuming Group A mean =72, Group B mean = 57.2, and the common SD =16.2, a two 
sample t-test with 20 patients in each group will provide 80% power with an alpha = 0.05. 
Note that the estimated SD = 16.2 days includes variation by provided as well as random 
variation and thus the estimated power is likely to be conservative as control of provider 
variation using a mixed-effects model should provide additional power.  
13.2.1 Statistical justification for change in hypothesis 
The sample size calculation was modified due to an interim review with the clinical trials 
team, the investigators, and the safety and monitoring committee.  It was determined by 
expert opinion and previously established data, that a reduced group B mean was 
clinically reasonable based on similar studies and prior results seen in similar situations, 
and this results in a reduced sample size necessary to achieve 80% power.   
13.3 
Population for analyses 
13.3.1 Evaluable for toxicity 
Subjects who have taken one dose of study therapy will be evaluable for toxicity.  
13.3.2 Evaluable for the primary endpoint 
Subjects who have completed study therapy lead-in, undergone surgery, and received one 
treatment of adjuvant radiation will be evaluable for the primary endpoint. Patients who 
do not start adjuvant radiation will be replaced.  


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13.4 
Statistical Analyses 
Appropriate descriptive statistics will be reported for all study variables, stratified by 
treatment arm. These will include mean, standard deviation and 95% confidence interval for 
continuous study variables. For categorical study variables the descriptive statistics will 
include counts, proportions and 95% binomial confidence intervals.  
13.4.1 Primary endpoint 
The primary endpoint is the number of days from surgery to adjuvant chemotherapy. A 
Gaussian mixed effects regression model will be used to compare the average number of 
days from surgery to the initiation of radiation between treatment and control groups. The 
model will contain fixed effects for treatment arm and provider and a nested random 
effect for patient within provider. The mean difference between treatment groups, two-
sided p-value and 95% confidence interval will be calculated from the model. 
13.4.2 Secondary endpoint 
The secondary endpoints fall into two categories for statistical analysis:  
A. Opioid use, subjective pain score, functional assessment of swallow, number of 
treatment days missed or delayed, and quality of life questionnaire (EORTC 
QLQ-H&N43 and MDASI-HN) individual items and summary scales. 
Each of the endpoint variables in Category A will be analyzed using a Gaussian 
mixed effects regression model. The model will contain fixed effects for treatment 
arm and provider and a nested random effect for patient within provider. The mean 
difference between treatment groups and a 95% confidence interval will be 
calculated from the model.  
B. G tube required (Y/N)  
G tube use will be analyzed using a mixed effects logistic regression model. The 
model will contain fixed effects for treatment arm and provider and a nested random 
effect for patient within provider. An odds ratio between treatment groups and a 
95% confidence interval will be calculated from the model. 
14 REGISTRATION GUIDELINES 
Study related screening procedures can only begin once the patient has signed a consent form.  
Patients must meet all of the eligibility requirements listed in Section 5 prior to registration.  
Patients must be registered before receiving any study treatment and must being treatment 
within five working days after registration.  
To register eligible patients on study, complete a Clinical Trials Office Patient Registration Form and 
submit to CTORegistrations@hci.utah.edu. 


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15 DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each patient that provides a 
record of the data generated according to the protocol. CRF’s should be created prior to the study being 
initiated and updated (if applicable) when amendments to the protocol are IRB approved. These forms 
will be completed on an on-going basis during the study. The medical records will be source of 
verification of the data. During the study, the CRFs will be monitored for completeness, accuracy, 
legibility and attention to detail by a member of the Research Compliance Office. The CRFs will be 
completed by the Investigator or a member of the study team as listed on the Delegation of Duties Log. 
The data will be reviewed no less than annually by the Data and Safety Monitoring Committee. The 
Investigator will allow the Data and Safety Monitoring Committee or Research Compliance Office 
personnel access to the patient source documents, clinical supplies dispensing and storage area, and 
study documentation for the above-mentioned purpose. The Investigator further agrees to assist the site 
visitors in their activities. 
Data capture should be restricted to endpoints and relevant patient information required for 
planned manuscripts. 
16 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 
Human Subject Protections 
The study will be conducted in accordance with the appropriate FDA, IRB, ICH GCP and 
other federal and local regulatory requirements, as applicable. Informed consent will be 
obtained from all research participants prior to performing any study procedures using the 
most recent IRB-approved version. All patients must be at least 18 years of age to participate. 
16.2 
Institutional Review 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials (e.g., 
advertisements), and any other applicable patient-facing documents. The investigator should 
also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling 
information. 
The investigator or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according 
to regulatory requirements or institution procedures.  
16.3 
Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman Cancer Institute 
(HCI) to ensure the well-being of patients enrolled on Investigator Initiated Trials that do not 
have an outside monitoring review. The roles and responsibilities of the DSMC are set forth in 
the NCI-approved Data and Safety Monitoring (DSM) plan. The activities of the committee 
include reviewing adverse events (including SAEs), deviations, important medical events, 
significant revisions or amendments to the protocol, and approving cohort/dose escalations. If 
the DSMC and/or the PI have concerns about unexpected safety issues, the study will be 


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stopped and will not be resumed until the issues are resolved. The DSMC also reviews and 
approves audit reports generated by the Research Compliance Office. 
This is a Phase II treatment study with no IND application classified as moderate risk per the 
NCI-approved DSM plan.  
Each moderate risk study may be assigned a physician member of the DSMC as medical 
monitor, or in rare cases, an external medical monitor. The medical monitor will be notified of 
all serious adverse events (SAEs). SAEs occurring in patients treated at HCI or its affiliates 
will also be reviewed by the full DSMC monthly.  
Each moderate-risk study will be assigned a dedicated research compliance officer who will 
monitor the trial. Moderate-risk trials will be monitored by RCO personnel after the first patient 
is enrolled and every six months thereafter during active enrollment. The RCO monitor will 
review the study status and summarize enrollment, toxicities, SAEs, dose escalation, statistical 
endpoints (e.g., stopping rules), deviations, etc. for the full DSMC membership at the regularly 
scheduled meetings. Amendments that increase risk, change dosing, or impact study objectives 
will be reviewed by the DSMC and approved by the PRMC and IRB. Moderate-risk trials will 
be formally reviewed by the DSMC after the first patient is enrolled and then semi-annually 
thereafter.  
An initial audit of moderate-risk studies will be conducted by the RCO approximately one year 
after enrollment begins and annually thereafter. Audits of moderate-risk studies may be 
conducted more frequently as requested by the DSMC, IRB, PRMC, RCO management, or the 
PI. 
16.4 
Adverse Events and Serious Adverse Events  
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for AE and SAE reporting.  
16.4.1 Adverse Events (AEs) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not 
considered to be related to study drug. For the purposes of this study, the terms toxicity 
and adverse event are used interchangeably. Medical conditions/diseases present before 
starting study drug are only considered adverse events if they worsen after starting study 
drug. Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms, are considered clinically significant, or require 
therapy. 
Collection of adverse events will begin from the first dose of study medication and until 
the end of treatment visit (or until a new cancer treatment is initiated).  
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or 
other means, will be collected and recorded and followed as appropriate. 
As far as possible, each adverse event should be evaluated to determine: 


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1. The severity grade based on CTCAE v5.0 (grade 1-5) 
2. Its relationship to the study drug(s) (definite, probable, possible, unlikely, not 
related) 
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken (no action taken; study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse event; 
concomitant medication taken; non-drug therapy given; hospitalization/prolonged 
hospitalization) 
5. Whether it constitutes an SAE 
All adverse events will be treated appropriately. Such treatment may include changes in 
study drug treatment as listed in the dose modification section of this protocol (see section 
8 for guidance). Once an adverse event is detected, it should be followed until its 
resolution, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
Information about common side effects already known about celecoxib are described in 
the Drug Information (section 3) and in the current product insert. This information will 
be included in the patient informed consent and will be discussed with the patient during 
the study as needed. 
All adverse events will be immediately recorded in the patient research chart.  
16.4.2 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded. A serious 
adverse event is an undesirable sign, symptom or medical condition which: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above 
• Causes congenital anomaly or birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
o Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition (procedures such as central line placements, 
paracentesis, pain control) 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since the start of study 
drug 


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o Treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission 
o Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
Collection of serious adverse events will begin after the first dose of study medication 
and end at the end of treatment visit or until a new cancer treatment is initiated, whichever 
happens the soonest. 
Any death from any cause while a patient is receiving treatment on this protocol or up to 
the end of treatment visit, or any death which occurs more than 30 days after protocol 
treatment has ended but which is felt to be treatment related, must be reported. 
Toxicities which fall within the definitions listed above must be reported as an SAE 
regardless if they are felt to be treatment related or not. Toxicities unrelated to treatment 
that do NOT fall within the definitions above, must simply be documented as AEs in the 
patient research chart.  
16.4.3 Reporting Serious Adverse Events 
All serious adverse events should be reported as soon as possible but no later than one business 
day after the Investigator becomes aware. All SAEs must be reported via the HCI CTMS (OnCore) 
and submitted to HCI-RCO@utah.edu. The HCI Clinical Site Monitor will in turn, submit the 
report to the Medical Monitor. The RCO will summarize and present all reported SAEs according 
to the Data and Safety Monitoring Plan at the monthly DSMC meeting. 
At a minimum, initial SAE reports must include a description of the event, assessment of event 
causality, event grade, and the expectedness of the event. Although the Investigator may not know 
all the information at the time of the event, the available information should be reported. An SAE 
follow-up may be submitted at a later date once more information is known. It is required that 
follow-up reports be submitted until the SAE is resolved. 
Follow-Up Information 
It is recommended that follow-up reports be submitted as new information becomes available, 
however, a follow-up report should be submitted within 7 days of knowledge of event resolution. 
Follow-up information will be added to the SAE in OnCore and submitted to the DSMC via RCO.   
16.4.4 FDA Notifications 
Per 21 CRF 600.80 adverse events and serious adverse events will be reported on a MedWatch 
3500A form to the FDA. Reportable events will be reported by the RCO according to the following 
guidelines: 
16.4.4.1 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic (Section A) and suspect medication 
information (Section C & D), the report should include the following information within the Event 
Description (Section B.5) of the MedWatch 3500A form: 
• Protocol number and title description 


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• Description of event, severity, treatment, and outcome if known 
• Supportive laboratory results and diagnostics (Section B.6) 
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
• Expectedness of the event (i.e., expected or unexpected event). 
16.4.4.2 
FDA Reporting Timelines: 
• 7 Calendar Day Report: 
Any event that is fatal or life-threatening, unexpected, and definitely, probably or possibly 
related to study medication will be reported to the FDA by telephone or fax within seven 
calendar days of first learning of the event. 
• 15 Calendar Day Report: 
Any event that is serious, unexpected, and definitely, probably or possibly related to study 
medication will be reported to the FDA in an IND safety report within 15 calendar days of 
first learning of the event. 
In accordance with 21 CFR 312.32, an Analysis of Similar Events should be included in 
the IND Safety Report. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light 
of the previous, similar reports commented on. 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
16.4.5 IRB Notification 
The University of Utah IRB requires any unanticipated problems that may increase the risk to 
research participants be promptly reported. All study-therapy related, unexpected adverse events 
whose nature, severity, or frequency is not consistent with either: 
• The unknown or foreseeable risk of adverse events that are described in the protocol 
related-documents, such as the IRB-approved research protocol, applicable investigator 
brochure, the current IRB-approved informed consent document, and/or other relevant 
sources of information, such as product labeling and package inserts; or 
• The expected natural progression of any underlying disease or condition of the subject(s) 
experiencing the adverse event. 
Adverse events meeting this criterion must be promptly reported to the IRB within 10 business 
days of awareness.  
16.5 
Reporting of Pregnancy  
Although pregnancy is not considered an adverse event, it is the responsibility of investigators 
or their designees to report any pregnancy or lactation in a subject as an SAE. Pregnancies or 


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lactation that occurs during the course of the trial or with 5 days of completing the trial or 
starting another new anticancer therapy, whichever is earlier, must be reported to the DSMC, 
IRB, FDA, and the sponsor as applicable. All subjects who become pregnant must be followed 
to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events.  
16.6 
Protocol Amendments 
Any amendments or administrative changes to an IRB approved protocol will not be initiated 
without submission of an amendment for IRB review and approval.   
These requirements for approval will in no way prevent any immediate action from being 
taken by the investigator in the interests of preserving the safety of all subjects included 
in the trial.  
Any amendments to the protocol that significantly affect the safety of subjects, scope of 
the investigation, or the scientific quality of the study are required to submit the 
amendment for FDA review. 
16.7 
Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and treatment 
plans as outlined in the protocol version submitted and previously approved by the IRB. 
Protocol deviations have the potential to place participants at risk and can also undermine the 
scientific integrity of the study thus jeopardizing the justification for the research. Protocol 
deviations are unplanned and unintentional events.  
Because some protocol deviations pose no conceivable threat to participant safety or scientific 
integrity, reporting is left to the discretion of the PI within the context of the guidelines below. 
The sponsor requires the prompt reporting to HCI RCO of protocol deviations which are: 
• 
Exceptions to eligibility criteria. 
• 
Intended to eliminate apparent immediate hazard to a research participant or  
• 
Harmful (caused harm to participants or others, or place them at increased risk of 
harm - including physical, psychological, economic, or social harm), or  
• 
Possible serious or continued noncompliance  
16.8 
FDA Annual Reporting  
This study is IND exempt therefore there are no annual reporting requirements to the FDA.   
16.9 
Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical Trials 
Reporting Program) by the Clinical Trials Office. 


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16.10 
Record Keeping 
Per 21 CFR 312.57, the Investigator records shall be maintained for a period of 2 years 
following the date a marketing application is approved; or, if no application is filed or the 
application is not approved, until 2 years after the investigation is discontinued and the FDA 
is notified. 
 
 


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17 BIBLIOGRAPHY 
 
1. Harris JP, Chen MM, Orosco RK, Sirjani D, Divi V, Hara W. Association of survival with 
shorter time to radiation therapy after surgery for US patients with head and neck cancer. 
JAMA Otolaryngol Head Neck Surg. 2018; 144(4): 349-59. 
2. Huang J, Barbera L, Brouwers M, Browman G, Mackillop WJ. Does delay in starting 
treatment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol. 2003; 
21(3):555-63. 
3. Graboyes EM, Garrett-Mayer E, Ellis MA et al. Effect of time to initiation of postoperative 
radiation therapy on survival in surgically managed head and neck cancer. Cancer. 2017; 
123(24): 4841-50. 
4. Ho AS, Kim S, Tighiouart M et al. Quantitative survival impact of composite treatment 
delays in head and neck cancer. Cancer. 2018; 124(15):3154-62. 
5. Shaikh T, Handorf EA, Murphy CT, Mehra R, Ridge JA, Galloway TJ. The impact of 
radiation treatment time on survival in patients with head and neck cancer. Int J Radiat 
Oncol Biol Phys. 2016; 96(5): 967-75. 
6. Xu C, Gu K, Yasen Y, Hou Y. Efficacy and safety of celecoxib therapy in osteoarthritis: 
A 
Meta-Analysis 
of 
Randomized 
Controlled 
Trials. 
Medicine 
(Baltimore) 
2016;95(20):e3585. 
7. Rudd R, Seth P, Scholl L, David F. Increases in drug and opioid-involved overdose deaths-
United States 2010-2015. MMWR Morb Mortality Wkly 2016;65(5051):1445-52. 
8. Carpenter PS, Shepherd HM, McCrary H et al. Association of celecoxib use with decreased 
opioid requirements after head and neck cancer surgery with free tissue reconstruction. 
JAMA Otolaryngol Head Neck Surg. 2018; 144(11):988-94. PMID: 29710229. 
9. Surveillance Epidemiology and End Results Program. (2019). Oral Cavity and Pharynx 
Cancer 
- 
Cancer 
Stat 
Facts. 
Available 
at: 
https://seer.cancer.gov/statfacts/html/oralcav.html [Accessed 4 Mar. 2019]. 
10. Song, S., Stenson, K. and Brockstein, B. (2019). Overview of treatment for head and neck 
cancer. Uptodate.com. Available at: https://www.uptodate.com/contents/overview-of-
treatment-for-head-and-neck-
cancer?search=head%20and%20neck%20cancer&source=search_result&selectedTitle=1
~150&usage_type=default&display_rank=1 [Accessed 4 Mar. 2019]. 
11. Donnelly, Ronald F et al. “Stability of celecoxib oral suspension.” The Canadian journal 
of hospital pharmacy vol. 62,6 (2009): 464-8. doi:10.4212/cjhp.v62i6.844 
 
 
 


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Appendix 1: Patient Dosing Diary 
 
Subject Number: __________________ 
 
 
 
Date: __________________ 
The study therapy should be stored in a well-ventilated area at 5-25°C (41-77° F—refrigeration is 
recommended, particularly during the summer months). Study therapy should be taken twice a day, every 
12 hours ± 2 hours, without regard to food. It should not be taken with aluminum- or magnesium-containing 
antacids (such as: Acid Gone, Di Gel, Milk of Magnesia, Mylanta, or Gaviscon) within two hours of taking 
study therapy.  
Date 
Time 
Amount of 
mLs Taken 
Comments: 
 
 
 
AM 
mL  
 
PM 
mL  
 
AM 
mL  
PM 
mL  
 
AM 
mL  
PM 
mL  
 
 
AM 
mL  
 
PM 
mL  
 
AM 
mL  
 
PM 
mL  
 
AM 
mL  
PM 
mL  
 
AM 
mL  
PM 
mL  
 
AM 
mL  
PM 
mL  
________________________________________________ 
 
__________________ 
Patient Signature 
 
 
 
 
 
 
 
Date 
 


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Appendix 2: Pain Management Diary 
 
Subject Number: __________________ 
 
 
 
Date: __________________ 
 
Date 
Medication Taken  
Dose Taken (mg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
__________________________________________ 
 
 
__________________ 
Patient Signature 
 
 
 
 
 
 
 
 
Date 


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Appendix 3: MDASI Head and Neck Cancer 
 


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Appendix 4: EORTC Q LQ-H&N43 
 


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Appendix 5: Pain Satisfaction Questionnaire 
 
Subject Number: __________________ 
 
 
 
Date: __________________ 
 
Please circle or mark one number per question to indicate your pain control satisfaction as it applies 
to the past 7 days  
1. How often was your pain well controlled? 
 
0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
2. How often did the staff do everything they could to help you with your pain 
 
0) Never 
1) Sometimes 
2) Usually 
3) Always 
 
3. How satisfied are you with your Overall pain control 
 
0) Very Dissatisfied 
1) Somewhat dissatisfied 
2) Neutral 
3) Somewhat satisfied 
4) Very satisfied 
 
4. Was there anything else that we could have done to make your pain control better during 
you treatment? 
 
 
__________________________________________ 
 
 
__________________ 
Patient Signature 
 
 
 
 
 
 
 
Date 
 


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Appendix 6: Pre-treatment Questionnaire 
 
Subject Number: __________________ 
 
 
 
Date: __________________ 
 
1. In the past, how effective are narcotic pain medications (such as morphine, Vicodin, Norco, 
Percocet, oxycodone, Dilaudid) at controlling your pain? 
 
0) Very ineffective 
1) Somewhat ineffective 
2) Somewhat effective  
3) Very effective 
 
2. In the past, how has your pain tolerance been? 
 
0) Very poor 
1) Somewhat poor 
2) Somewhat tolerant 
3) Very tolerant 
 
3. Do you experience a significant amount of pain on a daily basis aside from the pain due to 
your current head and neck condition 
 
0) Yes, I do. 
1) No, I do not. 
 
 
 
__________________________________________ 
 
 
__________________ 
Patient Signature 
 
 
 
 
 
 
 
Date 
 
 


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Appendix 7: Visual Analog Scale for Pain 
 
Subject Number: __________________ 
 
 
 
Date: __________________ 
Place an X on the line to indicate your pain intensity averaged as it applies to the past 7 days while 
at rest, with a swallow, and with a cough. 
 
While at rest: 
 
 
 
 
With a Swallow: 
 
 
 
With a Cough 
 
 
__________________________________________ 
 
 
__________________ 
Patient Signature 
 
 
 
 
 
 
 
Date 


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Appendix 8: Treating Investigator Patient Assessment Guidance 
 
 
Subject Number: __________________ 
 
 
 
Date: __________________ 
During a physical exam, complete the following questions by circling the applicable answer: 
1. Karnofsky Performace Status 
Score 
Definition 
100 
Normal, no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort, some signs or symptoms of disease 
70 
Cares for self but unable to carry on normal activity or to do active work  
60 
Requires occasional assistance but is able to care for most of personal needs  
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization is indicated although death not imminent 
20 
Very ill; hospitalization and active supportive care necessary 
10 
Moribund 
0 
Dead 
2. Functional Oral Intake Scale 
Score 
Performance 
Implication 
Deficit 
1 
Aspirates saliva 
Nothing by mouth 
Profound 
2 
Tube dependent 
Mothing by mouth/minimal trials 
Profound 
3 
Tube dependent 
Full trials by mouth 
Severe 
4 
Total Oral 
Single texture trials 
Moderate 
5 
Total Oral 
Multiple texture trials 
Mild  
6 
Total Oral 
By mouth/ restrictions 
Minimal  


Short Title: RESILIENCE 
Version Date: 18APR2023 
 
Page 56 of 56 
7 
Regular diet 
By mouth/ no restrictions 
normal 
 
Appendix 8: Treating Investigator Patient Assessment Guidance  
 
3. Does the patient use a feeding tube? 
Yes 
 
 
No 
 
 
 
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__________________ 
Investigator Signature  
 
 
 
 
 
 
Date