A Randomized Phase II/III Trial of De-Intensified Radiation Therapy for Patients With Early-Stage, P16-Positive, Non-Smoking Associated Oropharyngeal Cancer
Phase: PHASE2
Conditions: Basaloid Squamous Cell Carcinoma, Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Oropharyngeal Squamous Cell Carcinoma, Papillary Squamous Cell Carcinoma, Pathologic Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Squamous Cell Carcinoma
Sponsor: National Cancer Institute (NCI)

NRG-HN005 
1                     Version Date: August 21, 2023 
 
NRG ONCOLOGY  
 
NRG-HN005 
(ClinicalTrials.gov NCT #03952585)(04-NOV-2020) 
 
A RANDOMIZED PHASE II/III TRIAL OF DE-INTENSIFIED RADIATION THERAPY 
FOR PATIENTS WITH EARLY-STAGE, P16-POSITIVE, NON-SMOKING 
ASSOCIATED OROPHARYNGEAL CANCER 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the 
participation of the network of NCTN organizations: the Alliance for Clinical Trials in 
Oncology; ECOG-ACRIN Medical Group; and SWOG. 
 
Coordinating Center:  
NRG Oncology, Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team (19-APR-2023) 
 
Principal Investigator/Radiation Oncology  
Sue S. Yom, MD, PhD 
University of California, San Francisco 
1600 Divisadero St, Suite H1031 
San Francisco, CA 94143 
415-353-7175/FAX 415-353-98883 
sue.yom@ucsf.edu 
 
Medical Oncology Co-Chair 
Jessica Geiger, MD  
Cleveland Clinic Taussig Cancer Institute  
9500 Euclid Avenue 
Cleveland, OH 44195 
216-444-0888/FAX 216-444-9464 
geigerj@ccf.org 
 
Imaging Co-Chairs 
Rathan Subramaniam, MD, PhD, MPH 
Dunedin School of Medicine  
290 Great King Street 
Dunedin, 9016 NZ 
64-3-479-5056 
rathan.subramaniam@otago.ac.nz  
 
 
 
 
Radiation Oncology Co-Chairs  
John Waldron, MD 
Princess Margaret Hospital 
610 University Avenue 
Toronto, ON M5G 2M9, Canada 
416-946-6522/FAX 416-946-2111 
john.waldron@rmp.uhn.ca  
 
Jimmy J. Caudell, MD, PhD 
Moffitt Cancer Center/ 
University of South Florida 
12902 Magnolia Drive 
Tampa, FL 33612 
813-745-3547/FAX 813-745-7231 
jimmy.caudell@moffitt.org   
 
Quality of Life Co-Chair 
Canhua Xiao PhD, RN, FAAN 
Emory University  
1520 Clifton Road 
Atlanta, GA 30322 
404-712-9633 
canhua.xiao@emory.edu 
 
 
 
 

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Min Yao, MD, PhD 
Department of Radiation Oncology 
Penn State Health  
Penn State Cancer Institute 
Hershey, PA 17036 
717-531-1523/FAX 717-531-0446 
myao@pennstatehealth.psu.edu 
 
Medical Physics Co-Chair 
Nataliya Kovalchuk, PhD 
Stanford University 
875 Blake Wilbur Dr 
Stanford, CA 94305 
650-723-5746/FAX 650-725-8231 
nataliya.kovalchuk@stanford.edu  
 
Swallowing Outcomes Co-Chair 
Rosemary Martino, MA, MSc, PhD 
University of Toronto 
University Health Network-Princess Margaret 
Hospital 
160-500 University Avenue  
Toronto, Ontario M5G 1V7, Canada 
416-946-8644/FAX 416-978-1596 
rosemary.martino@utoronto.ca   
 
Pathology Co-Chair 
Richard Jordan, DDS, PhD 
University of California, San Francisco 
(UCSF) Medical Center-Mount Zion 
Department of Radiation Oncology 
2340 Sutter Street, Rm S341 
San Francisco, CA 94115 
415-608-9378 
richard.jordan@ucsf.edu 
 
Translational Science Co-Chair 
Maura Gillison, MD 
MD Anderson Cancer Center 
1400 Holcombe Blvd 
Houston, TX 77030 
713-792-6363 
mgillison@mdanderson.org  
 
Senior Statistician 
Pedro Torres-Saavedra, PhD 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-0851/FAX 215-928-0153 
torresp@nrgoncology.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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NRG Oncology Contact Information (21-AUG-2023) 
Data Management 
For questions concerning eligibility or 
data submission 
Holly LaPerriere 
Jessi Leichtnam 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-940-8887 (LaPerriere) 
215-574-3241 (Leichtnam) 
FAX 215-940-8830 
laperriereh@nrgoncology.org 
leichtnamj@nrgoncology.org  
RTQA 
For questions concerning RT data 
submission 
 
Marsha Radden, BS, R.T.(R)(T) 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-2757  
mradden@acr.org 
RT Credentialing 
 
http://irochouston.mdanderson.org 
OR 
IROC-Credentialing@mdanderson.org  
RT data submission to TRIAD 
 
Triad-Support@acr.org 
Protocol Development: 
For questions concerning protocol and 
informed consent versions & 
amendments 
Thien Nu Do, PharmD 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3174  
dot@nrgoncology.org  
Head and Neck Committee Chair 
Current Chair starting August 2021 
Sue S. Yom, MD, PhD, MAS, FASTRO 
University of California San Francisco 
1600 Divisadero St, Suite H1031 
San Francisco, CA 94143 
415-353-7175/FAX 415-353-98883 
sue.yom@ucsf.edu   
 
Prior Chair 
Quynh-Thu Le, MD 
Stanford University 
875 Blake Wilbur Drive, MC 5847 
Stanford, CA 94305 
650-498-5032/FAX 650-725-8231 
qle@stanford.edu  
 
 
 

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4                     Version Date: August 21, 2023 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Nivolumab 
CTEP/PMB 
748726 
 
DCTD, NCI 
Cisplatin 
Commercial 
119875 
 
Participating Sites (04-NOV-2020) 
 U.S. 
 Canada  
 Approved International Member Sites 
 
 
 
Document History 
 
Version Date 
Amendment 4 
August 21, 2023 
Amendment 3 
April 19, 2023 
Amendment 2 
February 16, 2021 
Amendment 1 
November 04, 2020 
Initial 
May 29, 2019 
 
 
 
 
 
 
 
  
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 

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NRG ONCOLOGY 
 
NRG-HN005 
 
A RANDOMIZED PHASE II/III TRIAL OF DE-INTENSIFIED RADIATION THERAPY 
FOR PATIENTS WITH EARLY-STAGE, P16-POSITIVE, NON-SMOKING 
ASSOCIATED OROPHARYNGEAL CANCER 
 
 
CONTACT INFORMATION (21-AUG-2023) 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must be 
submitted to the Cancer Trials Support 
Unit (CTSU) via the Regulatory 
Submission Portal. 
 (Sign in at https://www.ctsu.org, and 
select the Regulatory > Regulatory 
Submission.)  
Institutions with patients waiting that 
are unable to use the Portal should alert 
the CTSU Regulatory Office 
immediately by phone or email: 1-866-
651-CTSU (2878), or 
CTSURegHelp@coccg.org to receive 
further instruction and support. 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN related questions 
by phone or email : 1-888-823-
5923, or 
ctsucontact@westat.com. 
 
 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Refer 
to the data submission 
section of the protocol 
for further instructions.  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.   
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the Roster Maintenance application and in most cases 
viewable and manageable via the Roster Update Management System (RUMS) on the CTSU 
members’ website. 
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study Data 
Managers of the Lead Protocol Organization 

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For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) 
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For imaging data submission questions: 
IROCimagearchive@acr.org; please include trial number in the email subject line 
 
For TRIAD access and installation support: 
TRIAD-Support@acr.org 
Triadhelp.acr.org 
 
TRIAD Software Installation: 
https://triadinstall.acr.org/triadclient/ 

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7                     Version Date: August 21, 2023 
 
 
 
 
TABLE OF CONTENTS 
CURRENT Phase II/III SCHEMA (19-APR-2023) ......................................................................10 
PRIOR Phase II SCHEMA (19-APR-2023) ..................................................................................11 
1. 
OBJECTIVES ....................................................................................................................12 
1.1 
Primary Objective (19-APR-2023) ........................................................................12 
1.2 
Secondary Objectives (19-APR-2023) ..................................................................12 
1.3 
Exploratory Objectives (19-APR-2023) ................................................................12 
2. 
BACKGROUND ...............................................................................................................13 
2.1 
Rationale for Approach to De-Intensification for HPV-Associated 
Oropharyngeal Cancer ...........................................................................................13 
2.2 
Rationale for Reduced-Dose Radiation Therapy in Oropharyngeal Cancer 
Treatment ...............................................................................................................14 
2.3 
Rationale for Introduction of Immunotherapy for Oropharyngeal 
Carcinoma Patients ................................................................................................15 
2.4 
Clinical Data for Nivolumab in Head and Neck Cancer ........................................16 
2.5 
Rationale for the Duration of Nivolumab Before, Concurrently, and After 
Radiation Therapy ..................................................................................................17 
2.6 
Rationale for Patient-Reported Dysphagia-Related Outcome in HPV-
Associated Oropharyngeal Cancer Patients ...........................................................18 
2.7 
Rationale for Stratification by Zubrod Performance Status ...................................19 
3. 
ELIGIBILITY AND INELIGIBILITY CRITERIA ..........................................................19 
3.1 
Eligibility Criteria (19-APR-2023) A patient cannot be considered eligible 
for this study unless ALL of the following conditions are met. ..............................19 
3.2 
Ineligibility Criteria (04-NOV-2020) ....................................................................22 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP (19-
APR-2023) .........................................................................................................................24 
5. TREATMENT PLAN/Regimen description..............................................................................30 
5.1 
Systemic Therapy (04-NOV-2020) ........................................................................30 
5.2 
Radiation Therapy (19-APR-2023) ........................................................................32 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................53 
5.4 
Duration of Therapy ...............................................................................................54 
6. TREATMENT MODIFICATIONS/managEment .....................................................................54 
6.1 
Dose Modifications and Toxicity Management for Nivolumab (19-APR-
2023) ......................................................................................................................54 
6.2 
Recommended Dose Modifications and Toxicity Management for 
Cisplatin (14-MAR-2023) ......................................................................................62 

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7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................65 
7.1  Protocol Agents ...........................................................................................................65 
7.2 Adverse Events and Serious Adverse Events ..............................................................65 
7.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Nivolumab (NSC 78726) (21-AUG-2023) ............................................................66 
7.4 
Adverse Events for Commercial Study Agent: Cisplatin ......................................71 
7.5 
Expedited Reporting of Adverse Events (19-APR-2023) ......................................72 
7.6 
Routine Reporting Requirements for Adverse Events .....................................75 
7.6.1 Reporting PRO-CTCAE ........................................................................................75 
7.7 
Pregnancy .............................................................................................................75 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES (21-AUG-2023) ..................75 
8.1 
Cancer Trials Support Unit Registration Procedures (21-AUG-2023) ..................77 
8.2 
RT-Specific Pre-Registration Requirements (21-AUG-2023) ...............................81 
8.3      Patient Enrollment (21-AUG-2023) .......................................................................83 
9.0 
DRUG INFORMATION ...................................................................................................84 
9.1 
Agent Ordering and Agent Accountability (21-AUG-2023) .................................84 
9.2 
Investigational Study Agent: Nivolumab (IND, NSC 748726) (21-AUG-
2023) ......................................................................................................................85 
9.3 
Commercial Agent: Cisplatin (NSC# 119875) ......................................................87 
10. 
Pathology/BIOSPECIMEN................................................................................................87 
10.1 
Optional Biospecimen Submission Tables for Future Research (19-APR-
2023) ......................................................................................................................87 
11. 
SPECIAL studies (Non-Tissue) .........................................................................................91 
11.1 
Association of FDG-PET/CT Imaging with Locoregional Control and PFS ........91 
11.2 
Swallowing Substudy (04-NOV-2020)..................................................................94 
11.3 
Patient-Reported Outcomes (PROs) and Quality of Life (QOL) (19-APR-
2023) ......................................................................................................................96 
12. 
Modality Reviews ............................................................................................................100 
12.1 
Radiation Therapy Quality Assurance Reviews ..................................................100 
12.2 
Medical Oncology Modality Quality Assurance Reviews ...................................100 
13. 
DATA AND RECORDS .................................................................................................100 
13.1 
Data Management/Collection (19-APR-2023) ....................................................100 
13.2 
Summary of Data Submission (04-NOV-2020) ..................................................101 
13.3 
Data Quality Portal (21-AUG-2023) ...................................................................103 
13.4 
Global Reporting/Monitoring (04-NOV-2020) ...................................................103 
14. 
STATISTICAL CONSIDERATIONS.............................................................................104 
14.1 
Study Design (19-APR-2023) ..............................................................................104 
14.2 
Study Endpoints (04-NOV-2020) ........................................................................104 
14.3 
Primary Objectives Study Design (19-APR-2023) ..............................................104 
14.4 
Study Monitoring of Primary Objectives .............................................................108 

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14.5 
Accrual/Study Duration Considerations (19-APR-2023)                                                                   
..............................................................................................................................109 
14.6 
Secondary Endpoints (including correlative science aims) (19-APR-2023) .......109 
14.7 
Exploratory Endpoints (04-NOV-2020) ..............................................................113 
14.8 
Gender/Ethnicity/Race Distribution (19-APR-2023) ..........................................114 
REFERENCES (04-NOV-2020) .................................................................................................116 
APPENDIX I: Medidata Patient Cloud ePRO Operational Instructions .....................................127 
1.1 Introduction ................................................................................................................127 
1.2 ePRO Application Download ....................................................................................127 
1.3 CRA Site Users ..........................................................................................................127 
1.4 CRA Instructions for Setting the Patient Cloud App to Multi-User Mode................128 
1.5 Patient Users ..............................................................................................................128 
1.6 Patient Instructions for Accessing the Patient Cloud Using Your Personal 
Device ..................................................................................................................128 
1.7 Patient Compliance ....................................................................................................131 
1.8 Security ......................................................................................................................131 
1.9 Site checklist for activities prior to consenting a patient ...........................................132 
APPENDIX II: Instructions for Submission of Images to TRIAD ..............................................133 
APPENDIX III: Dental Assessment Tooth Count and Dental Management (04-NOV-2020) ...135 
APPENDIX IV: SUGGESTED ACQUISITION GUIDELINES for the Modified barium 
Swallow (MBS) Administration at Baseline and Post RT Year One and two .................140 
APPENDIX V: NCI/DCTD Collaborative Agreement ...............................................................144 
APPENDIX VI: Nivolumab Toxicity Management Algorithms .................................................146 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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NRG-HN005 
 
 
CURRENT PHASE II/III SCHEMA (19-APR-2023) 
Effective with Amendment 3 
 
 
x Oropharyngeal squamous cell carcinoma, p16-positive 
x ≤ 10 pack-year history of smoking 
x 8th ed. clinical stages T1-2N1M0 or T3N0-N1M0 (8th ed. stage I-II excluding T0, T1-
2N0, or any N2) 
 
                                                     ↓ 
STRATIFICATION 
Zubrod Performance Status: 0 vs.1 
 
                                                  RANDOMIZE* 
↓ 
 
↓ 
Arm 1** 
70 Gy radiation in 6 weeks using 6 
fractions per week 
+ 
Cisplatin  
 
 
Arm 3** 
 
60 Gy radiation in 5 weeks using 6 fractions 
per week + Nivolumab 
 
 
*Randomization is 1:1  
**See Section 5 for radiation and systemic therapy treatment details. 
Note: Arm 2 (see prior schema) eliminated after phase II interim futility analysis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PRIOR PHASE II SCHEMA (19-APR-2023) 
 
For patients enrolled prior to amendment 3; closed to accrual 03-FEB-2023 
 
 
x Oropharyngeal squamous cell carcinoma, p16-positive 
x ≤ 10 pack-year history of smoking 
x 8th ed. clinical stages T1-2N1M0 or T3N0-N1M0 (8th ed. stage I-II excluding T0, T1-
2N0, or any N2) 
 
 
 
↓ 
 
 
STRATIFICATION 
Zubrod Performance Status: 0 vs.1 
 
RANDOMIZE* 
↓ 
 
↓ 
 
↓ 
Arm 1** 
70 Gy radiation in 6 weeks 
using 6 fractions per week 
+ 
Cisplatin  
 
Arm 2** 
60 Gy radiation in 6 weeks 
using 5 fractions per week 
+ 
Cisplatin  
 
 
Arm 3** 
60 Gy radiation in 5 weeks 
using 6 fractions per week 
+ 
Nivolumab  
 
 
*Randomization is 1:1:1.  
**See Section 5 for radiation and systemic therapy treatment details. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. OBJECTIVES 
1.1 
Primary Objective (19-APR-2023) 
1.1.1 Phase II 
To demonstrate non-inferiority in terms of progression-free survival (PFS) of concurrent 
reduced-dose radiation therapy (RT) with cisplatin* or concurrent reduced-dose radiation therapy 
with nivolumab to the current standard of care (standard-dose RT with cisplatin). 
 
*Arm 2 (concurrent reduced-dose RT with cisplatin) was dropped after interim futility 
analysis in phase II. 
 
1.1.2 Phase II (REVISED) 
To demonstrate non-inferiority in terms of progression-free survival (PFS) of concurrent 
reduced-dose radiation therapy (RT) with nivolumab to the current standard of care (standard-
dose RT with cisplatin). 
 
1.1.3 Phase III 
To demonstrate co-primary endpoints of non-inferiority of PFS and superiority of quality of life 
(QOL) as measured by the MDADI of concurrent reduced-dose radiation with cisplatin* or 
concurrent reduced-dose radiation with nivolumab to the current standard of care (standard-dose 
RT with cisplatin).  
 
*Arm 2 (concurrent reduced-dose RT with cisplatin) was dropped after interim futility 
analysis in phase II. 
 
1.1.4 Phase III (REVISED) 
To demonstrate co-primary endpoints of non-inferiority of PFS and superiority of quality of life 
(QOL) as measured by the MDADI of concurrent reduced-dose radiation with nivolumab to the 
current standard of care (standard-dose RT with cisplatin).  
 
1.2 
Secondary Objectives (19-APR-2023) 
1.2.1    To compare patterns of failure (local and regional relapse versus distant) and overall 
survival between the experimental arm and the control arm; 
1.2.2    To assess long term PFS, overall survival, and toxicity between the experimental arm and 
the control arm; 
1.2.3    To determine acute and late toxicity profiles as measured by the CTCAE; 
1.2.4    To explore the symptomatic adverse events (AEs) for tolerability of each treatment arm 
as measured by the PRO-CTCAE; 
1.2.5    To compare changes in patient-reported outcomes (HHIA-S, EORTC-QLQ30) between 
the experimental arm and the control arm; 
1.2.6   To assess the association of FDG-PET/CT at baseline with locoregional control and PFS; 
1.2.7   To estimate the negative predictive value of the 12-14 weeks post-RT FDG-PET/CT in 
terms of locoregional control rates and PFS rates at 1 and 2 years. 
 
1.3 
Exploratory Objectives (19-APR-2023) 
1.3.1 To collect blood and tissue specimens for future translation research; 
1.3.2    To optimize radiotherapy treatment plan quality assurance methodology for radiotherapy 

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planning and imaging; 
1.3.3     To compare changes in patient-reported outcomes (EQ-5D-5L) between the 
experimental arm and the control arm; 
1.3.4    To collect Modified Barium Swallow (MBS) data for future review and analysis. 
 
2. BACKGROUND 
2.1 
Rationale for Approach to De-Intensification for HPV-Associated Oropharyngeal 
Cancer 
 
Major Network groups, including NRG Oncology and GORTEC, long ago established the standard 
of care for curative chemoradiation for oropharyngeal cancer to be a combination of 70 Gy of 
large-field radiation therapy with concurrent platinum-based chemotherapy (Ang 2010; Bourhis 
2012). These approaches are associated with a high level of short- and select long-term toxicities 
(Trotti 2007; Machtay 2008) which is a concern in patients anticipated to have long survivorship. 
In an RTOG 0129 recursive partitioning analysis of oropharyngeal cancer patients, the HPV-
positive group with ≤ 10 pack years of smoking was found to be at “low risk” for death. The 3-
year rates of overall survival were 93.0% in the low-risk group; 70.8% in the intermediate-risk 
group; and 46.2% in the high-risk group (Ang 2010). Intensive ongoing data analysis from accrued 
and maturing trials within the NRG Oncology group identified benchmark PFS estimates that were 
used to establish eligibility for NRG-HN002, a completed phase II study of reduced-dose radiation 
therapy (60 Gy to gross disease, 48-54 Gy to elective neck). While NRG-HN002 was in progress, 
the Universities of North Carolina and Florida reported a phase II study for HPV/p16+ T0-3 N0-
N2c (7th ed.) oropharyngeal cancer patients who received 60 Gy of radiation with concurrent 
cisplatin at 30 mg/m2 per week. At planned short-term (6-14 weeks) surgical sampling of the 
primary site and nodal dissection, the pathologic complete response rate was 86%  and at mature 
follow-up of 44 patients, the 3-year locoregional control and survival were 100% and 95% (Chera 
2015; Chera 2018). Other reduced-dose radiation single-arm phase II study results, as well as 
continued large-scale data accumulation within NRG Oncology, now form the basis for continued 
investigation of de-intensification. Our current proposed goal is to conduct a randomized phase III 
study to establish that reduced-dose radiation programs are equivalent to the current standard of 
care (SOC). 
The recently reported results of RTOG 1016, which compared concurrent cisplatin and concurrent 
cetuximab given with a modestly accelerated radiation course, confirmed that cisplatin remains 
the standard of care for the treatment of HPV-associated oropharyngeal cancer (Gillison 2018). In 
that study, cisplatin was administered at 100 mg/m2 for 2 cycles every 3 weeks with 70 Gy of 
radiation therapy delivered over 6 weeks coinciding with the two cycles. The accelerated radiation 
course was the practical and biological justification for delivery of only two cycles of concurrent 
cisplatin. 
This trial begins with a randomized phase II comparison of three arms: (1) control arm based on 
RTOG 1016: 70 Gy of radiation therapy over 6 weeks, with concurrent cisplatin at 100 mg/m2 
every 3 weeks x 2 cycles; (2) experimental arm: 60 Gy of radiation therapy over 6 weeks, with 
concurrent cisplatin at 100 mg/m2 every 3 weeks x 2 cycles; (3) experimental arm: 60 Gy of 
radiation therapy over 5 weeks, with concurrent nivolumab 240 mg every 2 weeks for 6 cycles 
(starting 1 week prior to radiation and continuing for 12 weeks; includes 3 cycles of continued 
nivolumab therapy post-RT). The experimental arm(s) found to be non-inferior in terms of PFS 

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in phase II will continue in a phase III comparison against the control, with a co-primary 
endpoint of PFS and QOL. 
The importance of this trial is three-fold: (1) to establish safety and efficacy of reduced-dose 
radiation therapy with either cisplatin or nivolumab in comparison to the current SOC; (2) to study 
patient-reported outcomes and toxicities of these de-intensified treatment regimens compared to 
the current SOC; and (3) to study long-term immunologic effects resulting from cisplatin or 
nivolumab with reduced-dose radiation therapy in comparison to the current SOC. The phase III 
component of this trial may establish a new equivalent SOC with superior QOL and non-inferior 
PFS compared to the current SOC (70 Gy with cisplatin) in place at present. 
 
2.2 
Rationale for Reduced-Dose Radiation Therapy in Oropharyngeal Cancer 
Treatment 
The toxicities of a high-dose radiation therapy approach are pertinent in this context, associated 
with lasting multiple functional and quality-of-life effects. In particular, increasing radiation doses 
to the pharynx and larynx have proportionately been associated with higher risks of dysphagia or 
difficulty in swallowing (Vlacich 2014; Caglar 2008; Caudell 2010; Frowen 2013; Schwartz 2010; 
Wopken 2014; Petkar 2016). Dysphagia is a major, dose-limiting side effect of radiotherapy for 
patients with head and neck cancer, including those with oropharyngeal cancer (Hutcheson 2017). 
In a study of 81 patients with oropharyngeal cancer, a steep dose-effect relationship was observed: 
the probability of dysphagia increased 19% with every additional 10 Gy (Levendag 2007). 
Researchers who conducted a prospective study of patients with oropharyngeal cancer observed a 
similar association between the mean radiation dose to higher swallowing organs and the 
worsening of swallowing 2 years after treatment (Eisbruch 2011). For this reason, dysphagia was 
considered an important patient-reported outcome both in RTOG 1016 and NRG-HN002. In 
keeping with the importance of this endpoint, in both the phase II and phase III components of this 
trial, dysphagia will be assessed from the patient’s perspective and acceptable patient-reported 
outcome is necessary for viability of any study arm. In addition, because this is the first 
comparative randomized dose-reduction study in this unique population, an objective functional 
assessment of dysphagia will be offered as an exploratory substudy, to provide an objective 
correlate to the endpoint of the patient’s experience. 
Other long-term side effects of radiation therapy also have a relationship to higher radiation dose. 
For example, even low or intermediate-level doses of radiation to the salivary glands, thyroid 
gland, and brachial plexus have been associated with xerostomia (Gabryś 2017; Beetz 2014), 
hypothyroidism (Chyan 2014; Bhatia 1996), and late neuropathy (Galecki 2006; Johansson 2000; 
Chen 2014; Olsen 1993; Bajrovic 2004). For this reason, the related organs at risk are considered 
important avoidance structures that are contoured in a standard head and neck cancer radiation 
treatment planning process. Furthermore, while neck and shoulder fibrosis are underreported and 
difficult to quantify (Deng 2016; Moloney 2015), following current standard of care treatments to 
the entire neck, there are reports of chronic spasm, pain, and shoulder dysfunction related to 
neurologic or musculature effects (Gelblum 2016; Ghosh 2015). This trial, as the first comparator 
trial of the standard of care regimen to a dose-reduced regimen, will set the stage in the future, if 
one or more of the experimental arms is successful, to aim at the further improvement of these and 
other known long-term side effects of radiation therapy. 
 

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2.3 
Rationale for Introduction of Immunotherapy for Oropharyngeal Carcinoma 
Patients 
 
The very long-term immune effects of radiation therapy, particularly given in conjunction with 
myelosuppressive chemotherapy have clinical implications. Head and neck radiotherapy delivers 
high radiation doses to multiple lymph node chains, abundant lymphoid tissue, and major blood 
vessels containing large volumes of hematologic cells (Hodge 2008). In studies of peripheral 
blood, nonspecific immune system responses are suppressed for years in patients receiving head 
and neck radiotherapy (Gray 1985; Kuss 2004) and effects are seen in CD4+ and CD8+ T cell 
subsets that last longer in patients irradiated to the head and neck than in patients irradiated to 
pelvic or brain tumors. In one study, patients remained lymphopenic up to 60 months after 
radiotherapy, and low lymphocyte levels predisposed to tumor recurrence (Verastegui 2003). 
These data raise the question of how best to modulate the systemic immunologic effects of 
radiation therapy for the greatest long-term therapeutic advantage in head and neck cancer patients.  
   
In response to radiation, increased expression of MHC-I and MHC-II molecules, CD80, adhesion 
molecules, stress ligands, Hsp70 and death receptors on tumor cell surfaces are observed. Immune-
activating chemokines, cytokines, exosomes and danger signals are released, resulting in activation 
of dendritic cells (DCs). These DCs are activated by the released danger signals and by taking up 
tumor peptides derived from irradiated cells, initiate innate and adaptive immune responses 
including the activation of T cells (Derer 2016). This process of T cell activation is controlled by 
the immune checkpoint inhibitory pathways. However, tumors exposed to ionizing radiation also 
acquire an immunosuppressive phenotype characterized by expression of PD-L1, secretion of 
TGF-β, infiltration of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) into 
the tumor, and induction of immunosuppressive apoptosis. During and after radiation, 
radioresistant cancer stem cells are selected, as well as Langerhans cells that generate 
immunosuppressive Treg (Frey 2016). Fractionated head and neck chemoradiation increases 
circulating CD-8+ T-effector cells, myeloid-derived suppressor cells, regulatory T cells, and 
checkpoint receptor-expressing T cells, particularly PD-1+ T cells (Sridharan, Margalit, Curreri 
2016). 
Preclinical evidence indicates that the abrogation of checkpoint blockade acts synergistically to 
overcome these immunosuppressive effects. Sharabi et al. (2015) used an in vivo flank tumor 
model (B16-OVA) which was irradiated and the draining lymph nodes were harvested on day 4. 
Radiation to the primary tumor resulted in antigen-specific T cell activation and proliferation in 
the draining lymph nodes, and dendritic cells in the draining lymph nodes expressed the MHC-
OVA complex, indicative of cross-presentation against the tumor in the specifically unirradiated 
lymph nodes. Of note, radiation-induced Treg increased in the tumor microenvironment but not in 
the unirradiated lymph nodes. Furthermore, the combination of radiation and PD-1 blockade 
uniquely increased the proportion of tumor-specific CD8+ T cells with an effector memory 
phenotype, indicating that limiting the extent of the radiation stimulated and enabled the full effect 
of checkpoint inhibitor therapy.  

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It has been observed in preclinical studies that p16+ oropharyngeal cancers arise in immune-
privileged sites (Lyford-Pike 2013). While response rates of recurrent/metastatic head and neck 
cancer (R/M SCCHN) patients are relatively low (13%-18%) in response to single-agent 
checkpoint blockade, the biology of heavily 
pretreated R/M SCCHN is likely very different 
from initially presenting tumors receiving 
radiation. Immunohistochemical expression of 
PD-L1, a potential biomarker of response to 
clinical immunotherapy, is higher in initially 
presenting head and neck cancers than metastatic 
cancers and higher in HPV-related head and neck 
cancer (Zandberg 2014). Preclinical data supports 
that this pathway may offer an opportunity for 
therapeutic benefit. In a longitudinal profiling 
study of circulating T-cell subsets among patients 
receiving seven weeks of fractionated head and 
neck radiation, lymphopenia was commonly seen as an effect of chemotherapy, while the radiation 
therapy induced increases in circulating T-cells expressing the exhaustion marker of PD-1 in up to 
10% and 20% of CD8+ and CD4+ T cells, an indication that counteracting exhaustion during the 
several weeks of fractionated radiation would be beneficial (Sridharan et al 2016). In a preclinical 
head and neck cancer mouse model, tumor immunogenicity was enhanced by radiation therapy, 
which resulted in higher expression of H2Kd, CD80, and PD-L1 on tumor cells as well as increased 
IFNJ+ CD8+ T cells in tumors and draining lymph nodes. IFNJ inducible chemokines CXCL9 and 
CXCL10 were increased with RT, indicating radiation-related effects on the upregulation of PD-
L1 and transforming the tumor to an inflamed and responsive phenotype. Survival of the mice was 
enhanced by the combination of PD-L1 blockade with radiation therapy (see figure) (Oweida 
2017).  
 
2.4 
Clinical Data for Nivolumab in Head and Neck Cancer 
 
Nivolumab (BMS-936558, MDX-1106, and ONO-4538) is a fully human monoclonal 
immunoglobulin G4 antibody that is specific for human programmed death-1 (PD-1, cluster of 
differentiation 279) cell surface membrane receptor (Investigator Brochure, 2014). PD-1, a 55-
kDa type 1 transmembrane protein, is a member of the CD28 family of T-cell co-stimulatory 
receptors that include Ig super family member CD28, CTLA-4, inducible co-stimulator (ICOS), 
and B and T lymphocyte attenuator (BTLA) (Investigator Brochure, 2014). PD-1 is transiently 
but highly expressed on activated T cells functioning to limit immune effectors at the site of 
activation. Chronic stimulation may prevent the re-methylation of the PD-1 gene leading to 
continuous expression and characterizes a state of “exhausted” T cells that lose function and 
proliferative capacity while enhancing a suppressive tumor microenvironment.   
 
In vitro, nivolumab bound specifically to PD-1 (and not to related members of the CD28 family 
such as CD28, ICOS, CTLA-4, and BTLA) with a dissociation constant (Kd) = 3.06 nM. In 
intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab alone was 
well tolerated (Investigator Brochure, 2014).   
The clinical use of monoclonal antibodies to T-cell inhibitory receptors has provided new insights 

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into the relationship of the immune system and cancer. In a phase 1 (1, 3, and 10 mg/kg nivolumab 
doses) dose-escalation study the 3 mg/kg dose was chosen for expanded cohorts. Among 236 
patients, objective responses (ORs) (complete or partial responses [CR or PR]) were seen in non-
small cell lung cancer, melanoma, and renal cell carcinoma. ORs were observed at all doses (Sznol 
2013). The phase III trial Checkmate 141 also tested an advanced R/M SCCHN population of 361 
patients (54.5% had received ≥ 2 lines of prior therapy) with nivolumab administered at 3 mg/kg 
every 2 weeks compared to single-agent therapy (methotrexate, docetaxel, or cetuximab). The 
overall median survival was significantly longer in nivolumab-treated patients (superior to 
chemotherapy or cetuximab) and the 1-year survival was 36% with nivolumab vs 16.6% with 
standard therapy. Importantly, the survival advantage of nivolumab was maintained among both 
the p16+ and p16- groups of patients. This benefit was prolonged with the 2-year update resulting 
in OS 16.9% vs. 6.0% in patients treated with nivolumab compared to chemotherapy or cetuximab 
(Ferris 2018).  
In the Checkmate 141 study, grade 3 or 4 toxicities occurred in 13.1% of nivolumab patients. 
However, an analysis of quality of life showed that patient-reported measures of physical, role, 
and social functioning, pain, sensory problems, and social contact were stable or improved in the 
nivolumab group but were worse in the standard therapy group receiving single-agent 
chemotherapy (Ferris 2016); the superior quality of life with immunotherapy was confirmed in a 
subsequent detailed report, with significant and clinically meaningful differences at weeks 9 and 
15 in favor of nivolumab for role functioning, social functioning, fatigue, dyspnea, and appetite 
loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35 
(Harrington 2017). In the end, nivolumab-treated patients had superior survival but significantly 
improved QOL compared to patients receiving single-agent chemotherapy. 
Combinations of PD-1/PD-L1 inhibition with radiation therapy are becoming a more common 
concept. RTOG 3504 reported initial safety evaluations of 20 patients receiving nivolumab 
combined with 70 Gy radiation and cisplatin followed by adjuvant nivolumab; this study included 
p16-negative patients or p16+ oropharyngeal cancer patients with high smoking history or T4 or 
N3 stage. Among evaluable patients, all received protocol-prescribed radiation therapy, 15/17 
completed 200 mg/m2 of cisplatin, and 14/17 stayed on nivolumab (Gillison 2018). A new phase 
III study, NRG-HN004, randomizes newly diagnosed cisplatin-ineligible patients, including p16+ 
oropharyngeal cancer patients, to either cetuximab or durvalumab with 70 Gy of standard 
radiation.  
 
2.5 
Rationale for the Duration of Nivolumab Before, Concurrently, and After Radiation 
Therapy  
 
The strongest data clearly supporting extended administration of post-radiation immunotherapy 
(1-year adjuvant treatment) was issued for the PACIFIC non-small cell lung cancer trial (Antonia 
2018), but for this trial’s population where toxicity reduction and cost-effectiveness are critical, 
extended therapy in this manner is not a viable proposition. The schedule of priming, concurrent, 
and short-duration adjuvant nivolumab was developed based on preclinical evidence summarized 
briefly here. It is consistent with, although shorter than, the schedule developed for the more 
heterogenous and higher-risk population in NRG-HN004, where one arm includes durvalumab 
given before, during, and after 70 Gy of radiation therapy. 
 

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- 
Radiation therapy alone causes increases in PD-L1 expression in tumor and myeloid cells 
and Tregs via TGFb. However, when radiation therapy is administered in the setting of PD-1 
inhibition, it upregulates MHC complexes, enhances antigen cross-presentation in draining 
nodes, and increases T-cell infiltration into tumors (Sharabi 2015). 
- 
Combining anti-PD1 antibodies with radiation generates CD8+ T cell responses and tumor 
antigen-specific memory immune response. Three different schedules were tested starting on 
day 1 or day 5 of radiation therapy versus 7 days after completion of radiation; survival was 
best for the earlier concurrent schedules (Dovedi 2014). 
- 
Because radiation causes transient increases in PD-L1 expression and Treg, stopping PD-1 
during or at the end of radiation would enable these mechanisms to suppress the effector T 
cell response. In vivo mechanistic experiments conducted by Twyman-Saint Victor et al. 
showed that similar responses were seen in animals who received radiation given before or 
concurrently with anti-CTLA4, but the failure of the majority to respond was associated with 
a low CD8+CD44+ to Treg ratio. In these treatment-resistant tumors, the failure of the 
CD8+CD44+ T cell population to expand was associated with a high level of T cell 
exhaustion markers. Reinvigoration of the T cells, marked by an increase in the proliferation 
marker Ki67 and the cytotoxic protein GzmB within the exhausted T-cell pool, was only seen 
with slightly extended administration of anti-PD-L1 or anti-PD1 blockade, and this 
corresponded to markedly improved survival and complete response rates. Blockade 
antibodies were administered before, during and after radiation therapy (Twyman-Saint 
Victor 2015).  
- 
The eventual clinical response to immunotherapy is determined by the balance between 
tumor cell burden and T cell reinvigoration. This effect appears to peak after the initial 
administration of PD-1 inhibition (at only a few to several weeks) but then starts to fall off. 
The major anti-PD-1-mediated T-cell reinvigoration appears to occur within a relatively short 
window of a few cycles of therapy, indicating the potential efficacy of a relatively short 
adjuvant administration assuming eradication of the major tumor burden by radiation therapy 
(Huang 2017).  
 
2.6 
Rationale for Patient-Reported Dysphagia-Related Outcome in HPV-Associated 
Oropharyngeal Cancer Patients  
 
Oncologists now accept that quality of life is a critical clinical endpoint in the design of clinical 
trials for patients with locally advanced cancers. Although clinician-reported toxicity can identify 
adverse events, patient-reported outcomes (PROs) are essential because they directly measure 
patients’ perception of symptom burden from treatment and its impact on quality of life (QOL) 
without clinician bias. As the treatment of human papillomavirus (HPV)-positive oropharyngeal 
cancer evolves, a high rate of acute and late-normal tissue complications from definitive 
radiation-based treatment may not be acceptable, if alternative treatments evolve with similar 
rates of cure and improved QOL.  
 
Measuring PROs and QOL in the proposed study is particularly important because it is a novel 
treatment paradigm, and no data exist on the outcomes of these regimens in this population. The 
oncologic and long-term QOL outcomes of the targeted patient group may improve decision 
making in future clinical practice and research. The purpose of collecting PRO and QOL data in 
this phase II/III clinical trial is to evaluate the potential reduction in the burden of toxicity from 

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the patient perspective among different treatment arms. Clinicians involved in cancer care may 
find these results of great value in selecting the least toxic treatment arm - from the patient 
perspective - to achieve better QOL while maintaining desirable progression-free survival (PFS). 
Dysphagia-related QOL will thus be a co-primary endpoint in this trial.  
 
2.7 
Rationale for Stratification by Zubrod Performance Status 
 
Based on NRG-HN002 data, preliminary results from Cox models with potential stratification 
factors for NRG-HN005 suggest that N stage and T stage did not have a significant effect on PFS 
or OS (p>0.1). Zubrod performance status had a significant effect for PFS (p <0.1) and for OS 
(p<0.05). Looking at the breakdown of all combinations of the possible stratification factors, 
there are several cells that have < 2% of patients which creates a problem about empty cells in 
this study. Since the distributions are highly imbalanced for T stage and N stage and neither has 
an impact on OS or PFS, we will stratify patients by Zubrod performance status (0 vs. 1) in this 
study.   
 
 
3. ELIGIBILITY AND INELIGIBILITY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (see protocol cover page). For radiation therapy-related eligibility 
questions, please contact RTQA (see protocol cover page). 
 
3.1 
Eligibility Criteria (19-APR-2023) A patient cannot be considered eligible for this 
study unless ALL of the following conditions are met. 
3.1.1 Pathologically (histologically or cytologically) proven diagnosis of squamous cell 
carcinoma (including the histological variants papillary squamous cell carcinoma and 
basaloid squamous cell carcinoma but not neuroendocrine phenotype) of the oropharynx 
(tonsil, base of tongue, soft palate, or oropharyngeal walls); cytologic diagnosis from a 
cervical lymph node is sufficient in the presence of clinical evidence of a primary tumor in 
the oropharynx. Clinical evidence should be documented, may consist of palpation, 
imaging, or endoscopic evaluation, and should be sufficient to estimate the size of the 
primary (for T stage). 
3.1.2 Patients must have clinically or radiographically evident measurable disease at the primary 
site or at nodal stations. Simple tonsillectomy or local excision of the primary without 
removal of nodal disease is permitted, as is excision removing gross nodal disease but with 
intact primary site. Limited neck dissections retrieving ≤ 4 nodes are permitted and 
considered as non-therapeutic nodal excisions.  
3.1.3 P16-positive based on local site immunohistochemical tissue staining (defined as greater 
than 70% strong diffuse nuclear or nuclear and cytoplasmic staining of tumor cells). Fine 
needle aspiration (FNA) biopsy specimens may be used as the sole diagnostic tissue. 
Centers are encouraged to contact the pathology chair for clarification.   
 
Note: Institutions must screen patients, whose tumors must be p16-positive by 
immunohistochemistry (IHC) in order to be eligible for the trial using a Clinical 

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Laboratory Improvement Amendments (CLIA)-certified laboratory. A rigorous 
laboratory accreditation process similar to the U.S. CLIA certification, such as the 
provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) 
Program in Canada, the College of American Pathologists (CAP), or an equivalent 
accreditation in other countries, is acceptable. The p16-positive results must be reported 
on the pathology report being submitted.  
 
Note: If p16 result is equivocal, positive HPV DNA test of tumor specimen is acceptable 
and fulfills the eligibility criteria. 
 
3.1.4    Clinical stage T1-2, N1, M0 (AJCC, 8th ed.) or T3, N0-N1, M0 (AJCC, 8th ed.) including 
no distant metastases based on the following diagnostic workup: 
x General history and physical examination within 56 days prior to registration; 
x Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) 
within 70 days prior to registration;  
x One of the following imaging studies is required within 56 days prior to registration: 
a)   FDG-PET/CT of the neck and chest (with or without contrast); FDG-PET/CT 
scan is strongly preferred and highly recommended to be used for eligibility  
   OR 
b) Chest CT (with or without contrast) 
x One of the following imaging studies is required within 28 days prior to registration: 
a) A diagnostic CT scan of neck (with contrast and of diagnostic quality)  
OR  
b) an MRI of the neck (with contrast and of diagnostic quality) 
 
Note: A diagnostic quality CT or MRI with contrast or FDG-PET/CT scan of neck 
performed for the purposes of radiation planning may serve as both staging and 
planning tools. 
3.1.5 Patients must provide their personal smoking history prior to registration. The lifetime 
cumulative history cannot exceed 10 pack-years. The following formula is used to calculate 
the pack-years during the periods of smoking in the patient’s life; the cumulative total of 
the number of pack-years during each period of active smoking is the lifetime cumulative 
history. 
 
Number of pack-years = [Frequency of smoking (number of cigarettes per day) × duration 
of cigarette smoking (years)] / 20 
 
Note: Twenty cigarettes is considered equivalent to one pack. The effect of non-cigarette 
tobacco products on the survival of patients with p16-positive oropharyngeal cancers is 
undefined. While there are reportedly increased risks of head and neck cancer associated 
with sustained heavy cigar and pipe use (Wyss 2013), such sustained use of non-cigarette 
products is unusual and does not appear to convey added risk with synchronous cigarette 
smoking. Cigar and pipe tobacco consumption is therefore not included in calculating the 
lifetime pack-years. Marijuana consumption is likewise not considered in this calculation. 
There is no clear scientific evidence regarding the role of chewing tobacco-containing 
products in this disease, although this is possibly more concerning given the proximity of 

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the oral cavity and oropharynx. In any case, investigators are discouraged from enrolling 
patients with a history of very sustained use (such as several years or more) of non-cigarette 
tobacco products alone. 
3.1.6 Zubrod Performance Status of 0-1 within 14 days prior to registration.  
3.1.7 Age ≥ 18.  
 
3.1.8 Normal organ and marrow function within 14 days prior to registration defined as follows: 
 
Absolute neutrophil count 
 
≥ 1,500/mcL 
 
Platelets  
 
≥ 100,000/mcL 
 
Hemoglobin ≥ 8.0 g/dL (Note: use of transfusion or other intervention to achieve Hgb 
≥ 8.0 g/dL is acceptable) 
 
Total bilirubin 
 
≤ 1.5× institutional upper limit of normal (ULN) 
 
AST(SGOT) or ALT(SGPT)  
≤ 3.0 × institutional ULN 
 
Serum creatinine 
≤ 1.5× ULN  
OR 
 
Creatinine clearance (CrCl) 
≥ 50 mL/min (if using the Cockcroft-Gault formula 
below): 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
72 x serum creatinine in mg/dL 
Male CrCl = (140 - age in years) x weight in kg x 1.00  
72 x serum creatinine in mg/dL  
3.1.9 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 
therapy with undetectable viral load within 6 months are eligible for this trial. 
3.1.10 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load 
must be undetectable on suppressive therapy, if indicated. 
Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating 
acute or chronic infection would make the patient ineligible unless the viral load becomes 
undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-
Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against 
hepatitis B). 
3.1.11 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured. For patients with HCV infection who are currently on treatment for the hepatitis, 
they are eligible if they have an undetectable HCV viral load. 
Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating 
acute or chronic infection would make the patient ineligible unless the viral load becomes 
undetectable on suppressive therapy.  
3.1.12 For women of childbearing potential (WOCBP), negative serum or urine pregnancy test 
within 24 hours prior to registration.  
x Women of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization 
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal.  
Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 
in the absence of other biological or physiological causes.  In addition, women 
under the age of 55 must have a documented serum follicle stimulating hormone 
(FSH) level less than 40 mIU/mL.   

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3.1.13 Women of childbearing potential (WOCBP) and men who are sexually active with 
WOCBP must be willing to use an adequate method of contraception during and after 
treatment (see Section 9.0).  
3.1.14  The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry. 
3.1.15  Only English, Spanish, or French speaking patients are eligible to participate as these are 
the only languages for which the mandatory dysphagia-related patient reported instrument 
(MDADI) is available. 
 
3.2 
Ineligibility Criteria (04-NOV-2020) 
Patients with any of the following conditions are NOT eligible for this study. 
3.2.1 Clinical stages T0; T4; T1-2, N0; or any N2 (AJCC, 8th ed); 
3.2.2    Recurrent disease. 
3.2.3 Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the 
clavicles.  
3.2.4  Cancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, 
buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if p16-positive, or 
histologies of adenosquamous, verrucous, or spindle cell carcinomas. 
3.2.5  Carcinoma of the neck of unknown primary site origin (T0 is ineligible, even if p16-
positive). 
3.2.6 Radiographically matted nodes, defined as 3 abutting nodes with loss of the intervening fat 
plane.  
3.2.7 Supraclavicular nodes, defined as nodes centered below the level of the cricoid cartilage. 
3.2.8 Gross total excision of both primary and nodal disease; this includes tonsillectomy, local 
excision of primary site, and nodal excision that removes all clinically and radiographically 
evident disease. In other words, to participate in this protocol, the patient must have 
clinically or radiographically evident gross disease for which disease response can be 
assessed. 
3.2.9 Patients with simultaneous primary cancers or separate bilateral primary tumor sites are 
excluded with the exception of patients with bilateral tonsil cancers. 
3.2.10 Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 
a minimum of 1095 days (3 years) (of note, the exclusion applies only for invasive cancers 
such that carcinoma in situ of the breast, oral cavity, or cervix are all permissible); 
3.2.11 Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a 
different cancer is allowable.  
3.2.12 Prior radiotherapy to the region of the study cancer that would result in overlap of radiation 
therapy fields.  
3.2.13 Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint 
pathways. 
3.2.14 History of severe hypersensitivity reaction to any monoclonal antibody. 
3.2.15 Severe, active co-morbidity defined as follows: 
x Unstable angina and/or congestive heart failure requiring hospitalization within the 
last 6 months. 
x Transmural myocardial infarction within the last 6 months. 

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23                     Version Date: August 21, 2023 
 
x Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration. 
x Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy within 30 days of registration. 
x Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects. 
x Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC 
definition with immune compromise greater than that noted in Section 3.1.9; note, 
however, that HIV testing is not required for entry into this protocol. The need to 
exclude patients with AIDS from this protocol is necessary because the treatments 
involved in this protocol may be significantly immunosuppressive. Protocol-
specific requirements may also exclude immuno-compromised patients. 
x Condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalents) or other immunosuppressive medications within 14 days 
of registration. Inhaled or topical steroids and adrenal replacement doses < 10 mg 
daily prednisone equivalents are permitted in the absence of active autoimmune 
disease. 
x Patients with active autoimmune disease requiring systemic treatment (i.e. disease 
modifying agents, corticosteroids, or immunosuppressive drugs) should be 
excluded. These include but are not limited to patients with a history of immune 
related neurologic disease, multiple sclerosis, autoimmune (demyelinating) 
neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune 
disease such as SLE, rheumatoid arthritis, connective tissue diseases, scleroderma, 
inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and 
patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson 
syndrome, or phospholipid syndrome should be excluded because of the risk of 
recurrence or exacerbation of disease.  
 
Note: Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement, psoriasis not requiring systemic treatment, or conditions not expected 
to recur in the absence of an external trigger (precipitating event). 
3.2.16 Patients who are pregnant, nursing, or expecting to conceive or father children (see 
Section 9.0). 
3.3.17 Prior allergic reaction to cisplatin.  
 
 
 
 
 
 
 
 
 
 
 

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24                     Version Date: August 21, 2023 
 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP (19-
APR-2023) 
 
ASSESSMENTS: PRE-TREATMENT (See section 3.1 for details) 
 
Timepoint 
Procedure/Test 
Notes 
Prior to registration 
 Pathologically (histologically or 
cytologically) proven diagnosis of 
squamous cell carcinoma of the 
oropharynx 
 Smoking history 
 
70 days prior to 
registration 
 Exam with laryngopharyngoscopy 
 
56 days prior to 
registration 
 History/physical examination* 
 FDG-PET/CT of the neck and chest 
(w/ or w/o contrast)  
OR 
Chest CT (w/or w/o contrast)** 
 
*For patients with evidence 
of CHF, MI, 
cardiomyopathy, or 
myositis, a cardiac 
evaluation including lab 
tests and cardiology 
consultations as clinically 
indicated including EKG, 
CPK, troponin, ECHO 
cardiogram. 
 
**FDG-PET/CT scan is 
strongly preferred and 
highly recommended for 
eligibility. 
28 days prior to 
registration 
 Diagnostic neck CT (w/contrast and 
of diagnostic quality)*  
OR  
Diagnostic neck MRI (w/ contrast 
and of diagnostic quality)  
 
*Radiation planning CT 
with contrast qualifies if 
acquired at diagnostic 
quality level with contrast. 
14 days prior to 
registration 
 CBC + Diff 
 CMP 
 Zubrod performance status 
 
CBC to include ANC, 
platelets, Hgb 
 
CMP to include total 
bilirubin, AST(SGOT) or 
ALT (SGPT), serum 
creatinine 
24 hours prior to 
registration 
 Serum or urine pregnancy test 
 
If female of child bearing 
potential 

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Prior to treatment 
 Adverse Event Evaluation 
 PRO-CTCAE* 
 Patient-Reported Outcomes:  
MDADI, HHIA-S, EORTC QLQ-
C30, EQ-5D-5L* 
 Modified Barium Swallow (MBS) 
(if institution routinely performs) 
 Specimen submissions for 
biobanking (optional)** 
 Dental Assessment***  
 
 
*This study uses Medidata 
Patient Cloud ePRO. 
Remember to register the 
patient to the Patient Cloud 
ePRO. For instructions on 
registering the patients, 
please refer to Appendix I. 
Baseline questionnaires will 
be completed on paper. 
Patients that consent to 
Medidata Patient Cloud 
ePRO will complete all 
questionnaires electronically 
using personal electronic 
device except baseline. The 
study-specific PRO-CTCAE 
items for this protocol can 
be found on the forms 
section of the CTSU 
protocol webpage and is 
titled “NRG-HN005 NCI 
PRO-CTCAE Item 
Library”.  
 
**See Section 10.1 for 
details 
 
***The study-specific 
Dental Assessment may be 
completed by the local 
investigator or a designee 
(such as a physician's 
assistant, nurse or nurse 
practitioner, or a 
dentist/hygienist) to assess 
number of teeth and overall 
dental health. This form can 
be found on the forms 
section of the CTSU 
protocol webpage. Please 
also refer Appendix III. 
 
 
 
 
 
 

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ASSESSMENTS: ON TREATMENT  
 
Drug dose modifications found in Section 6.0 of protocol; Radiation Therapy per Section 5.2. 
 
Timepoint 
 
Procedure/Test/Treatment 
 
Notes 
 
Arms 1 and 2 (Arm 2 closed to accrual 03-FEB-2023) 
Cycle 1 
(Days 1 and 22)  
 CBC + Diff* 
 BMP*, Mg* 
 Physical exam/ Zubrod Performance 
Status* 
 Adverse Event Evaluation* 
 Premedications** 
 Cisplatin 100 mg/m2 IV, given over 
60 min*** 
 
 
CBC to include ANC, 
platelets, Hgb 
 
BMP to include 
serum creatinine, Na, 
K, Cl, glucose 
 
*Assess weekly 
during RT 
**Recommended 
premedications per 
section 5.1.2 
 
***Cisplatin should 
start +/- 24 hours of 
the first scheduled 
radiation treatment 
 
 
Arm 3  
Cycles 1-6  
(Day 1 of Weeks -1, 2, 4, 
6, 8, and 10) 
 
 
 Nivolumab 240 mg IV, given over 
30 min* 
 CBC + Diff** 
 CMP 
 TSH 
 Physical exam/Zubrod Performance 
Status** 
 Adverse Event Evaluation** 
 
*Nivolumab is given 
every 2 weeks for 6 
cycles starting 1 
week (+/- 2 days) 
prior to radiation  
 
All labs are within 72 
hours prior to 
nivolumab dose 
 
CBC to include ANC, 
platelets, Hgb 
 
CMP to include total 
bilirubin, AST or 
ALT, serum 
creatinine, BUN, Ca, 
Na, K, Cl, glucose 
 

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TSH with reflex to 
free T4; T3 as 
clinically indicated 
 
**Prior to each 
nivolumab dose and 
weekly during 
radiation 
 
All Treatment Arms 
Week 2 or 3 of RT 
(obtained after 20 Gy RT 
but before 28 Gy) 
 
 Specimen submissions for 
biobanking (optional) 
 
See Section 10.1 for 
details 
 
During Week 2 of RT 
 PRO-CTCAE 
 
 
End of Radiation (weeks 
5-6) 
 PRO-CTCAE 
 Patient-Reported Outcomes:  
MDADI, HHIA-S, EORTC QLQ-
C30, EQ-5D-5L 
 Adverse Event Evaluation 
 
 
 
After completion - within 
4 weeks from end of all 
treatment 
 Specimen submissions for 
biobanking (optional) 
See Section 10.1 for 
details 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ASSESSMENTS:  FOLLOW-UP 
 
 
Assessments from end of radiation therapy 
Timepoint 
Procedure/Test/Treatment 
Notes 
After radiation therapy 
(per institution’s standard 
of care, recommended at 
approximately 8 weeks) 
Diagnostic CT or MRI of head and neck 
with contrast (unless contraindicated) 
Follow-up imaging is 
of the primary site in 
full, but does not 
require brain or orbit 
imaging. 
At 12-14 weeks from end 
of radiation therapy 
 
FDG-PET/CT of whole body and 
dedicated neck 
A post-therapy FDG-
PET/CT scan is 
highly recommended. 
If a post-therapy 
FDG-PET/ CT scan 
is taken, the site is 
required to submit the 
patient’s post-
treatment PET/CT 
scan.  
 
q3 months from end of  
radiation therapy for  
years 1-2 
(+/- 2 weeks)  
 
 Physical Exam/Zubrod Performance 
Status* 
 Adverse Event Evaluation* 
 Chest CT or Chest FDG-PET/CT**  
 PRO-CTCAE*** 
 Patient-Reported Outcomes:  
MDADI, HHIA-S, EORTC QLQ-
C30, EQ-5D-5L*** 
 Modified Barium Swallow (MBS) 
(if institution routinely 
performs)**** 
 Dental Assessment***** 
 
*A brief history and 
physical examination 
including adverse 
event evaluation by a 
Radiation or Medical 
Oncologist or an 
ENT or Head & Neck 
Surgeon 
 
**As clinically 
indicated 
(recommended 
yearly) 
 
***At 3, 6, 12, and 
24 months from end 
of radiation therapy 
 
****At 12 and 24 
months from end of 
radiation therapy 
 
*****q12 months 
 
 
 

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q6 months for years 3-5 
(+/- 4 weeks)  
 
 Physical Exam/Zubrod Performance 
Status* 
 Adverse Event Evaluation* 
 Dental Assessment** 
 
 
*A brief history and 
physical examination 
including adverse 
event evaluation by a 
Radiation or Medical 
Oncologist or an 
ENT or Head & Neck 
Surgeon 
 
**q12 months 
Yearly for years 6-lifetime 
(+/- 8 weeks) 
 
 Physical Exam/Zubrod Performance 
Status* 
 Adverse Event Evaluation* 
 Dental Assessment** 
 
 
*A brief history and 
physical examination 
including adverse 
event evaluation by a 
Radiation or Medical 
Oncologist or an 
ENT or Head & Neck 
Surgeon 
 
**q12 months 
 
Definition of Disease Assessments  
x Response versus “Tumor Clearance” versus Cancer Progression 
Response and confirmation of local (primary site) or regional (neck) “tumor 
clearance” are not endpoints in this study. Clinical or radiographic evidence of 
progressive local-regional disease beyond 20 weeks should be documented in the 
clinical record and ideally confirmed by local or regional biopsy, neck dissection, or 
salvage surgery. CT or MRI (of head and neck region, with Chest CT), or PET/CT 
(including chest anatomy) may be used as radiographic evaluation of overall cancer 
status. The primary, neck and chest portions of the scans should be evaluated and 
reported separately. The CT portion of a PET/CT may serve as sufficient radiographic 
evaluation of the chest. If CT or MRI is used for evaluation of the head and neck 
region, CT of chest will be needed to rule out distant disease or second primaries at 
the designated evaluation intervals. 
x Local or Regional Progression 
Local (primary site) or regional (neck) progression is defined as clinical or 
radiographic evidence of progressive disease at the primary site or neck. The location 
of progressive disease should be separately distinguished (local vs. neck) to document 
the precise pattern of failure if possible. Progression of local or regional disease 
should be confirmed by biopsy when possible but may be clinically assessed and 
documented in the clinical record at the judgment of the treating clinicians. Suspicion 
of disease progression exclusively on the basis of indeterminate or positive PET/CT 
scan should be confirmed with continued clinical follow-up or pathologically. 
x Distant Metastasis 

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Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended 
where possible. A solitary, spiculated lung mass/nodule is considered a second 
primary neoplasm unless proven otherwise.  
x Second Primary Neoplasm 
Tumor reappearing with the initial and immediate adjoining anatomical region of the 
primary will be considered local recurrence. Multiple lung nodules/masses are 
considered distant metastases from the index cancer unless proven otherwise. 
 
5. TREATMENT PLAN/REGIMEN DESCRIPTION 
    Protocol treatment must begin within 14 days after randomization. 
 
5.1 
Systemic Therapy (04-NOV-2020) 
5.1.1 Cisplatin 
Intravenous Cisplatin Administration Concurrent with Radiation 
Cisplatin: 100 mg/m2/day, every 3 weeks (on day 1 and 22) during radiation. Dose should be 
based on actual body weight. The first cisplatin infusion should be started within 24 hours 
before or after the first scheduled radiation treatment. Cisplatin is administered concurrent 
with radiation therapy. Doses of cisplatin that are not given or which are held for toxicities may 
be made up.   
 
Cisplatin should be administered on Mondays or Tuesdays to maximize overlap of daily 
radiation with cisplatin exposure.  
 
Administration on Wednesday prior to that day’s radiation dose is acceptable but not preferred. 
Cisplatin should be administered before or after radiation. Investigators should strive to 
administer cisplatin on schedule, but if the dose is not being held for toxicity reasons, a variance 
of 1 day is acceptable for vacations, holidays, etc. If radiation treatments are held for toxicity, 
cisplatin dosing should also be held. 
  
5.1.2  Cisplatin Concurrent with Radiation Administration Guidelines  
High-dose cisplatin is highly emetogenic and can cause both acute and delayed nausea 
(occurring > 24 hours after chemotherapy administration). Investigators should be prepared to 
use aggressive prophylactic antiemetics and hydration. Many institutions will have standard 
guidelines for the administration of cisplatin at the doses used in this study. For purposes of this 
protocol, individual investigators may use their local guidelines for cisplatin 
administration. The anti-emetic and hydration regimen and schedule is to be determined by the 
local investigator. Administration of mannitol is likewise determined by the local investigator.   
x All patients receiving cisplatin chemotherapy should be offered a combination of anti-
emetics. Examples of appropriate anti-emetic choices are provided. 
o Neurokinin 1 (NK1) receptor antagonist 
 Aprepitant 125 mg PO on day of cisplatin and 80 mg PO on days 2 and 3, 
or 
 Fosaprepitant 150 mg IV on day of cisplatin 
o Serotonin (5-HT3) receptor antagonist 
 Granisetron 1 mg IV on day of cisplatin, or 
 Ondansetron up to 16 mg IV on day of cisplatin, or 

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 Palonosetron 0.25 mg IV on day of cisplatin 
o Steroid 
 Dexamethasone up to 20 mg IV on day of cisplatin 
o Olanzapine  
 10 mg PO on day  of cisplatin 
x Dexamethasone (up to 8 mg PO daily) and olanzapine may be continued on days 2 to 4 of 
cisplatin administration to prevent delayed nausea. 
x A 5-HT3 receptor antagonist may also be used as needed for delayed nausea. 
x Cisplatin pre-hydration guidelines: Pre-hydration with 1 liter D5 ½ NS and 40 meq KCL/ 
liter x 1 liter prior to cisplatin. Mannitol 12.5 gm IV immediately prior to cisplatin.  
x Cisplatin administration: Cisplatin, 100 mg/m2 over 30-60 minutes IV in 250 cc NS. 
Infusion rate not to exceed 2 mg/min. See Section 6.2 for dose modifications. See above 
discussion on scheduling and number of doses concurrent with radiation.  
x Cisplatin post-hydration guidelines: Following the end of the cisplatin administration, an 
additional liter of ½ NS with 10 meq KCL/L, 8 meq MgSO4/L, and 25 g mannitol should 
be infused over 2 hours. On the second and third day following cisplatin, patient should 
be encouraged to take at least 2 liters of fluid per day orally. Patients unable to orally 
self-hydrate should be considered for additional IV hydration on these days with normal 
saline.  
 
5.1.3 Nivolumab 
Intravenous Nivolumab Administration Before, Concurrently, and After Radiation Therapy 
 
Nivolumab 240 mg fixed dose administered as a 30-minute IV infusion (+/- 5 minutes or per 
institutional standard of care) will be given every two weeks (+/- 2 days) for 6 cycles (starting 1 
week (+/- 2 days) prior to radiation and continuing for 12 weeks; includes 3 cycles of nivolumab 
therapy post-RT). Patients may be dosed no less than 12 days from the previous dose of drug. 
There will be no dose modifications allowed, although delayed doses are allowed to be made up. 
No premedications are required prior to nivolumab infusion. Steroids, such as dexamethasone, 
are strictly prohibited with nivolumab infusions. 
 
 
Week of IMRT 
 
-1 1 
2 
3 
4 
5 
6 
8 
10 
IMRT (60 Gy) 
 
X 
X 
X 
X 
X 
 
 
 
Nivolumab 
240 mg IV 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 

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5.2 
Radiation Therapy (19-APR-2023) 
 
Note: All participating institutions must be credentialed for head and neck IMRT and IGRT 
prior to registering patients to the study (see Section 8 for details).  
 
Intensity Modulated Radiation Therapy (IMRT) and Image-Guided Radiation Therapy (IGRT) are 
mandatory for this study. Proton therapy is not permitted. 
 
Radiation Therapy Schema  
 
Effective with Amendment 3 
x Phase II/III (Arms 1 and  3) 
Arm 1: 70 Gy radiation in 6 weeks using 6 fractions per week + cisplatin every 3 weeks 
(Days 1 and 22) 
Arm 3: 60 Gy radiation in 5 weeks using 6 fractions per week + nivolumab every 2 weeks x 
6 cycles 
 
For patients enrolled prior to amendment 3 
Arm 2 closed to accrual 03-FEB-2023 after phase II interim futility analysis. 
 
x Phase II (Arms 1, 2, 3) 
Arm 1: 70 Gy radiation in 6 weeks using 6 fractions per week + cisplatin every 3 weeks 
(Days 1 and 22) 
Arm 2: 60 Gy radiation in 6 weeks using 5 fractions per week + cisplatin every 3 weeks 
(Days 1 and 22) 
Arm 3: 60 Gy radiation in 5 weeks using 6 fractions per week + nivolumab every 2 weeks x 
6 cycles 
 
5.2.1 Treatment Technology 
 
Megavoltage energy photon beam irradiation with energy ≥ 4MV is required (6MV energy is 
preferred). Proton therapy is not allowed. IMRT techniques including static field IMRT, helical 
IMRT (Tomotherapy), and VMAT are allowed. Matched conventional anterior neck field is not 
allowed. MRIdian is allowed (only modality that allows Co-60 energy). Treatment machine must 
be equipped to provide daily MRI, kV, or MV image guidance. The minimum requirements for 
image guidance are given in Section 5.2.10. 
 
Table 5.2.1A: Treatment Technology 
Treatment Technology 
Requirements and Recommendations 
Beam Modality 
Photons (protons are not allowed) 
Beam Energy 
≥ 4MV (6MV preferred), with the exception of the 
MRIdian Co-60 delivery) 
Treatment Technique 
Static field and helical IMRT, VMAT, and MRIdian 
are allowed. Matched conventional anterior neck 
field is not allowed. 

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IGRT 
Treatment machine must be equipped to provide 
daily MRI, kV, or MV image guidance. The 
minimum requirements for image guidance are given 
in Section 5.2.10. 
 
5.2.2 Immobilization and Simulation 
 
Immobilization 
 
Proper immobilization is critical for this protocol. Patient setup reproducibility must be achieved 
using appropriate clinical devices. Patients will be treated supine and must have a secure head 
and neck immobilization (e.g. aquaplast mask) made prior to the treatment planning CT scan.  
Intraoral immobilization devices may be utilized for tongue position control or immobilization 
and should be considered when the targets involve the pharyngeal axis. It is strongly encouraged 
that the participating centers also include the shoulders in the immobilization to further ensure 
accurate patient set-up on a daily basis. 
 
Simulation Imaging  
 
The treatment planning CT scan is mandatory for defining target volumes and normal organs at risk. 
The planning CT scan should be performed with intravenous contrast (unless contraindicated). CT 
scan should be acquired with the patient in the same position and using the same immobilization 
device as for treatment. CT scan thickness should be ≤ 3 mm. All tissues receiving irradiation should 
be included in the CT scan limits. The scanning limits should at least encompass the orbits superiorly 
and extend at least 1 cm below the suprasternal notch inferiorly. Metal artifact reduction technique 
in CT scanner can be used for cases with dental filling or other high- density objects. For patients 
in whom contrast is contraindicated, FDG-PET/CT and MRI based imaging should be used to 
guide tumor and normal organ volume definition. 
 
A diagnostic CT or MRI may be fused to the planning CT scans to facilitate target and structure 
definition. All image sets used for structure delineation must be submitted with the RT digital 
data. 
 
5.2.3 FDG-PET/CT Imaging  
 
FDG-PET/CT imaging is strongly preferred as part of staging in all eligible patients.  
 
Many institutions will have standard guidelines for acquisition of FDG-PET/CT. For purposes of 
this protocol, individual investigators may use these local guidelines. One possible approach is 
outlined below which is suggested to optimize acquisition. 
 
Recommended FDG-PET/CT Imaging Sequence and Details  
• Serum glucose must be measured (ideally within 1 hour of FDG administration).   
• If the serum glucose concentration is found to be > 200 mg/dL, the study should be 
rescheduled. The referring physician or primary physician will be contacted to optimize blood 
glucose control.   

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• It is recommended that the PET/CT scan begin 60 minutes +/- 10 minutes after FDG injection. 
• It is recommended that patients be imaged from the orbits through the upper thigh.   
• A dedicated head and neck imaging acquisition (orbits to upper thorax) with the patient’s arms 
down is recommended given the higher sensitivity of this exam. The remainder of the body is to 
be scanned with the patient’s arms raised over the patient’s head. If patients cannot tolerate these 
positions for the PET/CT scan, investigators can use different patient positioning.  
• A low-dose CT scan is required for attenuation correction and anatomical localization of 
findings in the PET scan.  
• The acquisition parameters for the dedicated head and neck CT, low-dose CT scan should be 
approximately as follows: kV = 120; effective mAs = 90-150 (patient dependent, auto current 
modification acceptable); gantry rotation time < 0.5 sec; maximum reconstructed slice width = 
2.5 mm (overlap acceptable); standard reconstruction algorithm, maximum reconstruction 
diameter = 30 cm; and without iodinated contrast.  
• The acquisition parameters for the low-dose CT scan for attenuation correction should be 
approximately as follows: kV = 120; effective mAs = 30-80 (patient dependent, auto current 
modification acceptable); gantry rotation time < 0.5 sec; maximum reconstructed width = 3-5 
mm without overlap; standard reconstruction algorithm, minimum reconstruction diameter = 
outer arm to outer arm; and without iodinated contrast.  
• The axial field of view of the CT scan for attenuation correction should range from the mid 
thighs to the base of the skull. Arm positioning will be the same as for the PET scan (see above).  
• The CT scan will be performed during the patient’s normal breathing. No respiratory gating is 
needed.  
• After the CT scan, a PET scan covering the same axial field of view should be performed. This 
scan will start at the upper thighs. The number of bed positions and the acquisition time per bed 
position will be scanner specific. Typical parameters are 6 bed positions and an acquisition of 2 
to 5 minutes per bed position. The dedicated head and neck PET/CT will typically follow the 
body exam. Two bed positions will often suffice for orbits to upper thorax (top of aortic arch), 
and acquisitions must be at a minimum of 6 minutes per bed position and be reconstructed into a 
30 cm field of view (FOV) with a 256 x 256 matrix.  
• Additional diagnostic-quality CT of the neck should be performed with contrast if needed to 
fulfill requirements for anatomic post-treatment imaging.  
 
FDG-PET/CT Image Reconstruction  
The PET/CT data will be corrected for dead time, scatter, randoms, and attenuation using 
standard algorithms provided by the scanner manufacturers. For the dedicated head and neck 
views, a post-filter with a full-width at half maximum (FWHM) in the range of 5 mm is 
recommended.  
 
5.2.4 Definition of Target Volumes and Margins 
Note: All structures must be named for digital RT data submission as listed in the table below.  
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan. Structures marked as “Required when applicable” must be contoured and 
submitted when applicable. 
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM names listed. Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 

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Arm 1 
Table 5.2.4A: Definition of Target Volumes and Margins for Arm 1 
 
Standard Name 
 
Description 
 
Validation 
Required/Required when 
applicable/Optional 
GTV_7000 
Primary tumor and involved nodes  
Required 
CTV_7000 
GTV_7000 + 5 mm margin, excluding 
anatomic boundaries to tumor spread 
 
Required 
PTV_7000 
CTV_7000 + 3 mm margin  
 
Required 
 
PTV_Eval_7000 
PTV_7000 minus high risk OARs (subtract 5 
mm from skin if needed) 
Required when applicable 
CTV_5600 
• 
CTV_7000 + 5 mm  
• 
first echelon nodes  
• 
node levels including involved nodes 
• 
2 cm inferior/superior margin for gross 
nodal disease covering the fat of nodal 
chain  
• 
suspicious nodes < 1 cm + 5 mm 
 
Required  
PTV_5600 
CTV_5600 + 3 mm margin 
 
Required  
CTV_5250  
• 
Lower risk nodal levels that are not first 
echelon nodes and are not adjacent to 
levels containing grossly involved nodes 
• 
See Table 5.2.4C for details 
 
Required 
PTV_5250  
CTV_5250 + 3 mm margin 
 
Required 
CTV_6650* or 
CTV_6020* 
Original extent of the grossly involved tumor 
site, for isolated tumor or nodal sites that have 
been excised with focally positive 
microscopic or clearly negative margins 
Required when applicable 

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PTV_6650* or 
PTV_6020* 
CTV_6650 or CTV_6020 + 3mm margin 
 
 
Required when applicable 
PTV_Eval_6650* 
or 
PTV_Eval_6020* 
PTV_6650 or PTV_6020 minus high risk 
OARs (subtract 5mm from skin if needed) 
 
 
Required when applicable 
 
*Note: For Arm 1 only 
In the rare case that a primary tumor or pathologically involved lymph node is excised surgically 
for diagnostic purposes obtaining clearly negative or focally positive microscopic margins, it is 
acknowledged that there may be some risk of long-term wound healing if the doses prescribed in 
Arm 1 are given to the surgical bed. Therefore, for these unique situations, the original extent of 
the grossly involved tumor site may be delineated as a CTV_6650 prescribed to 6650 cGy (at 
190 cGy/fraction) over 35 fractions for a case of microscopically/focally positive margins or 
alternatively as a CTV_6020 (at 172 cGy/fraction) over 35 fractions for a situation of an excision 
with clearly negative margins. The usual PTV expansions would then apply to create the 
corresponding PTV_6650 or PTV_6020.  
 
It should be noted that any residual gross primary tumor and/or any grossly involved lymph 
nodes which are radiologically or clinically evident should be treated to the standard dose 
required in Arm 1, e.g. 7000 cGy. Furthermore, the presence of extant gross tumor is 
required for the eligibility of any patient on this study. Therefore, GTV_7000, CTV_7000, 
and PTV_7000 are required target volumes for any patient on Arm 1. 
 
For Arm 3 (Arm 2 closed to accrual 03-FEB-2023), if the primary tumor or a lymph node is 
excised, the prescribed doses should not be changed regardless of the extent of removal, meaning 
that the surgical bed would be treated to the required dose of CTV_6000. Likewise, for Arm 3 
(Arm 2 closed to accrual 03-FEB-2023), the presence of extant gross tumor is required for 
eligibility. 
 
Investigators are encouraged to contact the Principal Investigator to discuss these unusual 
situations and/or seek clinical guidance on these matters. 
 
 
 
 
 
 
 
 
 
 
 
 

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Arm 3 (Arm 2 closed to accrual 03-FEB-2023) 
 
Table 5.2.4B: Definition of Target Volumes and Margins for Arm 3 (Arm 2 closed to 
accrual 03-FEB-2023) 
 
Standard Name 
 
Description 
 
Validation 
Required/Required when 
applicable/Optional 
GTV_6000 
Primary tumor and involved nodes 
Required 
CTV_6000 
GTV_6000 + 5 mm margin, excluding 
anatomic boundaries to tumor spread  
Required 
PTV_6000 
CTV_6000 + 3 mm margin 
Required 
PTV_Eval_6000 
PTV_6000 - high risk OARs (subtract 5 mm 
from skin if needed) 
 
Required when applicable 
CTV_5400 
• 
CTV_6000 + 5 mm  
• 
first echelon nodes  
• 
node levels including involved nodes 
• 
2 cm inferior/superior margin for gross 
nodal disease covering the fat of nodal 
chain  
• 
suspicious nodes < 1 cm + 5 mm 
 
Required 
PTV_5400 
CTV_5400 + 3 mm margin 
Required 
CTV_4800 
• 
Lower risk nodal levels that are not first 
echelon nodes and are not adjacent to 
levels containing grossly involved nodes 
• 
See Table 5.2.4C for details 
 
Required 
PTV_4800 
CTV_4800 + 3 mm margin 
Required 
 
Detailed Specifications  
 
Setup margin (SM): Daily IGRT is required for this trial; therefore, the SM will be 3 mm in all 
directions. 
 
GTV_7000 (Arm 1) or GTV_6000 (Arm 3) (Arm 2 closed to accrual 03-FEB-2023): The 
primary tumor and clinically positive lymph nodes seen on clinical and endoscopic 
examinations, planning CT (> 1 cm short axis diameter) or pre-treatment PET scan (SUV > 3) 
will constitute the GTV. Grossly positive lymph nodes are defined as any lymph nodes > 1 cm or 
nodes with a necrotic center.     

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CTV_7000 (Arm 1) or CTV_6000 (Arm 3) (Arm 2 closed to accrual 03-FEB-2023): The 
CTV is defined to be the GTV plus a 0.5 cm to 1 cm margin as appropriate to account for 
microscopic tumor extension. When the tumor is infiltrative (endophytic) or when the border is 
ill defined, it might be desirable to deliver an intermediate dose to a volume (CTV 5600 or CTV 
5400) that is slightly larger than CTV 7000 or CTV 6000. The CTV margins can be narrower 
when GTV is in the proximity of the spinal cord or critical normal tissues. CTV should be 
cropped to exclude anatomical barriers to tumor spread such as air cavities, uninvolved bone, and 
external body contours. Guidelines for CT based delineation of lymph node levels for node 
negative patients can be found on the NRG Oncology website: 
https://www.nrgoncology.org/ciro-head-and-neck. For patients with positive neck nodes, consult 
Gregoire et al. (2014) for the delineation of the nodal CTV. 
 
PTV_7000 (Arm 1) or PTV_6000 (Arm 3) (Arm 2 closed to accrual 03-FEB-2023): The PTV 
is created from the CTV with additional margins to compensate for the variability of treatment 
setup and internal organ motion. A minimum margin of 3 mm around the CTV is required in all 
directions to define each respective PTV, except for situations in which: 
• 
the CTV is adjacent to spinal cord or other critical normal tissues. In such situations, the 
margin can be reduced judiciously at the discretion of the treating physician.  
• 
the CTV results in a PTV that extends beyond the patient’s body surface. The PTV 
should be constrained to at least 3 mm from within the external contour, while still 
including the CTV. The use of tissue equivalent bolus material is indicated in situations 
where the disease is at or just under the skin surface. The PTV should align with the skin 
surface when bolus is used. 
 
PTV_Eval_7000 (Arm 1) or PTV_Eval_6000 (Arm 3) (Arm 2 closed to accrual 03-FEB-
2023): PTV volume minus impinging high priority OARs created for dosimetric evaluation. In 
cases where PTV overlaps with critical organs, such as the brainstem and spinal cord, the 
PTV_Eval_7000 and the PTV_Eval_6000 should be created to limit the dose to the OARs 
(subtract 5 mm from the skin if needed). Other volumes, such as tuning or avoidance or 
optimization structures, can be employed to drive the IMRT treatment planning process. Such 
volumes should be considered to be treatment-planning tools that are not reported or sent for 
review. 
 
CTV_5600 (Arm 1) or CTV_5400 (Arm 3) (Arm 2 closed to accrual 03-FEB-2023): High-
risk subclinical sites are defined as areas of: 
x potential subclinical tumor infiltration beyond the primary site CTV_7000 or CTV_6000, 
x the first echelon node levels to the primary site irrespective of gross nodal involvement, 
x all node levels containing gross nodes.  
x In the event of a node excision (≤ 4 per protocol) that occurred at time of diagnosis, the 
nodal levels that contained grossly involved adenopathy should be included, even if there 
is no residual post-excision adenopathy. 
 
A CTV_5600 or CTV_5400 would specifically include the following: 
x 5 mm isotropic expansion of CTV_7000 or CTV_6000. 

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x 1st  echelon node levels based on standard anatomic definitions. In most cases 1st echelon 
would be ipsilateral level II, but in cases of midline primary site involvement this should 
include bilateral level II. In cases with soft palate or posterior pharyngeal wall 
involvement, this should include the lateral retropharyngeal lymph nodes. 
x All node levels containing a CTV_7000 or CTV_6000 that have been assigned to 
involved nodes (all grossly involved nodal levels). 
x At least a 2 cm margin covering the fat of the cervical nodal chain superior and inferior to 
the node levels that contain/contained gross nodal disease. 
x Other high-risk subclinical sites may include nodes < 1 cm not thought to harbor gross 
disease yet thought to be at risk of containing more than subclinical disease based on 
their location relative to the primary site. In such cases of clinical concern that do not 
meet the above criteria, a 5 mm expansion on these nodes can be added to the CTV_5600 
or CTV_5400 at the discretion of the treating clinician. 
 
PTV_5600 (Arm 1) or PTV_5400 (Arm 3) (Arm 2 closed to accrual 03-FEB-2023): The PTV 
is created from the CTV with additional margins to compensate for the variability of treatment 
setup and internal organ motion. A minimum margin of 3 mm around the CTV is required in all 
directions to define each respective PTV, except for situations in which: 
x the CTV is adjacent to spinal cord or other critical normal tissues. In such situations, the 
margin can be reduced judiciously at the discretion of the treating physician.  
x the CTV results in a PTV that extends beyond the patient’s body surface. The PTV 
should be constrained to at least 3 mm from within the external contour, while still 
including the CTV.  
 
CTV_5250 (Arm 1) or CTV_4800 (Arm 3) (Arm 2 closed to accrual 03-FEB-2023): The 
CTV will be defined to treat node levels without evidence of gross disease yet at risk of 
microscopic spread and not contained in CTV_5600 or CTV_5400. These levels are defined 
anatomically according to published Intergroup consensus guidelines (Gregoire 2014). The 
levels to be treated will depend on the site and extent of the primary tumor and any grossly 
involved lymph nodes and are indicated in Table 5.2.4C. 
 
Table 5.2.4C: Nodal Levels to Receive Prophylactic Microscopic Dose (CTV_5250 or 
CTV_4800)* 
 
CTV_5250 or 
CTV_4800* 
 
Ipsilateral Neck 
Contralateral Neck** 
N0 
• 
Ib (for primary oral cavity 
extension), 
• 
II-III 
• 
RP (lateral retropharyngeal LN) 
for primary extension to posterior 
pharyngeal wall or soft palate 
• 
II-III 
• 
RP (lateral retropharyngeal 
LN) for primary extension to 
posterior pharyngeal wall or 
soft palate 
N1  
• 
Ib  
• 
II-IV 
• 
II-III 
• 
RP (lateral retropharyngeal 
LN) for primary extension to 

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• 
RP (lateral retropharyngeal LN 
including retrostyloid space) for 
primary extension to posterior 
pharyngeal wall or soft palate 
posterior pharyngeal wall or 
soft palate 
N1 with node ≥ 3 
cm or multiple 
nodes 
• 
Ib, II, III, IV, V, RP including 
retrostyloid space 
• 
II-III 
• 
RP (lateral retropharyngeal 
LN) for primary extension to 
posterior pharyngeal wall or 
soft palate 
*Applies to neck levels not included in CTV_5600 or CTV_5400. 
** The contralateral neck may be omitted according to guidelines defined below. 
 
Contralateral Neck 
The use of unilateral radiation techniques should remain optional, in deference to the established 
practice and clinical judgment of the enrolling investigator, though 3 groups of patients with 
respect to neck irradiation are defined below. 
 
Unilateral radiotherapy is recommended (see guidelines below) if it is the institution’s 
established practice, if the primary tumor originates in the tonsillar fossa, and is well-lateralized, 
with less than 1 cm of involvement of the soft palate or base of tongue, no posterior pharyngeal 
wall involvement, and with minimal nodal disease burden (single node ≤ 3 cm) as assessed by 
clinical exam and staging radiology studies. For patients who share these characteristics but have 
larger nodal disease or multiple nodes confined to ipsilateral level II of the neck, unilateral 
radiotherapy is optional. Due to the imperative to maintain high PFS for this trial and the lack of 
prospectively collected data on this controversial subject, for patients with characteristics that 
fall outside these categorizations, bilateral treatment is required. 
 
Groups of Patients with Regards to Unilateral or Bilateral Neck Irradiation 
 
Group 1: Unilateral treatment is recommended 
T1 to T3 tonsillar fossa primaries with < 1 cm clinical or radiographic extension into tongue base 
and/or soft palate, no posterior pharyngeal wall extension, N0-N1 (single node ≤ 3 cm and no 
extranodal extension). 
 
Group 2: Unilateral treatment is optional 
T1 to T3 tonsillar fossa primaries with < 1 cm clinical or radiographic extension into tongue base 
and/or soft palate, no posterior pharyngeal wall extension, N0-N1 (multiple nodes, all nodes ≤ 3 
cm and no extranodal extension) with involved adenopathy confined to ipsilateral level II of the 
neck. 
 
Group 3: Bilateral treatment is mandatory 
Tongue base, soft palate, or posterior pharyngeal wall primaries or tonsil primaries with > 1 cm 
soft palate and/or tongue base extension or any posterior pharyngeal wall extension; patients 
with any extranodal extension or with involved adenopathy outside of ipsilateral level II of the 
neck. 
 

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PTV_5250 (Arm 1) or PTV_4800 (Arm 3) (Arm 2 closed to accrual 03-FEB-2023): The PTV 
is created from the CTV with additional margins to compensate for the variability of treatment 
setup and internal organ motion. A minimum margin of 3 mm around the CTV is required in all 
directions to define each respective PTV, except for situations in which: 
x the CTV is adjacent to spinal cord or other critical normal tissues. In such situations, the 
margin can be reduced judiciously at the discretion of the treating physician.  
x the CTV results in a PTV that extends beyond the patient’s body surface. The PTV 
should be constrained to at least 3 mm from within the external contour, while still 
including the CTV.  
 
5.2.5    Definition of Critical Structures and Margins 
Note: All structures must be named for digital RT data submission as listed in the table below. 
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan. Structures marked as “Required when applicable” must be contoured and 
submitted when applicable.   
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed. Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
 
Table 5.2.5A: Definition of Critical Structures and Margins 
 
Standard Name 
 
Description 
 
Validation 
Required/Required when 
applicable/Optional 
SpinalCord 
Spinal Cord 
Required 
SpinalCord_PRV05 
 
Spinal Cord with 5 mm expansion for 
Planning Risk Volume 
 
Required 
BrainStem 
Brainstem 
Required 
BrainStem_PRV03 
 
Brainstem with 3 mm expansion for 
Planning Risk Volume 
Required 
Parotid_R 
Right Parotid Gland  
Required 
Parotid_L 
Left Parotid Gland 
Required 
Larynx_SG 
Glottic and Supraglottic Larynx 
Required 
Pharynx 
Uninvolved posterior pharyngeal wall 
plus adjacent constrictor muscles 
Required 
Esophagus_S 
Upper Cervical Esophagus 
Required 
Cavity_Oral 
Uninvolved Oral Cavity 
Required 
Bone_Mandible 
Mandible 
Required 
Lips 
Lips 
Required 
Glnd_Submand_R 
Right Submandibular Salivary Gland 
Required  

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Glnd_Submand_L 
Left Submandibular Salivary Gland 
Required  
BrachialPlexus_R 
 
Right Brachial Plexus 
Required when gross disease 
extends below cricoid 
cartilage 
BrachialPlexus_L 
Left Brachial Plexus 
Required when gross disease 
extends below cricoid 
cartilage 
Cochlea_R 
Right Cochlea 
Required gross disease 
extends to skull base 
Cochlea_L 
Left Cochlea 
Required gross disease 
extends to skull base 
Thyroid 
Thyroid Gland 
Required 
E-PTV 
Unspecified tissue, External minus all 
PTVs  
Required 
External 
External border of the patient  
Required 
 
Detailed Specifications 
 
SpinalCord: The spinal cord begins at the cranial-cervical junction (i.e., the top of the C1 
vertebral body). Superior to this is brainstem and inferior to this is cord. The inferior border of 
the spinal cord volume will be defined at approximately T3-4 (i.e., 2-3 cm below the lowest slice 
level that has PTV on it). The spinal cord shall be defined based on the treatment planning CT 
scan.  
 
SpinalCord_PRV05: Planning Risk Volume (PRV) spinal cord defined as SpinalCord + 5 mm 
in all directions. 
 
BrainStem: The most inferior portion of the brainstem is at the cranial-cervical junction where it 
meets the spinal cord. For the purpose of this study, the most superior portion of the brainstem is 
approximately at the level of the top of the posterior clinoid. The brainstem shall be defined 
based on the treatment planning CT scan.  
 
BrainStem_PRV03: Planning Risk Volume (PRV) brainstem defined as Brainstem + 3 mm in 
all directions.  
 
Parotid_R/L: Parotid glands will be defined in their entirety (superficial and deep lobes) based 
on the treatment planning CT scan. The parotid gland is an irregular shaped gland wedged 
between the ramus of the mandible and the mastoid process. The superior border is the 
zygomatic arch, inferiorly, the gland extends to the angle of the mandible. The anterior border is 
the masseter muscle; in 20% of cases the parotid gland extends anteriorly over the surface of the 
masseter muscle, and posteriorly, to the anterior border of the sternocleidomastoid. Laterally, it 
extends to the platysma and medially, to the posterior belly of the digastric muscle, styloid 
process and parapharyngeal space. The retromandibular vein is included in the parotid gland 
contour. 

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Larynx_SG: This will be defined as the glottic and supraglottic larynx, including the tip of the 
epiglottis, the epiglottis, the aryepiglottic folds, arytenoids, false cords, and true cords, up to but 
not including the medial border of the thyroid cartilage, and including the cricoid cartilage to the 
inferior edge of the arytenoid cartilage, but not the hypopharynx. Posteriorly, the contour extends 
to the anterior edge of the pharyngeal wall. 
 
Pharynx: This will be defined as the pharyngeal mucosa and wall plus adjacent constrictor 
muscles deemed not to require treatment (external to PTVs). This extends from the superior 
constrictor region (level of the inferior pterygoid plates) to the cricopharyngeal inlet (inferior 
level of the posterior cricoid cartilage). The posterior border is the pre-vertebral muscle.  
See Figure 5.2.5.1 or 
https://www.sciencedirect.com/science/article/pii/S0167814009005659#bib14 for more details. 
 
Figure 5.2.5.1. From Bhide et al (2009): Each of the pharyngeal constrictors was outlined as an 
arch-shaped structure with concavity facing anteriorly, in line with the mucosa (a-c). Posterior 
border of each of the muscles was the pre-vertebral muscle. Pharyngeal mucosa lining the 
muscles was included in outlines as it is quite thin and difficult to exclude with great accuracy 
with currently available CT images. Superior constrictor was outlined from the base of the skull 
up to the superior end of hyoid. Middle constrictor was outlined from the superior end to the 
inferior end of the hyoid bone. Inferior constrictor was outlined from the inferior aspect of hyoid 
to inferior end of cricoid cartilage. A sagittal view of all of the outlined pharynx is shown (d). 
 
Esophagus_S: This will be defined as the cervical or superior (S) esophagus, a tubular structure 
that starts at the bottom of pharynx (cricopharyngeal inlet) and extends to the thoracic inlet. 
 
Cavity_Oral: The oral cavity will be defined as a composite structure posterior to lips consisting 
of the anterior 1/2 to 2/3 of the oral tongue/floor of mouth, buccal mucosa, and superiorly the 
palate, and inferiorly to the plane containing the tip of the mandible (external to PTVs). 
 
Bone_Mandible: This includes the entire bony structure of the mandible from TMJ through the 
symphysis. It is recognized that for oral cavity cancers, this may overlap with PTVs. 
 
Lips: The lip contour extends from the inferior margin of the nose to the superior edge of the 
mandibular body. The lateral border is at the lateral commissure. The lip contour should include 
the inner surface of the lips. Lips will be defined in their entirety (upper and lower) based on the 
treatment planning CT scan. 

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Glnd_Submand_R/L: Submandibular glands will be defined in their entirety based on treatment 
planning CT scan. The submandibular glands are paired salivary glands composed of a large 
superficial lobe and a smaller deep process that are continuous with each other around the 
posterior border of the mylohyoid muscle. The superior border is the mylohyoid muscle and 
medial pterygoid muscle. Inferiorly, the gland abuts fatty tissue. Anteriorly, the gland is adjacent 
to the lateral surface of the mylohyoid muscle and posteriorly it abuts the parapharyngeal space 
and sternocleidomastoid. The lateral border is platysma and the mandibular surface. The medial 
border is the lateral surface of the mylohyoid muscle and the anterior belly of the digastric. The 
submandibular gland is often hypodense on CT and can be distinguished from surrounding 
structures. 
 
BrachialPlexus_R/L: Please follow the RTOG Atlas definition: 
https://www.rtog.org/CoreLab/ContouringAtlases/BrachialPlexusContouringAtlas.aspx.  
To contour the brachial plexus use a 5-mm diameter paint tool. Start at the neural foramina from 
C5 to T1; this should extend from the lateral aspect of the spinal canal to the small space 
between the anterior and middle scalene muscles. For CT slices where no neural foramen is 
present, contour only the space between the anterior and middle scalene muscles. Continue to 
contour the space between the anterior and middle scalene muscles; eventually the middle 
scalene will end in the region of the subclavian neurovascular bundle. Contour the brachial 
plexus as the posterior aspect of the neurovascular bundle inferiorly and laterally to one to two 
CT slices below the clavicular head. The first and second ribs serve as the medial limit of the 
OAR contour. See Figure 5.2.5.2 and https://www.redjournal.org/article/S0360-3016(08)00416-
1/fulltext for more details. 

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Figure 5.2.5.2 From Hall et al (2008): Major anatomic landmarks (Anterior and Middle Scalene 
muscles, and the neurovascular bundle) for identifying the brachial plexus on the axial images of 
a treatment planning computed tomography scan. 
 
 
Cochlea_R/L: The cochlea should be defined using bone window (window width 3000 to 4500 
and window level of 400 to 800). It is well visualized near the most lateral extent of the internal 
auditory canal. The spiral canals of the cochlea appear as small curved or round lucencies within 
the temporal bone. The cochlea should be defined in its entirety limited by vestibular apparatus 
posteriorly and middle ear laterally. See Figure 5.2.5.2 and 
https://pdfs.semanticscholar.org/2e9b/73b254b27d7f8724348057291b5a776c7b37.pdf for more 
details. 
 

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Figure 5.2.5.3 From Pacholke et al (2005): Major anatomic landmarks for identifying the 
cochlea on the axial images of a treatment planning computed tomography scan. The best way to 
locate the cochlea is to first identify the internal auditory canal. The image on the left (A) shows 
the anatomy of the temporal bone at the level of the inner ear without outlines of auditory 
structures. Important landmarks on this image are the internal auditory canal, the semicircular 
canals of the vestibular apparatus, and the bony prominences that mark the attachment of the 
tympanic membrane (un-marked arrows). The spiral canals of the cochlea appear as small curved 
or round lucencies within the temporal bone (B). Note that portions of a mastoid air cell may 
look similar to a semicircular canal.  
Thyroid: The thyroid gland should be contoured in its entirety based on treatment planning CT 
scan. The thyroid gland has two connected lobes and is located inferior to the thyroid cartilage. 
The thyroid gland will have considerable contrast on contrast-enhanced CT compared to the 
surrounding tissues. 
 
E-PTV: This will be defined as tissue located within external contour of the patient outside of all 
PTVs.  
 
5.2.6 Dose Prescription 
 
Note: The information provided in this section can be used for adjusting the dose constraints for 
treatment planning purposes. This table together with the planning priority table should be used 
during dose optimization. It is important to remember that ideal plans might not be achievable in 
all cases. Thus, the Compliance Criteria table could be different than the information given here.  
Cases will be scored using the Compliance Criteria table. 
 
 
 
 

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Table 5.2.6A: Dose Prescription and Plan Normalization 
 
Arm 
Target 
Standard 
Name 
Dose 
(Gy) 
Fraction 
Size (Gy) 
# of 
fractions  
Frequency 
Dose specification 
technique 
Arm 1 
PTV_7000 
70 
2.0 
35 
6 fractions 
per week 
Covering 95% of 
PTV 
Arm 2 (Arm 2 
closed to 
accrual 03-
FEB-2023) 
PTV_6000 
60 
2.0 
30 
5 fractions 
per week 
Covering 95% of 
PTV 
 
Arm 3 
PTV_6000 
60 
2.0 
30 
6 fractions 
per week 
Covering 95% of 
PTV 
 
 
For Arm 1, radiotherapy will be delivered in an accelerated schedule over 6 weeks, which 
requires delivery of 6 fractions per week. The sixth fraction can be delivered either on a Saturday 
or as a second daily fraction (BID) on a weekday, with at least a 6 hour interfraction interval if 2 
fractions are given on one of the weekdays. 
 
For Arm 2, radiotherapy will be delivered once daily, 5 fractions per week for 6 weeks (Arm 2 
closed to accrual 03-FEB-2023). 
 
For Arm 3, radiotherapy will be delivered in an accelerated schedule over 5 weeks, which 
requires delivery of 6 fractions per week. The sixth fraction can be delivered either on a Saturday 
or as a second daily fraction (BID) on a weekday, with at least a 6 hour interfraction interval if 2 
fractions are given on one of the weekdays. 
 
Plan should be normalized such that 95% of the volume of PTV_7000 or PTV_6000 receives the 
prescribed dose with a minimum dose (defined as dose to 99% of PTVs) greater than 95% of the 
prescription dose and a maximum dose (defined as dose encompassing 0.03 cc of the PTV) less 
than 110-115% of the prescription dose.  
 
It is recognized that portions of PTV close to the skin or critical PRVs (spinal cord and 
brainstem) may receive significantly less than the prescription doses. PTV_Eval_7000, 
PTV_Eval_6650, PTV_Eval_6020, or PTV_Eval_6000 should be created in this situation to 
evaluate target coverage. When under-dosing PTV_7000, PTV_6650, PTV_6020, or PTV_6000, 
care should be taken to ensure that the cold spots within these PTVs do not exist within the GTV. 
In cases of high-dose PTVs close to skin, tissue equivalent bolus must be utilized to ensure 
adequate dose coverage. 
It is also recognized that PTVs abutting or enclosing higher dose PTVs will have regions of 
maximum dose that may exceed their prescribed dose in order to achieve acceptable minimal 
doses to the higher dose PTVs which are considered a higher priority target. 
 
 
 

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5.2.7 Compliance criteria 
 
The compliance criteria listed here will be used to score each case. Given the limitations inherent 
in the treatment planning process, the numbers given in this section can be different than the 
prescription table. The Per Protocol and Variation Acceptable categories are both considered to 
be acceptable. The Per Protocol cases can be viewed as ideal plans, and the Variation Acceptable 
category can include more challenging plans that do not fall at or near the ideal results. A final 
category, called Deviation Unacceptable, results when cases do not meet the requirements for 
either Per Protocol or Variation Acceptable. Plans falling in this category are considered to be 
suboptimal and additional treatment planning optimization is recommended. 
 
VxGy [cc], VxGy [%], Vx%[cc], Vx%[%]: Volume [cc or %] receiving Dose [Gy, or %] 
CVxGy[cc],CVxGy[%],CVx%[cc],CVx%[%]:Complement Volume [cc or %] receiving Dose 
[Gy, or %] 
Dxcc[Gy], Dxcc[%], Dx%[Gy], Dx%[%]: Dose [Gy or %] to Volume [cc or % of total volume] 
DCxcc[Gy], DCxcc[%], DCx%[Gy], DCx%[%]: Dose [Gy or %] to Complement Volume [cc or 
% of total volume] 
Minimum dose is defined to D99%[Gy] or D99%[%] 
Maximum dose is defined as D0.03cc[Gy] or D0.03cc[%] 
Mean[Gy] or Mean[%]: Mean dose in Gy or % 
 
Normalization of Dose: The plan is normalized such that 95% of the PTV_7000 or PTV_6000 
volume receives prescription dose. 
 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 
met. 
 
Target Volume and OAR Constraints and Compliance Criteria 
Arm 1 
 
Table 5.2.7A: Target Volume and OAR Constraints and Compliance Criteria for Arm 1 
 
Name of Structure 
Dosimetric parameter Per Protocol 
Variation 
Acceptable 
PTV_7000 
or PTV_Eval_7000 
 
D95%[Gy] 
70 
> 68.6 and < = 71.4 
D99%[Gy] 
> = 66.5 
> = 63  
D0.03cc[Gy] 
< = 77 
< = 80.5 
PTV_5600 
D95%[Gy] 
> = 56 
> = 53.2 
PTV_5250  
D95%[Gy] 
> = 52.5  
> = 49.9  
SpinalCord_PRV05 
D0.03cc[Gy] 
< = 50 
< = 52 
SpinalCord 
D0.03cc[Gy] 
< = 45 
< = 48 
BrainStem_PRV03 
D0.03cc[Gy] 
< = 52 
< = 54 
Per Protocol range is excluded from Variation Acceptable range. 
 

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PTV_6650* or 
PTV_Eval_6650* 
D95%[Gy] 
> = 66.5 
> = 65.2  
D99%[Gy] 
> = 63.2 
> = 59.9  
PTV_6020* or 
PTV_Eval_6020* 
D95%[Gy] 
> = 60.2 
> = 59 
D99%[Gy] 
> = 57.2 
> = 54.2  
 
* Note for Arm 1 only: In a rare case of an excised primary tumor or pathologically involved 
lymph node with microscopically/focally positive margins, PTV_6650 should receive 66.5 Gy at 
1.9 Gy/fraction over 35 fractions. For a case with an excision and clearly negative margins, 
PTV_6020 should receive 60.2 Gy at 1.72 Gy/fraction over 35 fractions. 
 
Arm 3 (Arm 2 closed to accrual 03-FEB-2023) 
 
Table 5.2.7B: Target Volume and OAR Constraints and Compliance Criteria for Arm 3 
(Arm 2 closed to accrual 03-FEB-2023) 
Name of Structure 
Dosimetric parameter Per Protocol 
Variation 
Acceptable 
PTV_6000 
or PTV_Eval_6000 
 
D95%[Gy] 
60 
> 58.8 and < = 61.2 
D99%[Gy] 
> = 57 
> = 54  
D0.03cc[Gy] 
< = 66 
< = 69 
PTV_5400 
D95%[Gy] 
> = 54 
> = 51.3 
PTV_4800 
D95%[Gy] 
> = 48 
> = 45.6 
SpinalCord_PRV05 
D0.03cc[Gy] 
< = 48 
< = 50 
SpinalCord 
D0.03cc[Gy] 
< = 45 
< = 48 
BrainStem_PRV03 
D0.03cc[Gy] 
< = 50 
< = 52 
Per Protocol range is excluded from Variation Acceptable range. 
 
Dose limitations to normal structures are described below. For the critical structures listed in 
Table 5.27B (SpinalCord, SpinalCord_PRV05, and BrainStem_PRV03), these are mandatory. 
For other structures recommended limits are provided, but the doses delivered should always be 
as low as reasonably achievable without compromising coverage to PTVs. 
 
Table 5.2.7C: Recommended dose acceptance criteria for other normal tissue, but not to be 
used for plan score. 
 
Structure 
Recommended dose acceptance criteria* 
BrachialPlexus_R/L 
D0.03cc[Gy] < = 66 
Parotid_R/L (at least one gland) 
Mean[Gy] < = 26 
Larynx_SG 
Mean[Gy] < = 40 
Pharynx (uninvolved) 
Mean[Gy] < = 45  
Cavity_Oral (uninvolved) 
Mean[Gy] < = 35 
Lips 
Mean[Gy] < = 20 
Esophagus_S 
Mean[Gy] < = 30 

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Glnd_Submand_R/L (contralateral) 
Mean[Gy] < = 39 
Cochlea_R/L 
Mean[Gy] < = 35 
Bone_Mandible  
D0.03cc[Gy] < = 73.5 
Thyroid 
Mean[Gy] < = 50 
E-PTV 
D1cc[Gy] < = 73.5 
* Please keep OAR doses as low as reasonably achievable without compromising coverage to 
PTVs. 
 
Delivery Compliance criteria 
Protocol treatment must begin within 14 days after randomization. Treatment breaks must be 
clearly indicated in the treatment record along with the reason(s) for the treatment break(s). 
Treatment breaks, if necessary, should not exceed 3 treatment days at a time and 5 treatment 
days total. Treatment breaks should be allowed only for resolution of severe acute toxicity and/or 
for intercurrent illness and not for social or logistical reasons. Any treatment break(s) exceeding 
4 treatment days for reasons other than toxicity/illness will be considered a protocol deviation. 
 
Given the importance of timeliness of treatment delivery in this study, it is strongly 
recommended that patients receive twice-daily treatments with a minimum 6-hour interfraction 
interval to compensate for missed days including holidays and those for toxicity or illness once 
sufficiently recovered with the goal of keeping the overall treatment time within the limits 
defined in Table 5.2.7D. 
 
Table 5.2.7D: Delivery Compliance Criteria 
 
 
Per Protocol 
Variation 
Acceptable 
Deviation Unacceptable 
RT Start date  
Arm 1 (Arm 2 closed to accrual 
03-FEB-2023)  
 
 
 
Arm 3 
 
≤ 14 days 
after 
randomization 
 
≤ 21 days 
after 
randomization 
   
15-18 days 
 
 
 
22-25 days 
 
> 19 days 
 
 
 
> 26 days 
Overall Treatment time 
Arm 1 (Arm 2 closed to accrual 
03-FEB-2023) 
≤ 45 days 
46-51 days 
> 52 days without medically 
appropriate indication for delay 
Overall Treatment time 
Arm 3  
< 38 days 
39-43 days 
> 44 days without a medically 
appropriate indication for delay 
Interruptions (without medical 
indication) 
≤ 2 days 
3-4 days 
 > 5 days 
 
 
 

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5.2.8 Treatment Planning Priorities and Instructions 
 
Critical Structure and Target priorities must be listed in order of decreasing importance. 
Prioritization for IMRT Planning: 
1. SpinalCord and SpinalCord_PRV05 
2. BrainStem and BrainStem_PRV03 
3. PTV_7000, PTV_6650, PTV_6020, or PTV_6000 
4. PTV_5600 or PTV_5400 
5. PTV_5250 or PTV_4800 
6. BrachialPlexus_R/L 
7. Contralateral Parotid_R/L 
 
8. a. Larynx_SG 
    b. Pharynx 
9. a. Cavity_Oral 
    b. Lips 
10. Esophagus_S 
11. Contralateral Glnd_Submand_R/L 
12. Ipsilateral Parotid_R/L 
13. Cochlea_R/L 
14. Bone_Mandible 
15. Thyroid 
16. E-PTV 
 
Required algorithms 
Acceptable choices of algorithm are listed at: http://rpc.mdanderson.org/RPC/home.htm  
 
For Convolution/Superposition type algorithms, dose should be reported as computed inherently 
by the given algorithm. For Monte Carlo or Grid Based Boltzmann Solver algorithms, 
conversion of Dm (dose-to-medium) to Dw (dose-to-water) should be avoided. Dm, computed 
inherently by these algorithms, should be reported. These principles hold for Pencil Beam type 
algorithms and for homogeneous dose calculations when allowed for a clinical trial (e.g., conical 
collimators in stereotactic radiosurgery). 
 
Primary dataset for dose calculation 
If treatment planning CT is acquired with IV contrast, whether the density of the contrast should 
be overridden to a representative background electron density should be tested to demonstrate 
such density overridden is negligible to dose calculation. In addition, image artifacts such as 
streaks near metal, dental implants, fillings, clips or other high-density objects should be 
overridden with appropriate HUs. 
 
Dose matrix resolution 
Dose grid size should be ≤ 3 mm in all directions. 
 
 
 

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Adaptive planning (Re-planning) 
In cases of weight loss > 10% or substantial shrinkage of lymphadenopathy during therapy, it is 
recommended that the immobilization mask be adjusted or re-made in order to preserve adequate 
immobilization, and that a repeated simulation CT be performed to assess the dose distributions 
in the current anatomy. There may be other extenuating circumstances requiring a re-CT and re-
planning process. Whether or not a new IMRT plan will be generated is at the discretion of the 
treating physician. If a new plan is made, the target and OAR nomenclature should be the same 
as those used for the initial plan and the target volumes should not be adjusted in cases of disease 
regression, except to respect clear anatomic barriers such as skin or fascial or muscle planes 
initially uninvolved by disease. Re-planning DICOM data and final plan sum dose statistics 
should be submitted at the end of treatment. 
 
5.2.9 Patient specific QA 
 
Any patient-specific QA that needs to be acquired should follow institutional guidelines and 
AAPM task group report recommendations.  
 
For IMRT/VMAT plans, patient specific QA is highly recommended. The recommended patient 
specific QA criteria is for 90% of the comparison points to pass a ± 3%/3 mm Gamma Index 
analysis. 
 
5.2.10 Treatment Localization/IGRT 
 
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate treatment 
accuracy and precision throughout its entire process. In this section we use the terminology 
IGRT to focus on image-guidance at the time of radiation delivery to ensure its adherence to the 
planned treatment, with computer assisted process, i.e. image handling together with calculation 
of shift and rotations (if available) must be determined with computer assistance.  
 
Daily image guidance of IMRT may be achieved using any one or more of the following 
techniques: 
• 
Orthogonal kilovoltage (kV) images (e.g. ExacTrac) 
• 
Linear-accelerator mounted kV and MV conebeam CT images 
• 
Linear-accelerator mounted MV helical CT images (e.g. Tomotherapy) 
• 
In room CT or CBCT  
• 
MRI scouts or MRI 2D/3D images  
• 
Other Mechanism, after discussion with the Radiation Oncology Co-chair 
                        
 
The institution’s procedure to register treatment day imaging dataset with the reference dataset 
should comply with the following recommendations: 
• 
Region-of-Interest (ROI) or “clip box” for fusion should be set to encompass the high 
dose PTV and adjacent spinal cord; 
• 
If the fusion software allows the user to create an irregular ROI (e.g., ExacTrac), 
treatment room objects seen on in-room X-rays should be excluded from the registration; 
• 
Both manual (e.g., based on bony anatomy) and automatic (e.g., based on mutual 
information) types of registration can be used; the result of the fusion must be visually 

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checked for the alignment of the bony anatomy, such as vertebral bodies and applicable 
soft tissue structures (e.g., optic nerves and/or optic chiasm). 
• 
Following the registration, the translational and (if the appropriate technology is 
available) rotational corrections should be applied to the treatment couch. If all the 
variances are less than 2.5 mm, the treatment can proceed without correction (however, 
the physician/team may elect to perform adjustments even for a variance < 2.5 mm). If 
one or more corrections are 2.5-5 mm, adjustment is necessary prior to treatment; 
however, re-imaging is not mandatory. If one or more of the corrections are larger than 5 
mm, the imaging must be repeated in addition to performing table/positioning 
adjustments. However, the use of numerous repeated IGRT should be avoided. 
 
 
Management of Radiation Dose to the Patient from IGRT 
 
NRG Oncology is concerned about the estimated doses given from IGRT and is committed to 
limiting the imaging dose when IGRT is used in any of its protocols. This can be accomplished 
by avoiding re-imaging to make shifts in patient positioning that are already less than the stated 
PTV margins. The imaging dose to the patient may become significant if repeated studies are 
done for patients with severe set up problems (e.g. requiring frequent corrections that are larger 
than the PTV margins). It is recommended that patients demonstrating severe set up problems 
during the first week of treatment be moved to a treatment with larger margins. 
 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
5.3.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication.  
 Anticonvulsants 
 Antiemetics 
 Anticoagulants 
 Antidiarrheals 
 Analgesics 
 Herbal products 
 Nutritional supplementation 
 Highly active antiretroviral therapy (HAART) 
 Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone 
equivalents are permitted 
5.3.2 Prohibited Therapies 
 Hematopoietic Growth Factors 
 Corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive 
medications (unless to treat immune-related adverse event). Corticosteroid use for 
chemotherapy premedication is allowed.   
5.3.3 Participation in Other Trials  
Patients are not to participate in other therapeutic trials. However, trials that do not include drug 
are allowed (e.g. imaging trials, quality of life, etc). 

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5.4 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as specified 
in the above treatment modality sections or until one of the following criteria applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), as described in Section 6 (see also specific nivolumab 
algorithms in the Investigator’s Brochure), 
 
For patients receiving nivolumab: Any dosing interruption lasting > 6 weeks, with the 
following exceptions: Dosing interruptions > 6 weeks that occur for non-drug-related 
reasons may be allowed if approved by the Investigator. Prior to re-initiating treatment in 
a subject with a dosing interruption lasting > 6 weeks, the Principal Investigator must be 
consulted. 
Note: Tumor assessments should continue as per protocol even if dosing is interrupted,  
 
Patient decides to withdraw consent for participation in the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
NOTE:  PRO-CTCAE data should not be used for determining dose delays or dose 
modifications or any other protocol directed action. 
 
6.1 
Dose Modifications and Toxicity Management for Nivolumab (19-APR-2023)  
Please refer to the Nivolumab Investigator Brochure or Appendix VI for nivolumab toxicity 
management algorithms which include specific treatment guidelines.  These algorithms should 
be followed unless there are specific clinical circumstances for which the treating physician 
decides an alternative treatment approach is clinically appropriate.  Consultation with the study 
PI or drug monitor is recommended.  When there are differences in recommendations between 
the aforementioned sources and the toxicity management tables provided below, the protocol 
tables determine when experimental treatment is to be held or stopped. 
 
Generally we strongly encourage early evaluation while withholding drug, and appropriate 
treatment as indicated in the management tables and event specific guidelines.   
 
ALL OTHER 
EVENTS 
Management/Next Dose for Nivolumab  
≤ Grade 1 
No change in dose.   
Grade 2  
Hold until ≤ Grade 1 OR baseline (exceptions as noted below).  
Grade 3  
Hold until ≤ Grade 1 OR baseline and patient no longer on steroid 
treatment if initiated (exceptions as noted below).  Permanently 
discontinue for events with a high likelihood of morbidity or 
mortality with recurrent events.  
Grade 4  
Off protocol therapy.  
Recommended management:  As clinically indicated   
 
o Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within the 

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re-treatment period OR requires systemic treatment should go off protocol 
treatment.   
 
o Any Grade 2, 3 or 4 drug-related laboratory abnormality or electrolyte 
abnormality, that can be managed independently from underlying organ 
pathology with electrolyte replacement, hormone replacement, insulin or that 
does not require treatment does not require discontinuation.   
 
o Any AE, laboratory abnormality, or intercurrent illness which, in the judgment 
of the investigator, presents a substantial clinical risk to the subject with 
continued study drug dosing should go off protocol treatment.   
 
 
Skin Rash and Oral 
Lesions  
  
Management/Next Dose for Nivolumab  
≤ Grade 1  
No change in dose*.  
Grade 2  
Hold* until 1 ≤ Grade resolved.  Resume at same dose level.   
Grade 3  
Hold* until ≤ Grade 1.  Resume at same level at investigator 
discretion   
Grade 4  
Off protocol therapy.  
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson 
syndrome, toxic epidermal necrolysis (TEN), and autoimmune bullous disease including oral 
lesions of bullous pemphigus/pemphigoid.  Pruritus may occur with or without skin rash and 
should be treated symptomatically if there is no associated liver or GI toxicity.  Note skin 
rash typically occurs early and may be followed by additional events particularly during 
steroids tapering.    
Recommended management:  AE management guidelines  
 
 
Liver Function  
AST, ALT, Bilirubin 
  
Management/Next Dose for Nivolumab  
≤ Grade 1  
Hold at investigator discretion until ULN or baseline.  Resume at 
same dose level. 
Grade 2  
Grade 2 (3X UNL to 5X UNL): Hold until grade 1 (UNL-3X 
UNL) or baseline.  Resume at same dose level at investigator 
discretion. 
Grade 3  
Grade 3 (5X UNL to 20X UNL) Hold until grade 1 or baseline.  
Resume at same dose level at investigator discretion with return to 
grade 1 or baseline within 7 days without steroids.  If persistent or 
steroids are required, off protocol therapy.   
Grade 4  
Off protocol therapy.  
Continued treatment of active immune mediated hepatitis may exacerbate ongoing 
inflammation.   

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Holding drug to evaluate liver function test (LFT) changes and early treatment are 
recommended.  LFT changes may occur during steroid tapers from other events and may 
occur together with other GI events including cholecystitis/pancreatitis.  
Please note:  Grades for liver function follow UNL rather than multiples of baseline. 
Recommended management:  see Hepatic AE management algorithm  
 
Diarrhea/Colitis 
Management/Next Dose for Nivolumab 
≤ Grade 1 
 
Hold until baseline.  No change in dose.  
Grade 2  
Hold until baseline.  No change in dose.  
Grade 3  
Resume at same dose level at investigator discretion if resolved 
to grade 1 within 7 days without steroids and no evidence of 
colitis.  If persistent or steroids are required off protocol 
therapy.  
Grade 4  
Off protocol therapy.  
See GI AE Algorithm for management of symptomatic colitis.   
Patients with Grade 2 symptoms but normal colonoscopy and biopsies may be retreated after 
resolution.   
Patients who require systemic steroids should be taken off study treatment.   
Please evaluate pituitary function prior to starting steroids if possible without compromising 
acute care. Evaluation for all patients for additional causes includes C. diff, acute and self-
limited infectious and foodborne illness, ischemic bowel, diverticulitis, and IBD.   
Recommended management:  see GI AE management Algorithm  
   
 
Pancreatitis 
Amylase/Lipase   
Management/Next Dose for Nivolumab  
≤ Grade 1  
Continue at same dose level if asymptomatic at investigator 
discretion.   
Grade 2  
Continue at same dose level if asymptomatic at investigator 
discretion.  If symptomatic, resume at same dose level when 
resolved  
Grade 3  
Continue at same dose level if asymptomatic at investigator 
discretion.  Patients should have imaging study when clinically 
indicated (grade 3 symptomatic pancreatitis) before resuming 
treatment.  Patients who develop diabetes mellitus should be 
taken off treatment.   
Grade 4  
Hold until grade 2.  Resume at same dose level if 
asymptomatic.  Patients who are symptomatic should have 
imaging study prior to resuming treatment and when clinically 
indicated.  Patients who develop grade 4 symptomatic 
pancreatitis or diabetes mellitus should be taken off treatment.   
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as 
diabetes mellitus and diabetic ketoacidosis (DKA).  Lipase elevation may occur during the 

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period of steroid withdrawal and with other immune-mediated events or associated with 
colitis, hepatitis, and patients who have asymptomatic lipase elevation typically have self-
limited course and may be retreated.   
For treatment management of symptomatic pancreatitis, please follow the Hepatic AE 
Management Algorithm.   
  
  
Pneumonitis  
Management/Next Dose for Nivolumab  
≤ Grade 1  
Hold dose pending evaluation and resolution to baseline 
including baseline pO2.  Resume no change in dose after 
pulmonary and/or infectious disease (ID) consultation excludes 
lymphocytic pneumonitis.   
Grade 2  
Hold dose pending evaluation. Resume no change in dose after 
pulmonary and/or ID consultation excludes ipilimumab and 
associated lymphocytic pneumonitis as the cause of the 
pneumonitis.  Off study if steroids are required.  
Grade 3  
Hold dose pending evaluation.  Resume no change in dose after 
pulmonary and/or ID consultation excludes ipilimumab and 
associated lymphocytic pneumonitis as the cause of the 
pneumonitis.  Off protocol treatment. 
Grade 4  
Off protocol therapy.  
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who 
do not respond to antibiotics and have no causal organism identified, including influenza.  
Most patients with respiratory failure or hypoxia will be treated with steroids.  
Bronchoscopy may be required and analysis of lavage fluid for lymphocytic predominance 
may be helpful.  Patients with new lung nodules should be evaluated for sarcoid like 
granuloma.  Please consider recommending seasonal influenza killed vaccine for all patients.  
Recommended management:  See Pulmonary AE Management Algorithm   
   
Other GI  
Nausea, Vomiting   
Management/Next Dose for Nivolumab  
≤ Grade 1  
No change in dose.   
Grade 2  
Hold pending evaluation for gastritis, duodenitis, and other 
immune AEs or other causes.  Resume at same dose level after 
resolution to ≤ Grade 1.    
Grade 3  
Hold pending evaluation until ≤ Grade 1.  Resume at same 
dose level.  If symptoms do not resolve within 7 days with 
symptomatic treatment, patients should go off protocol therapy.  
Grade 4  
Off protocol therapy.  
Patients with Grade 2 or 3 N-V should be evaluated for upper GI inflammation and other 
immune related events. 
   
Fatigue 
Management/Next Dose for Nivolumab  
  
Grade 2 
No change in dose. 

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Grade 3 
Hold until ≤ Grade 2.  Resume at same dose level.  
Grade 4 
Off protocol therapy.  
Fatigue is the most common AE associated with immune checkpoint therapy.  Grade 2 or 
greater fatigue should be evaluated for associated or underlying organ involvement including 
pituitary, thyroid, and hepatic, or muscle (CPK) inflammation.   
   
Neurologic Events 
Management/Next Dose for Nivolumab  
≤ Grade 1  
Hold dose pending evaluation and observation.  Resume with 
no change in dose when resolved to baseline.   
Grade 2  
Hold dose pending evaluation and observation.  Hold until ≤ 
Grade 1. Off protocol therapy if treatment with steroids is 
required.  Resume at same dose level for peripheral isolated n. 
VII (Bell’s palsy).   
Grade 3  
Off protocol therapy. 
Grade 4  
Off protocol therapy.   
Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic 
hypophysitis, or myopathy, peripheral demyelinating neuropathy, cranial neuropathy (other 
than peripheral n. VII), GB syndrome, and myasthenia gravis should be off study. 
Recommended management:  See Neurologic AE Management Algorithm   
  
  
 
Endocrine 
Hypophysitis  
Adrenal Insufficiency 
Management/Next Dose for Nivolumab  
≤ Grade 1  
*Hold pending evaluation for evidence of adrenal 
insufficiency or hypophysitis.  Asymptomatic thyroid 
stimulating hormone (TSH) elevation may continue treatment 
while evaluating the need for thyroid replacement.  
Grade 2  
Hold until patients are on a stable replacement hormone 
regimen.  If treated with steroids, patients must be stable off 
steroids for 2 weeks.   
Resume at same dose level.   
Grade 3  
Hold until patients are on a stable replacement hormone 
regimen.  If treated with steroids, patients must be stable off 
steroids for 2 weeks.  
Resume at same dose level.  
Grade 4  
Off protocol therapy.  
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, 
but including severe headache or enlarged pituitary on MRI should be considered Grade 3 
events.  Isolated thyroid or testosterone deficiency may be treated as Grade 2 if there are no 
other associated deficiencies and adrenal function is monitored.   
Please evaluate pituitary function before beginning steroid therapy or replacement therapy 
of any kind.  *Note patients with thyroiditis may be retreated on replacement therapy.  
Patients must be evaluated to rule out pituitary disease prior to initiating thyroid 

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replacement.  
Recommended management:  See Endocrine Management Algorithm   
  
 
Renal 
Management/Next Dose for Nivolumab  
≤ Grade 1  
Monitor closely and continue therapy.  
Grade 2  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 3  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 4  
Off treatment.  
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over 
the course of 1-2 weeks should be done for other autoimmune events that may present as 
fever.   
  
  
Infusion Reaction   
Management/Next Dose for Nivolumab  
≤ Grade 1  
Monitor closely and continue therapy.  
Grade 2  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 3  
Off treatment.  
Grade 4  
Off treatment.  
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over 
the course of 1-2 weeks should be done for other autoimmune events that may present as 
fever.   
  
  
Fever   
Management/Next Dose for Nivolumab  
≤ Grade 1  
Evaluate and continue at same dose level.  
Grade 2  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 3  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 4  
Off treatment.  
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over 
the course of 1-2 weeks should be done for other autoimmune events that may present as 
fever.  
See section 6.1.1 – Treatment of Nivolumab-Related Infusion Reactions.    
 
Any patients who require additional immune suppressive treatment beyond steroids 
should go off study treatment.  
  
Prior to starting corticosteroids or hormone replacement for any reason, appropriate 
endocrine testing including cortisol, Cortrosyn® adrenocorticotrophic hormone 
(ACTH), thyroid stimulating hormone (TSH), and thyroxine (T4) must be obtained 

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to document baseline.   
  
Please note that in some cases the treatment algorithms recommend steroids if 
symptoms do not resolve in 7 days.  However, this recommendation is not meant to 
delay steroid treatment at any time it is clinically indicated. 
Any patient started on corticosteroids initially, who is determined to not require steroid 
treatment for an autoimmune AE, may resume therapy after a 2-week observation period 
without further symptoms at the discretion of the PI or investigator.  
 
Cardiac Dysfunction 
x Drug will be held for any indication suggestion of cardiac dysfunction of any 
grade pending evaluation 
x Drug will be permanently discontinued for treatment related grade 3 or 4 
cardiac dysfunction and grade 2 events that do not recover to baseline or that 
reoccur 
x Treatment as clinically indicated for cardiomyopathy   
 
 
Cardiac *   
Management/Next Dose for BMS-936558 (Nivolumab) 
Cardiac Toxicities 
Less than grade 2 
Hold dose pending evaluation and observation.**  Evaluate for 
signs and symptoms of CHF, ischemia, arrhythmia or myositis.  
Obtain history EKG, CK (for concomitant myositis), CK-MB.  
Repeat troponin, CK and EKG 2-3 days.  If troponin and labs 
normalize without evidence of myocarditis may resume therapy.   
If labs worsen or symptoms develop then treat as below.   
Grade >2 with suspected 
myocarditis 
Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out 
MI and other causes of cardiac disease.  Cardiac Monitoring.  
Cardiac Echo.  Consider cardiac MRI and cardiac biopsy.  
Initiate high dose methylprednisolone and immune suppression 
as clinically indicated. .  If no improvement within 24 hours 
consider adding either infliximab, ATG or tacrolimus.. May 
resume therapy if there is a return to baseline and myocarditis is 
excluded or considered unlikely. 
Grade >2 with confirmed 
myocarditis   
Off protocol therapy.  Admit to CCU (consider transfer to 
nearest Cardiac Transplant Unit).  Treat as above.  Consider high 
dose methylprednisolone   
Add ATG or tacrolimus if no improvement.   Off protocol 
treatment. 

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Cardiac *   
Management/Next Dose for BMS-936558 (Nivolumab) 
Cardiac Toxicities 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other 
event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been 
established.  Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.   
 
 
6.1.1 
Treatment of Nivolumab-Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions.  However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, urticaria, angioedema, 
pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms.  
 
Infusion reactions should be graded according to NCI CTCAE version 5.0 guidelines. 
 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as medically appropriate: 
 
Remain at bedside and monitor subject until recovery from symptoms.  
 
For Grade 1 symptoms:   
(Mild reaction; infusion interruption not indicated; intervention not indicated)  
 
Infusion rate may be slowed or interrupted and restarted at 50% of the original infusion rate 
when symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor patient closely.   
 
The following prophylactic premedications are recommended for future infusions:  
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at 
least 30 minutes before additional nivolumab administrations, slowing infusion rate as above. 
 
For Grade 2 symptoms:   
(Moderate reaction requires therapy or infusion interruption but responds promptly to 
symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, narcotics, 
corticosteroids, bronchodilators, IV fluids]; close observation for recurrence and treatment 
medications may need to be continued for 24-48 hours).   
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); 
remain at bedside and monitor patient until resolution of symptoms.  Corticosteroid or 
bronchodilator therapy may also be administered as appropriate.  If the infusion is interrupted, 
then restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further 

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complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
rate.  Monitor patient closely.  If symptoms recur, re administer diphenhydramine 50 mg IV, and 
remain at bedside and monitor the patient until resolution of symptoms.  The amount of study 
drug infused must be recorded on the electronic case report form (eCRF). 
 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and (acetaminophen) (or paracetamol) 325 to 1000 mg 
should be administered at least 30 minutes before additional nivolumab administrations.  If 
necessary, corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) 
may be used. 
 
For Grade 3 or Grade 4 symptoms: (Severe reaction) 
Grade 3 symptoms: prolonged [i.e., not rapidly responsive to symptomatic medication and/or 
brief interruption of infusion]; recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae [e.g., renal impairment, pulmonary 
infiltrates]).   
 
Grade 4 symptoms: (life threatening; pressor or ventilatory support indicated).  
 
Nivolumab will be permanently discontinued. 
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and 
bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 
0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed.  
Patient should be monitored until the investigator is comfortable that the symptoms will not 
recur.   
 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor patient until recovery from symptoms.  
 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., 
oral antihistamine, or corticosteroids). Additional treatment prior to next dose as per guidelines 
above.  
 
Please note that late occurring events including isolated fever and fatigue may represent the 
presentation of systemic inflammation. Please evaluate accordingly.  
 
6.2 
Recommended Dose Modifications and Toxicity Management for Cisplatin (14-
MAR-2023) 
 
The following cisplatin dose modification and toxicity management guidelines are 
recommendations; sites may follow their institutional standards for cisplatin administration as 
well as the FDA labeling.  
 

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Note: If adverse events prevent the administration of cisplatin, the patient may continue to 
receive radiation.  
 
Note: Substitution of carboplatin for cisplatin during adverse events is NOT allowed. 
 
Patients will be examined and graded for subjective/objective evidence of developing toxicity 
weekly according to CTCAE, v5.0 while receiving concurrent cisplatin with radiotherapy.  
 
Radiation treatment interruptions are only allowed if there are significant toxicities or 
comorbidities, in the judgment of the clinician, necessitate a break. For chemotherapy-
attributable AEs requiring a break in treatment, resumption of concurrent cisplatin may begin 
when AEs have recovered to the levels specified below. Chemotherapy should be discontinued in 
the event of more than 2 events requiring dose reduction (e.g. if grade 3 or greater non-
hematologic or hematologic event occurs at the reduced dose of cisplatin).  
 
If an AE does not resolve to the levels specified in the sections below prior to the calendar week 
of the last radiation treatment (See Section 5.1.1 for details concerning parameters for timing of 
last allowable concurrent cisplatin dose), then chemotherapy should be discontinued.  
 
There will be no dose re-escalation for concurrent cisplatin.  
 
Chemotherapy dosage modifications are based upon lab values obtained prior to cisplatin and 
interim non-hematologic toxicities during the week prior to a particular cisplatin dose.  
 
6.2.1    Cisplatin Dose Modifications for Hematologic Adverse Events during Concurrent 
Radiation  
 
Neutropenia and thrombocytopenia: Chemotherapy must not be administered until the ANC is ≥ 
1200 mm3 and platelets are ≥ 75,000 mm3. If not, delay 7 days. Cisplatin should be held every 
week (but RT continued) until the above ANC and platelet parameters are met, then treat at 100 
mg/m2 dose. Any thrombocytopenia resulting in bleeding will require a dose reduction to 75 
mg/m2 of the second cisplatin dose. 
 
Note: Hematologic growth factors for neutropenia or anemia are not allowed during 
concurrent cisplatin and radiation treatment. 
 
Neutropenic Fever: Grade 3 (CTCAE, v5.0) neutropenic fever (ANC < 1000/mm3 with a single 
temperature of  > 38.3 degrees C [101 degrees F] or a sustained temperature of  ≥ 38 degrees C 
[100.4 degrees F] for more than 1 hour will require a dose reduction to 75 mg/m2 of the second 
cisplatin dose.  
 
6.2.2  Cisplatin Dose Modifications for Non-Hematologic Adverse Events during Concurrent 
Radiation  
Renal Adverse Events: Dose will be modified based on the serum creatinine prior to each 
cisplatin dose. If the serum creatinine is ≤ 1.5 mg/dL, creatinine clearance is not necessary for 
treatment with full dose. If the serum creatinine is > 1.5 mg/dL, a creatinine clearance should be 

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obtained by urine collection or nomogram calculation (valid only if serum creatinine is not 
changing rapidly).  
 
Cisplatin must not be administered until creatinine is ≤ 1.5 or creatinine clearance ≥ 50. 
Once the creatinine has met the above parameters, cisplatin may be restarted with the below 
modifications. In general, cisplatin should be held for weekly intervals (rather than restarting 
cisplatin later in the same week that a dose limiting AE is seen). 
 
Cisplatin dose modifications for creatinine during concurrent radiation 
Creatinine (mg/dL) 
 
Creatinine 
clearance, 
measured or 
calculated ml/min 
Cisplatin dose  
≤ 1.5 
Or 
> 50 
100 mg/m2 
> 1.5 
And 
40-50 
50 mg/m2 
> 1.5 
And 
< 40 
Hold drug* 
*Cisplatin should be held (but RT continued) and the creatinine measured weekly until it is < 1.5 
mg/dl or the creatinine clearance is > 50 ml/min, and then the second dose of cisplatin should be 
given at the reduced dose of 50 mg/m2. 
 
Neurologic (neuropathy) Adverse Events: 
 
Grade (CTCAE, v. 5) 
Dose Reduction 
0-1 
None 
2 
 Hold until toxicity improves to Grade 1 
then reduce dose to 75 mg/m2 
3-4 
Discontinue drug 
 
Ototoxicity: Should patients develop clinical evidence of ototoxicity, further audiometric 
evaluation is required. A neurologic deficit should be distinguished from a conductive loss from 
obstruction of the Eustachian tube leading to a middle ear effusion. Because no AE scale, 
including the CTCAE, v5.0, has been validated in terms of correlation with clinically relevant 
hearing loss, there are no protocol mandates requiring dose reduction for audiogram-determined 
sensorineural hearing loss without an analogous clinical high grade ( > grade 2) hearing loss. 
However, for clinical grade 3 or higher hearing loss, cisplatin should be held and for grade 2 
clinical hearing loss, reduce to cisplatin 50 mg/m2. For hearing loss requiring a hearing aid, 
discontinue cisplatin. For grade 2-3 tinnitus, at the time of retreatment, hold cisplatin until 
improvement to grade 1 or less and then reduce the 2nd dose to 50 mg/m2. If tinnitus does not 
improve to grade 1 or less by the last day of radiation therapy, discontinue cisplatin. An 
audiogram is strongly recommended when there is any report of significant change in hearing 
and/or an increase in tinnitus. 
 
All Other Non-Hematologic Adverse Events Attributable to Cisplatin during Concurrent 
Radiation: For all other non-hematologic adverse events in which toxicity is ≥ grade 2 (CTCAE 
v5.0), investigators are advised to evaluate and manage correctable issues promptly to prevent 
worsening of toxicity. For these events in which toxicity is ≥ grade 3, investigators should hold 

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cisplatin, with weekly re-evaluation until AE grade falls to 0-1, then restart cisplatin at one lower 
dose level at 75 mg/m2. Note: Grade 3 mucositis is commonly experienced by head and neck 
cancer patients; the investigator generally would not hold the cisplatin dosing in this case, unless 
there is unusual concern for progression to grade 4 mucositis. 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1  Protocol Agents 
Investigational Agent 
The investigational agent administered in NRG-HN005, nivolumab, is being made available 
under an IND sponsored by CTEP.   
Commercial Agent 
The commercial agent in NRG-HN005 is cisplatin. 
 
 
7.2 Adverse Events and Serious Adverse Events 
7.2.1 NCI Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs reporting of 
adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0. 
 
For determination of whether an adverse event meets expedited reporting criteria, see the 
reporting tables in section 7.5 of the protocol. 
PRO-CTCAE is not intended for expedited reporting, real time review, or safety reporting. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product (attribution of unrelated, unlikely, possible, probable, or definite). 
(International Conference on Harmonisation [ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol treatment 
including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy 
of a study participant must be reported via CTEP-AERS in an expedited manner. 
 
Clinician graded CTCAE is the AE (adverse event) safety standard.  PRO-CTCAE items are to 
complement CTCAE reporting.  Patients will respond to PRO-CTCAE items but no protocol 
directed action will be taken. The specific PRO-CTCAE items for this protocol can be found on 
the forms section of the CTSU protocol webpage and is titled “NRG-HN005 NCI PRO-CTCAE 
Item Library. PRO-CTCAE is not intended for expedited reporting, real time review or safety 

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reporting. PRO-CTCAE data are exploratory and not currently intended for use in data safety 
monitoring or adverse event stopping rules. 
NOTE:  PRO-CTCAE data should not be used for determining dose delays or dose modifications 
or any other protocol directed action. 
 
7.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Nivolumab 
(NSC 78726) (21-AUG-2023) 
 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements'  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2069 patients. Below is the CAEPR for 
Nivolumab. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
Version 2.5, June 10, 20231 
 
 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Blood and lymphatic system 
disorders - Other (lymphatic 
dysfunction) 
  
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2 
  
 
 
Pericarditis 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency3 
 
  
 
Hyperthyroidism3 
 
  
 
Hypophysitis3 
 
  
 
Hypothyroidism3 
 
  
EYE DISORDERS 
  
 
 
Blurred vision 
  

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Dry eye 
  
 
 
Eye disorders - Other (diplopia)3   
 
 
Eye disorders - Other (Graves 
opthalmopathy)3 
  
 
 
Eye disorders - Other (optic 
neuritis retrobulbar)3 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada)3 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis3 
 
  
 
 
Colonic perforation3 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Enterocolitis 
  
 
 
Gastritis 
  
 
 
Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - Other 
(Immune-related hepatitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release syndrome5 
  
 
 
Immune system disorders - 
Other (GVHD in the setting of 
allotransplant)3,6 
  
 
 
Immune system disorders - 
Other (sarcoid granuloma, 
sarcoidosis)3 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased3 
 
 Alanine aminotransferase 
increased3 (Gr 3) 
 
Aspartate aminotransferase 
increased3 
 
 Aspartate aminotransferase 
increased3 (Gr 3) 
 
Blood bilirubin increased3 
 
 Blood bilirubin increased3 
(Gr 2) 
 
CD4 lymphocytes decreased 
 
 CD4 lymphocytes decreased 
(Gr 4) 
 
Creatinine increased 
 
  

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Lipase increased 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count 
decreased (Gr 4) 
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
Serum amylase increased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus with ketoacidosis) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  
 
 
Guillain-Barre syndrome3 
  
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - 
Other (demyelination 
myasthenic syndrome) 
  
 
 
Nervous system disorders - 
Other (encephalitis)3 
  
 
 
Nervous system disorders - 
Other (meningoencephalitis) 
  
 
 
Nervous system disorders - 
Other (meningoradiculitis)3 
  
 
 
Nervous system disorders - 
Other (myasthenic syndrome) 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy   
 
 
Reversible posterior 
leukoencephalopathy syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  
 
 
Renal and urinary disorders - 
Other (Immune-related nephritis) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia (BOOP))3 
  

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  
 
Pruritus3 
 
 Pruritus3 (Gr 2) 
 
Rash maculo-papular3 
 
 Rash maculo-papular3 (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (bullous 
pemphigoid) 
  
 
Skin and subcutaneous tissue 
disorders - Other (Sweet's 
Syndrome)3 
  
  
 
Skin hypopigmentation3 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision. The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3Nivolumab being a member of class of agents involved in the inhibition of “immune 
checkpoints”, may result in severe and possibly fatal immune-mediated adverse events probably 
due to T-cell activation and proliferation.  This may result in autoimmune disorders that can 
include (but are not limited to) autoimmune hemolytic anemia, acquired anti-factor VIII immune 
response, autoimmune aseptic meningitis, autoimmune hepatitis, autoimmune nephritis, 
autoimmune neuropathy, autoimmune thyroiditis, bullous pemphigoid, exacerbation of Churg-
Strauss Syndrome, drug rash with eosinophilia systemic symptoms [DRESS] syndrome, facial 
nerve disorder (facial nerve paralysis), limbic encephalitis, hepatic failure, pure red cell aplasia, 
pancreatitis, ulcerative and hemorrhagic colitis, endocrine disorders (e.g., autoimmune 
thyroiditis, hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, 
thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia gravis, polymyositis, 
and Guillain-Barre syndrome. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with 
accompanying fever and pancytopenia. 
 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have 
occurred in patients receiving allo stem cell transplant (SCT) after receiving Nivolumab.  These 
complications may occur despite intervening therapy between receiving Nivolumab and allo-
SCT. 

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7Infusion reactions, including high-grade hypersensitivity reactions which have been observed 
following administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, 
hypertension or hypotension, or difficulty breathing during and immediately after administration 
of nivolumab. 
 
 
Adverse events reported on Nivolumab trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that Nivolumab 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; 
Heart failure; Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; 
Periorbital edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; 
Gastrointestinal disorders - Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Chills; Edema limbs; Malaise; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - 
Other (autoimmune thrombotic microangiopathy); Immune system disorders - Other 
(limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; 
Sepsis; Upper respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; 
Investigations - Other (protein total decreased); Lymphocyte count increased; Weight 
loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back 
pain; Musculoskeletal and connective tissue disorder - Other (musculoskeletal pain); 
Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); 
Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (Histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial 
hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - 
Other (tubulointerstitial nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Bronchospasm; Cough; Dyspnea; Hypoxia 

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SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; Pain of skin; Photosensitivity; Rash acneiform; Skin and subcutaneous 
tissue disorders - Other (rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
 
Note: Nivolumab in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
7.4       Adverse Events for Commercial Study Agent: Cisplatin 
Refer to the package insert for detailed pharmacologic and safety information. 
 
7.4.1  Adverse Events and PRO-CTCAE 
PRO-CTCAE 
The PRO-CTCAE instrument will be used to assess patient reported toxicity outcomes.  
 
PRO-CTCAE is a validated instrument developed by the National Cancer Institute to assess 
clinical trial toxicity outcomes by patient report; it complements information collected by 
physician-reported CTCAE. PRO-CTCAE is available in English, Spanish, and French for this 
study. Patients participating on the electronic patient-reported outcome (Medidata Patient Cloud 
ePRO) will only have the option to complete the English and Spanish language PRO-CTCAE. 
French language PRO-CTCAE is not currently available on the Medidata Patient Cloud ePRO. 
French speaking patients will only have the option to complete the PRO-CTCAE on paper. 
Collection time points are listed in Section 4. 
 
Assessments will be collected before and at the end of radiation treatment and in follow-up as 
specified in the Section 4 assessment tables. 
 
The patient-reported AEs that will be assessed using PRO-CTCAE are listed in the table below. 
These adverse events are considered expected and, if reported, should also be clinician graded 
using the CTCAE v5.0. 
 
 
CTCAE v5.0 
PRO-CTCAE Items With Attributes 
1 
Dry mouth 
Dry mouth (Severity) 
2 
Esophagitis 
Dysphagia 
Difficulty swallowing (Severity) 
3 
Mucositis oral 
Pharyngeal mucositis 
Mouth or throat sores (Severity) 
4 
Voice alteration 
Voice quality changes (Presence) 
5 
Dysgeusia 
Taste changes (Severity) 
6 
Rash acneiform  
Rash maculo-papular 
Rash (Presence) 
7 
Pruritus 
Itching (Severity) 
8 
Dermatitis radiation 
Radiation skin reaction (Severity) 

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9 
Peripheral sensory 
neuropathy 
Numbness & tingling (Severity) 
10 
Tinnitus 
Ringing in ears (Severity) 
11 
Concentration 
impairment 
Concentration (Severity) 
12 
Memory Impairment 
Memory (Severity) 
13 
Depression 
Sad (Severity) 
14 
Blurred vision 
Blurred vision (Severity) 
15 
Abdominal pain 
Abdominal pain (Severity) 
 
 
7.5 
Expedited Reporting of Adverse Events (19-APR-2023) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table 
below will be reported via the CTEP Adverse Event Reporting System, CTEP-AERS, accessed 
via the CTEP web site, https://ctepcore.nci.nih.gov/ctepaers/security/login.  
 
Submitting a report via CTEP-AERS serves as notification to the NRG Biostatistical/Data 
Management Center and satisfies NRG requirements for expedited adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
CTEP by telephone at 301-897-7497 and the NRG Oncology by phone at 1-215-574-3191. An 
electronic report must be submitted immediately upon re-establishment of the Internet 
connection. 
 
7.5.1 Expedited Reporting Methods 
x Per CTEP NCI Guidelines for Adverse Events Reporting, a CTEP-AERS 24-hour 
notification must be submitted within 24 hours of learning of the adverse event. Each CTEP-
AERS 24-hour notification must be followed by a complete report within 5 days.  
x Supporting source documentation is requested by NRG as needed to complete adverse event 
review. Supporting source documentation should include the protocol number, patient ID 
number, and CTEP-AERS ticket number on each page; fax supporting documentation to 
CTEP at 301-897-7404 and contact NRG Oncology at 1-215-574-3191 for source 
documentation assistance. 
x A serious adverse event that meets expedited reporting criteria outlined in the AE Reporting 
Tables but is assessed by the CTEP-AERS as “an action not recommended” must still be 
reported to fulfill NRG safety reporting obligations. Sites must bypass the “NOT 
recommended” assessment; the CTEP-AERS allows submission of all reports regardless of 
the results of the assessment.  
 
7.5.2 Expedited Reporting Requirements for Adverse Events  
Arms 1 and 2 (Arm 2 closed to accrual 03-FEB-2023):  Any Phase Study Utilizing a 
Commercial Agent1 

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73                     Version Date: August 21, 2023 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they are considered 
related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH 
E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Attribution 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
10 day 
10 day 
Possible 
Probable 
Definite 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
Unexpected Grade 4 and all Grade 5 AEs 
 
 
Arm 3: Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of Nivolumab1, 2 

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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning 
of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the 
nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.5.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board (IRB) or 
Research Ethics Board (REB) responsible for oversight of the patient according to institutional 
policy. 
 
7.5.4 Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 

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CTEP requires all secondary malignancies that occur during or subsequent to treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, secondary malignancies 
following radiation therapy must be reported via CTEP-AERS. Three options are available to 
describe the event: 
x 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
x 
Myelodysplastic syndrome (MDS) 
x 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified. 
 
7.6 
Routine Reporting Requirements for Adverse Events 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
7.6.1 Reporting PRO-CTCAE  
Symptomatic Adverse Events reported by patients through PRO-CTCAE are not safety reporting 
and should also be clinician graded using the CTCAE v5.0 and reported as routine AE data. 
 
7.7 
Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS. In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 5 months or 7 months, respectively, after the last dose of nivolumab or 6 months after 
the last dose of cisplatin must be reported and then followed for outcome. Newborn infants 
should be followed until 30 days old. Please see the “NCI Guidelines for Investigators: Adverse 
Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” (at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on how to 
report pregnancy and its outcome to CTEP.  
 
8. REGISTRATION AND STUDY ENTRY PROCEDURES (21-AUG-2023) 
CTEP Registration Procedures and Access requirements for OPEN, Medidata Rave, and 
TRIAD 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy require all individuals contributing to NCI-
sponsored trials to register with their qualifications and credentials and torenew their registration 
annually.  To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam.  
Investigators and clinical site staff who are significant contributors to research must register in 
the Registration and Credential Repository (RCR). The RCR is a self-service online person 

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76                     Version Date: August 21, 2023 
 
registration application with electronic signature and document submission capability. 
RCR utilizes five person registration types. 
x Investigator (IVR) — MD, DO, or international equivalent; 
x Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD); 
x Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry access to 
CTSU applications such as the Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
x Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
x Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
 
 
 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following: 
x Added to a site roster 
x Selection as the treating, credit, or drug shipment investigator or consenting person in 
OPEN 
x Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval 
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, must be rostered at the 
enrolling site with a participating organization.  
 
Refer to the NCI RCR page on the CTEP website for additional information.  For questions, 

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please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
8.1 
Cancer Trials Support Unit Registration Procedures (21-AUG-2023) 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on the person and site roster assignment housed in the Roster Maintenance application and 
in most cases viewable and manageable via the Roster Update Management System (RUMS) on 
the Cancer Trials Support System  Unit (CTSU) members’ website. 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval  
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB) in order to participate in Cancer Therapy Evaluation Program 
(CTEP) and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases. 
In addition, U.S.-based sites must accept the NCI CIRB review to activate new studies at the site 
after March 1, 2019. Local IRB review will continue to be accepted for studies that are not 
reviewed by the CIRB, or if the study was previously open at the site under the local IRB. 
International sites should continue to submit Research Ethics Board (REB) approval to the 
CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) for 
Local Context to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
x Local IRB documentation; 
x IRB-signed CTSU IRB Certification Form; and/or 
x Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria for the site to be able to have an Approved status 
following processing of the IRB/REB approval record: 
x Have an active CTEP status; 
x Have an active status at the site on the IRB/REB approval and on at least one participating 
roster; 

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x If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
x Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
x List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
x Have the appropriate CTEP registration type for the protocol  
 
Additional Requirements for Protocol NRG-HN005 Site Registration:  
Additional requirements to obtain an approved site registration status include: 
x An active Federal Wide Assurance (FWA) number 
x An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); 
x An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only);  
x Compliance with all protocol-specific requirements (PSRs); 
x This is a study with a radiation and/or imaging (RTI) component and the enrolling site 
must be aligned to an RTI provider (see further information below). 
x IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC Houston 
to verify credentialing status or to begin a new modality credentialing process  
 
RTI Provider 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site must be 
aligned to an RTI provider. To manage provider associations or to add or remove associated 
providers, access the Provider Association page from the Regulatory section on the CTSU 
members’ website at https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to 
at least one Imaging and Radiation Oncology Core (IROC) provider to participate on trials with 
an RTI component. Enrolling sites are responsible for ensuring that the appropriate agreements 
and IRB approvals are in place with their RTI provider. An individual with a primary role on any 
roster is required to update provider associations, though all individuals at a site may view 
provider associations. To find who holds primary roles at your site, view the Person Roster 
Browser under the RUMS section on the CTSU members’ website. 
 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC Houston to 
verify credentialing status or to begin a new modality credentialing process. 
To complete protocol-specific credentialing the RTI provider or enrolling site should follow 
instructions in the protocol to submit documentation or other materials to the designated IROC 
Quality Assurance (QA) center. Upon the IROC QA center approving the RTI provider for the 
study modality, IROC will send the approval to the provider and/or enrolling site. The provider 
and/or enrolling site will need to upload the approval letter to the Regulatory Support System 
(RSS) to comply with the protocol-specific requirement. 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments. The enrolling site will select their credentialed provider treating the subject in the 

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OPEN credentialing screen and may need to answer additional questions related to treatment in 
the eligibility checklist.   
 
Additional Requirements for sites in Canada  
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines [per section 6.2.5 of ICH E6(R2)]. 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result essential documents must be retained for 15 years following the completion of the trial at 
the participating site (15years post final analysis, last data collected, or closure notification to 
REB, whichever is later), or until notified by the sponsor, NRG Oncology, that documents no 
longer need to be retained [per C.05.012 (4) of the FDR].  In addition, upon request by the 
auditor, REB or regulatory authority, the investigator/institution must make all required trial-
related records available for direct access [per section 4.9.7 of ICH]. Prior to clinical trial 
commencement, sites in Canada must also complete and submit to NRG Regulatory 
(CanadianRegulatory@NRGOncology.org): 
x Clinical Trial Site Information Form,  
x Qualified Investigator Undertaking Form  
x Research Ethics Board Attestation Form 
x Protocol Signature Page 
x Investigator Brochure (IB) Signature Page  
x Delegation of Tasks (DTL) Log  
x List of Laboratories  
x SIV/Training Confirmation of Completion Form – Research Associate (please 
refer to the activation memo for details)  
x SIV/Training Confirmation of Completion Form – Qualified Investigator (please 
refer to the activation memo for details)  
x IRB/REB approved consent (English and native language versions*). Must submit 
English version of consent form to NRG Regulatory for review prior to 
submission to local IRB/REB.  
 
The following items are collected by NRG Oncology Regulatory on a yearly or biyearly basis:   
x IRB/REB Membership Roster  
x Laboratory Certificates and Normal Values  
x CVs for Qualified Investigator and Sub-Investigators noted on the DTL log 
 
Record Retention: The sponsor, NRG Oncology, shall maintain records identified in 
Health Canada guidelines Part C, Division 5, section C.05.012 for a period of at least 15 
years. 
 
*Note: Certification/verification of IRB/REB consent translation must be provided with 
submission to CTSU (described below).  
Translation of documents is critical. The institution is responsible for all translation costs. 
All regulatory documents, including the IRB/REB approved consent, must be provided in 
English and in the native language. Certification of the translation is optimal but due to 

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the prohibitive costs involved NRG will accept, at a minimum, a verified translation. A 
verified translation consists of the actual REB approved consent document in English and 
in the native language, along with a cover letter on organizational letterhead/stationery 
that includes the professional title, credentials, and signature of the translator as well as 
signed documentation of the review and verification of the translation by a neutral third 
party. The professional title and credentials of the neutral third party translator must be 
specified as well. 
 
Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents 
is restricted to institutions and their associated investigators and staff on a participating roster. To 
view/download site registration forms:   
x Log on to the CTSU members’ website (https://www.ctsu.org)  
x Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select NRG and protocol 
number NRG-HN005. 
x 
Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to the 
CTSU.)  
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to receive further instruction and support. 
Checking Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.   
 
x Click on Regulatory at the top of the screen; 
x Click on Site Registration; and 
x Enter the site’s 5-character CTEP Institution Code and click on Go 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration requirements 
as within the protocol. It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with NCI or their affiliated 
networks. 

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8.2 
RT-Specific Pre-Registration Requirements (21-AUG-2023) 
For detailed information on the specific technology requirement required for this study, please 
refer to the table below and utilize the web link provided for detailed instructions. The check marks 
under the treatment modality columns indicate whether that specific credentialing requirement is 
required for this study. Specific credentialing components may require you to work with various 
QA centers; however, IROC Houston will notify your institution when all credentialing 
requirements have been met and the institution is RT credentialed to enter patients onto this study.  
This document must be uploaded by the site to the CTSU Regulatory Submission Portal for RSS 
to be updated.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RT 
Credentialing 
Requirements 
Web Link for Credentialing Procedures and Instructions 
http://irochouston.mdanderson.org 
Treatment 
Modality 
 
Photon 
Key Information 

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Credentialing  
Status Inquiry 
Form 
    x 
To determine if your institution has 
completed the requirements above, please 
complete a “Credentialing Status Inquiry 
Form” found under Credentialing on the 
IROC Houston QA Center website 
(http://irochouston.mdanderson.org). 
Facility 
Questionnaire 
    x 
The IROC Houston electronic facility 
questionnaire (FQ) should be completed or 
updated with the most recent information 
about your institution.  To access this FQ, 
email irochouston@mdanderson.org to 
receive your FQ link. 
Phantom  
Irradiation 
     x 
An IMRT Head & Neck phantom study 
provided by the IROC Houston QA Center 
must be successfully completed. 
Instructions for requesting and irradiating 
the phantom are found on the IROC 
Houston web site 
(http://irochouston.mdanderson.org).  
IGRT  
 
    x 
Instructions for IGRT credentialing may be 
found on the IROC Houston website 
(http://irochouston.mdanderson.org).   
Credentialing Notification Issued to: 
Institution 
 
Institution will be credentialed for the 
treatment modality that they intend to use 
on all patients. IROC Houston QA Center 
will notify the institution and NRG 
Headquarters that all desired credentialing 
requirements have been met. 
 
8.2.1 Digital Radiation Therapy Data Submission Using Transfer of Images and Data 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s (ACR) 
image exchange application. TRIAD provides sites participating in clinical trials a secure 
method to transmit images. TRIAD anonymizes and validates the images as they are 
transferred. 
 
TRIAD Access Requirements: 
x Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems;  
x Registration type of: Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR) registration type. Refer to the CTEP 
Registration Procedures section for instructions on how to request a CTEP-IAM 
account and complete registration in RCR. 
x TRIAD Site User role on an NCTN ETCTN, or other relevant roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access 

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to TRIAD and may submit images for credentialing purposes, or for enrollments to which 
the provider is linked in OPEN. 
 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to install 
the TRIAD application on their workstation. TRIAD installation documentation is 
available at https://triadinstall.acr.org/triadclient/. 
 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR 
registration. 
 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
8.3      Patient Enrollment (21-AUG-2023) 
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria 
have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients must have 
signed and dated all applicable consents and authorization forms.   
 
Informed Consent: Patients must be aware of the neoplastic nature of their disease and informed 
of the procedure(s) to be followed, the experimental nature of the therapy, alternatives, potential 
benefits, side-effects, risks, and discomforts prior to signing the informed consent in accordance 
with institutional and federal guidelines. Current IRB/REB/REC approval of this protocol and a 
consent form is required prior to patient consent and registration. The model consent form created 
for this study adheres to the NCI informed consent template requirements. 
 
8.3.1 Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
x Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems  
x To perform enrollments or request slot reservations:  Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
x Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 

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Form FDA 1572 in RCR.  
 
Prior to accessing OPEN, site staff should verify the following: 
x Patient has met all eligibility criteria within the protocol stated timeframes; and  
x All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
9.0 DRUG INFORMATION  
9.1 
Agent Ordering and Agent Accountability (21-AUG-2023) 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution. The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents. The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF). If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead investigator at that institution. Submit agent requests through the PMB Online 
Agent Inventory Management System (AURORA) application. Access to (AURORA) requires 
the establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person registration 
status. For questions about drug orders, transfers, returns, or accountability, call or email PMB 
any time. Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
 
Sites can order study agents in AURORA when a patient is enrolled to treatment.  Agent orders 
can be expedited overnight Monday-Thursday when sites provided expedited courier 
information. 
 
 
9.1.1 Starter supplies are not being provided. Patients must be registered prior to sites ordering 
study agents.   
Refer to the Policy and Guidelines for Investigational Agent Ordering and the contact 
information below for order processing time and conditions. Normal order processing time is two 
business days. An express courier account number must be provided for next-day delivery.  
 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/    
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov   
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 

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PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/ 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/    
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov   
PMB email: PMBAfterHours@mail.nih.gov   
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET)  
IB Coordinator: IBCoordinator@mail.nih.gov  
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
9.1.2 Investigator Brochure 
To supplement the toxicity information contained in this document, investigators must obtain the 
current version of the investigator brochure (IB), if available, for comprehensive pharmacologic 
and safety information. The current version of the Investigator Brochure (IB) will be accessible 
to site investigators and research staff through the PMB AURORA application. Access to 
AURORA requires the establishment of a CTEP IAM account and the maintenance of an 
“active” account status, a “current” password, and active person registration status. Questions 
about IB access may be directed to the PMB IB Coordinator via email.  
 
9.2 
Investigational Study Agent: Nivolumab (IND, NSC 748726) (21-AUG-2023) 
Sites must refer to the investigator brochure for detailed pharmacologic and safety information. 
The Investigator Brochure will be provided by the Pharmaceutical Management Branch (PMB). 
See Section 9.1. 
 
Amino Acid Sequence:   4 polypeptide chains, which include 2 identical heavy chains with 440 
amino acids and 2 identical light chains. 
 
Other Names: 
  BMS-936558, MDX1106 
 
Classification: 
   Anti-PD-1MAb 
 
M.W.:  146,221 Daltons 
 
Mode of Action:   Nivolumab targets the programmed death–1 (PD-1, cluster of differentiation 
279 [CD279]) cell surface membrane receptor. PD-1 is a negative regulatory receptor expressed 
by activated T and B lymphocytes. Binding of PD-1 to its ligands, programmed death–ligand 1 
(PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation. Nivolumab 
inhibits the binding of PD-1 to PD-L1 and PD-L2.  Inhibition of the interaction between PD-1 
and its ligands promotes immune responses and antigen-specific T-cell responses to both foreign 
antigens as well as self-antigens. 
 
Description:   Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; light 

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(few) particulates may be present. The drug product is a sterile, nonpyrogenic, single-use, 
isotonic aqueous solution formulated in sodium citrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid) and polysorbate 80 (Tween® 80), and water for 
injection. Dilute solutions of hydrochloric acid and/or sodium hydroxide may be used for pH 
adjustment (pH 5.5-6.5). 
 
How Supplied:   Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg vials (10 mg/mL) with a 0.7mL 
overfill.  It is supplied in 10 mL type I flint glass vials, with fluoropolymer film-laminated rubber 
stoppers and aluminum seals. 
 
Preparation:   Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose.  When the dose is based on patient weight (i.e., 
mg/kg), nivolumab injection can be infused undiluted or diluted to protein concentrations as low 
as 0.35 mg/mL. When the dose is fixed (eg, 240 mg), nivolumab injection can be infused 
undiluted or diluted so as not to exceed a total infusion volume of 160 mL. For patients weighing 
less than 40 kilograms (kg), the total volume of infusion must not exceed 4 mL per kg of patient 
weight.  During drug product preparation and handling, vigorous mixing or shaking is to be 
avoided. 
 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles. 
 
Storage:   Vials of Nivolumab injection must be stored at 2°- 8°C (36°- 46°F) and protected from 
light and freezing. The unopened vials can be stored at room temperature (up to 25°C, 77°F) and 
room light for up to 48 hours. 
 
If a storage temperature excursion is identified, promptly return Nivolumab to 2°C-8°C and 
quarantine the supplies.  Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability. 
 
Stability:   Shelf-life surveillance of the intact vials is ongoing. 
 
Following the preparation of nivolumab injection, it is preferred to administer the drug product 
immediately. If not used immediately, the infusion solution may be stored under refrigeration 
conditions (2°-8°C (36°-46°F)) and protected from light for up to 7 days, including the product 
administration period or as described in the instructions provided to the clinical site. The infusion 
solution may be stored at room temperature (up to 25°C, 77°F) and room light for a maximum of 
8 hours, including the product administration period. 
 
*Caution: The single-use dosage form contains no antibacterial preservative or bacteriostatic 
agent. Therefore, it is advised that the product be discarded 8 hours after initial entry.  
 
Route of Administration:   Intravenous infusion over 30 minutes.  Do not administer as an IV 
push or bolus injection. 

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Method of Administration:   Administer through a 0.2 micron to 1.2 micron pore size, low-
protein binding (polyethersulfone membrane) in-line filter.  
 
Potential Drug Interactions:   The indirect drug-drug interaction potential of nivolumab was 
assessed using systemic cytokine modulation data for cytokines known to modulate CYP 
enzymes.  There were no meaningful changes in cytokines known to have indirect effects on 
CYP enzymes across all dose levels of nivolumab. This lack of cytokine modulation suggests 
that nivolumab has no or low potential for modulating CYP enzymes, thereby indicating a low 
risk of therapeutic protein-drug interaction. 
 
Patient Care Implications: Women of childbearing potential (WOCBP) receiving nivolumab 
must continue contraception for a period of 5 months after the last dose of nivolumab. Men 
receiving nivolumab and who are sexually active with WOCBP must continue contraception for a 
period of 7 months after the last dose of nivolumab. Should a woman become pregnant or suspect 
she is pregnant while she or her partner is participating in this study, she (or the participating 
partner) should inform the treating physician immediately. 
 
9.3 
Commercial Agent: Cisplatin (NSC# 119875) 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
 
9.3.1 Availability/Supply 
Drug will be supplied commercially. Please see Section 5.1 for administration instructions. 
Please refer to the current FDA approved package insert provided with each drug and the site-
specific pharmacy for toxicity information and instructions for drug preparation, handling and 
storage. 
 
9.3.2 Patient Care Implications 
Females of childbearing potential must use adequate contraception during treatment and for 6 
months after the last dose of cisplatin chemotherapy. Male patients must use highly effective 
contraception for a total of 6 months after last dose of cisplatin chemotherapy. 
 
10. PATHOLOGY/BIOSPECIMEN 
10.1 
Optional Biospecimen Submission Tables for Future Research (19-APR-2023) 
See detailed specimen collection/processing/shipping instructions on the protocol-specific 
website. 
(Patients must be offered the opportunity to consent to optional specimen collection. If the 
patient consents to participate, the site is required to submit the patient’s specimens as specified 
per protocol. Sites are not permitted to delete the specimen component from the protocol or from 
the sample consent.) 
 
See detailed specimen collection/processing/shipping instructions on the protocol-specific 
website, www.ctsu.org. 
 
This study will include collection of biospecimens for future analyses. An amendment for any 
correlative science studies to be performed on biological samples will be submitted to CTEP, 

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NCI for review and approval according to NCTN guidelines or via the Navigator portal after the 
trial has been reported. Amendments to the protocol and/or proposals for use of banked tissue or 
blood samples will include the appropriate background, experimental plans with assay details, 
and a detailed statistical section. Samples for testing will not be released for testing until the 
appropriate NCI approvals have been obtained. 
 
 
FFPE Specimen Collection for Biobanking for Potential Future Research  
(to be offered to all patients) 
 
x H&E stained slides and block (or punch biopsy of paraffin block) to the Biospecimen 
Bank at UCSF  
x Required Forms: ST form and pathology reports with study and case # on each page, 
date of procedure, pathology accession number; any other personal health information 
(PHI) should be redacted by sites before sending. Pathology reports must include the 
p16-positive staining result for each patient. 
x FFPE Punch Kits can be requested from the Biospecimen Bank when requesting the 
frozen specimen kits. 
x Shipping costs: Submitting site pays cost of shipping FFPE samples and returns. 
x FFPE specimens will be retained at the Biospecimen Bank unless needed for 
immediate patient continuing care. One to two 3-mm punches will be taken from the 
blocks before shipping to sites that have requested the return of their blocks. 
 
Ship all biospecimens to: 
NRG Oncology Biospecimen Bank – San Francisco 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
415-476-7864; FAX 415-476-5271 
NRGBB@ucsf.edu   
 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
One H&E slide from 
primary tumor; H&E 
slides can be duplicate 
cut slides, they do not 
have to be the diagnostic 
slide 
 
Pre-Treatment 
Baseline tumor 
specimen 
H&E stained slide. 
Slides shipped 
ambient to NRG 
Biospecimen Bank 
San Francisco 
FFPE Block or one to 
two 3-mm punches taken 
from the tumor block 
(embedded*) 
Pre-Treatment 
Baseline tumor 
specimen 
Corresponding FFPE 
Block or one to two 3-
mm punches from the 
same block as the 
H&E slide that is being 
Shipped ambient or 
with cold pack to 
the NRG 
Biospecimen Bank 
San Francisco 

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submitted. An H&E 
from the punch block 
must be included.  
(embedded*) 
 
 
 
*For sites with the capability to do so, the one to two punch biopsies should be embedded into 
one new paraffin block from which an H&E slide should be obtained. The constructed block 
containing the punch and the H&E slide must then be submitted to the NRG Oncology 
Biospecimen Bank in San Francisco. An H&E from the original block must still be submitted. 
Alternatively, sites can either 1) send the block to the Biospecimen Bank, and the bank will 
punch and embed the blocks for the sites before returning them, or 2) send the one to two 3-mm 
punches to the bank to be embedded by the Biospecimen Bank. 
 
 
Plasma, Serum, and Whole Blood Collection for Biobanking for Potential Future Research  
(to be offered to all patients) 
 
Forms: ST Form – filled out completely with study, case, date of procedure, institution name, 
NCI ID and time points. 
 
Kits: Can be requested from the NRGBB-SF at NRGBB@ucsf.edu. Allow 5-10 business days for 
kits. Sites must have IRB approval before requesting kits.  
 
Shipping: One prepaid return label provided for each case for batch shipping frozen 
biospecimens only. 
Batch ship frozen samples Monday-Wednesday (US sites) and Monday-Tuesday (Canadian 
Sites). 
 
Processing Instructions: Located on the CTSU website protocol specific documents.  
 
Ship all frozen specimens on dry ice in batches by overnight courier to:  
NRG Oncology Biospecimen Bank – San Francisco 
UCSF – Dept of Radiation Oncology 
2340 Sutter Street- Room S341 
San Francisco, CA 94115 
 
For questions, please contact the San Francisco Bank at:  
Email: NRGBB@ucsf.edu 
415-476-7864/Fax 415-476-5271 
 
Specimen Type  
Collection Time Points 
 
Collection Information and  
Requirements/Instructions 
for Site 
Shipping 
 
Plasma: Two 
Purple Top EDTA 
● Baseline Pre-treatment 
Process plasma and aliquot a 
minimum of 1.5 mL plasma 
Batch ship 
frozen samples 

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tubes 
(10 mL each, 
centrifuged and 
processed for 
plasma collection) 
● During RT treatment, 
obtained after 20 Gy RT 
but before 28 Gy 
● After completion - 
within 4 weeks from end 
of all treatment* 
into five 2 mL cryovials.  
 
Place into biohazard bag and 
immediately freeze tubes 
upright at -70 to -90ºC.  
 
Samples should be frozen and 
stored at -80⁰C until ready to 
batch ship. 
  
on Dry Ice by 
Overnight 
Courier to 
NRGBB-San 
Francisco 
 
Serum: One 10 mL 
red top (clot) tube 
● Baseline Pre-treatment 
● During RT treatment, 
obtained after 20 Gy RT 
but before 28 Gy 
● After completion - 
within 4 weeks from end 
of all treatment* 
Serum centrifuged and 
aliquotted. 
Frozen serum samples 
containing a minimum of 0.5 
mL per aliquot in 1 mL 
cryovials (up to 5 per tube 
drawn).  
 
Place into biohazard bag and 
immediately freeze tubes 
upright at -70 to -90ºC. 
 
Samples should be frozen and 
stored at -80⁰C until ready to 
batch ship. 
 
Batch ship 
frozen samples 
on Dry Ice by 
Overnight 
Courier to 
NRGBB-San 
Francisco 
 
Whole Blood: One 
5-10 mL EDTA 
tube 
 
Baseline Pre-treatment 
Note: If site missed this 
collection, they may 
collect at any other time 
but must note this on the 
ST form when submitting 
Collect blood, mix and aliquot 
1-1.5 mL of whole blood per 
vial into three 2 mL cryovials.   
 
Place into biohazard bag and 
immediately freeze tubes 
upright at -70 to -90ºC. 
 
Samples should be frozen and 
stored at -80⁰C until ready to 
batch ship. 
  
Batch ship 
frozen samples 
on Dry Ice by 
Overnight 
Courier to 
NRGBB-San 
Francisco 
 
*Arm 1 (Arm 2 closed to accrual 03-FEB-2023): Specimen will be collected at the end of RT. 
  Arm 3: Specimen will be collected after the last dose of Nivolumab. Note: If Nivolumab is 
discontinued prior to end of RT then the specimen will be collected at the end of RT. 
 
 
 
 
 
 

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11. SPECIAL STUDIES (NON-TISSUE) 
11.1 
 Association of FDG-PET/CT Imaging with Locoregional Control and PFS  
All patients are highly recommended to have a baseline FDG-PET/CT scan (see section 3.1.4).  
A post-therapy FDG-PET/CT scan is highly recommended at 12-14 weeks post-therapy for 
assessment of response to therapy. Scans that are obtained will be submitted per Section 11.1.5.  
 
11.1.1 Rationale for FDG-PET/CT and Association with Clinical Outcomes 
 
The purpose of studying FDG-PET/CT in the context of NRG-HN005 is to determine the 
association of baseline and12-14 week post therapy FDG-PET/CT for locoregional control and 
PFS.  
At pre-therapy baseline PET/CT imaging, the intensity of FDG uptake is highly associated with 
patients’ survival outcomes. Intense FDG uptake is significantly associated with worse survival 
outcomes in HNSCC. Zhang et al (2010) analyzed eight clinical trials dedicated to HNSCC and 
determined the values of SUVmax and mean SUV as related to outcomes. They concluded that 
increased SUV of the primary tumor is a poor prognostic factor and has a potential value in its 
association to local control, disease-free survival and OS. Another similar meta-analysis by Xie 
et al (2011) confirmed that low primary tumor SUVs were associated with better survival 
outcomes. Other PET-derived parameters for the primary tumor such as MTV and TLG have 
also been studied in a meta-analysis by Pak et al (2014). Authors reviewed 13 studies including 
1180 patients and found these volumetric measurements to be valuable for  their association to 
future recurrence, progression, or both. 
  
The sensitivity and specificity of post-treatment FDG-PET/CT depend on the time interval 
between the completion of therapy and FDG-PET/CT. In a study of 26 patients, Goerres et al. 
(2004) observed a sensitivity and specificity of 91% and 93%, respectively, for PET/CT scans 
performed as early as 6 weeks after chemoradiotherapy. However, other studies have not been 
able to reproduce these data (Porceddu 2005, Yao 2005) and instead suggest that PET/CT after 
chemoradiotherapy should not be performed before 10-12 weeks after the end of radiation 
treatment. By that time, most of the post-treatment inflammatory changes will have subsided, 
reducing the number of potentially false-positive interpretations. In general, the rate of false-
positive cases declines with the interval between the end of therapy and PET/CT imaging 
(Lonneux 2000). The optimal timing of the first response assessment FDG-PET/CT after 
definitive (chemo) radiation is not precisely known, but an interval of at least 12 weeks has 
generally been recommended to balance the drawbacks of imaging too early versus too late. In 
rare cases, early detection of residual/recurrent disease is central to successful surgical salvage 
if appropriate, while a demonstration of a clinical and radiographic complete response obviates 
the need for further unnecessary and potentially morbid interventions. A recent meta-analysis 
involving 51 studies and 2335 patients (Gupta 2011) estimated the sensitivity and specificity of 
post-treatment FDG-PET/CT at 91.9% and 86.9% for primary tumor and 90.4% and 94.3% for 
neck nodes, respectively, when the PET/CT was performed > 12 weeks after completion of 

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concurrent chemoradiation therapy. 
 
PET-NECK was a standard-setting, multicenter randomized Phase III non-inferiority trial 
comparing an FDG-PET/CT-guidance versus planned neck dissection for head and neck cancer 
patients receiving chemoradiation for N2/N3 nodal metastases. This study showed that 
surveillance based on 10-12 week post-treatment FDG-PET/CT resulted in noninferior survival 
to neck dissection but was more cost-effective and resulted in fewer complications. At 36 
months of follow-up, the true-negative rate of FDG-PET/CT in the neck was 86.4% and the 
true-negative rate in the primary was 84.9% (Mehanna 2017). Another small retrospective 
study indicated that a post-treatment FDG-PET/CT-directed policy could specifically ensure 
low rates of 3-year locoregional failure even for patients presenting with very bulky neck 
adenopathy (> 6 cm) (Adams 2014). It should be noted that all of these research findings have 
been in head and neck cancer patients receiving traditional chemoradiation and standard 
radiation doses. 
 
Currently, FDG-PET/CT is commonly used for staging and assessment of treatment response in 
head and neck cancer. The Centers for Medicare and Medicaid services and most third party 
payers in USA provide reimbursement for a pre-treatment and a post-treatment FDG-PET/CT in 
head and neck cancer patients scheduled to receive definitive-intent radiotherapy.  
 
Because of the frequent use of PET/CT in local centers, it is of interest to the study investigators 
to document the performance of PET/CT under “real-world” conditions. This approach may 
increase the future generalizability of any findings. Therefore, we will collect clinical 
accreditation of PET/CT scanners of the participating institutions as well as minimum standard 
for parameters for performing a PET/CT for head and neck cancers. Because the PET/CT images 
will be scored on a standardized basis, the impact of variations in the imaging technique should 
be substantially lessened. Regarding PET/CT technique, the study investigators recommend that 
the standard-of-care guidelines from the National Cancer Institute and ACRIN Imaging 
Standards for PET should be followed as closely as possible (Shankar 2006).    
 
11.1.2 Post-acquisition scoring methodology for FDG-PET/CT scans 
 
To provide a platform for standardizing research interpretations of the PET/CT scans, the study 
investigators have developed a reader-based scoring system to minimize the effect of varying 
acquisition techniques. This ordinal scoring system (see below) was utilized in NRG-HN002 and 
identifies those patients who have complete metabolic response and those who did not have 
complete metabolic response, retrospectively. Submitted baseline and post-treatment PET/CT 
images will be reviewed at the end of the recruitment period and correlated with the clinical 
treatment outcomes. 
 
The scoring system (“Hopkins criteria”) was modified from the well-validated and clinically 
most useful five-point scoring system for mid-therapy and post-therapy assessment for 
lymphoma (Deauville criteria). This scoring system has been previously validated as a collapsed 
three-point categorization (negative for tumor, indeterminate, positive for tumor) for head and 
neck FDG-PET/CT scans performed between 4 and 24 months after therapy completion 
(Paidpally 2013). The scoring system successfully predicted outcome in these patients and added 

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value to the clinical assessment at the time of the scans. In addition, the five-point scoring system 
has been recently validated in head and neck FDG-PET/CT scans performed between five weeks 
and 6 months after therapy completion in 214 head and neck squamous cell carcinoma patients. 
There was 90%, 97.2%, 94.9% and 91.3% agreement between the readers for overall, left neck, 
right neck and primary tumor site response scores, respectively. The corresponding Kappa 
coefficients for inter-reader agreement were k=0.70 (p<0.0001), k=0.81 (p<0.0001), k= 0.69 
(p<0.0001), and k=0.67 (p<0.0001), respectively. The accuracy of the scoring system against a 6 
month clinical follow up as the reference standard is excellent with ROC area under the curve 
0.98 (95% CI 0.97-0.99; P < 0.001). Cox regression analysis showed a significant difference in 
overall survival between the patients who had a score between 1-3 (negative for tumor) and those 
who had a score 4 or 5 (positive for tumor) (log-rank, P<0.0001 with a hazard ratio of 0.056 
[95% CI 0.022-0.138] (Marcus 2014).  This system of standardization is now well validated in 
multicenter clinical trial (Van den Wyngaert 2017). 
 
 
Harmonization of FDG-PET/CT Ordinal Scoring and Classification of Results 
 
The baseline diagnosis and post treatment tumor response evaluation will be carried out using a 5-
point ordinal scale.  
 
(a) At baseline neck lymph node standardized interpretation:  
 
Score 1: Definitely benign lymph node: The FDG uptake in the nodal sites is less than the 
background blood pool FDG uptake. 
Score 2: Likely benign lymph node: The FDG uptake in the nodal sites is greater than the 
background blood pool uptake but it is equal to or less than the liver FDG uptake. 
Score 3: Likely inflammatory uptake: There is diffuse FDG uptake at nodal sites. This diffuse 
FDG uptake is greater than the liver FDG uptake and likely related to inflammation and 
unlikely tumor. 
Score 4: Likely nodal metastasis: There is focal FDG uptake in the nodal sites. The focal FDG 
uptake is greater than the liver FDG uptake. 
Score 5: Definite nodal metastasis: There is intense focal FDG uptake in the nodal sites. This focal 
FDG uptake is 3 – 4 times greater than the liver FDG uptake.  
 
(b) Post therapy primary site and neck lymph node standardized interpretation:  
 
Score 1: Definite complete metabolic response: The FDG uptake in the primary tumor or nodal 
sites is less than the background blood pool FDG uptake. 
Score 2: Likely complete metabolic response: The FDG uptake in the primary tumor or nodal sites 
is greater than the background blood pool uptake but it is equal to or less than the liver 
FDG uptake. 
Score 3: Likely inflammatory: There is diffuse FDG uptake in the primary tumor or nodal sites. 
This diffuse FDG uptake is greater than the liver FDG uptake and likely related to post-
radiation inflammation. 
Score 4: Likely residual metabolic disease: There is focal FDG uptake in the primary or nodal 
sites. The focal FDG uptake is greater than the liver FDG uptake. 
Score 5: Definite residual metabolic disease: There is intense focal FDG uptake in the primary 

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tumor or nodal sites. This focal FDG uptake is 3 – 4 times greater than the liver FDG 
uptake.  
 
 
 
Definitions of ‘Positive,’ ‘Negative’ and ‘Indeterminate’ FDG Uptake and PET/CT Results 
A score of 1 or 2 will be interpreted as ‘Negative,’ a score of 3 as ‘Indeterminate,’ and a score of 
4 or 5 as ‘Positive.’ A ‘Negative’ result at the primary or nodal sites is defined as equal or less 
FDG uptake than the blood pool and liver FDG uptake. Uptake for the local blood pool reference 
value will be measured from the carotid or the aortic arch. The ‘Indeterminate’ result is defined as 
diffuse FDG uptake in the treatment field with intensity of the uptake greater than the liver FDG 
uptake. A ‘Positive’ result is defined as focal uptake visually greater than the background and at a 
higher level than the activity seen in the liver. 
 
It is important to note that local sites will decide the post-therapy management and may 
incorporate the information from FDG-PET/CT into decision making according to these 
guidelines. However, determination of PFS events should be confirmed with clinical follow-up 
and/or pathologic confirmation from biopsy or surgery directed by the local site according to its 
institutional practices; and an indeterminate or positive reading on FDG-PET/CT in itself will 
not be considered to affect the primary endpoint unless the local site reports and/or confirms 
disease recurrence. 
 
11.1.3 Recommended FDG-PET/CT Imaging Sequence and Details 
See section 5.2.3. 
 
11.1.4 FDG-PET/CT Image Reconstruction 
See section 5.2.3. 
 
11.1.5 Submission of FDG-PET/CT Image and Site Read 
x Following the completion of PET/CT imaging at the site, the institution will submit 
images in DICOM format via TRIAD to IROC Imaging; See section 8.2 for details 
regarding TRIAD. 
x Institutions must submit a case report form (CRF) for each PET/CT image in which a 
site reader characterizes the baseline disease state (baseline scan) and patient’s 
therapy response (post treatment scan) using the 5-point scale outlined in Section 
11.1.2 (i.e. the local site read). 
 
11.1.6 FDG-PET/CT Research-Directed Image Evaluation 
For study purposes, PET/CT images will be retroactively interpreted by an NRG Oncology 
Imaging Core Panel (NRGICP) of expert PET/CT readers who will have no involvement or 
knowledge of the participant’s clinical care and who will be blinded to the participant’s 
diagnosis, local PET/CT scan results, and clinical history.  
 
 
11.2 
Swallowing Substudy (04-NOV-2020) 
Submitted data from institutions that routinely administer a Modified Barium Swallow (MBS) 

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study to patients at baseline and at 12 and 24 months post radiation therapy will be part of an 
exploratory analysis (See Sections 1.3.4; Section 4/Pre-Treatment and Follow-Up Assessment 
tables; and Appendix IV).  
 
The MBS is an objective dynamic, radiographic imaging study, where the patient is administered 
a series of increasing volumes of radiopaque labeled standardized liquid and solid food 
consistencies to examine oropharyngeal swallow physiology, aspiration and/or pharyngeal 
residue. Many institutions will have standard guidelines for acquisition of MBS. For purposes of 
this protocol, individual investigators may use their local guidelines to acquire the MBS. One 
possible approach is outlined in Appendix IV which is suggested to optimize MBS scan 
acquisition. Please refer to Appendix IV to see specifics. 
 
The submitted digital DICOM images from the MBS will be collected and stored via TRIAD. 
They will be retroactively scored, pending funding, by an NRG Oncology Swallowing Core 
Panel (NRGSCP) of expert speech-language pathologists who will have no involvement or 
knowledge of the participant’s clinical care and who will be blinded to the participant’s 
diagnosis, local PET/CT scan results, and clinical history. The evaluation will be carried out 
using the following 4 measures:  
 
Modified Barium Swallow Impairment Profile (MBSImPTM©)  
The MBSImP™© profiles 17 components of the oropharyngeal swallow physiology along a 3- to 
5-point ordinal scale from normal to severe impairment. The component ratings for each patient 
generate two continuous overall summary scores: the oral total (OT) and pharyngeal total (PT) 
for each patient. The OT is derived from adding scores of components 1# to #6 and ranges from 
0-22, where a score of 22 is worse. The PT is derived from adding scores of components #7 to 
#16 and ranges from 0-29, where a score of 29 is worse. The rating of esophageal motility, item 
#17, will be excluded as it is beyond the focus of this study. 
 
Pharyngeal Constriction Ratio (PCR) 
The PCR is a pixel-based measure computing area of the pharynx at maximum constriction at 
peak swallow over the resting area of the pharynx from the mid-sagittal radiograph. PCR 
provides a reliable radiographic surrogate measure of pharyngeal strength (measured against 
gold standard pharyngeal manometry), and discriminates aspiration status in dysphagia 
populations. 
 
Penetration-Aspiration Scale (PAS)  
The PAS is an 8-point ordinal scale of swallow airway safety capturing bolus penetration and 
aspiration, where a score <2 indicates a safe swallow, 2-5 indicates penetration, and 6-8 indicates 
aspiration. PAS ratings are highly reliable (ICC for inter- and intra-rater reliability: 0.96 and 
0.95-0.97, respectively) and predictive of aspiration pneumonia after chemoradiation (p<0.001, 
AUC=0.72). 
 
 
 
DIGEST grade  
The DIGEST was developed and validated as a CTCAE compatible MBS-derived severity grade 

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of pharyngeal dysphagia. The DIGEST is highly reliable (intra- and inter-rater weighted k 0.82-
0.84 and 0.67-0.81, respectively) and discriminates pharyngeal pathophysiology (r = 0.77, 
p<0.001), perceived dysphagia (r = -0.41, p<0.001), and diet (r = -0.49, p<0.001) in HNC 
survivors. 
 
11.3 
Patient-Reported Outcomes (PROs) and Quality of Life (QOL) (19-APR-2023) 
All participating centers will be required to participate in the patient-reported outcome 
and quality of life assessments. 
 
11.3.1 Rationale for QOL/PRO 
Dysphagia-related QOL is one of two primary endpoints in this Phase II/III trial. In this trial, the 
hypothesis is that dysphagia-related QOL in a reduced-dose arm with cisplatin or nivolumab 
would not be worse than in a standard-of-care arm, while desirable PFS would be maintained in 
one of these experimental arms. This major endpoint of dysphagia-related QOL will be measured 
with the MDADI, the MD Anderson Dysphagia Inventory. This is a well-validated, reliable, self-
reported questionnaire that has been designed to evaluate the impact of dysphagia on the QOL of 
patients with head and neck cancer (Chen 2001).  
 
To measure the generic aspects of QOL, we will use the EORTC-QLQ-C30, a well-developed 
questionnaire that has been used in multiple NRG Oncology Group trials. This questionnaire has 
also been used in a recent Phase III trial that used nivolumab for patients with recurrent or 
metastatic squamous-cell carcinoma of the head and neck (Harrington 2017). In this trial, 
patients treated with nivolumab were stable across functional and symptom domains as measured 
by the EORTC QLQ-C30, while patients in a standard therapy group had clinically meaningful 
worsening in 8 of those 15 domains. Further, the differences between the two treatment arms 
were statistically and clinically significant (Harrington 2017). However, the effect of nivolumab 
on QOL remains unclear for patients newly diagnosed with HPV-associated oropharyngeal 
cancer and in the aforementioned study, because the reported difference between the two arms 
was only measured during 15 weeks of treatment, the long-term effect of nivolumab on QOL for 
patients with head and neck cancer is still unclear. For these reasons, it is meaningful and novel 
to study the generic aspects of QOL in our trial.  
 
As a National Cancer Institute (NCI)-funded initiative to improve the accuracy and precision of 
clinician-reported CTCAE, the PRO-CTCAE will be used to measure symptomatic adverse 
events associated with oropharyngeal cancer and the proposed cancer treatments. The goal of the 
PRO-CTCAE project is to standardize use in all clinical trials on cancer (Basch 2014). 
Validation studies, which have been conducted at NCI-designated, comprehensive cancer centers 
and by the NRG/RTOG, have shown favorable validity, reliability, and responsiveness in 
patients undergoing cancer treatment (Dueck 2015). Using this reporting system for symptomatic 
adverse events is particularly important for patients receiving immunotherapy because it captures 
novel immunotherapy-related side effects while other questionnaires, which were developed 
prior to advent of immunotherapy, do not. Additionally, core physical symptoms and side effects 
associated with radiotherapy and chemotherapy for head and neck cancer patients are also 
included in the PRO-CTCAE.  
Hearing loss has a significant, negative impact on patients’ QOL by hampering speech, 
communication, and social life (Cioba 2012). Cisplatin, a platinum-based chemotherapy drug, 

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will be used in this trial. However, cisplatin can damage the cochlea, leaving 40-80% of adults 
with significant, permanent hearing loss. Regrettably, no cures or preventive treatments have yet 
become part of the standard of care for cisplatin-induced ototoxicity (Rybak 2009). Cisplatin-
induced hearing loss is particularly serious in patients with head and neck cancer because 
radiation of the base of the skull adds to the risk of damage (Chen 2006).  Moreover, patients 
with HPV-positive oropharyngeal cancer might be at high risk of hearing changes after treatment 
because they are usually younger and have better hearing than HPV-negative patients (Ang 
2010). Thus, we will study auditory damage from chemoradiation in this population and examine 
whether reducing radiation or substituting cisplatin with immunotherapy would measurably 
improve this aspect of QOL.  
 
In the light of growing concerns about the increasing cost of cancer and health care, clinicians 
must carefully consider the economic consequences of introducing new agents, especially those 
that are exorbitantly expensive. The goal of such considerations should be to reach a balance 
between best cost and effectiveness and to inform clinical decision making. Immunotherapies 
such as nivolumab have been associated with better disease outcomes and QOL (Ferris 2016; 
Harrington 2017), but the current cost is high (Couzin-Frankel 2013; Tringale 2018). In this trial, 
we will use a cost-utility analysis, including utilities like QOL, to compare different treatment 
choices. Specifically, the ratio of the incremental cost to gain an extra, quality-adjusted life-year 
(QALY) will be used to compare different treatment arms. The EQ-5D-5L, a well-validated 
instrument for calculating QALY and cost-utility analysis, will be used in this trial. 
 
All QOL/PRO instruments will be administrated at baseline, end of RT, at 12 weeks from end of 
RT, at 6 months, 12 months, and 24 months post-RT. These time points were selected to best 
capture the changes in QOL/PRO throughout the various phases of treatment across the arms and 
follow-ups. Evidence from published studies and other NRG Oncology trials have also indicated 
that those time points reflect the acute and late effects of treatment on patients QOL/PRO status 
(Xiao 2017; Truong 2017; Ringash 2017).   
 
11.3.2 Description of QOL/PRO Instruments 
 
MD Anderson Dysphagia Inventory (MDADI) 
Swallowing will be evaluated using the validated PRO swallowing instrument, the MD Anderson 
Dysphagia Inventory (MDADI). The MDADI is a 20-item self-administered patient reported 
dysphagia-specific instrument consisting of global, emotional, functional, and physical subscales 
(Chen 2001), and is currently being used on several prospective multicenter randomized NRG 
oncology clinical trials. Two summary scores: global and composite, can be obtained from the 
MDADI. The global score is from a single item to assess the overall impact of swallowing 
abilities on QOL. The composite score summarizes the remaining 19 items, as a weighted 
average of the physical, emotional, and functional subscales. The scores range from 0 (extremely 
low functioning) to 100 (high functioning). Hutcheson et al. (2016) evaluated the MDADI 
questionnaire (scored out of 100) for swallowing-related QOL in 1,136 patients with HNC. 
Using anchor-based methods, a ten-point difference between groups in composite MDADI 
scores was identified as clinically meaningful (Hutcheson 2016). This recommendation is from a 
cross-sectional study, but there are no published recommendations with a longitudinal design. A 
range of 5%-10% differences in instrument range has also been recommended for clinical 
meaningful changes (Ringash 2007). To be consistent with prior use of the survey in NRG-

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HN002, a 5% difference in the MDADI global change scores from baseline to one year after 
radiation between arms will be considered as being clinically meaningful in this proposed trial. 
The time for administration is about 7-10 minutes. 
 
NRG Oncology has obtained permission to use the MDADI for this study in English, Spanish, 
and French.  
 
Hearing Handicap Inventory for Adults-Screening (HHIA-S) Instrument 
The Hearing Handicap Inventory for Adults (HHIA) was developed to target hearing impaired 
adults and a screening version of the HHIA (HHIA-S) was subsequently developed as a 
screening tool (Newman CW, 1990). The HHIA-S includes 10 items with a high test-retest 
reliability of 0.97. The overall score is the sum of the 10 items, and ranges from 0 to 40. A score 
from 0-8 indicates no self-perceived handicap; a score from 10-24 indicates mild to moderate 
handicap; and a score from 24-40 indicates severe handicap (Ventry & Weinstein 1982). HHIA-
S was used in RTOG 1016 successfully to assess the hearing loss. The time for administration is 
about 3-5 minutes. Since a recommended clinical meaningful change has not been published for 
HHIA-S, we will use a similar approach as MDADI: a range of 5% to 10% differences in 
instrument range will be considered as clinical meaningful changes (Ringash 2007).  
 
NRG Oncology has obtained permission to use the HHIA-S for this study in English and 
Spanish. The HHIA-S has not been validated in French.  
 
EORTC QLQ-C30  
The European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC 
QLQ-C30 Version 3.0) (Aaronson NK, 2012, Sherman AC, 2000) is a well-established, 30-item 
self-reporting questionnaire developed to assess overall QOL of patients with cancer. The 
EORTC QLQ-C30 is grouped into five functional subscales (role, physical, cognitive, emotional 
and social functioning), three multi-item symptom scales (fatigue, pain, and nausea and 
vomiting), individual questions concerning common symptoms in cancer patients, and two 
questions assessing overall QOL. The subscales and symptom measures range in score from 0 to 
100; a high scale score represents better functioning or higher symptom burden (symptom scales 
will be reversed to facilitate presentation). The EORTC QLQ-C30 has been used in clinical trials 
using nivolumab for patients with recurrent or metastatic head and neck cancer (Ferris 2016, 
Harrington 2017) and using the EORTC QLQ-C30 in this trial will provide a reliable comparison 
among trials. The time for administration is about 7-10 minutes. Clinical meaningful changes in 
the EORTC QLQ-C30 will be defined as a 10-point difference (Osoba 1998, Mazieres 2019). 
 
NRG Oncology has obtained permission to use the EORTC QLQ-C30 for this study in English, 
Spanish, and French.  
 
 
 
 
 
EQ-5D-5L 
The EQ-5D™, a trademark of the EuroQol Group, is a standard measure of health status. The 

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EQ-5D-5L provides a simple descriptive profile and a single index value for health status that 
can be used for clinical and economic evaluation of health care (EuroQol Group 1990). The EQ-
5D-5L is a 2-part questionnaire and has been translated into multiple languages. The first part is 
the descriptive system and consists of 5 items covering 5 dimensions, including mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is graded on 5 
levels: 1-no problems, 2-slight problems, 3-moderate problems, 4-severe problems, and 5-unable 
to perform/extreme problems.  The score from the descriptive system will be converted into a 
single index value to compare the health status and facilitate the calculation of QALYs that will 
inform economic evaluation of this intervention. The second part is a visual analogue scale 
(VAS) valuing current health state, measured on a 20 cm, 10 point-interval scale. The score of 
VAS ranges from 100 to 0, with 100 indicating the best health the patient can imagine and 0 
indicating the worst health the patient can imagine. Patients can complete in a few minutes. 
 
NRG Oncology has obtained permission to use the EQ-5D-5L for this study in English, Spanish, 
and French.  
 
11.3.3 Administration of NRG-HN005 Patient-Completed Questionnaires 
Time points for administration are located in Section 4. 
 
11.3.4 Administration Instructions  
Questionnaires are to be administered per section 4. For patient opting out of ePRO, the PRO 
Forms should be administered during an office visit if at all possible, preferably while the patient 
is waiting to be seen. Once the questionnaires are completed by the patient, the staff member 
should review it to ensure that no items were unintentionally left blank. When absolutely 
necessary, it may also be administered by mail or phone.   The completed forms will be data 
entered in Medidata Rave. 
 
Patients who never initiate NRG-HN005 study therapy or who experience disease progression 
should continue participating in the PRO study. If a patient does not come in to clinic, the 
questionnaires will either be mailed to the patient or the research assistant will call the patient to 
complete the forms. If the patient does not return the forms within two weeks the patient will be 
called and either another set will be sent or the patient will complete the questionnaires over the 
phone with the research assistant. 
  
If a patient declines to complete a scheduled PRO forms or if the questionnaire is not completed 
for any other reason (and cannot be completed by phone or mail), the QOL coversheet must be 
completed in Rave. For patients who agree to use ePRO for PRO collection please refer to 
Appendix II. 
 
 
 
 
 
 

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12. MODALITY REVIEWS 
12.1 
Radiation Therapy Quality Assurance Reviews 
The Principal Investigator and Radiation Oncology Co-Chairs or NRG Oncology Headquarters 
approved designee(s) will perform an RT Quality Assurance Review after NRG Headquarters has 
received complete data for each case. These reviews will be ongoing and will be facilitated by 
IROC Philadelphia RT. The goal of the review is to evaluate protocol compliance. The review 
process is contingent on timely submission of radiotherapy treatment data. 
 
The scoring mechanism is: 1) Per Protocol, 2) Variation Acceptable, 3) Deviation 
Unacceptable, and 4) Not Evaluable.   
 
12.2 
Medical Oncology Modality Quality Assurance Reviews 
The Medical Oncology Co-Chair or NRG Oncology Headquarters approved designee(s) will 
perform a Chemotherapy Assurance Review of all patients who receive or are to receive 
chemotherapy in this trial.  The goal of the review is to evaluate protocol compliance.  The review 
process is contingent on timely submission of chemotherapy treatment data. The scoring 
mechanism is: 1) Per Protocol, 2) Variation Acceptable, 3) Deviation Unacceptable, and 4) 
Not Evaluable.   
 
The Medical Oncology Co-Chair or designee will perform a Quality Assurance Review after NRG 
Headquarters has received complete data for each case enrolled. The reviews will be ongoing.  
 
13. DATA AND RECORDS 
13.1 
Data Management/Collection (19-APR-2023) 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
x 
A valid CTEP-IAM account and linked ID.me account (ID.me accounts are required for 
all newly created CTEP-IAM accounts and by July 1, 2023 for all users); and  
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
Upon initial site registration approval for the study in Regulatory application, all persons with 

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Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff will not be able 
to access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in the Regulatory application will receive a separate 
invitation from iMedidata to activate their account. Account activation instructions are located 
on the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > Rave 
section or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
 
13.2 
Summary of Data Submission (04-NOV-2020) 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during the trial using Medidata Rave®. Additionally, certain adverse events must be 
reported in an expedited manner for more timely monitoring of patient safety and care. See 
Section 7 for information about expedited and routine reporting. PRO-CTCAE is not intended 
for expedited reporting, real time review, or safety reporting. PRO-CTCAE data are exploratory 
and not currently intended for use in data safety monitoring or adverse event stopping rules. 
 
Summary of Data Submission: Refer to the CTSU website.  
 
 
 
 

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Digital Data Submission Requirements 
Summary of Dosimetry Digital Data Submission 
Submit Digital RT Data via TRIAD; see Section 8.2.1 for TRIAD account access and installation 
instructions.  
 
DICOM 
DIGITAL 
DATA  
DICOM CT IMAGE SET 
TRIAD submission time point = 
          
         RT DIGITAL PLAN  
 
Due within 1 week of the start of RT 
 
 
 
 
 
 
 
  
DICOM RT STRUCTURE 
 
DICOM RT DOSE  
DICOM RT PLAN 
*DICOM PET (Required when applicable) 
*DICOM PET/CT (Required when 
applicable) 
*DICOM MRI (Required when 
applicable) 
*All image data sets used for structure delineation 
must be submitted with RT data (Section 5.2.2). 
     
All required structures MUST be labeled per the tables 
in Sections 5.2.4 and 5.2.5. 
Upon submission of the Digital Data via TRIAD, 
complete an online Digital Data Submission 
Information Form (DDSI) 
 
https://www.irocqa.org/Resources/TRIAD-for-RT-QA  
 
NOTE: ALL SIMULATION AND PORTAL FILMS AND OR DIGITAL FILM IMAGES WILL 
BE KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED. 
 
 
 
 

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13.3 
Data Quality Portal (21-AUG-2023) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, forms 
with current status, and timeliness reports. Site staff should review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to the 
CTSU website. Staff who have Rave study access can access the Rave study data via 
direct links available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a 
month. These notifications serve as alerts that queries and/or delinquent forms require 
site review, providing a summary count of queries and delinquent forms for each Rave 
study that a site is participating in. Additional site staff can subscribe and unsubscribe to 
these notifications using the CTSU Report and Information Subscription Portal on the 
CTSU members’ website. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
13.4 
Global Reporting/Monitoring (04-NOV-2020) 
Data for this study will be submitted via the Data Mapping Utility (DMU).  Cumulative protocol- 
and patient-specific data will be submitted weekly to CTEP electronically via the DMU.  DMU 
Light reporting consists of Patient Demographics, On/Off Treatment Status, Abbreviated 
Treatment and Course information, and Adverse Events as applicable.  Instructions for setting up 
and submitting data via DMU are available on the CTEP Website: 
https://ctep.cancer.gov/protocolDevelopment/dmu.htm.   
 
Note:  All adverse events (both routine and serious) that meet the protocol mandatory reporting 
requirements must be reported via DMU in addition to expedited reporting of serious adverse 
events via CTEP-AERS.   
 
 
 
 
 
 

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14. STATISTICAL CONSIDERATIONS 
14.1 
Study Design (19-APR-2023) 
This is a prospective randomized phase II/III trial comparing the standard of care (70 Gy over 6 
weeks plus concurrent high-dose cisplatin) to two experimental arms: reduced-dose RT (60 Gy 
over 6 weeks) plus concurrent high-dose cisplatin (Arm 2) and reduced-dose RT (60 Gy over 5 
weeks) plus concurrent nivolumab (Arm 3). Patients will be stratified by Zubrod performance 
status (0 vs. 1) and then randomized to one of the arms in a 1:1:1 ratio. Arm 2 was dropped 
after an interim futility analysis in phase II. The randomization ratio for Arms 1 and 3 is 
1:1. The experimental arm(s) found to be non-inferior in terms of PFS in phase II will continue 
in a phase III comparison against the control, with co-primary hierarchical endpoints of non-
inferiority for PFS and superiority for QOL. A QOL interim futility analysis will be conducted at 
the time of phase II primary endpoint to determine whether to proceed to phase III. Patients 
enrolled in phase II will contribute to the phase III target accrual. 
 
14.2 
Study Endpoints (04-NOV-2020) 
14.2.1  Primary endpoints: 
x Phase II:  
o Progression-free survival 
x Phase III: 
o Progression-free survival 
o Quality of life, as measured by the MDADI global QOL score 
 
14.2.2   Secondary endpoints: 
x Locoregional failure 
x Distant failure 
x Overall survival 
x Toxicity, as measured by the CTCAE and PRO-CTCAE 
x Hearing, as measured by the HHIA-S 
x Quality of life, as measured by the EORTC QLQ-C30  
x Association of baseline FDG-PET/CT locoregional control and PFS 
x Negative predictive value of post-RT FDG-PET/CT for locoregional control and 
PFS at 1 and 2 years 
 
14.2.3   Exploratory endpoints: 
x Quality of life, as measured by EQ-5D-5L 
x Swallowing physiology, as measured by a Modified Barium Swallow (MBS) test  
 
14.3 
Primary Objectives Study Design (19-APR-2023) 
14.3.1 Primary Hypothesis and Endpoints 
For patients with early-stage, p16-positive oropharyngeal cancer with a smoking history of ≤ 10 
pack-years, reduced-dose radiation therapy given with either concurrent cisplatin or concurrent 
nivolumab is non-inferior to the current standard of care in terms of progression-free survival 
(PFS) in Phase II. In phase III, experimental arm(s) shown to have non-inferior PFS as compared 
to the standard arm is hypothesized to have superior QOL, as measured by the MDADI global 
QOL score. 
 

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REVISED: For patients with early-stage, p16-positive oropharyngeal cancer with a smoking 
history of ≤ 10 pack-years, reduced-dose radiation therapy given with nivolumab is non-inferior 
to the current standard of care in terms of progression-free survival (PFS) in Phase II. In phase 
III, reduced-dose radiation therapy given with nivolumab shown to have non-inferior PFS as 
compared to the standard arm is hypothesized to have superior QOL, as measured by the 
MDADI global QOL score. 
 
14.3.2 How Primary Endpoints Will Be Analyzed 
Like in its predecessor NRG-HN002 trial, progression-free survival (PFS) is defined as from 
time of randomization to local- regional failure, distant metastasis, or deaths due to any causes. 
The following are considered a PFS failure: local-regional progression or recurrence, distant 
metastasis, death due to study cancer or unknown causes, death due to any other reason, salvage 
surgery of primary with tumor present/unknown, salvage neck dissection with tumor 
present/unknown, > 20 weeks from end of RT (PFS failures are listed in table in Section 14.6.1). 
Patients without a PFS failure at the time of the analysis will be censored at the last follow-up. 
 
PFS rates will be estimated for all treatment arms using the Kaplan-Meier method (1958). The 
primary phase IIR and co-primary phase III endpoint will be tested using a confidence interval 
(CI) approach. The null hypothesis for each comparison in phase II will be rejected if the 90% 
upper confidence limit excludes the HR=2.4. Similarly, the null hypothesis for each comparison 
in phase III will be rejected if the 95% upper confidence limit excludes the HR=1.75. 
Multivariate analysis will be performed using the Cox proportional hazards model.  
 
Quality of life scores for the phase III co-primary endpoint, will be compared between arms 
using a two-sample independent t-test at a one-sided significance level of 0.05 for each 
experimental arm comparison. MDADI global score and change from baseline will be 
summarized using mean and standard deviation at each time point for each arm. Missing data 
will be assessed and appropriate analysis techniques will be used according to the missing data 
mechanism as further described in Section 14.6.2. 
 
The table below outlines the decision algorithm. 
 
Phase II PFS result 
Phase II QOL futility analysis result Phase III trial 
Both experimental 
arms are non-
inferior to the 
control arm 
Did not cross futility boundary 
3 arm trial with 2 
experimental arms 
Both experimental 
arms are non-
inferior to the 
control arm 
One experimental arm did not cross 
the futility boundary and one 
experimental arm did cross the futility 
boundary 
2 arm trial with 1 
experimental arm that did 
not cross the futility 
boundary 
Both experimental 
arms are non-
inferior to the 
control arm 
Both experimental arms crossed the 
futility boundary  
No phase III trial 
Only one 
This experimental arm did not cross 
2 arm trial with 1 

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experimental arm is 
non-inferior to the 
control arm 
the futility boundary 
experimental arm 
Only one 
experimental arm is 
non-inferior to the 
control arm 
This experimental arm crossed the 
futility boundary 
No phase III trial 
Both experimental 
arms are inferior to 
the control arm 
N/A 
No phase III trial 
 
A decision regarding both experimental arms in phase II must be made prior to opening to phase 
III. 
 
In phase III, the experimental arms will first be compared to the standard arm in terms of PFS. If 
the experimental arm(s) is found to be non-inferior, then the MDADI global QOL score change 
from baseline to 1 year will be compared between the experimental arm(s) and the standard arm. 
If only 1 experimental arm is shown to have non-inferior PFS and superior QOL, then that arm is 
the winner. If both experimental arms meet these thresholds, then the experimental arms will be 
compared first with respect to PFS and then with respect to MDADI global QOL score in order 
to determine which is superior. If no difference exists between the experimental arms, then 
experimental arms will be compared with respect to toxicity and other QOL measures. 
 
14.3.3 Sample Size and Power Calculations:  
Phase II 
The estimated 9 month PFS for this population is 96.5% based on the eligible population of 
patients on the RT + cisplatin arm of RTOG 1016 (n=179 patients). A lower threshold of the 9 
month PFS rate that is considered acceptable is 91.8% which is based on the eligible population 
of patients on both arms in RTOG 0129 (n=61) which results in a non-inferiority margin of 
4.7%. Under the null hypothesis, the hazard ratio is 2.4 while under the alternative hypothesis the 
hazard ratio is 1.0. With one-sided type I error rate of 10% (20% after Bonferroni adjustment for 
each experimental arm comparison), 80% power, 24 months of accrual (rate of 10 patients/month 
per comparison) with 1 year of additional follow-up, and 1% increasing yearly rate of drop-out 
up to 3%, a log rank test requires 22 events from 266 patients per comparison resulting in 133 
patients per arm (399 patients in total).  
 
Arm 2 was dropped after an interim futility analysis in phase II. The original phase II 
sample size calculations remain unchanged due to the Bonferroni adjustment for each 
comparison versus the control arm. For clarity, the phase II accrual target for Arms 1 and 3 is 
266 randomized patients.  
 
Phase III 
The study will be on hold to analyze the phase II PFS endpoint and be reopened once PFS non-
inferiority is established in at least 1 experimental arm. The co-primary endpoints of PFS and 
QOL will be assessed in a hierarchical manner with PFS being assessed first. If PFS is found to 
be non-inferior for the experimental arm(s), the QOL of the experimental arm(s) will be 

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compared to that of the control arm. The estimated 2 year PFS for this population is 92.3% based 
on the eligible population of patients on the RT + cisplatin arm of RTOG 1016. A lower 
threshold of the 2-year PFS rate that is considered acceptable is 86.9% which is based on the 
eligible population of patients on both arms in RTOG 0129 which results in a non-inferiority 
margin of 5.4%. Under the null hypothesis, the hazard ratio is 1.75 while under the alternative 
hypothesis the hazard ratio is 1.0. A smaller hazard ratio, as compared to the phase IIR, is 
desired due to the definitive nature of this phase III trial. With one-sided type I error rate of 5%, 
80% power, and 1% increasing yearly rate of drop-out up to 5%, a log rank test requires 79 
events from 237 patients/arm.  
 
Effective with Amendment 3: Given that the actual accrual rate in the trial prior to Amendment 
3 is about 10 patients/month (same accrual rate for a comparison vs the control arm with the 
original design), if Arm 3 moves forward, 474 patients will be randomized in about 21 months 
from activation of phase III portion. After accrual completion, patients will be followed for 
additional 2.7 years for phase III primary endpoint completion (Arms 1 vs 3). Patients enrolled 
on phase II will contribute to the phase III target accrual resulting in 104 patients/arm to be 
enrolled when phase III opens to accrual. 
 
Additional phase III design details prior to Amendment 3: If only 1 experimental arm moves 
forward, 474 patients will be enrolled at a rate of 15 patients/month (10 patients/month during 
phase II accrual) with 3.25 years of additional follow-up. If both experimental arms move to the 
phase III, the overall type I error rate will be 10% after a Bonferroni correction and 711 patients 
will be enrolled at a rate of 10 patients/comparison (5 patients/month in the standard arm and 5 
patients/month in each experimental arm) with 2.7 years of additional follow-up. Patients 
enrolled on phase II will contribute to the phase III target accrual resulting in 104 patients/arm to 
be enrolled when phase III opens to accrual. 
 
The change from baseline to 1 year in global MDADI score will be assessed once PFS non-
inferiority is established. Change in  global MDADI score will be assessed only if the 
experimental Arm 3 is shown to be non-inferior. Using data from NRG-HN002, a change score 
of -5 with a standard deviation of 22 will be assumed for the experimental arm(s). Since some 
non-compliance is expected, the projected number of evaluable patients per comparison is 378, 
which assumes a 20% rate of non-compliance. As reported by Ringash et al (2017), a change 
score of -11 will be used for the control arm which results in an effect size of 0.27. A two-sample 
t-test with a one-sided type I error of 5% and 1 interim look will provide 82.7% statistical power 
to detect a difference from -11 to -5 in 378 patients (for a two-arm comparison). 
 
Note: Arm 2 was dropped after interim futility analysis in phase II. Please see the sample sizes 
for phases II and III with arms 1 and 3 after Amendment 3 in Table 3; 116 patients were already 
randomized to Arm 2 in phase II. 
 
 
 
 
 
 

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Tables 1 and 2 below provide the number of randomized patients if one or both experimental 
arms move to phase III. 
 
Table 1. Number of randomized patients if both experimental arms move to phase III 
 
Phase II 
Phase III 
Phase II/III 
Arm 1 (Control) 
133 
104 
237 
Arm 2 
133 
104 
237 
Arm 3 
133 
104 
237 
Total 
399 
312 
711 
 
Table 2. Number of randomized patients if one experimental arm move to phase III 
 
Phase II 
Phase III 
Phase II/III 
Arm 1 (Control) 
133 
104 
237 
Arm 2 
133 
104* 
237* 
Arm 3 
133 
Total 
399 
208 
607 
*If one experimental arm (2 or 3) moves to phase III 
 
Table 3. Accrual target (number of randomized patients) for phases II and III with Arms 1 and 3 
effective with Amendment 3 
 
Phase II 
Phase III 
Phase II/III 
Arm 1 (Control) 
133 
104 
237 
Arm 3 
133 
104 
237 
Total 
266 
208 
474 
 
14.4 
Study Monitoring of Primary Objectives 
Interim reports will be prepared twice each year until the final analysis has been accepted for 
presentation or publication. These reports will contain information about the accrual rate with 
projected completion date for the accrual phase, exclusion rates, pretreatment characteristics of 
patients accrued, and the frequency and severity of adverse events. 
 
Monitoring of MDADI Compliance 
Completion rates of the MDADI will be monitored monthly. Since not all patients will have 1 
year MDADI data by the time the study closes to accrual, the end of RT, 6 months and 1 year 
time points will be used to monitor compliance (noting that the 2 year time point will also be 
monitored). If the MDADI non-compliance rate is ≥ 20% at any of these time points, the study 
PI and QOL co-chair will work in collaboration with the NRG Oncology Statistics and Data 
Management Center to contact sites and RAs with delinquent data, assessments completed too 
early or too late, and assessments not completed due to institution errors. If the MDADI non-
compliance rate is > 30% at any of these time points, the study will be presented to the NRG 
Oncology Data Monitoring Committee (DMC) for reassessment of feasibility or change in study 
design. 
 
Interim Analysis 
The phase IIR will have an early interim analysis to assess futility once 50% of the events 
(11/22) have occurred. This is projected to occur approximately at the time of study closure. 

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There will be a futility interim analysis during the phase III trial as well. This will occur once 
50% of the events (40/79) have occurred. If the observed HR at either of these looks is equal to 
or worse than the non-inferiority margin, the study statistician will recommend to the DMC that 
the trial should be terminated for futility (Korn 2018). 
 
At the time of the projected phase II final analysis, an interim futility analysis for the phase III 
QOL primary endpoint will occur. It is projected that 51% of patients (approximately 96 patients 
per arm) will contribute to the analysis at this time. The phase II primary endpoint analysis is 
projected to occur approximately 1 year from study closure which is also the required length of 
follow-up required for the QOL interim analysis. The O’Brien & Fleming boundary will be used 
to assess futility for the MDADI global QOL 1 year change score. The table below specifies the 
boundary. 
 
MDADI Global QOL Futility Bound 
Analysis 
Sample size 
per arm 
Cumulative β 
spent 
Futility Boundary 
(|z scale|) 
Futility Boundary 
(|δ|) 
Interim 
96 
0.057 
0.311 
0.986 
Final 
189 
0.173 
1.645 
3.722 
 
Interim Analysis for the DMC 
The NRG Oncology DMC will review the study twice a year with respect to patient accrual and 
morbidity. The DMC also will review the study on an “as needed” basis. 
  
14.5 
Accrual/Study Duration Considerations (19-APR-2023)                                                                          
NRG/RTOG 1016 enrolled 15 patients/month and HN002 accrued 16.2 patients/month in 
the last 6 months of accrual. Therefore, a rate of 15 patients/month will be expected on 
this trial. After a ramp-up period of 6 months with no expected enrollment, it will take 
approximately 2.7 years for 382 patients to be enrolled in the randomized phase II. If 
granted, an additional 1.8 years of accrual will complete the randomized phase III (474 
randomized patients with Arms 1 and 3) after a hold of approximately 1 year to analyze 
the phase II. 
  
14.6 
Secondary Endpoints (including correlative science aims) (19-APR-2023) 
14.6.1 Secondary Hypotheses and Endpoints: 
x Phase II/III: 
o Locoregional failure 
Hypothesis: The rate of locoregional failure will be similar between arms. 
o Distant failure 
Hypothesis: The rate of distant failure will be similar between arms. 
o Overall survival 
Hypothesis: The survival rate will be similar between arms. 
o Toxicity, as measured by the CTCAE and PRO-CTCAE 
Hypothesis: The experimental arms will experience less toxicity than the control arm. 
 
o Hearing, as measured by the HHIA-S 
Hypothesis: Hearing will be affected more on the control arm as compared to the 

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experimental arms. 
o Quality of life, as measured by the EORTC QLQ-C30  
Hypothesis: Worsening in quality of life will be less in the experimental arms than the 
control arm. 
o Association of baseline FDG-PET/CT for locoregional control and PFS 
Hypothesis: Baseline FDG-PET/CT will be associated with locoregional control and 
PFS. 
 
14.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Time-to-Event Endpoints 
Overall survival (OS) will be measured from the date of randomization to the date of death or 
last known follow-up date, with patients alive at the last known follow-up time treated as 
censored. OS will be estimated using the Kaplan-Meier method and treatment arms compared 
using the log-rank test (Kaplan 1958).   
 
All other secondary time to event endpoints have precluding events that act as competing risks. 
Failure events and competing risks for local-regional and distant metastasis failure endpoints is 
outlined in the table below. 
 
First event 
Progression-
Free Survival 
Local-regional 
failure 
Distant 
metastasis 
None 
Censored 
Censored 
Censored 
Local-regional progression or 
recurrence 
Failure 
Failure 
Competing risk 
Distant metastasis 
Failure 
Competing risk 
Failure 
Death due to study cancer or 
unknown causes 
Failure 
Failure 
Competing risk 
Death due to any other reason 
Failure 
Competing risk 
Competing risk 
Salvage surgery of primary with 
tumor 
present/unknown 
Failure 
Failure 
Competing risk 
Salvage neck dissection with tumor 
present/unknown, > 20 weeks from 
end of RT 
Failure 
Failure 
Competing risk 
 
Time to locoregional failure will be measured from the time of randomization to the date of 
failure, date of precluding event, or last known follow-up date. Time to distant metastasis will 
similarly be measured from the time of randomization to the date of distant metastasis, date of 
precluding event, or last known follow-up date. Definitions of locoregional and distant failure 
are provided in Section 4. The cumulative incidence estimator will be used to estimate time to 
event distributions for locoregional failure and distant metastasis with between arm differences 
tested using cause-specific log-rank test.  
 
For all efficacy endpoints, Cox proportional hazards models will be used to determine hazard 
ratios (cause-specific hazard ratios in the case of endpoints with competing risks)  and to assess 
the effects of covariates of interest, such as age, race, ethnicity, T stage, and ECOG performance 

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status on outcomes (Cox 1972). The Fine-Gray subdistribution hazards model may be applied to 
further explore outcomes by treatment arm and other covariates for endpoints with competing 
risks (Fine and Gray 1999). 
 
All efficacy endpoints will be reported at the time of the primary endpoint analysis. A two-sided 
significance level of 0.05 will be used to determine significance for these secondary endpoints. 
The long-term analysis will be performed after initial reporting, if warranted, for the PFS and OS 
endpoints.  
 
Toxicity 
Adverse events (AEs) will be graded using CTCAE v5.0. Counts of all AEs by grade will be 
provided by treatment arm. Counts and frequencies will be provided for the worst grade AE 
experienced by the patient by treatment arm. The number of patients with at least 1 grade 3 or 
higher AE will be compared between the treatment arms. A comparison between treatment arms 
of grade 3 and higher AEs related to treatment will also be tested. There is a list of pre-specified 
AEs in the table in Section 7.4.1. A comparison of grade 3 and higher events will be compared 
between treatment arms. All comparisons will be tested using a Chi-Square test, or Fisher’s exact 
test if cell frequencies are < 5, with a significance level of 0.05. 
 
Adverse events will also be assessed using PRO-CTCAE items. The specific symptoms to be 
evaluated for this study are listed in the table in Section 7.5. Assessments will be collected before 
the start of radiotherapy treatment and as specified in the Section 4 assessment tables. For each 
symptom, counts and frequencies will be provided for the worst score experienced by the patient 
by treatment arm. The proportion of patients with scores ≥ 1 and ≥ 3 will be compared between 
groups using a Chi-square test, or Fisher’s exact test if cell frequencies are < 5, using a 
significance level of 0.05. Analysis of changes in patient reported outcomes over time will 
analyzed by fitting GEE models using a logit link (dichotomizing the symptom scores as 0 vs. > 
1 and 0-2 vs. 3-4) with time of assessment, treatment arm, and treatment-by-time interaction 
terms in the model. 
 
All toxicity analyses will be conducted at the time of the primary endpoint analysis. Additional 
toxicity analyses will be conducted during the time of the long-term analysis to assess late effects 
of RT. 
 
Patient-Reported Outcomes (PROs) 
The EORTC QLQ-C30, MDADI, and HHIA-S are collected at baseline, end of RT, 12 weeks from 
end of RT, 6, 12, and 24 months. 
 
There are several scores that will be assessed from the EORTC QLQ-C30: global health status 
(higher score represents high QOL), functional scales (high score represents higher level of 
functioning), and symptom scales excluding dyspnea and financial difficulties (high score 
represents high level of symptoms). The MDADI has 4 scores, all with higher scores indicating 
better QOL/functioning: a global QOL question and function, emotional, and physical subscale 
scores. The overall score (higher scores indicates handicap) will be assessed from the HHIA-S.   
 
 

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For all scores, change from baseline will be summarized using mean and standard deviation at 
the end of RT, 12 weeks from the end of RT, 6, 12, and 24 months. A longitudinal analysis 
incorporating the baseline, end of RT, 12 weeks, 6, 12, and 24 month time points will be 
conducted separately for the HHIA-S overall score, EORTC QLQ-C30 global QOL, functional 
and symptom scale scores, and MDADI global QOL, emotional, functional and physical scale 
scores using mixed effects models with the effect of time, treatment and its interaction. 
Adjustment for additional covariates such as race, and other clinical variables will be done if it is 
deemed necessary based on missing data patterns. The treatment by time interaction will be of 
primary interest.  Due to the multiple tests involving treatment by time interaction terms across 
tools and scales, a Hochberg’s multiplicity adjustment will be made when testing these eight 
hypotheses (Hochberg 1988): HHIA-S (overall score), MDADI (global QOL, emotional, 
functional and physical scales), and the EORTC (global QOL, functional and symptom scales). If 
individual tests for change from baseline scores between arms for specific time points are further 
required, the adjusted alpha from the Hochberg’s multiplicity procedure leading to the rejection 
of the interaction hypotheses will be used. 
 
Prior to performing analyses, an evaluation of the amount, reasons and patterns of missing data 
will be performed, using the well-known categories of missing completely at random (MCAR), 
missing at random (MAR) and missing not at random (MNAR) (Fairclough 2010, Verbeke 2000). 
If ≥ 15% of the data is missing at any time point for the PROs, patient characteristics will be 
compared between patients with completed assessments and those with missing assessments. If 
any are found to differ significantly, they will be included in the mixed effects model, which 
assumes that the data is MAR. If the missingness is determined to be non-ignorable, other methods 
may be applied. Specifically, a joint model that allows a shared parameter between the repeated 
measurements and time to death or drop out can be used if considered MNAR due to the high 
number of patient deaths or dropouts (Rizopoulos 2012). Other options for MNAR data are pattern 
mixture and selection models (Fairclough 2010, Little 1995). Sensitivity analyses will be 
performed to compare the results of different analytic strategies (Fairclough 1998). 
 
All QOL analyses will be conducted at the time of the primary endpoint analysis. For patients on 
an arm not moving to phase III, phase II patients will be analyzed. 
 
Association of Baseline FDG-PET/CT Imaging with Locoregional Control and PFS 
The association between baseline FDG-PET/CT and locoregional failure/PFS will be assessed 
using (cause-specific) Cox proportional hazards models (unadjusted and adjusted by key 
covariates including the stratification factor; 0.05 two-sided alpha). In phase III, it is projected that 
approximately 75% of patients (~355) will have a FDG-PET/CT at baseline (i.e., approximately 
59 PFS events available for analysis). Based on NRG-HN002 data, about 75-80%, 11-12% , and  
8-14% are expected to have a negative, positive, and indeterminate read, respectively (see 
definitions of a negative, indeterminate, and positive FDG-PET/CT read in Section 11.1.2). The 
table below shows the statistical power to detect an HR for the FDG-PET/CT of 2.5. For instance, 
if 20% of patients have a positive FDG-PET/CT, then a Cox model will have at least a 81% power 
to detect such an effect.  
 
 
 

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% of patients with positive PET/CT at baseline 
Power 
20% 
81% 
15% 
71% 
10% 
56% 
 
 
Indeterminate cases in both PET/CT analyses will be removed from this analysis, however if the 
rate of indeterminate scans > 10% then sensitivity analyses for both outcome variables will be 
conducted assuming all are positive and all are negative. This analysis will be conducted at the 
time of the PFS and locoregional failure analyses. 
 
Negative Predictive Value (NPV) of 12-14 Weeks Post-RT FDG-PET/CT vs. Locoregional Control 
and PFS 
Based on data from NRG-HN002, about 35% of the patients will have a 12-14 week post-RT FDG-
PET/CT. The expected number of patients with 12-14 weeks post-RT FDG-PET/CT are listed in 
the table below. About 65% of the FDG-PET/CT’s are expected to come from patients enrolled in 
the phase II. 
 
 
 
Number of 
enrolled 
patients  
Expected number of patients with 
FDG-PET/CT at 12-14 weeks post-
RT 
Phase II 
382 
134 
Phase III with 2 arms 
208*  
73  
Phase II/III with 2 arms in phase III 
590** 
207 
*Additional number of patients enrolled in phase III portion (Arms 1 and 3). 
** It includes 382 patients randomized in phase II (Arms 1, 2, and 3) and 208 additional patients randomized in phase 
III (Arms 1 and 3). 
 
At 12-14 weeks post-RT, it is projected that approximately 98% will be negative and, 2% positive 
for residual tumor based on NRG-HN002. The negative predictive value (NPV) of FDG-PET/CT 
for 1-yr and 2-yr locoregional control, and PFS will be estimated using binomial proportions and 
confidence intervals (CI) based on normal approximation. A negative result in the computation of 
the NPV refers to the absence of a PFS event or a locoregional failure at the specified time points. 
From the table above, about 202 patients are expected with negative FDG-PET/CT at 12-14 weeks 
post-RT in the phase III trial with two arms. The half-widths of the 90% CIs when the true NPV 
is equal to 80%, 85%, 90% and 95% are 4.6%, 4.1%, 3.4%, and 2.5%, respectively. These true 
NPV’s cover potential values for locoregional control and PFS rates at 1 and 2 years. 
 
14.7 
Exploratory Endpoints (04-NOV-2020)  
14.7.1 Definitions of Exploratory Endpoints and How These Will Be Analyzed 
Cost effectiveness 
The EQ-5D-5L is collected at baseline, end of RT, 12 weeks from end of RT, 6, 12, and 24 months.  
The VAS and index scores will be assessed with higher scores indicating better QOL.  Missing 
data will be assessed as described in Section 14.6.2.  The change from baseline will be calculated 
at the end of RT, 12 weeks from end of RT, 6, 12, and 24 months and compared between arms 
using a t-test. A longitudinal analysis incorporating the end of RT, 12 weeks from end of RT, 6, 

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12, and 24 month time points will be conducted for the EQ-5D index score using mixed effects 
models, adjusting for baseline score and treatment arm. A treatment by time interaction will also 
be assessed in each model. 
 
The following analysis will only be conducted if the nivolumab arm is shown to be non-inferior to 
the control arm for PFS and has at least 1 significant difference in index change score. Quality-
adjusted life years (QALYs) is defined by the weighted sum of different time episodes added up 
to a total quality-adjusted survival time. A Markov model will be used to model cost for this 
analysis. The Medicare reimbursement in dollars/QALY will be calculated as a function of the 
monetary cost per relative value of each health state and its duration. The EQ-5D-5L index score 
at end of RT, 12 weeks from end of RT, 6, 12, and 24 months will be used for the cost-utility 
analysis. The z-test will be used to test the hypothesis that the cost-utility in the two treatment arms 
is the same with significance level of 0.05. The cost-utility using the Medicare reimbursement in 
dollars/QALY will be compared between the two treatment arms after adjusting for baseline 
variables.   
Swallowing 
The determination of aspiration (yes vs. no) will be assessed by sites as a SOC exam. Therefore, 
the proportion of aspiration (yes) for each arm will be estimated assuming a binomial distribution 
and between arm comparison will be performed using a Fisher’s exact test. 
 
14.8 
Gender/Ethnicity/Race Distribution (19-APR-2023) 
The following distribution is based on the accrual target of 590 randomized patients, which 
includes 116 already randomized to Arm 2 (arm dropped in phase II) and 474 randomized 
patients in Arms 1 and 3 (266 in phase II + 208 in phase III portion). 
 
 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
1 
4 
0 
0 
5 
Asian 
2 
12 
0 
0 
14 
Native Hawaiian or Other 
Pacific Islander 
1 
4 
0 
0 
5 
Black or African American 
2 
12 
0 
1 
15 
White  
83 
322 
5 
18 
428 
More Than One Race 
1 
4 
0 
0 
5 
Total 
90 
358 
5 
19 
472 
 
 
 
 
 

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Racial Categories 
INTERNATIONAL (including Canadian participants) 
PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
1 
2 
0 
0 
3 
White  
22 
90 
0 
1 
113 
More Than One Race 
0 
2 
0 
0 
2 
Total 
23 
94 
0 
1 
118 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX I: Medidata Patient Cloud ePRO Operational Instructions 
 
1.1 Introduction 
Electronic collection of patient-reported outcomes (ePRO) through Medidata Patient Cloud 
ePRO is preferred but not mandatory.  Traditional paper submission is the other option. Patients 
who will be submitting PRO data via Patient Cloud ePRO must be registered to Patient Cloud 
ePRO by an authorized site user after the patient has been registered to the study. Patients may 
use their own device or one provisioned by the site.  
 
Sites can use a site-specific tablet for multiple study participants.  If a site-specific tablet is used, 
CRAs need to setup the tablet for multiple users.  Multi-user mode lets multiple study 
participants log in to Patient Cloud ePRO with their passwords or their PIN codes on the same 
device.  
1.2 ePRO Application Download 
Note that there are multiple versions of the Medidata Patient Cloud ePRO Application.  Patients 
should be instructed to download the version chosen by the study team for the protocol.  The 
patient will receive an error if the wrong version is downloaded.  
  
Patient Cloud ePRO 
 
 
 
Patient Cloud 
 
 
 
 
1.3 CRA Site Users 
Site users of Patient Cloud ePRO require the same access as Rave. Access to the trial in the 
Patient Cloud ePRO is granted through the iMedidata. Site users will receive an invitation to 
Patient Cloud application and the site user must accept the invitation to begin patient registration. 
Users who have not previously activated their iMedidata/Rave account at the time of initial 
approval of site registration will also receive a separate invitation from iMedidata to activate 
their account. Account activation instructions are located on the CTSU website, Rave tab under 
the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). 
Please note, site users will not be able to access the study in the Patient Cloud application until 
all required Rave and study specific trainings are completed. 
 
Additional information on iMedidata/Rave is available on the CTSU members’ website under the 
Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or 
by e-mail at ctsucontact@westat.com.   
 

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1.4 CRA Instructions for Setting the Patient Cloud App to Multi-User Mode 
Sites conducting studies entirely on-premise, where participants travel to the sites to fill out 
questionnaires, can use multi-user mode. Multi-user mode lets multiple study participants log in 
to Patient Cloud with their passwords or their PIN codes on the same device. If patients will be 
using devices supplied by the institution, site staff will need to help the patient to access the 
device if the device is locked. 
 
The study provider will download the Patient Cloud app to the device and set the Patient Cloud 
ePRO App to multi-user mode if applicable.  **Verify the correct version is downloaded per the 
study build requirements.  Note only 1 version of the app is active per protocol. 
To switch from personal mode (default setting) to multi-user mode: 
1.     Tap About at the bottom of the log in screen. 
2.     Scroll to the bottom and tap Advanced User. 
3.     Tap Mode, then select Multi-User. 
4.     Tap Yes to confirm. 
5.     Tap the back arrows to return to the log in screen. 
Note: If enabling multi-user mode on a device, it is highly recommended that completion 
reminders are turned off on that device. 
 
For a video demonstration, see Show Me How to Switch to Multi-User Mode. 
1.5 Patient Users 
To use the Patient Cloud application, patients will need to use their own device (IOS, Android 
phone or tablet).  Short term data will only appear on the patient’s device until responses are 
completed and submitted.  The patient data will import directly into the database once the patient 
selects the “Submit” button and will no longer be visible on the patient's device.  
 
Sites can provide a site-specific tablet for multiple study participant use on site.  If a site-specific 
tablet is used, study staff need to setup the tablet for multiple users.  Multi-user mode lets 
multiple study participants log into Patient Cloud ePRO with their passwords or their PIN codes 
on the same device. Refer to Appendix E on Setting the Patient Cloud App to Multi-User 
Mode.   
1.6 Patient Instructions for Accessing the Patient Cloud Using Your Personal Device 
Downloading the Patient Cloud ePRO App 
If you are using your personal device, and you do not have the Patient Cloud app, use the 
following instructions. When downloading the app, you must use the Apple ID or Google 
account associated with the device. If the Patient Cloud app is already on the device, or if you are 
using a provider's device, you can skip this section. There are multiple versions of the app 
available. Ensure that the correct version of the ePRO app is downloaded by the patient. 
 
You will need an email address that you agree to use for this purpose. The e-mail address is 
needed to identify you on the Patient Cloud Application and for you to receive notifications to let 
you know when forms are due. Your e-mail address will only be used for this survey study, and 
will not be used for mail or marketing purposes. 
 
If you decide to use the electronic method to complete the questionnaires, and do not have an e-

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mail address, you may sign up for one at no charge at many different websites.  A few sites that 
are commonly used and will allow you to create an email address very easily are Yahoo, Gmail, 
and Outlook. 
 
For iOS:  
 
1. An Apple ID is required for downloading the Patient Cloud app. 
2. Tap the App Store icon. 
3. Search for the appropriate Medidata Patient Cloud ePRO application and 
follow the installation instructions.  
Note: Patient Cloud is listed as an iPhone App in the App store. When using an iPad, please view 
the search results under iPhone apps. 
   
For Android: 
1. A Google account is required for downloading the Patient Cloud app 
2. Tap the Play Store icon. 
3. Search for the appropriate Medidata Patient Cloud ePRO application and 
follow the installation instructions.  
Registering 
You must register in order to complete and submit your study forms. When you register, you will 
create a username, which is your email address, and a password that allows you to log in to the 
Patient Cloud ePRO app. 
 
Note: You must have an activation code to begin this process. If you do not have an activation 
code, please contact your provider.  
There are two possible ways to register. Your provider may have sent you a link to a web address 
where you may register from any web browser, including the one on your device. The other way 
to register is on the Patient Cloud app. 
1. If registering from the Patient Cloud app, tap Register on the bottom of the 
log in page. If registering on the web, open the URL shield.imedidata.com 
on a web browser. 
2. Enter your activation code and tap Activate. 
3. On the next page, read the instructions and tap Next. 
4. Read the privacy notice and tap I agree. Then tap OK to confirm. 
5. Enter and confirm your email address. Tap Next. 
6. Enter and confirm your password. Tap Next. 
7. Choose a security question by scrolling through the dropdown menu to 
display the question of your choice. 
8. Enter your security question response. 
9. Tap Create my account to complete your registration.  
If you registered on the Patient Cloud app, it automatically logs you out. If you registered on the 

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web, you are presented with the option to download the Patient Cloud app. You can then proceed 
to log in with the credentials you created.
Logging in to the App
1. Enter your Email and Password that you created during the registration 
process. (If you previously set a PIN code, just enter your four-digit PIN.)
2. Tap Log in.
Note: If you do not remember your password, tap Forgot Password, and follow 
the instructions provided.
Setting a PIN Code
The first time you log in to the Patient Cloud app, you are given the option to create a PIN code. 
A PIN code allows you to bypass the step of entering your email and password every time you 
need to log in to the Patient Cloud app. Instead, you can enter a four-digit PIN.
1. If you wish to set a PIN code the first time you log in, tap Yes when 
prompted.
2. Note: You can also set your PIN at a later time by tapping the options 
menu on the top left of most pages and selecting Set PIN.
3. Enter a four-digit PIN.
4. Re-enter the four-digit PIN to confirm.
If you forget your PIN code, tap Forgot PIN and you can access the app using your email and 
password. You may reset your PIN by tapping the options menu on the top left of most pages 
and selecting Set PIN.
Resetting Your Password
You can reset your password by using the options menu at the top left of most pages.
1. Tap the options menu icon.
2. Tap Reset Password.
3. Follow the instructions to reset your password.
Completing and Submitting Forms
Once logged in, forms related to your study display on the Tasks page. If you are enrolled in 
multiple studies, select the appropriate study first, and then select a form. New forms can appear 
on the Tasks page at any time, depending on how the study is designed.
There are two types of forms displayed on the Task List page:
x
Scheduled Forms (with a 
icon): These forms have a "Due Date" indicator 
in them so you are aware of the last day by which you will need to complete 
the form. If the form is due in less than one day, you will see the due time in 
hours.

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x
Anytime Forms (with a
icon): These forms have "Last Completed Time" 
indicator on them which tells the most recent date or time when you 
completed the form. If you start a form, but do not complete it, you will see an 
'Incomplete" status beneath the form name, along with a half-moon icon. 
To complete and submit form(s):
1. Select the appropriate form.
2. Follow the on-screen instructions until you reach the end of the form 
where you are given the opportunity to review and change your responses 
prior to submitting.
3. Review your responses by scrolling down the list.
4. If you need to change an answer, tap the question to go back and change 
the answer.
5. When you are ready to submit, tap Submit Your Data.
Note: Once a form is submitted, you will be unable to edit any of your responses. In some cases, 
you may be asked to acknowledge your submission by entering your password. 
1.7 Patient Compliance
The patient data imports directly from a device into the Rave database.  There are no documents 
to audit.  The patient-submitted electronic responses are the source documentation.
1.8 Security
All data is encrypted on the device (256 bit encryption and Hyper Text Transfer Protocol Secure 
[https]) and the app requires each user to have a unique username and password for access.  If 
the user is idle for too long (5 minutes inactivity time), the app will time out and the user will 
need to log in again.
The data will only reside on the device for a short period of time.  Once the user clicks “Submit,” 
the data is securely transferred over HTTPS between the device and internal relay to the Rave 
database.  Except for the patient's email address, no identifying information is stored in 
iMedidata. The email address is stored for what purpose?  The patient’s email links the device 
(used) and (ePRO) account to where the data is stored.  The patient’s email is not visible to 
anyone in the system.
The Patient information (email/password) does not reside in Medidata Rave EDC and the patient 
accounts are hidden in iMedidata from sites and LPOs.
The Patient Cloud application is 21 CFR Part 11 compliant and acts as a gateway between the 
device and Medidata Clinical Cloud (MCC).  
Messages and information communicated to and from the Patient Cloud are encrypted and 
therefore this information cannot be read if intercepted while in transit.

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1.9 Site checklist for activities prior to consenting a patient 
 Site staff must have already completed required eLearning for the Patient Cloud ePRO 
application. See last bullet with hyperlink to training video library. Contact the LPO to 
request appropriate Rave access to register patients in Patient Cloud ePRO 
 Accept study invitation at iMedidata.com 
o Note: you must be rostered in RSS and have received an invitation to Patient Cloud 
ePRO 
 Verify the IOS or Android operating system is using the most current version 
 Verify the correct Patient Cloud app is being used. Note only 1 version of the 
app is active per protocol. 
 Include an image of the app icon to document version used per the protocol in 
the appendix of the protocol. 
 If using institutional shared devices, first patient only: Verify Patient Cloud application is in 
Multi-User mode  
 Refer to Review Quick Reference Guides for videos and other procedural information 
Patient withdraws study consent or withdraws consent from participating on ePRO 
CRA must instruct the patients that are participating on ePRO who decide to withdraw 
consent to delete the App from their smart phones. This will prevent QOL reminders from 
being sent to the patient.

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APPENDIX II: INSTRUCTIONS FOR SUBMISSION OF IMAGES TO TRIAD 
 
1. Download and install TRIAD 4.13 via https://triadinstall.acr.org/triadclient/  
2. Launch TRIAD, click the dropdown to select Clinical Trials (NCI Oncology). Login using your 
CTEP ID and password (see Section 8 for access requirements for OPEN, Medidata Rave, and 
TRIAD).  
 
 
3. To begin file submission: A. Select the HN005 Trial from the Trial dropdown. B. Select your 
Hospital from the Site dropdown. C. Once these options are selected, select Import Folder (to 
select a group of video files), or Import Files (to import an individual video file). 
 
 
 
 
 
 
 
 
 

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4.  Your selected file(s) will appear in the preview screen for review. Select Move to Submission 
Queue to move your files to the submission queue. 
 
 
5. To complete, enter subject information (Subject ID, Time Point ID, Time Point Description, 
Submission Type, etc.), then select Submit.  
 
 
 
 
 
 
 
 
 
 

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APPENDIX III: Dental Assessment Tooth Count and Dental Management (04-NOV-2020) 
 
Dental Tooth Count Diagram 
Use the diagram below as a guide to count the number of native teeth in place, not including full or partial 
dentures or bridges.  
 
The exact location of teeth does not need to be recorded, only the total number of native teeth in place 
(attached to bone in mandible or maxilla) on the day of evaluation. 
 
This exam should be completed by a physician or designee, such as a physician's assistant, nurse or nurse 
practitioner, or a dentist/hygienist. 
 
Date of evaluation:  
 
Total number of native teeth in place (0-32):  
 
 
 
 
Right 
Left 

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APPENDIX III (Continued) 
 
Dental Effects Health Scale 
 
 
0 Normal: Edentulous, with no gingival disease; native teeth in place with gingiva in excellent 
condition. 
 
1 Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 
restorations indicated; no extractions indicated. 
 
2 Moderate/fair dental health: moderate periodontal inflammation; deep periodontal cleaning indicated; 
6 or more restorations indicated; less than full mouth extractions indicated. 
 
3 Severe changes in dental health: widespread periodontal disease with extensive procedure/surgery 
indicated; full mouth extractions indicated. 
 
4 Life-threatening dental condition: extensive abscess, extensive soft issue or bone infection, sepsis; 
urgent intervention indicated.  
  
 
 
 

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APPENDIX III (Continued) 
 
Management of Dental Problems in Irradiated Patients 
 
Goals for a dental care program include: 
1. 
To reduce incidence of bone necrosis. 
2. 
To reduce incidence of irradiation caries. 
3. 
To allow proper fitting of dentures following treatment. 
 
Pre-irradiation Care and Procedures 
The patients may be grouped into four groups in accordance with the problems they present prior to 
irradiation. 
 
x Group 1: Includes edentulous patients.  They may require surgical removal of any symptomatic 
cysts, infected retained root tips, or alveolar hyperplasia.  These patients require hygiene 
instruction and precautionary instruction about trauma with premature use of a prosthesis. 
 
x Group 2: Includes those with poor dental hygiene, including those patients whose teeth are 
beyond repair by ordinary dental procedure, those with generalized oral sepsis, those with 
generalized periodontal disease, and those with chronic periapical abscesses or granulomas. 
 
Procedures performed on this group include removal of all remaining teeth prior to irradiation 
with primary closure and surgical preparation of the alveolar ridges to laterally support a 
prosthesis.  There should be antibiotic coverage during the healing stage and adequate time prior 
to the start of radiation therapy.  These patients need complete hygiene instruction and 
precautionary instruction about premature use of a prosthesis. 
 
x Group 3: Includes those in whom dental condition is fair, including those patients whose teeth are 
restored, ordinary dental procedures, periodontal pockets are less than 3 mm deep, carious lesions 
are not in proximity to the pulp, and no more than 20 restorable carious lesions are present.  X-
ray examinations show at least 1/2 of the bone still present around root surfaces.  These patients 
require removal of any teeth that are non-salvageable in accordance with the above and 
restorations of the remaining teeth as required.  The patients are instructed for dental prophylaxis 
and the patients utilize custom-made fluoride carriers. 
 
x Group 4: Includes those in whom dental hygiene is good.  This includes patients who do not have 
severe malocclusion in whom few carious lesions are present.  Carious lesions are not in close 
proximity to the pulp and are correctable by conventional methods.  These patients require 
periodontal evaluation and dental prophylaxis training, restorations as needed, no extractions 
prior to radiation therapy, and fitting for custom carriers. 

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APPENDIX III (Continued) 
Management of Dental Problems in Irradiated Patients (continued) 
 
Extraction of Teeth 
If extraction of teeth is necessary prior to radiation therapy, the bone must be contoured so that closure at 
the extraction site is possible.  All loose spicules and sharp projections must be removed.  The 
approximation of the gingival tissue must be such that the closure is neither too loose nor too tight.  At 
least 10 days are required for adequate healing prior to initiation of therapy. 
 
Causative Factors 
The major causative factors appear to be the reduction of the amount of saliva and secondarily, reduced 
pH in the mouth.  This occurs following high dose radiation to the major salivary glands using parallel 
opposed fields.  The decay process usually occurs in the first year following radiation therapy.  It tends 
to occur more quickly in teeth which have a large amount of root cementum exposed to those teeth with 
large amounts of plaque formation present.  Doses of radiation in excess of 20 Gy to salivary tissue place 
the teeth at risk. 
 
 Preventive Program 
The rationale behind the use of fluoride treatments is to make the tooth surfaces less susceptible to the 
decay process.  This is accomplished by a combination of increasing fluoride concentration on the tooth 
surface and by the effect of fluoride on the plaque and flora that are present in the oral cavity.  Adequate 
results are obtained by:  1) cleansing the teeth thoroughly, followed by a good home care dental 
prophylaxis program, 2) construction of  
fluoride carriers, custom-made mouth guards, which provide local application of fluoride solution to the 
gingiva and tooth surfaces.  Fluoride carriers are made individually with the use of casts.  Material used 
for making a mouth guard is "Sta-Guard" plastic used in conjunction with vacutrole unit produced by 
Jelrus Technical Products, Corp., both of which are available through local dental supply.  This material 
is molded to the cast impression and allowed to harden.  A fluoride solution prepared at the M.D. 
Anderson Hospital is now available from the Emerson Laboratories, Inc., Dallas, Texas 75221.  It has 
been used to coat the plastic carrier for use in the mouth.  The patients are instructed to cleanse their 
teeth prior to placement of the carrier.  It is then worn in place for 5 minutes each day.  The patients are 
instructed to rinse their mouths thoroughly following the use of the carrier.  This will be continued for an 
indefinite period of time.  Close follow-up is necessary. 
 
Results 
In the 5-1/2 year program at the M.D. Anderson Hospital beginning in 1966, a study of 304 patients 
shows that the incidence of necrosis of the jaw was reduced to approximately 21% compared to 37% 
prior to initiation of the study.  Groups 3 and 4 patients randomized with and without fluoride treatment 
showed reduction in radiation carries from 67% to 34% among Group 3 patients, and from 65% to 22% 
among Group 4 patients. 
 
 
 

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APPENDIX III (Continued) 
Management of Dental Problems in Irradiated Patients (continued) 
 
Failure to Control Decay 
Management of failure to control radiation decay includes silver fillings with continued use of fluoride 
treatments.  If the decay process is sufficiently advanced that a filling will no longer stay in place, these 
teeth are merely smoothed so that there will be no sharp, irritating edges.  The mere existence of such a 
decayed tooth is not necessarily reason for extraction, for it must be remembered that extraction could 
lead to complications such as bone necrosis. 
 
Pulp exposure resulting from the decay process can usually be handled by use of antibiotics and/or root-
canal therapy. 
 
Hypersensitivity of Teeth 
Occasionally, a patient will exhibit extreme sensitivity of the teeth secondary to diminished amounts of 
saliva.  This has been shown to be reduced in incidence with the fluoride treatments.  Should this 
problem become manifest, increasing the fluoride treatment to 10 to 15 minutes 3 times a day is 
recommended. 
 
Infections 
Infections occurring in patients under or after radiation therapy are best managed conservatively with 
good oral hygiene, irrigation and flushing procedures, and systemic antibiotics. 
 
Bone Necrosis 
The patients receiving radiation therapy to a high dose to the head and neck region have increased 
susceptibility to bone necrosis for several reasons including:  impairment of normal metabolism, 
increased susceptibility to infection and severely limited repair process.  Bone necrosis occurs most often 
after dental or oral surgery in patients who have been previously radiated.  Conservative management 
should be tried first, though in more aggressive lesions a more radical approach may ultimately be 
necessary. 
 
 
 

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APPENDIX IV: SUGGESTED ACQUISITION GUIDELINES FOR THE MODIFIED BARIUM SWALLOW (MBS) 
ADMINISTRATION AT BASELINE AND POST RT YEAR ONE AND TWO 
 
For questions, please contact Rosemary Martino, MA, MSc, PhD at rosemary.martino@utoronto.ca. 
Many institutions will have standard guidelines for acquisition of MBS. For purposes of this protocol, individual 
investigators may use these local guidelines. One possible approach is outlined below which is suggested to optimize 
acquisition. 
 
MBS Administration Parameter 
Pulse rate on fluoroscopy unit set at continuous or no less than 30 fps 
Capture of images set at uncompressed 
Capture of images set at 30 fps 
MBS test stimuli procedural conducted as per Table 1 below 
Preparation of standardized barium liquids and foods as per Table 2 below (or Varibar) 
Audio stamp for each video clip to label series (i.e., to record SLP 
audio cue of the amount/texture bolus trial, e.g., “5-mL thin”) 
Series descriptions for each video clip to label series (as per Table 3 below) 
Have the capacity to remove all patient health information/or 
hospital identifying information typically embedded in the video 
Capture each lateral image with full view the regions of Interest (ROI): C1 vertebrae (superiorly); posterior spine 
(posteriorly); cervical esophagus (inferiorly) 
Capture each A/P image with full view the regions of Interest 
(ROI): hard palate (superiorly); cervical esophagus (inferiorly) 

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TABLE 1. RECOMMENDED MBS CONDUCT PROTOCOL 
 
Many institutions will have standard guidelines for acquisition of modified barium swallow. For purposes of this protocol, individual 
investigators may use these local guidelines. One possible approach is outlined below which is suggested to optimize acquisition. 
x 
Before starting the MBS, place a standardized coin under patient’s chin secured with surgical tape for lateral views. For A/P the quarter can only be 
along the lateral neck just below the ear lobe. 
x 
Provide audio label of Amount-Texture during each bolus trial, as per table below. 
x 
Protocol deviations (i.e. additional texture trials, compensatory strategies, etc.) are permitted at the SLP’s discretion, but only AFTER the MBS 
protocol (sequence 1-13) is completed. 
 
Sequence 
View 
Amount – Texture 
Instruction * 
1 
Lateral 
1-ml Tsp– Thin liquid 
Hold this liquid in your mouth until I ask you to swallow 
2 
Lateral 
5-ml – Thin liquid 
Hold the liquid in your mouth, then swallow when ready. 
3 
Lateral 
5-ml – Thin liquid 
4 
Lateral 
10-ml cup sip – Thin liquid 
Hold the liquid in mouth, then try to drink the entire amount 
when ready. 
5 
Lateral 
10-ml cup sip – Thin liquid 
6 
Lateral 
Cup sip – Thin liquid 
Take a sip from the cup and hold it in your mouth, then 
swallow when ready. 
7 
Lateral 
Cup sip – Thin liquid 
8 
Lateral 
5-ml – Pudding thick barium 
Hold the pudding in your mouth, then swallow when ready. 
9 
Lateral 
5-ml – Pudding thick barium 
10 
Lateral 
Half of digestive cookie or cracker 
Take your usual bite, then chew and swallow when ready. 
11 
Lateral 
Half of digestive cookie or cracker 
12 
A/P 
Cup sip – Thin liquid 
Take a sip from the cup and hold it in your mouth, place the 
cup down on your lap, then swallow when ready. 
13 
A/P 
5-ml – Pudding thick barium 
Hold the pudding in your mouth, then swallow when ready. 

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TABLE 2. BARIUM FOOD RECIPES 
 
Texture 
Recipe 
Thin liquid 
135 mL Water 
+ 
45 mL Polibar Plus Barium Sulfate Suspension 105% w/v 
Pudding thick 
99 g Pudding cup (99g package) 
+ 
40g EZ HD barium Sulfate powder 
Solid 
Coat Social Tea cookie with layer of pudding +barium (above recipe) 
Nectar thick liquid * 
120mL Sysco Nectar thickened liquid 
+ 
10mL water 
+ 
15g EZ HD barium Sulfate powder 
Honey thick liquid* 
120mL Sysco Nectar thickened liquid 
+ 
48 g EZ HD barium Sulfate powder 
 
*Thickened fluids are not part of the recommended standard MBS protocol. If deemed appropriate to add to MBS procedure by the 
Speech Language Pathologist (SLP), this should be given AFTER completion of the above-mentioned protocol, unless safety 
concerns arise to preclude completion of standard protocol. 
 

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TABLE 3. RECOMMENDED VIDEO LABEL LIST 
 
Sequence 
Label 
1 
q1: 1-ml – Thin liquid 
2 
q2: 5-ml – Thin liquid 
3 
q3: 5-ml – Thin liquid 
4 
q4: 10-ml – Thin liquid 
5 
q5: 10-ml – Thin liquid 
6 
q6: Cup sip – Thin liquid 
7 
q7: Cup sip – Thin liquid 
8 
q8: 5-ml – Pudding thick 
9 
q9: 5-ml – Pudding thick 
10 
q10: Bite size solid 
11 
q11: Bite size solid 
12 
q12: Cup sip – Thin liquid, A/P 
13 
q13: 5-ml – Pudding thick barium, A/P 
 

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APPENDIX V: NCI/DCTD Collaborative Agreement 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 

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4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 
 

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APPENDIX VI: NIVOLUMAB TOXICITY MANAGEMENT ALGORITHMS 
 
 
 
 
 
 

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APPENDIX IV (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX IV (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX IV (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX IV (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX IV (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX IV (continued)