HYHOPE: Phase I Study of De-intensified Hypofractionated Radiation Therapy for Human Papilloma Virus-associated Oropharynx Cancer
Phase: PHASE1
Conditions: Human Papillomavirus-Related Carcinoma, Oropharyngeal Cancer
Sponsor: University of Texas Southwestern Medical Center

 
STU2020-1079, Moon, FormA-Protocol, Mod_17, 04-02-24 (2) 
 
 
 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016; 12/2018; 07/2020; 07/2022 
 
STU 2020-1079 
HYHOPE: Phase I study of de-intensified hypofractionated radiation therapy for human papilloma 
virus-associated oropharynx cancer 
 
Principal Investigator:  
Dominic Moon, MD 
Department of Radiation Oncology 
University of Texas Southwestern Medical Center 
2280 Inwood Rd 
Dallas, TX 75390 
214-645-7615  
214-645-8527 (fax) 
dominic.moon@utsouthwestern.edu 
 
Sub-Investigator(s): 
 
David Sher, MD, MPH  
Department of Radiation Oncology 
 
Randall Hughes, MD 
Department of Medical Oncology 
 
Biostatistician: 
 
Chul Ahn, PhD 
University of Texas Southwestern Medical Center 
5323 Harry Hines Blvd 
Dallas, TX 75390 
214-648-9418 
chul.ahn@utsouthwestern.edu 
 
Study Drug/Treatment: 
De-intensified hypofractionated intensity modulated radiation therapy 
with concurrent cisplatin 
 
Funding Source:  
Gateway for Cancer Research 
 
NCT Number: 
NCT04580446  
 
Initial version: 
1.0; 10/01/2020 
 
Amended: 
 
2.0; 06/16/2021 
 
 
3.0; 10/20/2021 
 
 
4.1; 11/01/2022 
 
 
4.2; 01/30/2024 
 
UT Southwestern Medical Center (UTSW) 
Radiation Oncology Clinical Research Office 
2280 Inwood Rd 
Dallas, Texas 75390-9303  
 

 
STU2020-1079, Moon, FormA-Protocol, Mod_17, 04-02-24 (2) 
 
 
 
 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Comprehensive Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor. 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015; 11/2016; 12/2018; 07/2020; 07/2022 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
Amendment/Version #_____Version 4.2_____________ 
STU 2020-1079 
HYHOPE: Phase I study of de-intensified hypofractionated radiotherapy for human papilloma 
virus-associated oropharynx cancer 
 
 
Principal Investigator (PI) Name: ___Dominic Moon, MD_____ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 

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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ............................................................................................................. 1 
Study Schema ................................................................................................................................. 3 
STUDY SUMMARY .......................................................................................................................... 4 
1.0   BACKGROUND AND RATIONALE ........................................................................................ 5 
1.1 
Disease Background........................................................................................................ 5 
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities ................. 5 
1.3 
Other Agents .................................................................................................................... 6 
1.4 
Rationale .......................................................................................................................... 6 
 
2.0   STUDY OBJECTIVES .............................................................................................................. 7 
2.1 
Primary Objectives ........................................................................................................... 7 
2.2 
Secondary Objectives ...................................................................................................... 7 
2.3 
Endpoints ......................................................................................................................... 7 
 
3.0   SUBJECT ELIGIBILITY ........................................................................................................... 8 
3.1 
Inclusion Criteria .............................................................................................................. 8 
3.2 
Exclusion Criteria ............................................................................................................. 9 
 
4.0   TREATMENT PLAN ................................................................................................................. 9 
4.1 
Radiation Treatment Dose and Administration ................................................................ 9 
4.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 15 
4.3 
Concomitant Medications/Treatments ........................................................................... 15 
4.4 
Other Modalities or Procedures ..................................................................................... 15 
4.5 
Duration of Therapy ....................................................................................................... 15 

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4.6 
Duration of Follow Up .................................................................................................... 16 
4.7 
Removal of Patients from Protocol Therapy .................................................................. 16 
4.8 
Patient Replacement ..................................................................................................... 16 
 
5.0   STUDY PROCEDURES ......................................................................................................... 16 
5.1 
Screening/Baseline Procedures .................................................................................... 16 
5.2 
Procedures During Treatment ....................................................................................... 17 
5.3 
Follow-up Procedures .................................................................................................... 17 
5.4 
Time and Events Table .................................................................................................. 18 
5.5 
Removal of Subjects from Study ................................................................................... 18 
 
6.0   Measurement of Effect ......................................................................................................... 19 
6.1 
Antitumor Effect ............................................................................................................. 19 
6.2 
Safety/Tolerability .......................................................................................................... 20 
6.3 
Quality of life .................................................................................................................. 20 
 
7.0   ADVERSE EVENTS ............................................................................................................... 20 
7.1 
Experimental Therapy.................................................................................................... 20 
7.2 
Adverse Event Monitoring ............................................................................................. 21 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 23 
7.4 
Unblinding Procedures .................................................................................................. 26 
7.5 
Stopping Rules .............................................................................................................. 26 
 
8.0   DRUG/TREATMENT INFORMATION ................................................................................... 26 
8.1 
Cisplatin ......................................................................................................................... 26 
 
9.0   STATISTICAL CONSIDERATIONS ...................................................................................... 27 
9.1 
Study Design/Study Endpoints ...................................................................................... 27 

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9.2 
Sample Size and Accrual .............................................................................................. 28 
9.3 
Data Analyses Plans...................................................................................................... 28 
 
10.0   STUDY MANAGEMENT ...................................................................................................... 29 
10.1 
Conflict of Interest .......................................................................................................... 29 
10.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 29 
10.3 
Required Documentation ............................................................................................... 29 
10.4 
Registration Procedures ................................................................................................ 30 
10.5 
Data Management and Monitoring/Auditing .................................................................. 30 
10.6 
Amendments to the Protocol ......................................................................................... 32 
10.7 
Record Retention ........................................................................................................... 32 
10.8 
Obligations of Investigators ........................................................................................... 32 
 
11.0   REFERENCES ..................................................................................................................... 33 
12.0   APPENDICES ...................................................................................................................... 35 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
BED 
Biological Effective Dose 
CBCT 
Cone Beam Computed Tomography 
CR 
Complete Response 
CRO 
Clinical Research Office 
CMS 
Centers for Medicare and Medicaid Services 
CT 
Computed Tomography 
CTV 
Clinical Target Volume 
CTCAE 
Common Terminology Criteria for Adverse Events 
DM 
Distant Metastasis 
DOT 
Disease Oriented Team 
DSMC 
Data Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
ENE 
Extranodal Extension 
EQ-5D-5L 
EuroQol-5 Dimensions Questionnaire 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GTV 
Gross Tumor Volume 
H&P 
History & Physical Exam 
HFRT 
Hypofractionated Radiation Therapy 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HRPP 
Human Research Protections Program 
HUD 
Humanitarian Use Device 
IMRT 
Intensity-modulated Radiation Therapy 
IRB 
Institutional Review Board 
IV 
Intravenously 
KPS                 Karnofsky performance status  
LRC 
Locoregional Control 
LRR 
Locoregional Recurrence 
LVI 
Lymphovascular Invasion 
MDADI 
MD Anderson Dysphagia Inventory 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose/fractionation 
NCI 
National Cancer Institute 
OAR 
Organ at Risk 
ORR 
Overall Response Rate 
OS 
Overall Survival 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PNI 
Perineural Invasion 

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PFS 
Progression Free Survival 
PR 
Partial Response 
PTV 
Planning Target Volume 
QOL 
Quality of Life 
RO-APM 
Radiation Oncology-Alternative Payment Model 
ROSAC 
Radiation Oncology Safety Assurance Committee 
RT 
Radiation Therapy 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
UPIRSO 
Unanticipated Problems Involving Risks to Subjects or Others 
UTSW 
University of Texas Southwestern Medical Center 
UW-QOL 
University of Washington Quality of Life Questionnaire 
VMAT 
Volumetric Modulated Arc Therapy 
 
 

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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: Rolling 6 design 
Hypofractionated radiotherapy with concurrent chemotherapy 
(weekly cisplatin 40 mg/m2) 
 
Level 
Dose 
1* 
44.4 Gy in 12 fractions, 4 fractions/week 
0 
46.5 Gy in 15 fractions, 5 fractions/week 
-1 
52 Gy in 20 fractions, 5 fractions/week 
 
*Level 1 has been eliminated in an amendment 
Patient registration: 
T1-3 (≤6 cm), N0-2 (except T1-2N0) 
p16 positive oropharyngeal squamous cell carcinoma  
≤10 pack-year smoking history and no active smoking 
Assessment of clinical response: 
Clinical and radiographic evaluation with PET/CT 12-14 weeks post-treatment 
• 
Clinical complete response (cCR): routine surveillance 
• 
<cCR of primary site: directed biopsy of suspected site(s); if positive, 
proceed with salvage transoral robotic surgery 
• 
<cCR of nodes: proceed with neck dissection of suspected node level(s) 
Follow-up: 
Assessment of endpoints at 6 and 12 months 
Assessment of primary endpoint: 
Maximum tolerated dose/fractionation (MTD) 
Dose limiting toxicity: Any CTCAE grade 4 acute toxicity or 
persistent grade 3 mucositis at 3 months post-treatment (per 
section 9.1) 
Dose expansion cohort 
Enroll additional patients at the MTD to reach  
a total of 24 patients  

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STUDY SUMMARY 
 
Title 
HYHOPE: Phase I study of de-intensified hypofractionated radiation 
therapy for human papilloma virus-associated oropharynx cancer 
Short Title 
HYHOPE: De-intensified hypofractionated radiation therapy for HPV-
associated oropharynx cancer 
Protocol Number 
STU 2020-1079 
Phase 
Phase I 
Methodology 
Rolling 6 dose finding cohort followed by dose expansion cohort 
Study Duration 
3 years to accrue, additional 1 year of follow-up 
Study Center(s) 
Single-center 
Objectives 
To assess the maximum tolerated dose/fractionation and signal for 
efficacy of de-intensified hypofractionated radiotherapy for favorable 
HPV-associated oropharynx cancer 
Number of Subjects 
24 
Diagnosis and Main 
Inclusion Criteria 
T1-3 (≤6 cm), N0-2 (except T1-2N0) p16 positive oropharyngeal 
squamous cell carcinoma with ≤10 pack-year smoking history 
Study Product(s), Dose, 
Route, Regimen 
Hypofractionated intensity modulated radiotherapy with concurrent 
chemotherapy (weekly cisplatin) 
Duration of administration 
3-4 weeks 
Reference therapy 
Conventionally fractionated radiotherapy (60-70 Gy) over 6-7 weeks with 
concurrent chemotherapy (historical control) 
Statistical Methodology 
Phase I: standard rolling 6 design to determine the maximum tolerated 
dose/fractionation. Additional patients will be enrolled to reach 24 
patients to achieve 20 evaluable patients for the clinical response 
endpoint assuming a 15% attrition rate. 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
The incidence of Human Papilloma Virus-associated oropharyngeal squamous cell 
carcinoma (HPVOPSCC) is increasing in the United States accounting for 70-80% of 
newly-diagnosed oropharyngeal cancers. With the recognition of HPVOPSCC as a 
distinct disease process from the smoking- or alcohol-related head and neck cancers and 
the associated favorable prognosis (1), investigations are ongoing to determine the best 
strategy to de-intensify therapy while maintaining good oncologic outcomes. Recently 
published results of reduced dose radiotherapy (RT) of 60 Gy with weekly cisplatin (30 
mg/m2) have shown excellent outcomes with 2- and 3-year progression free survival 
(PFS) of 86% and 85%, respectively, and 2- and 3-year overall survival (OS) of 95% (2). 
Preliminary results of NRG-HN002 was also recently presented at ASTRO 2019 with 2-
year PFS of 90.5% in the 60 Gy RT plus weekly cisplatin (40 mg/m2) arm while 
surpassing the pre-specified MD Anderson Dysphagia Inventory scale threshold (3). 
Although we do not have randomized data compared to the current standard of 70 Gy, 60 
Gy with concurrent weekly chemotherapy is likely to become an important treatment 
strategy for favorable HPVOPSCC, perhaps representing the purest de-intensification 
paradigm without the addition of upfront surgery or induction chemotherapy.  
1.2 
Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
Standard of care RT for head and neck squamous cell carcinoma (HNSCC) involves 
conventionally fractionated treatment of 2 Gy per fraction delivered over a course of 6-7 
weeks, representing one of the longest RT courses among all cancers. In other disease 
sites including breast and prostate, moderately hypofractionated RT (HFRT) has been 
demonstrated to provide equivalent oncologic outcomes with similar toxicities (4, 5). 
However, concerns for potential increase in side effects have limited attempts of HFRT in 
HNSCC except in early stage glottic larynx cancer where treatment volumes are relatively 
small. In this disease subsite, moderately HFRT delivered in 2.25 Gy per fraction were 
shown to have superior local control with no significant increase in adverse reactions (6). 
 
A small number of prospective trials using moderately HFRT in other HNSCC subsites 
have been reported. In a study of definitive chemoradiation delivering 55 Gy in 20 
fractions (2.75 Gy/fraction) with concurrent carboplatin in 19 patients with HNSCC, all 
patients were able to complete RT with a complete response rate of 84% and 2-year local 
control of 75% (7). Acute grade 3 dermatitis and mucositis were seen in 26% and 84% of 
patients, respectively. In another small single arm trial, 20 patients were treated with 55 
Gy in 20 fractions with concurrent weekly cisplatin (8). All patients were able to complete 
RT as prescribed with acute grade 3 dermatitis, grade 3 mucositis, and nasogastric tube 
rate of 30%, 40%, and 75%, respectively. Although the acute adverse reaction appeared 
to be comparable to conventionally fractionated RT, neither trial reported long term 
complication rates.  
 
There are currently two ongoing multicenter randomized trials outside of the United 
States randomizing patients to HFRT vs conventionally fractionated RT in the definitive 
setting. In a trial sponsored by the International Atomic Energy Agency (IAEA-HYPNO), 
patients with stage I-IV HNSCC are being randomized to 55 Gy in 20 fractions 5 times a 
week vs 66 Gy in 33 fractions six times a week with primary endpoints of 3-year 
locoregional control and late toxicity. In another trial from the United Kingdom 
(COMPARE), patients with intermediate and high risk oropharyngeal cancers are being 
randomized to four different arms, two of which involve 64 Gy in 25 fractions (2.56 
Gy/fraction) vs 70 Gy in 35 fractions with the primary endpoint of overall survival. Both 
trials are scheduled to complete accrual in 2021 with results likely reported in mid- to late-

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2020s. There are no published or active trials assessing curative HFRT regimen with less 
than 20 fractions. 
 
Study of HFRT is of particular interest as the health care system transitions to value-
based care model. A change in the reimbursement model for radiation oncology in the 
Unites States will likely significantly affect the way RT is delivered in the near future. 
Centers for Medicare and Medicaid Services (CMS) have recently unveiled the radiation 
oncology alternative payment model (RO-APM), which is scheduled to take effect 
between now and 2022. Participation will be mandatory, and radiation oncology centers 
will receive a fixed payment for a 90-day episode of care in contrast to the current fee-for-
service model where each visit and fraction is billed for and reimbursed (9). RO-APM is 
designed to incentivize cost-effective treatments while maintaining high quality. As a 
result of this change, the radiation oncology community will seek safe and effective 
strategies to decrease total costs per episode. A prospective study to assess HFRT with 
fewer number of fractions is thus timely and potentially paradigm changing for practices 
across the United States. 
 
The current COVID-19 pandemic is highlighting the cost and risk to our society at large of 
a lack of viable alternatives to a 6-7 week daily RT course for patients with HNSCC. 
Patients and medical staff are exposed to increased risk of SARS-CoV-2 infection during 
a prolonged daily RT course. A well-validated HFRT regimen for HNSCC is urgently 
needed similar to other disease sites such as breast, prostate, rectum, and brain where 
safe and effective HFRT regimens have been established and are increasingly utilized. 
1.3 
Other Agents 
The standard concurrent chemotherapy for the treatment of HNSCC consists of bolus 
cisplatin (100 mg/m2) every 3 weeks for 2-3 cycles, which is associated with significant 
grade 3-4 toxicity (10, 11). As noted above, multi-institutional and national trials 
assessing low dose weekly cisplatin (30-40 mg/m2) with RT for favorable HPVOPSCC 
have shown excellent oncologic results with a favorable toxicity profile (2, 3). The current 
trial will test HFRT with concurrent weekly cisplatin at 40 mg/m2. 
1.4 
Rationale 
1.4.1 
Dose de-intensification 
Analysis of multiple prospective trials have confirmed improved PFS and OS of 
patients with HPVOPSCC vs non-HPV associated cancers (12–14). Given the 
significant toxicity associated with standard chemoradiation of 70 Gy with 
concurrent cisplatin, it is imperative to identify optimal strategies to de-intensify 
therapy for favorable HPVOPSCC to achieve comparable outcomes to standard 
therapy while minimizing toxicity. Several Phase II studies have shown promising 
results using 60 Gy vs the current standard of 70 Gy (2, 3). 
1.4.2 
Volume de-escalation 
Elective nodal volumes for head and neck cancer currently used for intensity-
modulated RT (IMRT) is extrapolated from conventional RT fields. Assessment of 
patterns of failure following IMRT treatments have shown that regional 
recurrences almost always occur in the high-dose region and solitary failure in 
the elective volume/dose is rare (15–18). Trials assessing a reduction in the 
elective nodal volume following induction chemotherapy have shown no solitary 
elective volume failures (19, 20). More recently, a UT Southwestern Medical 
Center prospective study of volume de-escalation, where patients with 
oropharynx cancer received elective dose RT only to the involved and 
immediately adjacent cervical nodal levels, found no solitary nodal recurrences in 

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the treated or untreated elective neck volumes, with a minimum follow-up of 
nearly 2 years (21). Decreasing the volume of elective treatment can improve the 
toxicity profile of treatment and is currently being incorporated into the standard-
of-care arm in large cooperative group trials such as NRG-HN005. 
1.4.3 
Hypofractionation 
Cost of oncologic care has continued to increase with efforts in recent years to 
transition to a value-based care model. In this environment, especially with the 
implementation of the RO-APM described above, there is an economic rationale 
to elucidate ways to provide quality care while decreasing resource utilization. 
Also, there is a strong radiobiological rationale for HFRT in HNSCC to decrease 
the overall treatment time and thus minimize the effects of accelerated 
repopulation seen in this disease entity. Accelerated fractionation with its 
associated decrease in overall treatment time has been shown to improve local 
control and progression free survival compared to conventional fractionation in 
HNSCC (22). Effective and safe radiation treatment in a fraction of the time 
currently required will also improve patient quality of life by decreasing 
interruptions to their personal and professional lives. Moreover, reducing the 
overall treatment time may increase completion rates and compliance by 
reducing the time burden of the therapy. Shortened treatment time will lead to 
reduced number of weekly cisplatin cycles with concomitant decrease in total 
cumulative dose, which may also decrease potential chemotherapy side effects 
such as ototoxicity or nephrotoxicity.   
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To determine the maximally tolerated dose/fractionation (MTD) of HFRT 
2.2 
Secondary Objectives 
2.2.1 
To assess physician-reported acute and late toxicities of HFRT  
2.2.2 
To assess the oncologic outcomes of HFRT 
2.2.3 
To assess patient-reported QOL of HFRT 
2.2.4 
To assess feeding tube dependence rate of HFRT 
2.3 
Endpoints 
2.3.1 
Primary endpoint: MTD of HFRT 
2.3.2 
Secondary endpoints: 
• 
Physician-reported acute and late toxicities 
o 
Rate of ≥grade 3 acute toxicities during treatment, and at 1 and 3 
months after treatment using National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 
o 
Rate of ≥grade 3 late toxicities at 6 and 12 months after treatment 
using CTCAE v5.0 
• 
Oncologic outcomes: locoregional control (LRC), progression-free survival 
(PFS), and overall survival (OS) 

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• 
Patient-reported QOL: 
o 
MDADI, University of Washington QOL questionnaire (UW-QOL) 
version 4, and EuroQol-5 dimensions (EQ-5D-5L) scores at baseline, 
1, 3, 6, and 12 months after treatment. QOLs will be completed 
either on paper (included in Appendix C, D & E of the protocol) or 
electronically via MyChart. 
• 
Feeding tube dependence rate at baseline, 1, 3, 6, and 12 months after 
treatment 
o 
Feeding tube dependence defined as daily use of the feeding tube with 
≥2 nutritional supplements (e.g. Ensure, Boost, etc.) per day at the time 
of consultation. 
3.0 
SUBJECT ELIGIBILITY 
Eligibility waivers are not recommended; however, if warranted, prior approvals are required per 
section 10.5.1. Subjects must meet all inclusion and exclusion criteria to be registered to the 
study. Study treatment may not begin until a subject is registered. Once registered, a subject is 
still required to meet all inclusion and exclusion criteria on the first day of treatment, prior to 
treatment. 
3.1 
Inclusion Criteria 
3.1.1 
Pathologically-proven diagnosis of T1-3 (up to 6 cm), N0-2 (AJCC 8th edition) 
p16 positive squamous cell carcinoma of the oropharynx (except T1-2N0 as 
noted in the exclusion criteria) 
3.1.2 
≤10 pack-year smoking history and not actively smoking 
3.1.3 
Age ≥18 years 
3.1.4 
ECOG performance status 0-2 or Karnofsky Performance Status of 50-100 
3.1.5 
Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and for 90 days following 
completion of therapy. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
 
3.1.5.1  A female of child-bearing potential is any woman (regardless of sexual 
orientation, marital status, having undergone a tubal ligation, or 
remaining celibate by choice) who meets the following criteria: 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
3.1.6 
Negative serum or urine pregnancy test within 2 weeks before registration for 
women of childbearing potential. 
3.1.7 
Ability to understand and the willingness to sign a written informed consent. 
 

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3.2 
Exclusion Criteria 
3.2.1 
Distant metastasis 
3.2.2 
T1-2N0 (AJCC 8th edition) p16 positive squamous cell carcinoma of the 
oropharynx (candidates for definitive RT alone or surgery alone) 
3.2.3 
Inability to receive concurrent weekly cisplatin due to comorbid conditions 
3.2.4 
Synchronous non-skin cancer primaries outside of the oropharynx, oral cavity, 
larynx, and hypopharynx except for low- and intermediate-risk prostate cancer 
and well-differentiated thyroid cancer. For prostate cancer, patient should not be 
receiving active treatment. For thyroid cancer, thyroid surgery may occur before 
or after radiation treatment, provided all other eligibility criteria are met. 
3.2.5 
Prior invasive malignancy with an expected disease-free interval of less than 3 
years 
3.2.6 
Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation fields 
3.2.7 
Subjects may not be receiving any other investigational agents for the treatment 
of the cancer under study. 
3.2.8 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to the chemotherapy agents in this study 
3.2.9 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that, in the opinion of the 
investigator, would limit compliance with study requirements 
3.2.10 Subjects must not be pregnant or nursing due to the potential for congenital 
abnormalities and the potential of this regimen to harm nursing infants. 
3.2.11 History of severe immunosuppression, including HIV, organ or autologous or 
allogeneic stem cell transplant, or active immunosuppressive medication at the 
time of enrollment 
4.0 
TREATMENT PLAN 
4.1 
Radiation Treatment Dose and Administration 
 
Patients will be enrolled on the trial in cohorts of up to 6 per the rolling 6 dose escalation 
design as outlined in section 9.1.1.  
4.1.1 
CT simulation 
Patients will be simulated supine in a thermoplastic mask extending from the 
scalp through upper chest (e.g. “5 point mask”) or a thermoplastic mask covering 
the head in combination with shoulder retractors. IV contrast is recommended but 
not mandatory. 

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4.1.2 
Dose and fractionation 
Dose calculation for HFRT was based on the biologically effective dose (BED) 
model accounting for time/repopulation observed in HNSCC: 
 
 
n = number of fractions 
d = dose per fraction 
T = overall treatment time 
Conventionally fractionated RT: 40 days (30 fractions) 
Hypofractionated RT: 19 days (12-15 fractions), 26 days (20 fractions) 
Tk = time delay of repopulation (21 days for tumor, 7 days for mucosa) 
Tp = cell doubling time (3 days for tumor, 2.5 days for mucosa) 
α/β = 3 for late complications, 10 for tumor/mucosa 
α = 0.35 Gy-1 
 
Dose and fractionation were selected to satisfy two parameters (see Table): 
• 
≤ BED3 vs conventional fractionation (60 Gy), i.e. late toxicity dose to normal 
tissue  
• 
≥ BED10 vs conventional fractionation (60 Gy), i.e. dose to tumor 
 
Table. Total dose BED calculation for HFRT (vs comparison [conventional fractionation]) 
Level 
Dose 
BED /w 
repopulation 
α/β = 10 
(tumor) 
BED /w 
repopulation 
α/β = 10 
(acute mucosa) 
BED 
α/β = 3 
(late normal 
tissue) 
1* 
44.4 Gy/12 fx (3.7 Gy/fx), 
4 fx/week 
61 
52 
99 
0 
46.5 Gy/15 fx (3.1 Gy/fx), 
5 fx/week 
61 
51 
95 
-1 
52 Gy/20 fx (2.6 Gy/fx),  
5 fx/week 
62 
50 
97 
Comparison 
60 Gy/30 fx (2 Gy/fx),  
5 fx/week 
59 
46 
100 
Abbreviations: fx, fraction(s) 
*Level 1 eliminated at time of amendment. See the end of the section for details. 
 
Level 0 will test a 15-fraction HFRT regimen treated 5 times a week for 3 weeks. 
If successful, level 1 will test a 12-fraction HFRT regimen treated 4 times a week 
for 3 weeks. If level 1 is well-tolerated, this regimen will be considered maximally 
tolerated dose/fractionation (i.e. no further reduction in the number of fractions). 
 
If Level 0 is deemed intolerable, patients will be enrolled on level -1, which will 
test a 20-fraction HFRT regimen treated 5 times a week for 4 weeks. Given 
published literature on 20-fraction regimens, we anticipate that a 20-fraction 
regimen will be tolerable.  
 
The calculated BED for acute toxicity such as the normal mucosa may be slightly 
increased vs conventionally fractionated RT, but the dose ranges are well below 
the limits deemed tolerable (<59-63 Gy10) based on analysis of toxicities 
associated with various head and neck cancer fractionation regimens published 
to date (23). 

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High risk (HR: regions of positive disease) and standard risk (SR: other regions 
at risk) volumes will receive doses as outlined below using dose painting 
intensity-modulated radiotherapy (IMRT): 
 
Level 1: 
• 
PTVHR: 370 cGy x 12 = 4440 cGy 
• 
PTVSR: 330 cGy x 12 = 3960 cGy 
 
Level 0: 
• 
PTVHR: 310 cGy x 15 = 4650 cGy 
• 
PTVSR: 270 cGy x 15 = 4050 cGy 
 
Level -1: 
• 
PTVHR: 260 cGy x 20 = 5200 cGy 
• 
PTVSR: 230 cGy x 20 = 4600 cGy 
 
Table. Standard risk dose BED calculation for HFRT (vs comparison) 
Level 
Dose 
BED /w 
repopulation 
α/β = 10 
(tumor) 
BED /w 
repopulation 
α/β = 10 
(acute mucosa) 
BED 
α/β = 3 
(late normal 
tissue) 
1* 
39.6 Gy/12 fx (3.3 Gy/fx) 
53 
43 
83 
0 
40.5 Gy/15 fx (2.7 Gy/fx) 
51 
42 
77 
-1 
46 Gy/20 fx (2.3 Gy/fx) 
53 
41 
81 
Comparison 
54 Gy/30 fx (1.8 Gy/fx) 
51 
37 
86 
Abbreviations: fx, fraction(s) 
*Level 1 eliminated at time of amendment. See the end of the section for details. 
 
Elimination of Level 1 
Upon a preliminary review of the toxicity profile of patients enrolled on a parallel 
Phase I trial in the post-operative setting with the same fractionation scheme, an 
apparent increase in acute grade 2 and grade 3 toxicities related to 
oral/pharyngeal mucositis and pain was observed on dose level 1 vs level 0. 
Although dose limiting toxicity is not expected at the conclusion of the evaluation 
period for patients on level 1 on that trial, the investigators have made a decision 
to forgo escalation to level 1 (i.e. eliminate level 1) for this current trial in light of 
potential increase in toxicity. As delineated in the tables above, the fractionation 
schemes of level 0 and 1 have the same biologically effective dose to the tumor 
and treatment length (3 weeks). The trial will proceed with the dose expansion 
phase once level 0 is confirmed to be without dose limiting toxicities. 
4.1.3 
Target volume delineation 
 
4.1.3.1 Gross tumor volume (GTV) 
 
The primary gross tumor volume (GTVp) will be contoured on the planning CT 
using radiographic and clinical information to define its extent. Image registration 
of staging scans including diagnostic CT, PET/CT, and/or MRI as available to aid 
delineation of GTVp is recommended, but not mandatory.  
 

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The nodal gross tumor volume (GTVn) will be contoured on the planning CT 
using radiographic and clinical information. Nodes meeting the criteria below will 
be considered positive and included in GTVn: 
• 
Max SUV greater 3.0 
• 
The short-axis diameter is ≥1.5 cm (level II), ≥1.0 cm (level I, III, IV, and V), 
or ≥0.8 cm (retropharyngeal) 
• 
The node shows central necrosis  
 
Suspicious nodes will be defined as those that do not meet the above criteria, but 
satisfy any of the criteria below: 
• 
The combined diameter of the lymph node ≥ 17 mm on axial imaging 
• 
FDG uptake greater than the adjacent blood pool 
• 
Any size retropharyngeal node 
• 
Heterogeneous enhancement or rounded appearance 
 
At the discretion of the treating radiation oncologist, suspicious nodes can be 
included either as part of GTVn or included in CTVn as discussed below. 
 
4.1.3.2 Clinical target volume (CTV) 
 
CTVSR 
GTVp will be expanded by 5 mm to create CTVp. CTVp may be expanded further 
to include surrounding anatomic structures at risk for microscopic spread such as 
the adjacent soft palate or glossotonsillar sulcus for tonsil cancers or the adjacent 
contralateral base of tongue for base of tongue cancers at the discretion of the 
treating radiation oncologist. CTVp should exclude structures that are a natural 
barrier to spread (e.g. bone). 
 
CTVn will include the following: 
-Bilateral level II 
-Except in well-lateralized tonsil cancers (defined as having no invasion 
of the base of tongue and minimal invasion of the soft palate with >1 cm 
distance from the uvula), where the node negative contralateral level II 
may be omitted 
-In the node positive neck, cranial extent of level II will be the base of 
skull 
-In the node negative neck, cranial extent of level II will be the transverse 
process of C1 vertebrae or where the posterior belly of the digastric 
muscle crosses over the jugular vein 
-Nodal level(s) with an involved node (i.e. GTVn) 
-Nodal level(s) immediately adjacent to involved node (e.g. if level II has an 
involved node, levels III is included) 
-Nodal level(s) with suspicious nodes 
-Ipsilateral lateral retropharyngeal nodal region  
-Level V is included if there are 2 or more involved nodal levels in the ipsilateral 
neck 
-Level IB is included only if it harbors an involved or suspicious node 
 
4.1.3.3 Planning target volume (PTV) 
 
GTVp and GTVn will be expanded by 5 mm in all directions to create PTVHR. 
 
CTVp will be expanded by 5 mm in all directions to create PTVp. CTVn will be 
expanded by 3 mm in all directions to create PTVn. PTVp and PTVn will be 
combined to create PTVSR. 

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4.1.4 
Treatment planning 
Radiotherapy must be delivered using IMRT. IMRT may be implemented using 
any delivery platform, including volumetric modulated arc therapy (VMAT), step 
and shoot IMRT, or helical tomotherapy.  
 
4.1.4.1 Coverage constraints 
Target 
volume 
Per protocol 
Acceptable variation 
(Minor deviation) 
Major deviation 
PTVHR 
-At least 95% of the PTV 
should be covered by 
the prescription dose 
-At least 99% of the PTV 
should receive 93% of 
the prescription dose 
-Dose should not exceed 
107% of prescription 
dose 
-None 
 
 
-At least 97% of the PTV 
should receive 93% of 
the prescription dose 
-Dose should not exceed 
110% of prescription 
dose 
-<95% of the PTV is 
covered by the 
prescription dose 
-<97% of the PTV 
receives 93% of the 
prescription dose 
-Maximum dose is 
>110% of prescription 
dose 
PTVSR 
-At least 95% of the PTV 
should be covered by 
the prescription dose 
-At least 93% of the PTV 
should be covered by the 
prescription dose 
-<93% of the PTV is 
covered by the 
prescription dose 
 
4.1.4.2 Organ at risk (OAR) constraints  
 
12 fractions 
Mandatory: 
Organ 
Per protocol 
Acceptable variation 
(Minor deviation) 
Major deviation 
Spinal cord 
Max < 34 Gy 
None 
Max ≥ 34 Gy 
Spinal cord + 5 mm 
Max < 38 Gy 
Max < 41 Gy 
Max ≥ 41 Gy 
Brainstem 
Max < 38 Gy 
Max < 41 Gy 
Max ≥ 41 Gy 
Brainstem + 5 mm 
Max < 44 Gy 
None 
Max ≥ 44 Gy 
Mandible 
Max < 46.6 Gy 
Max < 48.8 Gy 
Max ≥ 48.8 Gy 
  
Recommended: 
Contralateral parotid: mean < 16-21 Gy 
Contralateral submandibular gland: mean < 22-27 Gy 
Cochlea: maximum < 28-34 Gy, mean < 23-28 Gy 
Oral cavity (excluding PTV): mean < 16-20 Gy 
Constrictors: mean < 29-34 Gy 
Post-arytenoid and cricoid space: mean < 19-24 Gy 
Larynx: mean < 22-27 Gy 
Cervical esophagus: mean < 16-20 Gy 
Brachial plexus: max < 44-47 Gy 
Brain: max < 44 Gy 
 
15 fractions 
Mandatory: 
Organ 
Per protocol 
Acceptable variation 
(Minor deviation) 
Major deviation 
Spinal cord 
Max < 37 Gy 
None 
Max ≥ 37 Gy 
Spinal cord + 5 mm 
Max < 43 Gy 
Max < 44 Gy 
Max ≥ 44 Gy 
Brainstem 
Max < 43 Gy 
Max < 44 Gy 
Max ≥ 44 Gy 
Brainstem + 5 mm 
Max < 48 Gy 
None 
Max ≥ 48 Gy 
Mandible 
Max < 48.9 Gy 
Max < 51.5 Gy 
Max ≥ 51.5 Gy 

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Recommended: 
Contralateral parotid: mean < 17-22 Gy 
Contralateral submandibular gland: mean < 23-29 Gy 
Cochlea: maximum < 30-37 Gy, mean < 25-30 Gy 
Oral cavity (excluding PTV): mean < 17-21 Gy 
Constrictors: mean < 30-37 Gy 
Post-arytenoid and cricoid space: mean < 20-25 Gy 
Larynx: mean < 23-29 Gy 
Cervical esophagus: mean < 17-21 Gy 
Brachial plexus: max < 46-49 Gy 
Brain: max < 46 Gy 
 
20 fractions 
Mandatory: 
Organ 
Per protocol 
Acceptable variation 
(Minor deviation) 
Major deviation 
Spinal cord 
Max < 40 Gy 
None 
Max ≥ 40 Gy 
Spinal cord + 5 mm 
Max < 46 Gy 
Max < 49 Gy 
Max ≥ 49 Gy 
Brainstem 
Max < 46 Gy 
Max < 50 Gy 
Max ≥ 50 Gy 
Brainstem + 5 mm 
Max < 52 Gy 
None 
Max ≥ 52 Gy 
Mandible 
Max < 54.6 Gy 
Max < 57.2 Gy 
Max ≥ 57.2 Gy 
  
Recommended: 
Contralateral parotid: mean < 19-23 Gy 
Contralateral submandibular gland+: mean < 26-30 Gy 
Cochlea: maximum < 33-40 Gy, mean < 27-32 Gy 
Oral cavity (excluding PTV): mean < 19-22 Gy 
Constrictors: mean < 33-40 Gy 
Post-arytenoid and cricoid space: mean < 22-26 Gy 
Larynx: mean < 26-30 Gy 
Cervical esophagus: mean < 19-22 Gy 
Brachial plexus: max < 52-54 Gy 
Brain: max < 52 Gy 
 
4.1.4.3 Treatment delivery 
All patients will receive one fraction per day, 5 days per week (except at dose 
level 1, where patients will receive one fraction per day, 4 days per week). 
Patients who miss more than 1 planned treatment (or encounter more than 1 
holiday during treatment) should attempt to make up the missed day(s) with a 
second daily fraction more than 6 hours apart. Daily cone-beam CT (CBCT) must 
be used for patient set-up (image-guided RT). Patients will preferentially start RT 
on a Monday, but this is not mandatory.  
 
Total elapsed days 
 
Per protocol 
Acceptable variation 
(Minor deviation) 
Major deviation 
12 fractions 
18-20 
21-25 
>25 
15 fractions 
18-21 
22-26 
>26 
20 fractions 
26-28 
29-33 
>33 
30 fractions 
40-42 
43-47 
>47 
 
4.1.4.4 Re-planning 
If a patient loses a significant amount of weight on treatment, or the tumor 
contour changes substantially, repeat CT simulation and planning is allowed.  

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4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table in section 5.4. Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 5.0.  
 
The dose constraints for radiation therapy are described in sections 4.1.4.2. No 
alterations in treatment doses are allowable per protocol. 
4.3 
Concomitant Medications/Treatments 
Supportive medications may be given at any point during the treatment course at the 
discretion of the treating physicians. These medications include: 
• 
Anti-emetics 
• 
Non-opiate and opiate pain medications 
• 
Antidiarrheals 
• 
Nutritional supplementation 
• 
Anti-depressants 
4.4 
Other Modalities or Procedures 
4.4.1 
Concurrent systemic therapy  
Concurrent systemic therapy will be administered using weekly cisplatin of 40 
mg/m2. Dose modifications should be performed per the standard of care at the 
treating facility. Patients are recommended to receive concurrent weekly cisplatin 
as long as it is tolerated as determined by the treating medical oncologist. Details 
of the systemic therapy can be found in section 8.0. 
4.4.2 
Gastric tubes 
Gastrostomy tubes (feeding tubes) are optional for patients on this study. 
Physicians should attempt to avoid gastrostomy if patients are receiving 
ipsilateral radiotherapy. However, gastrostomy tubes are strongly recommended 
in the following scenarios: 
• 
More than 10% body weight loss prior to diagnosis (prophylactic) 
• 
Baseline BMI < 25 (prophylactic) 
• 
More than 10% body weight loss on treatment (reactive) 
 
The gastrostomy tube should be removed after patients maintain a stable or 
increasing weight for 1-2 weeks without enteral supplementation (or as clinically 
indicated). 
4.4.3 
Speech language pathology 
Patients are strongly recommended to have evaluation and ongoing therapy as 
appropriate by a speech language pathologist before, during, and after radiation 
therapy. 
4.5 
Duration of Therapy 
Duration of therapy will be per the treatment schedule as outlined in section 4.1.2 (3-4 
weeks depending on the dose level).  
 
Protocol therapy will end under the following conditions: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 

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• 
Subject decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 
4.5.1 
Subject Withdrawal 
In the event a subject chooses to withdraw from the study, document if the  
 
is withdrawing from treatment only (and willing to be included in follow-up data 
collection), or if they are withdrawing from all study participation. For subject 
safety, the subject should be encouraged to return for a follow-up visit per the 
Time and Events Table in section 5.4. 
 
Notify the Principal Investigator/Sponsor-Investigator and document the reason 
for withdrawal from study and the date of discontinuation.  
4.6 
Duration of Follow Up 
Patients will be followed for 1 year from the completion of treatment according to the 
Time and Events table in section 5.4. 
4.7 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in section 5.5 apply. 
Notify the Principal Investigator (or the co-Investigators if not available) and document the 
reason for treatment discontinuation and the date of discontinuation. The subject should 
be followed-up per protocol.  
4.8 
Subject Replacement 
Subjects may be replaced in the study if they do not complete RT for reasons not related 
to toxicities associated with treatment. Because inadequate receipt of treatment may lead 
to a spuriously high rate of recurrence and/or inaccurate assessment of treatment side 
effects, these patients may be replaced. Patient replacement must be verified through 
review of the case by the Principal Investigator (or the co-Investigators if Principal 
Investigator is not available). 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 30 days prior to registration into the 
study unless otherwise stated. The screening procedures include: 
5.1.1 
Informed Consent 
5.1.2 
Medical history 
• 
Complete medical and surgical history 
 
5.1.3 
Demographics 
• 
Age, gender, race 

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5.1.4 
Review subject eligibility criteria 
5.1.5 
Review previous and concomitant medications 
5.1.6 
Physical exam including vital signs 
• 
Temperature, pulse, blood pressure 
5.1.7 
Performance status 
• 
ECOG Performance status (0-2) or Karnofsky Performance Status (50-100) 
5.1.8 
Adverse event assessment 
• 
Baseline adverse events will be assessed pre-treatment using CTCAE v5.0. 
See section 7.2 for adverse event monitoring and reporting. 
5.1.9 
Pregnancy test (for females of child bearing potential) 
• 
See section 3.1.5.1 for definition 
5.1.10 Completion of PRO instruments (before start of radiation treatment) 
• 
MDADI 
• 
UW-QOL 
• 
EQ-5D-5L 
5.1.11 Feeding tube dependence assessment 
• 
See section 2.3.2 for definition 
5.1.12 Standard lab work including creatinine 
• 
Assessment for cisplatin eligibility per medical oncologist 
5.2 
Procedures During Treatment 
Dose escalation phase: 
During each week of radiotherapy, following will be evaluated: 
• 
Vital signs 
• 
Physical exam  
• 
ECOG performance status or Karnofsky performance status  
• 
Adverse events assessment using CTCAE v5.0  
 
Dose expansion phase: 
Weekly visits will be conducted by the care team as per standard of care and not as part 
of trial procedures. 
5.3 
Follow-up Procedures 
Patients will be assessed by a radiation oncologist and/or advanced practice provider at 1 
month (+/- 1 week) and 3 months (+/- 2 weeks) from the completion of treatment per 
Time and Events Table (Section 5.4). More frequent visits are encouraged if the patient 
requires additional help with recovery and rehabilitation. Restaging PET/CT must be 
performed between 12-14 weeks from the completion of treatment.  
 
Patients with a clinical complete response (cCR) based on history and physical exam and 
restaging PET/CT at 12-14 weeks as defined in Section 6.1.1 will undergo routine 
surveillance. Patients with less than cCR in the primary site will undergo directed biopsy 
of suspected site(s), and if positive, proceed with salvage transoral robotic surgery 

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(TORS). Patients with less than cCR in the neck will undergo neck dissection, with the 
extent of the neck dissection to be determined by surgeon discretion.  
 
Patients with pathologically confirmed viable residual primary disease will be considered 
to have locoregional failure. Since the viability of residual nodal disease on pathology is 
often questionable at this time point (12-14 weeks post-treatment), and because adjuvant 
neck dissection is typically considered part of the original treatment package, residual 
nodal disease at neck dissection will not be considered a locoregional failure.  
 
Patients will then be seen at 6 and 12 months (+/- 4 weeks) from the completion of 
treatment per Time and Events Table (Section 5.4). Patients with pathologically 
confirmed recurrent disease following assessment at these times points will be 
considered to have locoregional failure/recurrence. Subsequent and intervening follow-up 
visits will be made per physician preference. 
5.4 
Time and Events Table  
Procedures/ Times 
Pre-
treatment 
Weekly 
during 
treatmenta 
1b, 3c, 6d, 
12d months 
post 
treatment 
History and PE 
Xe 
X 
X 
Performance status 
(ECOG/ KPS)  
Xe 
X 
X 
AE assessment 
Xf 
X 
X 
DLT assessment (only 
during dose escalation 
phase) 
 
X 
X 
Patient reported 
outcomes (MDADI, UW-
QOL, EQ-5D-5L) 
Xf 
 
X 
Feeding tube 
dependence 
assessment 
Xg 
 
X 
Pregnancy test 
Xh 
 
 
Lab work (creatinine) 
X 
 
 
Restaging PET/CT 
 
 
Xi 
a Only during the dose escalation phase 
b +/- 1 week 
c +/- 2 weeks 
d +/- 4 weeks 
e ≤ 30 days prior to registration  
f Prior to initiation of RT  
g At the time of radiation oncology consultation 
h Urine or serum in applicable female within 2 weeks of registration 
i At 12-14 weeks post RT only 
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted) 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up, see section 
4.5.1) 

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5.5.3 
Subject is unable to comply with protocol requirements 
5.5.4 
Subject demonstrates disease progression, however, continued treatment with 
study drug/treatment is permissible at the discretion of the investigator 
5.5.5 
Subject experiences toxicity that makes continuation in the protocol unsafe 
5.5.6 
Treating physician determines continuation on the study would not be in the 
subject’s best interest 
5.5.7 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event) 
5.5.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study 
5.5.9 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of one year, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the one year must be documented. 
6.0 
MEASUREMENT OF EFFECT 
6.1 
Antitumor Effect 
6.1.1 
Definitions 
Evaluable for toxicity: All subjects will be evaluable for toxicity from the time of 
their first treatment with radiotherapy. 
 
Clinical complete response (cCR): Disappearance of all lesions on 
physical/clinical exam and negative PET/CT (12-14 weeks post-treatment), 
defined as no focal FDG avidity at the primary site (i.e. may have diffuse avidity 
consistent with post-radiation inflammation) and no focal FDG avidity above 
blood pool or liver of treated pathological lymph nodes per the Hopkins criteria 
(24). There can be no appearance of new lesions. 
 
Locoregional recurrence (LRR): Biopsy-proven viable cancer originating from the 
primary tumor site (i.e. oropharynx) or a lymph node basin above the clavicles. 
 
Locoregional control (LRC): Freedom from locoregional recurrence 
 
Distant metastasis (DM): Recurrent cancer below the clavicles. Biopsy is strongly 
recommended but not mandated. If biopsy is not obtained, the initiation of anti-
cancer therapy is assumed to indicate metastasis, with the date of scan 
prompting therapy serving as the date of metastasis. 
 
Progression: locoregional recurrence or distant metastasis 
 
Progression-free survival (PFS): Duration of time from start of treatment to time 
of progression or death. 
 
Overall survival (OS): Duration of time from start of treatment to time of death. 
6.1.2 
Response Assessment 
Patients who do not meet the cCR definition (section 6.1.1) during the evaluation 
at 12-14 weeks post-treatment will undergo pathologic evaluation as outlined in 
section 5.3. 

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6.1.3 
Outcomes Assessment 
Patients will be assessed for oncologic outcomes including LRC, PFS, and OS at 
12-14 weeks post-treatment and at subsequent follow-ups at 6 and 12 months. 
6.2 
Safety/Tolerability 
Analyses will be performed for all subjects having received at least one fraction of 
radiation. The study will use the CTCAE version 5.0 for reporting of adverse events.  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
6.3 
Quality of life 
6.3.1 
UW-QOL 
UW-QOL (Appendix C) is a concise patient-reported QOL survey with 12 
domains including pain, appearance, activity level, recreation, swallowing, 
chewing, speech, shoulder function, taste, saliva, depression, and anxiety (25). A 
composite score can be derived for physical and social/emotional subscales. The 
most recent version, version 4, has incorporated mood and anxiety to capture the 
emotional QOL of patients with head and neck cancer (25). 
 
6.3.2 
MDADI 
MDADI (Appendix D) is a validated self-assessment to specifically assess 
dysphagia’s impact on the quality of life of patients with head and neck cancer 
(26). It is scored on a scale of 20 to 100 with higher score denoting better quality 
of life. MDADI is divided into subscales including functional, physical, emotional, 
and global domains with a combined composite score. A 10-point difference in 
score has been shown to be clinically meaningful (27). 
6.3.3 
EQ-5D-5L 
EQ-5D-5L (Appendix E) is one of the most widely used assessment of health 
status and QOL internationally, composed of 5 items to address mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression with an update in 
2011 to expand each response to five levels (from three levels previously) (28).   
7.0 
ADVERSE EVENTS 
7.1 
Experimental Therapy 
Experimental therapy is de-intensified hypofractionated radiation therapy. Concurrent 
chemotherapy is considered standard of care. 
7.1.1 
Contraindications 
There are no special contraindications for this study beyond typical 
contraindications to radiation therapy or chemotherapy. 
7.1.2 
Special Warnings and Precautions for Use 
None 
7.1.3 
Interaction with other medications 
None 
7.1.4 
Adverse Reactions 
Head and neck radiotherapy and chemoradiotherapy are associated with 
potential acute and late toxicities. 

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• 
Acute adverse reactions: 
o 
Fatigue and weight loss 
o 
Loss of taste and appetite 
o 
Dysphagia and odynophagia 
o 
Mucositis 
o 
Dermatitis 
• 
Late adverse reactions: 
o 
Dysphagia 
o 
Xerostomia 
o 
Altered taste 
o 
Lymphedema 
o 
Soft tissue damage (rare) 
o 
Osteoradionecrosis (rare) 
o 
Nerve or neurologic damage (rare) 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies. Adverse events are assessed in a routine manner at 
scheduled times during a trial. Additionally, certain adverse events must be reported in an 
expedited manner to allow for optimal monitoring of subject safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study 
therapy, will be monitored until:  
➢ the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline or is stable in the opinion of the investigator;  
➢ there is a satisfactory explanation other than the study therapy for the changes 
observed; or 
➢ death. 
 
7.2.1 
Definitions  
An adverse event is defined as any untoward or unfavorable medical occurrence 
in a human research study participant, including any abnormal sign (for example, 
abnormal physical exam, imaging finding or clinically significant laboratory 
finding), symptom, clinical event, or disease, temporally associated with the 
subject’s participation in the research, whether or not it is considered related to 
the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse 
events occur most commonly in the context of biomedical research, although on 
occasion, they can occur in the context of social and behavioral research. 
Adverse events may be expected or unexpected. 
Acute Adverse Events  
Adverse events occurring in the time period from the signing of the informed 
consent, through 90 days post treatment will be considered acute adverse 
events. The protocol will separately define Dose Limiting Toxicity in section 9.1 
as applicable. 
Late Adverse Events 
Adverse effects occurring in the time period from the end of acute monitoring, to 
12 months post treatment, will be defined as late adverse events. The study team 
will review encounters in the following select specialty categories relevant to study 
endpoints: radiation oncology, medical oncology, and otolaryngology. The queried 

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encounters will be limited in scope based on categorization of events; namely, 
encounters that are related to any head and neck or gastrointestinal event or 
problem. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. 
Adverse events not specifically defined in the NCI CTCAE will be scored on the 
Adverse Event log according to the general guidelines provided by the NCI 
CTCAE and as outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life 
threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
OHRP and UTSW HRPP define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
• 
results in death; 
• 
is life-threatening (places the subject at immediate risk of death from the 
event as it occurred); 
• 
results in inpatient hospitalization1,2 or prolongation of existing 
hospitalization; 
• 
results in a persistent or significant disability/incapacity; 
• 
results in a congenital anomaly/birth defect; or 
• 
based upon appropriate medical judgment, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of 
the other outcomes listed in this definition. 
 
Note: A “Serious adverse event” is by definition an event that meets any of the 
above criteria. Serious adverse events may or may not be related to the research 
project. A serious adverse event determination does not require the event to be 
related to the research. That is, both events completely unrelated to the condition 
under study and events that are expected in the context of the condition under 
study may be serious adverse events, independent of relatedness to the study 
itself. As examples, a car accident requiring >24 hour inpatient admission to the 
hospital would be a serious adverse event for any research participant; likewise, 
in a study investigating end-stage cancer care, any hospitalization or death which 
occurs during the protocol-specified period of monitoring for adverse and serious 
adverse events would be a serious adverse event, even if the event observed is 
a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. 
Note: If events occur during a pre-planned hospitalization or surgery, that prolong 
the existing hospitalization, those events should be evaluated and potentially 
reported as SAEs.   
2NCI defines hospitalization for expedited AE reporting purposes as an inpatient 
hospital stay equal to or greater than 24 hours. Hospitalization is used as an 
indicator of the seriousness of the adverse event and should only be used for 
situations where the AE truly fits this definition and NOT for hospitalizations 

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associated with less serious events. For example: a hospital visit where a patient 
is admitted for observation or minor treatment (e.g. hydration) and released in 
less than 24 hours. Furthermore, hospitalization for pharmacokinetic sampling is 
not an AE and therefore is not to be reported either as a routine AE or in an 
expedited report. 
7.2.2 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is 
found, but not defined in the HHS regulations at 45 CFR 46, and the FDA 
regulations at 21 CFR 56.108(b)(1) and 21 CFR 312.66. Guidance from the 
regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied;  
 
 
 
 
AND 
• 
Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. Note: According to OHRP, if the adverse 
event is serious, it would always suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
7.3 
Steps to Characterize a Serious Adverse Event for Reporting to the SCCC DSMC 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to treatment must also be reported as 
indicated in the sections below. 
 
Step 4: Determine the expectedness of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the treatment. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 

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• 
the current known adverse events listed in the Agent Information Section of this 
protocol (if applicable); 
• 
the drug package insert (if applicable); 
• 
the current Investigator’s Brochure (if applicable) 
• 
the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
7.3.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
SAEs and UPIRSOs at all sites, which occur in research subjects on protocols 
for which the SCCC is the DSMC of record require reporting to the DSMC 
regardless of whether IRB reporting is required. All SAEs occurring during the 
protocol-specified monitoring period and all UPIRSOs should be 
submitted to the SCCC DSMC within 5 business days of the study team 
members awareness of the event(s). In addition, for participating centers 
other than UTSW, local IRB guidance should be followed for local reporting of 
serious adverse events or unanticipated problems. 
 
The UTSW study PI is responsible for ensuring SAEs/UPIRSOs are submitted to 
the SCCC DSMC Coordinator. This may be facilitated by the IIT project manager, 
study team, sub-site or other designee. Electronic versions of the eIRB 
Reportable Event report; FDA Form #3500A forms, or other sponsor forms, if 
applicable; and/or any other supporting documentation available should be 
submitted to the DSMC.  
 
UT Southwestern and affiliated will submit documentation via the SAE submission 
portal. All subsites participating in multi-center study may utilize the Serious 
Adverse Event Template and submit to the IIT Project Manager, or designee. The 
DSMC Coordinator will route the form to the DSMC Chair who determines if 
immediate action is required.  Follow-up eIRB reports, and all subsequent SAE 
or UPIRSO documentation that is available are also submitted to the DSMC Chair 
who determines if further action is required via the same process. (See Appendix 
V of the SCCC DSMC Plan for instructions on how to submit SAEs through the 
portal and for a template Serious Adverse Event Form which may be utilized by 
subsites on multi-center IIT studies). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW 
Simmons Comprehensive Cancer Center, the IIT Project Manager or designee 
ensures that all participating sites are notified of the event and resulting action, 
according to FDA guidance for expedited reporting. DSMC Chair reviews all 
SAEs and UPIRSOs upon receipt from the DSMC Coordinator.  The DSMC 
Chair determines whether action is required and either takes action 
immediately, convenes a special DSMC session (physical or electronic), or 
defers the action until a regularly scheduled DSMC meeting.  
 
Telephone reports to: 
Sarah Neufeld, Clinical Research Manager 
214-648-1836 
Written reports to: 
Department of Radiation Oncology 
Clinical Research Office 
The University of Texas Southwestern Medical Center 
Attention: Sarah Neufeld, Project Manager 
 

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2201 Inwood Road 
Dallas, Texas  75390-9303 
FAX #: 214-648-5923 
Email: sarah.hardee@utsouthwestern.edu 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit a Reportable Event via eIRB with a copy of the final sponsor report as attached 
supporting documentation 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs) to the UTSW HRPP 
 
UTSW reportable event guidance applies to all research conducted by or on 
behalf of UT Southwestern, its affiliates, and investigators, sites, or institutions 
relying on the UT Southwestern IRB. Additional reporting requirements apply for 
research relying on a non-UT Southwestern IRB. 
 
According to UTSW HRPP policy, UPIRSOs are incidents, experiences, 
outcomes, etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in 
a subject’s underlying condition or not expected as a risk of the study; 
therefore, not included in the investigator’s brochure, protocol, or informed 
consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized.  Note: According to OHRP, if the adverse 
event is serious, it would always suggest a greater risk of harm. 
 
UPIRSOs must be promptly reported to the UTSW HRPP within 5 working days 
of study team awareness. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, 
summarized, and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/hrpp/assets/policy_9.5reportable.pdf 
7.4 
Unblinding Procedures 
Not applicable to current protocol. 
7.5 
Stopping Rules 
The primary hypothesis of the phase 1 study is that de-intensified HFRT is safe and 
tolerable. The trial will terminate during the rolling 6 dose escalation phase if it has 
reached level -1 and 2 patients experience dose limiting toxicity (DLT) at this dose level. 
 
The secondary hypothesis is that the crude 1-year LRC rate is at least 85% (based on 
historical controls). In other words, for the target of 20 evaluable patients at 1 year, up to 3 

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patients can have a LRR and satisfy the pre-specified hypothesis. Thus, if a 4th patient 
enrolled on the trial experiences LRR within 1 year of completing the study treatment, the 
trial will be terminated for futility. 
8.0 
DRUG/TREATMENT INFORMATION 
8.1 
Cisplatin 
• 
Other names for the drug(s): Platinol 
 
• 
Classification - type of agent: Cytotoxic chemotherapy 
 
• 
Mode of action: The dominant mode of action of cisplatin appears to be inhibition 
of the incorporation of DNA precursors, although protein and RNA synthesis are 
also inhibited. Although this drug seems to act as an alkylating agent, there are 
data to indicate that its mode and sites of action are different from those of 
nitrogen mustard and the standard alkylating agents. 
 
• 
Storage and stability: Please refer to the cisplatin prescribing information for 
storage and stability of the cisplatin commercial product 
 
• 
Protocol dose: Weekly 
 
• 
Preparation: Please refer to the cisplatin prescribing information for storage and 
stability of the cisplatin commercial product. 
 
• 
Route of administration for this study: Intravenous 
 
• 
Incompatibilities: Cisplatin may interact with metal aluminium to form a black 
precipitate of platinum. All aluminium-containing IV sets, needles, catheters and 
syringes should be avoided. There is a total loss of cisplatin in 30 minutes at 
room temperature when mixed with metoclopramide and sodium metabisulphite 
in concentrations equivalent to those that would be found on mixing with a 
commercial formulation of metoclopramide. Cisplatin and sodium bisulphite have 
been known to react chemically. Such antioxidants might inactivate cisplatin 
before administration if they are present in intravenous fluids. 
 
• 
Availability: Commercially available 
 
• 
Side effects: Human toxicity includes nausea, vomiting, renal toxicity (with an 
elevation of BUN and creatinine and impairment of endogenous creatinine 
clearance, as well as renal tubular damage, which appears to be transient), 
ototoxicity (with hearing loss that initially is in the high-frequency range, as well 
as tinnitus), and hyperuricemia. Much more severe and prolonged toxicity has 
been observed in patients with abnormal or obstructed urinary excretorytracts. 
Myelosuppression, often with delayed erythrosuppression, is expected. Please 
see the package insert for a comprehensive list of adverse events.  
 
• 
Nursing implications: Not applicable 
8.1.1 
Return and Retention of Study Drug 
Not applicable 
9.0 
STATISTICAL CONSIDERATIONS 

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9.1 
Study Design/Study Endpoints 
9.1.1 
Study design:  
Phase I Rolling 6 design with dose expansion cohort 
Study design will be a rolling 6 dose escalation study, a modification to the 
standard 3 + 3 design (29). In contrast to the 3 + 3 design where patients are 
enrolled in cohorts of 3, the rolling 6 design allows for continuous enrollment up 
to a total of 6 patients at the same dose level. The dose level assigned to a new 
patient is based on the number of patients currently enrolled and evaluable, and 
the number of patients experiencing a DLT. Once six patients have been enrolled 
at the current dose level, enrollment will stop until at least 5 of the 6 patients 
have completed evaluation for DLT. Escalation to the next dose level occurs if at 
time of enrollment 3/3, 4/4, 5/5, 5/6, or 6/6 patients at the dose level are 
evaluated for and without DLT. De-escalation occurs if at the time of enrollment, 
2 or more patients have experienced a DLT at the dose level. 
 
DLT definition: 
• 
Any CTCAE grade 4 toxicity (generally described as life-threatening 
consequences with urgent intervention indicated) attributed to RT during 
and up to 3 months post-treatment 
• 
Persistent CTCAE grade 3 mucositis at 3 months post-treatment 
o 
CTCAE definitions: 
▪ 
Oral mucositis: severe pain; interfering with oral intake 
▪ 
Pharyngeal mucositis: severe pain; unable to adequately 
aliment or hydrate orally; limiting self-care ADL 
o 
To decrease subjectivity of interpretation by each clinician, the 
definition for grade 3 mucositis was consolidated as below: 
▪ 
Severe pain defined as needing daily opioid use of >30 
morphine equivalent dose during the past week for 
mucositis, AND 
▪ 
The pain interferes with oral intake or swallowing defined 
as tolerating a liquid only diet or requiring tube feeds 
(with the exception of patients who were on a liquid only 
diet at baseline prior to RT, in which case they would 
need to be feeding tube dependent to satisfy this 
definition). 
 
MTD definition: highest dose/fractionation level among those listed in section 
4.1.2 at which ≤1 of 6 patients have experienced a DLT. 
 
During the dose expansion phase, patients will be enrolled at MTD to reach the 
total accrual goal of 24 patients.  
9.1.2 
Primary endpoint 
• 
MTD of HFRT 
9.1.3 
Secondary endpoints 
• 
Physician-reported acute and late toxicities 
o 
Rate of ≥grade 3 acute toxicities during treatment, and at 1 and 3 months 
after treatment using CTCAE v5.0 
o 
Rate of ≥grade 3 late toxicities at 6 and 12 months after treatment using 
CTCAE v5.0 
• 
Oncologic outcomes: LRC, PFS, and OS from start of treatment 
• 
Patient-reported QOL: 

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o 
MDADI, UW-QOL, and EQ-5D-5L scores at baseline, 1, 3, 6, and 12 
months after treatment 
• 
Feeding tube dependence rate at baseline, 1, 3, 6, and 12 months after 
treatment 
9.2 
Sample Size and Accrual 
We anticipate 3-6 patients in each cohort with a maximum of 12 total patients (e.g. 6 in 
level 0, 6 in level 1 or -1) during the Rolling 6 dose escalation phase. 
 
During the dose expansion phase, patients will be accrued until a total sample size of 24 
is reached to ensure at least 20 evaluable patients at 1 year assuming an attrition rate of 
15%. We anticipate accruing 3 patients per month for a total accrual period of 
approximately 3 years accounting for time to reach the primary endpoint at 3 months prior 
to enrolling on to the next cohort. 
9.3 
Data Analyses 
9.3.1 
Primary endpoint  
 
9.3.1.1 MTD  
Acute toxicity will be assessed weekly during treatment and 2 weeks, 1, 2, and 3 
months post-treatment to assess for DLT to determine the MTD as outlined in 
Section 9.1.1. 
9.3.2 
Secondary endpoints 
 
9.3.2.1 Locoregional control 
LRC will be analyzed based on the definition in section 6.2 and estimated using  
cumulative incidence statistics, with death serving as a competing risk.  
 
9.3.2.2 Progression free survival and overall survival 
PFS and OS outcomes will be analyzed based on the definition in section 6.2  
and estimated using the Kaplan-Meier method. Survival endpoints will be  
calculated from the initiation of RT. 
 
9.3.2.3 Physician-reported toxicity 
Only adverse events assessed to be definitely, probably, or possibly related to  
protocol treatment will be considered. The rates of all Grade 3-5 adverse events  
will be characterized at each time point as outlined in section 5.4.  
 
9.3.2.4 Patient-reported outcomes 
The patient reported outcomes (MDADI, UW-QOL and EQ-5D-5L) will be  
collected as numeric scores at each time point as outlined in Section 5.4.  
Patients with disease recurrence will be excluded. The changes in these  
outcomes from baseline to the subsequent time points will be analyzed using  
generalized estimating equations. 
 
9.3.2.5 Feeding tube dependence 
The prevalence of feeding tube use will be described at each time point as  
outlined in section 5.4.  
10.0 STUDY MANAGEMENT 

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10.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy 
on Conflicts of Interest.  All investigators will follow the University conflict of interest 
policy. 
10.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB of record will have the proper representation and function in 
accordance with federally mandated regulations. The IRB of record must approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the 
informed consent discussion. 
10.3 
Registration/Randomization Procedures 
All patients will be registered electronically through Velos. All research data will be 
recorded and entered into Case Report Forms using REDCap (when applicable). 
 
All subjects must be registered with the Research Office before enrollment to study. Prior 
to registration, eligibility criteria must be confirmed with the Research Office Study 
Coordinator. 
 
New subjects will receive a number beginning with 01 upon study consent such that the 
first subject consented is numbered 01, the second subject consented receives the 
number 02, etc.  
 
Upon confirmation of eligibility and enrollment as per the afore-mentioned instructions, 
the subject will be assigned a secondary number in the order of enrollment. For example, 
subject 01 will become 01-101 upon enrollment. If subject 02 screen fails, and subject 03 
is the next subject enrolled, subject 03 will become 03-102 and so-on.  
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration/randomization code 
according to the numbering schema outlined above, which should then be entered as the 
patient study id in Velos upon updating the status to enrolled. 
 
The numbering schema should clearly identify the site number; the sequential number of 
the subject consented as well as the status of the subjects enrolled so that the number of 
subjects consented versus the number of subjects actually enrolled may be easily 
identified.   

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10.4 
Data Management and Monitoring/Auditing 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic 
case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements, as appropriate for the project. 
 
Trial monitoring will be conducted according to the study specific monitoring plan. For 
guidance on creating a monitoring plan, refer to the UTSW SCCC IIT Management 
Manual.   
 
Toxicity and dose escalation reviews will be performed at least annually and at time of 
dose escalation or de-escalation on this Phase I study. This review includes but is not 
limited to accuracy of case report forms, protocol compliance, timeless and accuracy of 
Velos entries and AE/SAE management and reporting. Documentation of trial monitoring 
will be maintained along with other protocol related documents and will be reviewed 
during internal audit.   
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the SCCC DSMC reviews all 
local and sub-site serious adverse events and UPIRSOs in real time as they are reported 
and reviews adverse events on a quarterly basis.  The quality assurance activity for the 
Clinical Research Office provides for periodic auditing of clinical research documents to 
ensure data integrity and regulatory compliance.  A copy of the DSMC plan is available 
upon request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The Quality Assurance 
Coordinator (QAC) works as part of the DSMC to conduct regular audits based on the 
level of risk. Audit findings are reviewed at the next available DSMC meeting.  In this 
way, frequency of DSMC monitoring is dependent upon the level of risk.  Risk level is 
determined by the DSMC Chairman and a number of factors such as the phase of the 
study; the type of investigational agent, device or intervention being studied; and 
monitoring required to ensure the safety of study subjects based on the associated risks 
of the study. Protocol-specific DSMC plans must be consistent with these principles.  
10.5 
Adherence to the Protocol 
Except for an emergency situation, in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
 
Any deviation from the protocol requirements, whether pre-approved or unexpected, are 
to be recorded/logged as a protocol deviation and reported per institutional policy.  
10.5.1 Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
• Intentional on part of the investigator; and/or 
• In the investigator’s control; and/or 
• Not intended as a systemic change (e.g., single-subject exceptions to 
eligibility [inclusion/exclusion] criteria) 
➢ Reporting requirement*: Exceptions are non-emergency deviations that 
require prospective IRB approval before being implemented. Call the IRB if 

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your request is urgent. If IRB approval is not obtained beforehand, this 
constitutes a major deviation. For eligibility waivers, studies which utilize the 
SCCC-DSMC as the DSMC of record must also obtain approval from the 
DSMC prior to submitting to IRB for approval.  
10.5.2 Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
• Avoid immediate apparent harm, and/or 
• Protect the life or physical well-being of subjects or others 
➢ Reporting requirement*: Emergency deviations must be promptly 
reported to the IRB within 5 working days of occurrence. 
10.5.3 Serious Noncompliance (formerly called major deviations or violations): 
include any departure from IRB-approved research that: 
• Increase risk of harm to subjects; and/or 
• Adversely affects the rights, safety, or welfare of subjects (any of which may 
also be an unanticipated problem); and/or  
• Adversely affects the integrity of the data and research (i.e., substantially 
compromises the integrity, reliability, or validity of the research) 
➢ Reporting requirement*: Serious Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 
 
 
10.5.4 Continuing Noncompliance: includes a pattern of repeated noncompliance (in 
one or more protocols simultaneously, or over a period of time) which continues 
after initial discovery, including inadequate efforts to take or implement corrective 
or preventive action within a reasonable time frame. 
➢ Reporting requirement*: Continuing Noncompliance must be promptly 
reported to the IRB within 5 working days of discovery. 
 
10.5.5 Noncompliance (that is neither serious nor continuing; formerly called 
minor deviations) any departure from IRB-approved research that: 
• Does not meet the definition of serious noncompliance or continuing 
noncompliance 
➢ Reporting requirement*: Noncompliance that is neither serious nor 
continuing should be tracked and summarized the next IRB continuing review, 
or the notice of study closure- whichever comes first. 
 
*Reporting Requirements reflect UTSW HRPP/IRB guidelines; participating sites should follow 
the reporting guidelines for their IRB of record 
10.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  

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10.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory & essential documents (e.g., protocol and amendments, IRB correspondence 
and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
10.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered into the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
 
 
 
 
 
 
 
 
11.0 REFERENCES 
1. O’Sullivan B, Huang SH, Su J, et al. Development and validation of a staging system for HPV-related 
oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging 
(ICON-S): a multicentre cohort study. Lancet Oncol. 2016;17:440–451. 
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12.0 APPENDICES 
Appendix A: AJCC Staging, 8th Edition 
1.0 Primary 
1.1 Oropharynx (p16+) 
T1: Tumor ≤2 cm 
T2 Tumor >2 but ≤4 cm 
T3: Tumor >4 cm or extension to lingual surface of epiglottis 
T4: Tumor invades larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, mandible, or beyond 
 
1.2 Oropharynx (p16-) 
T1: Tumor ≤2 cm 
T2 Tumor >2 but ≤4 cm 
T3: Tumor >4 cm or extension to lingual surface of epiglottis 
T4a: Tumor invades larynx, extrinsic muscles of tongue, medial pterygoid, hard palate, or mandible 

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T4b: Tumor invades lateral pterygoid, pterygoid plates, lateral nasopharynx, skull base, or encasing 
carotid a. 
 
2.0 Node 
2.1 Oropharynx (p16+) 
cN1: one or more ipsilateral lymph node(s) ≤6 cm 
cN2: contralateral or bilateral lymph node(s) ≤6 cm 
cN3: Lymph node >6 cm 
pN1: <5 lymph nodes 
pN2: ≥5 lymph nodes 
 
2.2 Oropharynx (p16-) 
c/pN1: single lymph node (≤3 cm) and no extranodal extension (ENE) 
cN2a: single ipsilateral lymph node (>3 cm but ≤6 cm) and -ENE  
pN2a: single ipsilateral lymph node (>3 cm but ≤6 cm) and -ENE OR single ipsilateral LN ≤3 cm and 
+ENE 
c/pN2b: multiple ipsilateral lymph nodes (≤6 cm) and -ENE 
c/pN2c: bilateral or contralateral lymph node (≤6 cm) and -ENE 
c/pN3a: Lymph node >6 cm and -ENE 
cN3b: clinically overt ENE 
pN3b: lymph node >3 cm and +ENE 
 
 
Appendix B: ECOG Performance Status / Karnofsky Performance Status 
0 Fully active, able to carry on all predisease activities without restriction (Karnofsky 90-100). 
 
1 Restricted in physically strenuous activity but ambulatory and able to carry work of a light or sedentary 
nature. For example, light housework, office work (Karnofsky 70-80). 
 
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more 
than 50% of waking hours (Karnofsky 50- 60). 
 
3 Capable of only limited self-care, confined to bed or chair 50% or more of waking hours (Karnofsky 30-
40). 
 
4 Completely disabled. Cannot carry on self-care. Totally confined to bed or (Karnofsky 10-20). 
 
5 Death (Karnofsky 0). 
 
 
 
Appendix C: UW-QOL 

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Appendix D: MDADI 
 
 

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Appendix E: EQ-5D-5L 
 

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