Randomized Phase II/III Trial of Radiotherapy With Concurrent MEDI4736 (Durvalumab) vs. Radiotherapy With Concurrent Cetuximab in Patients With Locoregionally Advanced Head and Neck Cancer With a Contraindication to Cisplatin
Phase: PHASE2
Conditions: Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Head and Neck Squamous Cell Carcinoma, Hypopharyngeal Squamous Cell Carcinoma, Laryngeal Squamous Cell Carcinoma, Oral Cavity Squamous Cell Carcinoma, Oropharyngeal Squamous Cell Carcinoma, Pathologic Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Squamous Cell Carcinoma of Unknown Primary, Stage III Hypopharyngeal Carcinoma AJCC v8, Stage III Laryngeal Cancer AJCC v8, Stage III Lip and Oral Cavity Cancer AJCC v8, Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVA Hypopharyngeal Carcinoma AJCC v8, Stage IVA Laryngeal Cancer AJCC v8, Stage IVA Lip and Oral Cavity Cancer AJCC v8, Stage IVA Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IVB Hypopharyngeal Carcinoma AJCC v8, Stage IVB Laryngeal Cancer AJCC v8, Stage IVB Lip and Oral Cavity Cancer AJCC v8, Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8
Sponsor: National Cancer Institute (NCI)

i 
 
For Protocol Amendment 7 to: NRG-HN004, Randomized Phase II/III Trial of Radiotherapy 
with Concurrent MEDI4736 (Durvalumab) vs. Radiotherapy with Concurrent Cetuximab in 
Patients with  Locoregionally Advanced Head and Neck Cancer with a Contraindication to 
Cisplatin 
 
NCI/Local Protocol #: NRG-HN004 
 
NCI Protocol Version Date: March 09, 2022 
 
Section 
Change 
 
Global 
• The protocol version date was updated in the document footer.  
• Formatting and typographical errors were corrected as needed. 
Cover pages 
• Contact information for the Head & Neck Cancer Committee Chair 
was updated.  
• This amendment was added to the Document History table.  
 
CTSU Contact 
Information 
8.2.1, 8.2.2, 8.2.3 
8.3.1 
8.4.1 
13.1 
13.2 
13.3 
 
These sections were updated per current CTSU logistics. 
9.1.3 
The durvalumab agent-specific information was updated for consistency 
with the FDA approved package insert. 
12.1 
Details for RT Quality Assurance Reviews using a sampling scheme 
were added.  
14.3.3 
14.4.2 
14.5.2 
The target number of randomized patients in the phase II portion was 
revised, and key sensitivity analysis to the primary endpoint was added 
following an interim futility analysis and toxicity monitoring results.  
 
 
 
 
 

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NRG ONCOLOGY 
 
NRG-HN004 
(ClinicalTrials.gov NCT # 03258554) (22-MAR-2018) 
 
Randomized Phase II/III Trial of Radiotherapy with Concurrent MEDI4736 (Durvalumab) 
vs. Radiotherapy with Concurrent Cetuximab in Patients with Locoregionally Advanced 
Head and Neck Cancer with a Contraindication to Cisplatin (15-JAN-2019) 
 
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; SWOG; and the Canadian Cancer Trials Group 
(CCTG). 
 
Coordinating Center:  
NRG Oncology, Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team (13-JAN-2021) 
 
Principal Investigator / Radiation Oncology 
Loren K. Mell, MD  
University of California San Diego 
3855 Health Sciences Drive, MC0843 
La Jolla, CA 92093 
858-246-0471 / FAX 858-822-5568 
lmell@ucsd.edu  
 
Senior Adult Oncology Co-Chair 
Julie A. Kish, MD 
Moffitt Cancer Center 
12902 Magnolia Drive, Tampa, FL 33612 
813-745-3822 / FAX 813-745-1908 
julie.kish@moffitt.org  
Medical Oncology Co-Chair 
Stuart Wong, MD 
Medical College of Wisconsin 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226 
414-805-4603 / FAX 414-805-4606 
swong@mcw.edu  
 
Translational Science Co-Chair 
Andy Minn, MD, PhD 
University of Pennsylvania 
421 Curie Blvd, Room 510 
Philadelphia, PA 19104 
215-746-5515 / FAX 215-746-5511 
andyminn@upenn.edu 
 
Surgical Oncology Co-Chair 
Steven S. Chang MD FACS 
Henry Ford Cancer Institute 
Henry Ford Health System 
2799 West Grand Blvd K-8 
Detroit MI 48202 
313-916-5741 / FAX 313-916-7263 
schang1@hfhs.org 
 
Pathology Co-Chair 
Richard Jordan, DDS, PhD 
NRG Oncology Biospecimen Bank 
2340 Sutter Street, Rm S341 
San Francisco, CA 94115 
415-476-7864 / FAX 415-476-5271 
richard.jordan@ucsf.edu 
 
 
 

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Study Team Continued 
 
Physics Co-Chair 
Tian Liu, PhD, DABR 
Emory University 
Department of Radiation Oncology 
1365 Clifton Road, Clinic A 
Atlanta, GA 30322 
404-778-1848 / FAX 404-778-4139 
tliu34@emory.edu  
 
Senior Statistician 
Pedro Torres-Saavedra, PhD 
NRG Oncology 
50 South 16th St, Suite 2800 
Philadelphia, PA 19102 
215-717-0851 / FAX 215-928-0153 
torresp@nrgoncology.org    
Quality of Life Co-Chair 
Minh Tam Truong, MD 
Department of Radiation Oncology 
Boston Medical Center 
Boston University School of Medicine 
Moakley Building, LL237 
830 Harrison Ave 
Boston, MA 02118 
617-638-7070 / FAX 617-638-7037 
minh-tam.truong@bmc.org 
Canadian Cancer Trials Group (CCTG) Medical 
Oncology Co-Chair 
Eric W. Winquist, MD 
London Regional Cancer Program 
790 Commissioners Road East 
London, ON N6A 4L6  
Canada 
519-685-8640 / FAX 519-685-8624 
eric.winquist@lhsc.on.ca  
 
NRG Oncology Contact Information (09-MAR-2022) 
 
Data Management 
For questions concerning eligibility or data 
submission 
Vanita Patel, MS  
Lisa Abate 
NRG Oncology 
50 South 16th St, Suite 2800 
Philadelphia, PA 19102  
215-574-3170 (Patel) 
215-574-3178 (Abate) 
FAX 215-940-8830 
patelv@nrgoncology.org  
abatel@nrgoncology.org  
 
RTQA:  
For questions concerning RT data submission 
 
Dosimetrist  
Marsha Radden, BS, R.T.(R)(T) 
NRG Oncology 
50 South 16th St, Suite 2800 
Philadelphia, PA 19102 
215-717-2757  
mradden@acr.org 
 
 
 
 
 

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NRG Oncology Contact Information Continued 
 
RTQA:  
For questions concerning RT Credentialing 
 
http://irochouston.mdanderson.org 
OR 
IROC-Credentialing@mdanderson.org  
 
RTQA:  
For questions concerning data submission to 
TRIAD 
 
Triad-Support@acr.org 
Protocol Development: 
For questions concerning protocol and informed 
consent versions & amendments 
Protocol Administrator 
Thien Nu Do 
NRG Oncology 
50 South 16th St, Suite 2800 
Philadelphia, PA 19102 
215-574-3174 
dot@nrgoncology.org  
Head and Neck Cancer Committee Chair:  
Sue S. Yom, MD, PhD 
University of California, San Francisco 
San Francisco, CA 
415-353-7175 
sue.yom@ucsf.edu 
 
 
Protocol Agent 
 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Durvalumab (MEDI4736) 
CTEP/PMB 
778709 
 
DCTD 
Cetuximab 
Commercial 
714692 
 
Participating Sites (15-JAN-2019) 
 U.S. 
 Canada through CCTG 
 Approved International Member Sites  
 
 
 
 
Document History 
 
 
Version Date 
Amendment 7 
March 09, 2022 
Amendment 6 
January 13, 2021 

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Amendment 5 
October 4, 2019 
Amendment 4 
August 21, 2019 
Amendment 3 
January 15, 2019 
Amendment 2 
July 5, 2018 
Amendment 1 
March 22, 2018 
Initial 
December 5, 2017  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NRG ONCOLOGY  
 
NRG-HN004 
 
Randomized Phase II/III Trial of Radiotherapy with Concurrent MEDI4736 (Durvalumab) 
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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vs. Radiotherapy with Concurrent Cetuximab in Patients with Locoregionally Advanced 
Head and Neck Cancer with a Contraindication to Cisplatin 
 
CONTACT INFORMATION (09-MAR-2022) 
 
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 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) 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_SYSTEM/ 
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 page located on the CTSU member’s website (https://www.ctsu.org). Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires user log in with a 
CTEP-IAM username and password. 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 CTSU 
Regulatory Support System (RSS).   
 
For clinical questions (i.e. patient eligibility or treatment-related) Contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
 
 
 
NRG-HN004 ..................................................................................................................................10 
PHASE II/III SCHEMA ................................................................................................................10 

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1. OBJECTIVES ............................................................................................................................12 
1.1 
Primary Objective ..................................................................................................12 
1.2 
Secondary Objectives .............................................................................................12 
1.3 
Exploratory Objectives ..........................................................................................12 
2. BACKGROUND .......................................................................................................................13 
2.1 
Background of Head and Neck Cancer  .................................................................13 
2.2 
Epidemiology, Treatment, and Outcomes for Medically Unfit HNC 
Patients ...................................................................................................................13 
2.3 
Comparative Effectiveness of Radiosensitizers in Elderly/Medically Unfit 
HNC Patients .........................................................................................................14 
2.4 
Aging and the Immune System ..............................................................................15 
2.5 
Preclinical Data Supporting RT+ Anti-PD-L1 Therapy in HNC...........................16 
2.6 
Clinical Data Supporting RT and Anti-PD-1 Therapy in HNC .............................17 
2.7 
Clinical Data for Anti-PD-L1 Therapy [MEDI4736 (Durvalumab)] ....................17 
2.8  
Pharmacokinetic/Pharmacodynamic Data on MEDI4736 (durvalumab) 
and Anti-MEDI4736 Antibodies............................................................................18 
2.9 
Evidence-Based Standard of Care for HNC Patients Medically Unfit for 
Cisplatin .................................................................................................................19 
2.10 
Correlative Science ................................................................................................19 
3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA ........................25 
3.1 
Patient Selection Guidelines ..................................................................................25 
3.2 
Eligibility Criteria  .................................................................................................25 
3.3 
Ineligibility Criteria ...............................................................................................29 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP     ..............31 
5.  TREATMENT PLAN/REGIMEN DESCRIPTION.................................................................40 
5.1 
Systemic Therapy ...................................................................................................40 
5.2 
Radiation Therapy ..................................................................................................43 
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 Guidelines for Immune-
Mediated, Infusion-Related, and Non-Immune Mediated Reactions for 
MEDI4736 (Durvalumab) ......................................................................................54 
6.2 
Dose Modification for Cetuximab .........................................................................84 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................91 
7.1  
Protocol Agents ......................................................................................................91 
7.2 
Adverse Events and Serious Adverse Events ........................................................92 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for ...............94 
 
MEDI4736 (Durvalumab, NSC 778709) ...............................................................94 
7.4 
Adverse Events for Commercial Study Agents: Cetuximab..................................98 
7.5 
Expedited Reporting of Adverse Events  ...............................................................98 
7.6 
Routine Reporting Requirements for Adverse Events  ........................................101 

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7.7 
Pregnancy  ............................................................................................................101 
8. REGISTRATION AND STUDY ENTRY PROCEDURES ...................................................101 
8.1 
CTEP Registration Procedures and Access requirements for OPEN, 
Medidata Rave, and TRIA ...................................................................................101 
8.2 
CTSU Registration Procedures ............................................................................103 
8.3 
RT-Specific Pre-Registration Requirements ........................................................106 
8.4  
Patient Enrollment ...............................................................................................107 
8.5 
Medidata Patient Cloud ePRO Registration ........................................................109 
9. 
DRUG INFORMATION .................................................................................................110 
9.1 
Investigational Study Agent: MEDI4736 (Durvalumab) (NSC 778709, 
IND)  ....................................................................................................................110 
9.2 
Commercial Agent: Cetuximab NSC# 714692....................................................112 
10.  
PATHOLOGY/BIOSPECIMEN .....................................................................................113 
10.1 
Biospecimen Submissions ...................................................................................113 
10.2   Pre-hoc Central Review of Oropharyngeal and Unknown Primaries ..................114 
10.3 
Tissue Blocks for Central Review of PD-L1 and p16 status ( .............................116 
10.4 
Optional Specimen Submissions..........................................................................117 
11. SPECIAL STUDIES (NON-TISSUE) ...................................................................................120 
11.1 Quality of Life Instruments Description ..................................................................120 
12. MODALITY REVIEWS (09-MAR-2022) ............................................................................124 
12.1 
Radiation Therapy Quality Assurance Reviews  .................................................124 
12.2 
Medical Oncology Modality Quality Assurance Reviews ...................................124 
13.       DATA AND RECORDS .................................................................................................125 
13.1 
Data Management/Collection ..............................................................................125 
13.2     Data Quality Portal  .............................................................................................126 
13.3     Rave-CTEP-AERS integration  ...........................................................................126 
13.4 
Summary of Data Submission  ............................................................................127 
13.5 
Global Reporting/Monitoring ..............................................................................128 
14.       STATISTICAL CONSIDERATIONS.............................................................................128 
14.1 
Study Design ........................................................................................................128 
14.2 
Study Endpoints ...................................................................................................129 
14.3 
Primary Objectives Study Design ........................................................................130 
14.4     Study Monitoring of Primary Objectives .............................................................133 
14.5  Accrual/Study Duration Considerations ..............................................................135 
14.6  Secondary Endpoints ...........................................................................................136 
14.7     Exploratory Analyses  ..........................................................................................140 
14.8   Gender/Ethnicity/Race Distribution .....................................................................142 
REFERENCES  ...........................................................................................................................144 
APPENDIX I: CTEP Collaborative Agreements Language ........................................................154 

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APPENDIX II: PREPARATION, PROCESSING ......................................................................156 
AND SHIPPING OF PERIPHERAL BLOOD ............................................................................156 
APPENDIX III  ............................................................................................................................158 
 
 
 

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NRG-HN004 
 
Randomized Phase II/III Trial of Radiotherapy with Concurrent MEDI4736 (Durvalumab) 
vs. Radiotherapy with Concurrent Cetuximab in Patients with Locoregionally Advanced 
Head and Neck Cancer with a Contraindication to Cisplatin 
 
PHASE II/III SCHEMA (15-JAN-2019) 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
ARM 2 
 
RT  
+ MEDI4736 (durvalumab) **  
 
STEP 1: REGISTRATION 
 
For patients with oropharyngeal or unknown primaries:  
p16 determination by immunohistochemistry confirmed by  
central pathology review prior to Step 2 Registration.  
 
Note: For patients with oral cavity, laryngeal, and hypopharyngeal primaries,  
analysis of p16 status prior to Step 2 Registration is not required. 
 
 
STEP 2: REGISTRATION  
 
STRATIFICATION  
 
• AJCC 8th Edition stage (T0-3 and N0-2 vs. T4 and/or N3) 
• Performance status/comorbidity (PS=0 and modified CCI* =0 vs. PS=1–2 and/or modified CCI > 0) 
• Primary site (p16+ OPX/CUP vs. Other [Larynx, HPX, Oral Cavity, or p16- OPX/CUP]) 
 
*Modified CCI (Charlson Comorbidity Index) will be calculated excluding age, albumin, and cancer diagnosis (see Section 3). 
ARM 1 
 
RT + Cetuximab ** 
 
**See Section 5.0 for radiation therapy and systemic therapy details.  
RANDOMIZATION 1:2 

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NRG-HN004 
 
Randomized Phase II/III Trial of Radiotherapy with Concurrent MEDI4736 (Durvalumab) 
vs. Radiotherapy with Concurrent Cetuximab in Patients with Locoregionally Advanced 
Head and Neck Cancer with a Contraindication to Cisplatin 
 
LEAD-IN SCHEMA (15-JAN-2019) 
 
Note: Please note that the lead-in phase has been completed and all relevant schema and 
dosing have been grayed out throughout the protocol.  
 
 
 
STEP 1: REGISTRATION  
 
For patients with oropharyngeal or unknown primaries:  
p16 determination by immunohistochemistry confirmed by  
central pathology review prior to Step 2 Registration.  
 
Note: For patients with oral cavity, laryngeal, and hypopharyngeal primaries,  
analysis of p16 status prior to Step 2 Registration is not required. 
 
STEP 2: REGISTRATION  
 
INVESTIGATIONAL THERAPY 
Two Weeks Prior to Radiation Therapy (RT):  MEDI4736 (durvalumab) 1500 mg 
 
Concurrent with RT (70 Gy over 7 weeks):  MEDI4736 (durvalumab) 1500 mg on 
Weeks 2 and 6 
 
Following RT:  MEDI4736 (durvalumab) 1500 mg every 4 Weeks x 4 cycles 

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1. OBJECTIVES 
1.1 
Primary Objective 
1.1.1 Lead-In: To determine the safety of radiotherapy (RT) with concurrent and adjuvant 
anti-PD-L1 therapy [MEDI4736 (durvalumab)] is safe in patients with locoregionally 
advanced head and neck cancer (HNC) who have a contraindication to cisplatin. 
1.1.2 Phase II: To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves 
PFS compared to standard therapy (RT with concurrent cetuximab) in patients with 
locoregionally advanced HNC who have a contraindication to cisplatin. 
1.1.3 Phase III: To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves 
overall survival compared to standard therapy (RT with concurrent cetuximab) in patients 
with locoregionally advanced HNC who have a contraindication to cisplatin. 
 
1.2 
Secondary Objectives 
1.2.1 To compare toxicity using CTCAE and PRO-CTCAE between patients treated with RT + 
anti-PD-L1 therapy versus RT/cetuximab. 
1.2.2 To test the effect of anti-PD-L1 therapy in the subpopulation of patients with tumors that 
overexpress PD-L1. 
1.2.3 To compare overall survival, response (at 4-month FDG-PET-CT), locoregional failure, 
distant metastasis, and competing mortality in the two arms by known risk factors, 
including p16 status and ω score. 
1.2.4 To test the hypothesis that MEDI4736 (durvalumab) therapy arm will have less decline in 
the physical function domain of European Organization for Research and Treatment of 
Cancer Core Questionnaire (EORTC QLQ-C30 Version 3.0) based on the change in 
score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in 
patients with locoregionally advanced HNC who have a contraindication to cisplatin.   
1.2.5 To test the hypothesis that MEDI4736 (durvalumab) therapy arm at 1 year (from end of 
RT) will have less decline in swallowing related QOL using the MDADI total composite 
score, based on the change in score from baseline to 12 months from end of RT, 
compared to the cetuximab-RT arm in patients who are medically unfit for cisplatin. 
1.2.6 To compare swallowing related performance and function short and long term using the 
PSS-HN. 
1.2.7 To evaluate gastrostomy tube retention rates between arms. 
 
 
1.3 
Exploratory Objectives 
1.3.1 To test the hypothesis that radiation combined with MEDI4736 (durvalumab) enhances 
the adaptive immune response using three types of immunophenotyping compared to 
radiation combined with cetuximab. 
1.3.2 To compare overall QOL short term (end RT-8 months) and long term (12-24 months 
from end of RT) between arms using the EORTC QLQ-C30 Version 3.0/HN35. 
1.3.3 To evaluate swallowing related QOL short term (end RT-8 months) and long term (12-24 
months from end of RT) using the EORTC HN35 swallowing domain and MDADI 
(subscales) between arms in patients with locoregionally advanced HNC who have a 
contraindication to cisplatin. 
1.3.4 To evaluate patient reported fatigue using the fatigue items in the EORTC QLQ and 
PRO-CTCAE. 
1.3.5 To compare clinician and patient reported toxicity using CTCAE and PRO CTCAE. 

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1.3.6 To explore health utilities between cetuximab and MEDI4736 (durvalumab) RT using the 
EQ5D-5L. 
 
 
 
2. BACKGROUND 
2.1 
Background of Head and Neck Cancer (15-JAN-2019) 
Head and neck cancer (HNC) is among the most common malignancies in the United 
States, with globally more than 500,000 new cases and 350,500 deaths annually (WHO 
2015). The majority of patients present with locoregionally advanced HNC, which is 
generally treated with multi-modality therapy consisting of radiation therapy (RT) and 
chemotherapy, with or without surgery. Despite advances in the therapy of HNC and the 
understanding of its causes (including human papillomavirus [HPV]), outcomes remain 
poor, with 5-year progression-free survival (PFS) generally less than 50%, excepting 
HPV-associated oropharyngeal cancer (Adelstein 2000, Ang 2010, Bernier 2004, Brizel 
1998, Cooper 2004).  
 
2.2 
Epidemiology, Treatment, and Outcomes for Medically Unfit HNC Patients 
Concurrent RT+cisplatin is considered the standard of care for many locoregionally 
advanced head/neck cancers (LRA-HNC). However, many LRA-HNC patients cannot 
receive cisplatin due to contraindications such as advanced age or comorbidity. More 
than 30% of the LRA-HNC population in the United States is older than age 65, 
approximately 32% of the population has at least moderate comorbidity, and 8% has 
severe comorbidity (Dansky-Ullmann 2012, Rose 2011). Dansky-Ullmann et al. (2012) 
reported that 38.7% of oral cavity, oropharynx, larynx, and hypopharynx cancer patients 
potentially eligible for chemotherapy and radiation receive either no chemotherapy or 
receive alternatives to cisplatin. An analysis of the LORHAN prospective HNC registry 
also showed that cisplatin was the concurrent agent in only 51% of patients. Thus, there 
is evidence that much of the HNC population cannot receive cisplatin, even if otherwise 
indicated. 
  
Cisplatin is generally considered to be contraindicated due to toxicity and/or lack of 
efficacy in patients with poor organ function, performance status, pre-existing 
comorbidities, or advanced age (Ahn 2016). There is considerable evidence that patients 
older than 70 do not benefit from cisplatin (Pignon 2009, Kish 2015). However, 
alternative radiosensitizers have proven to be well-tolerated in such patients, albeit with 
uncertain efficacy. Outcomes with RT alone are poor. Newer therapies with promising 
efficacy and toxicity profiles are likely to be well-tolerated and could improve survival in 
this population. Patients with severe dysfunction are excluded because of their low 
likelihood of tolerating systemic therapy and high risk of competing mortality and 
treatment-related morbidity and mortality. Never-smokers with p16+ oropharynx 
primaries/localizing carcinoma of unknown primary (CUP) have a low probability of 
recurrence and may not benefit from radiosensitizers. The rationale for comorbidity 
measures come from several validated predictive models (Carmona 2016, Hurria 2005, 
Kallogjeri 2014, Pottel 2015). 
 
Treatment options in medically unfit patients vary extensively from RT alone, to 
RT+carboplatin or RT+cetuximab. However, RT/cetuximab is the most widely accepted 

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approach for treatment intensification in patients who are unfit for cisplatin (Ang 2012, 
Baxi 2014, Wong 2011). Cetuximab is a monoclonal antibody against the epidermal 
growth factor receptor (EGFR). Support for RT+cetuximab is based on a randomized trial 
indicating a survival advantage to RT+cetuximab over RT alone (Bonner 2006, 2010). In 
the LORHAN study, among patients who were not prescribed concurrent cisplatin, 
cetuximab was the next most commonly used regimen (21%), followed by carboplatin + 
paclitaxel (7%) (Wong 2011).  
 
Outcomes for patients unable to receive cisplatin due to age or comorbidity are 
particularly poor (Siddiqui 2012). These patients frequently have organ dysfunction that 
alters their tolerance to aggressive chemotherapy, and they are at high risk for both 
cancer recurrence and competing mortality. Elderly and less healthy patients have been 
clearly under-represented in clinical trials; as such, clinical trial data frequently do not 
adequately convey the effectiveness of new therapies in these patients (Carmona 2016, 
Mell 2010, 2014, Rose 2011, Sarris 2014). Given the aging of the U.S. population and the 
increasing prevalence of HNC patients with comorbidities, it is widely recognized in the 
oncology community that there is an increased need for clinical trials representing and 
addressing the specific needs of this population (Wildiers 2013). 
 
2.3 
Comparative Effectiveness of Radiosensitizers in Elderly/Medically Unfit HNC 
Patients 
Cetuximab is the only non-platinum radiosensitizing regimen with level I evidence 
supporting its use in HNC (Pfister 2015). The phase III randomized trial by Bonner et al. 
found that RT/cetuximab improved overall survival (hazard ratio [HR] 0.73, 95% CI 
0.56-0.95; p=0.018) compared to RT alone in patients with locoregionally advanced 
HNC. Five-year overall survival was 45.6% in the RT + cetuximab group and 36.4% in 
the RT-alone group. Toxicity was tolerable in the RT + cetuximab arm. 
 
Nonetheless, the effectiveness of cetuximab in the elderly/medically unfit population is 
controversial. The median age of patients receiving RT+cetuximab on the Bonner trial 
was 56 years. Of these patients, 110 (26%) were older than 65, and 135 (32%) patients 
had KPS < 90. On post-hoc analysis of both of these subpopulations, the effect of 
cetuximab was not statistically significant, in contrast to younger and healthier patients 
(Bonner 2010), but these findings are hypothesis-generating. Also, many patients with 
medical comorbidities were ineligible. In addition, RTOG 0522 did not find a benefit to 
the combination of RT with concurrent cisplatin and cetuximab compared to RT and 
cisplatin (Ang 2014). An Italian trial (Magrini 2016) also closed early with only 70 
patients due to a higher number of treatment interruptions in the RT/cetuximab arm 
compared to RT with weekly cisplatin. However, subsequent studies—including a phase 
II trial—specifically support the safety and efficacy of RT/cetuximab in the elderly 
and/or medically unfit population (Alongi 2012, Jensen 2010). Unpublished data from 
RTOG 0920 and RTOG 1016 also have shown tolerability of RT/cetuximab in the elderly 
population. Therefore, RT+cetuximab is safe in this population, but its efficacy is 
unclear. 
 
Given the paucity of clinical trials tailored toward the elderly/medically unfit population, 
it is prudent to further investigate the use of concurrent cetuximab in this population. 

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Retrospective studies suggest that RT+cetuximab may be as effective as bolus cisplatin 
(Strom 2015) and that bolus cisplatin may be more effective than weekly cisplatin (Rades 
2016). Among elderly patients in the LORHAN database, only 43% received RT with 
concurrent systemic therapy, with cetuximab the most common regimen (21%), followed 
by cisplatin (18%) and other (4%). Therefore, some elderly patients do receive cisplatin. 
However, there is considerable evidence from meta-analyses and population studies that 
even elderly patients healthy enough to receive cisplatin do not benefit from it (Pignon 
2009, VanderWalde 2014, Kish 2015). A possible explanation is that small gains in 
efficacy with concurrent radiosensitizers are outweighed by adverse effects in patients 
who are more susceptible to treatment-related morbidity and mortality. This provides a 
strong rationale to investigate alternative regimens with the potential for heightened 
efficacy and reduced toxicity, such as immune checkpoint blockade. 
 
Presently, there is no known subgroup of elderly patients who benefit from cytotoxic 
chemotherapy. Multivariable models incorporating complementary comorbidity indices 
such as the Charlson Comorbidity Index (CCI) and ACE-27 are known to be an effective 
approach for risk-stratifying this population according to survival (Kallogjeri 2014, Rose 
2011). Additionally, nomograms exist to help predict patient’s likelihood for high-grade 
toxicity from chemotherapy (Firat 2002, Hurria 2005, Pottel 2015, Miller 1992). 
Furthermore, recent evidence suggests that generalized competing event (GCE)-based 
risk-stratification methods could be used to identify groups most likely to benefit from 
treatment intensification in variety of malignancies, including head/neck cancer 
(Carmona 2016). These validated instruments can be useful in identifying subgroups of 
patients who are more/less likely to benefit from treatment intensification, but have been 
rarely implemented in clinical trial designs. 
 
2.4 
Aging and the Immune System 
Combining standard RT with immune modulation is an attractive strategy in elderly 
patients, given their poorer anti-tumor T cell function and the favorable toxicity profile of 
emerging immunotherapy strategies, particularly PD1 and PD-L1 inhibitors. The 
importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades, and abundant evidence is available 
indicating that aging-associated dysfunction of host immunity plays an important role in 
the development of cancer. Multiple mechanisms related to aging are thought to 
contribute to the heightened risk for cancer. Functional variations of cellular T cell 
response have been shown to be age-related and predisposing to development of cancer 
(Haynes 2005). Other mechanisms, demonstrated in mouse models and humans, include 
decreases in dendritic cell number and function associated with aging (Sprecher 1990; 
Zavala 2006). In addition, there is considerable evidence to indicate that aging affects the 
immune system and anti-tumor response through distortions in T-cell maturation, 
function, proliferation, and receptor repertoire (Gottesman 1984, Haynes 2009, 
Lustgarten 2004, Mosley 1998, Thoman 1993).  
 
Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes 
(TILs) in cancer tissue and favorable prognosis in various malignancies. In particular, the 
presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-
cells correlates with improved prognosis and long-term survival in many solid tumors.  

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2.5 
Preclinical Data Supporting RT+ Anti-PD-L1 Therapy in HNC  
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-
L2). PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail 
which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 
contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition 
motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-
cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM 
motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules 
such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  
 
The mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins. PD-1 is expressed on activated lymphocytes including peripheral CD4+ and 
CD8+ T-cells, B-cells, T regs and natural killer cells (MacFarlane 2014). Expression also 
has been shown during thymic development on CD4-CD8- (double negative) T-cells as 
well as subsets of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-
L2) are constitutively expressed or can be induced in a variety of cell types, including 
non-hematopoietic tissues as well as in various tumors. Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular 
region and contain short cytoplasmic regions with no known signaling motifs. Binding of 
either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. 
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 
is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves 
to dampen unwarranted T-cell function in peripheral tissues. Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor. This suggests that the PD-1/PD-L1 pathway plays a critical 
role in tumor immune evasion and should be considered as an attractive target for 
therapeutic intervention.  
 
It has been observed in pre-clinical studies that HNC can arise in immune-privileged sites 
(Lyford-Pike 2013) and that PD-L1 expression is characteristically associated with virus-
associated malignancies (Chen 2013). Multiple studies further indicate that 
immunotherapy, particularly PD-1:PD-L1 checkpoint blockade, acts synergistically with 
radiotherapy (Liang 2013, Sharabi, Lim 2015, Sharabi, Nirschl 2015, Tyman-Saint 2015, 
Zandberg 2014).  
 
 

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2.6 
Clinical Data Supporting RT and Anti-PD-1 Therapy in HNC  
There is considerable clinical evidence for the safety and effectiveness of PD-1:PD-L1 
checkpoint inhibitors in patients with solid tumors, including elderly patients. Recently, a 
meta-analysis found that immune checkpoint inhibitors benefited both older and younger 
patients in improving overall survival across a spectrum of cancers (Nishijima 2016). The 
Checkmate-141 trial found a survival advantage with nivolumab compared to standard 
therapy in patients with recurrent/metastatic head/neck cancer (Ferris 2106). In this study, 
68 patients over age 65 were treated with nivolumab and with no increased toxicity. The 
Keynote trial (Seiwert 2014) reported an 18% response rate with pembrolizumab in 
patients with recurrent head/neck cancer.  
 
2.7 
Clinical Data for Anti-PD-L1 Therapy [MEDI4736 (Durvalumab)]  
MEDI4736 (durvalumab) is a human mAb of the immunoglobulin G1 kappa subclass that 
inhibits binding of PD-L1 with PD-1 on antigen-presenting cells and T-cells resulting in 
stimulation of the patient’s anti-tumor immune response. A fixed-dosing approach is 
preferred by the prescribing community and has been selected for the present trial due to 
ease of use and reduction of potential dosing errors. Given expectation of similar PK 
exposure and variability, it is considered feasible to utilize a fixed-dosing regimen. Based 
on an average body weight of 75 kg, a fixed dose of 750 mg q2 weeks of MEDI4736 
(durvalumab) is equivalent to 10 mg/kg q2 weeks and 1500 mg q4 weeks of MEDI4736 
(durvalumab) is equivalent to 20 mg/kg q4 weeks. MEDI4736 (durvalumab) is being 
studied in humans, as a single drug or in combination with other drugs, as part of ongoing 
clinical trials including patients with recurrent or metastatic HNC (D4190C00011, 
D4193C00001/HAWK, D4193C0003/CONDOR, D4193C0002/EAGLE).  
 
The majority of the safety data currently available for MEDI4736 (durvalumab) are based 
on the first-time-in-human, single-agent study (Study CD-ON-MEDI4736-1108) in 
patients with advanced solid tumors. In patients receiving MEDI4736 (durvalumab) at 10 
mg/kg every 2 weeks, 71.8%) had at least 1 treatment-emergent adverse event (TEAE). 
The most frequently reported (10% of patients) TEAEs (all National Cancer Institute 
[NCI] Common Terminology Criteria for Adverse Event [CTCAE] grades) were fatigue, 
dyspnea, nausea, constipation, and decreased appetite. The important potential risks, 
based on the mechanism of action of MEDI4736 (durvalumab), as well as data from 
studies of relevant or similar therapies, include immune-mediated reactions, such as 
enterocolitis, dermatitis, hepatitis/hepatotoxicity, endocrinopathy, pneumonitis, 
neuropathy, and other events such as serious infections, infusion-related reactions, 
anaphylaxis or serious allergic reactions, and immune complex disease. The development 
of a serious infection is a theoretical risk based on findings from non-clinical safety 
studies. Thus far, no patients have experienced immune complex disease following 
exposure to MEDI4736 (durvalumab). Antidrug antibodies (ADAs) have been identified 
in 3 of the 31 patients tested.  
 
Preliminary data from ongoing MEDI4736 HNC studies have indicated that MEDI4736 
(durvalumab) is safe. Segal et al. (2015) presented on 62 patients in 2015, with mean age 
58 (range: 24-96) treated with MEDI4736 (durvalumab). 86% were male, 64% were prior 
smokers, 60% were HPV negative or unknown HPV status. Grade ≥ 3 related AEs were 
reported in 7% of pts: rash (2 pts), and increased GGT, fatigue, and tumor inflammation 

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(1 patient each). No drug-related AEs led to discontinuation or death. No colitis or grade 
≥ 3 pneumonitis was observed. ORR was 12% (25% in PD-L1+ pts), and DCR at 24 
weeks was 16% (25% in PD-L1+ pts). Median duration of response was not reached. The 
safety profile in SCCHN was manageable and responses were durable, with higher 
responses in PD-L1+ pts. The ongoing KESTREL trial is testing MEDI4736 
(durvalumab) in the recurrent/metastatic population and no untoward toxicity has been 
observed to date (Seiwert 2016).  
 
The current trial will have a lead-in component to verify the safety of RT with 
MEDI4736 (durvalumab) in this population. Based on the favorable toxicity profile of 
PD-1:PD-L1 checkpoint inhibitors in a wide variety of populations, the safety profile of 
RT/ MEDI4736 (durvalumab) is hypothesized to be as good or better than RT/cetuximab, 
which is already known to be safe in this population.  
 
2.8  
Pharmacokinetic/Pharmacodynamic Data on MEDI4736 (durvalumab) and Anti-
MEDI4736 Antibodies (05-JUL-2018) 
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses 
ranging from 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, MEDI4736 (durvalumab) exhibited 
non-linear (dose-dependent) PK consistent with target-mediated drug disposition. The PK 
approached linearity at ≥3 mg/kg Q2W, suggesting near complete target saturation 
(membrane-bound and sPD-L1), and further shows that the MEDI4736 (durvalumab) 
dosing frequency can be adapted to a particular regimen given the linearity seen at doses 
higher than 3 mg/kg. The expected half-life with doses ≥3 mg/kg Q2W is approximately 
21 days. A dose-dependent suppression in peripheral sPD-L1 was observed over the dose 
range studied, consistent with engagement of MEDI4736 (durvalumab) with PD-L1. A low 
level of immunogenicity has been observed. No patients have experienced immune-
complex disease following exposure to MEDI4736 (durvalumab) (For further information 
on immunogenicity, please see the current IB).  
 
Data from Study D4190C00006 [Phase I trial in NSCLC patients using the combination of 
MEDI4736 (durvalumab) and tremelimumab] also show an approximately dose-
proportional increase in PK exposure for MEDI4736 (durvalumab) over the dose range of 
3 to 20 mg/kg MEDI4736 (durvalumab) Q4W or Q2W. (For further information on PK 
observations in Study 006, please see the current IB).  
 
The observed MEDI4736 (durvalumab) PK data from the combination study were well in 
line with the predicted monotherapy PK data (5th median and 95th percentiles) for a Q4W 
regimen.  
 
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 
mg/kg Q2W or 15 mg/kg Q3W (Error! Reference source not found.). Multiple 
simulations indicate that a similar overall exposure is expected following both 10 mg/kg 
Q2W and 20 mg/kg Q4W regimens, as represented by AUCss (4 weeks). Median Cmax,ss is 
expected to be higher with 20 mg/kg Q4W (~1.5-fold) and median Ctrough,ss is expected to 
be higher with 10 mg/kg Q2W (~1.25-fold). Clinical activity with the 20 mg/kg Q4W 
dosing regimen is anticipated to be consistent with 10 mg/kg Q2W with the proposed 
similar dose of 20 mg/kg Q4W expected to (a) achieve complete target saturation in 

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majority of patients; (b) account for anticipated variability in PK, pharmacodynamics, and 
clinical activity in diverse cancer populations; (c) maintain sufficient PK exposure in case 
of anti-drug antibody (ADA) impact; and (d) achieve PK exposure that yielded maximal 
antitumor activity in animal models. 
 
Given the similar area under the plasma drug concentration-time curve (AUC) and 
modest differences in median peak and trough levels at steady state, the observation that 
both regimens maintain complete sPD-L1 suppression at trough, and the available clinical 
data, the 20 mg/kg Q4W and 10 mg/kg Q2W regimens are expected to have similar 
efficacy and safety profiles, supporting further development with a dose of 20 mg/kg 
Q4W. In summary, the dose and schedule of durvalumab in NRG-HN004 (1500 mg flat 
dosing, 3-week interval between dose 1 and 2, with an every-4-week interval after cycle 
2) is supported by the above PK data. 
 
2.9 
Evidence-Based Standard of Care for HNC Patients Medically Unfit for Cisplatin 
Outcomes for HNC patients who are medically unfit for cisplatin remain poor, and these 
patients have been historically under-represented in randomized trials. Furthermore, the 
aging of the U.S. population and rising prevalence (Zumsteg 2016) makes this an 
increasingly relevant problem. Evidence from clinical trials to support current community 
practice patterns is lacking. This would be the first trial to investigate PD-L1 inhibition in 
conjunction with radiotherapy in this population in an effort to define a standard of care, 
so the proposal is novel in this regard. This trial would also be the first in the U.S. to test 
the comparative effectiveness of immunotherapy versus EGFR therapy in this population.  
 
A fundamental question this study will address is whether treatment intensification is a 
potential strategy to improve outcomes in head/neck cancer patients with a 
contraindication to cisplatin, or whether, regardless of efficacy, treatment intensification 
is unlikely to be successful. It is possible that existing treatment intensification strategies 
are effective but too toxic to be beneficial to this population in the net, but less toxic 
strategies such as immunotherapy could be. On the other hand, it is possible that any 
treatment, regardless of its effectiveness and toxicity profile, would be unable to augment 
survival due to the mortality risk posed by competing comorbidities. These answers are 
not knowable outside of conducting a clinical trial that specifically addresses this 
population. 
 
 
2.10 
Correlative Science (21-AUG-2019) 
Biology 
This study aims to incorporate correlative translational science to identify subpopulations 
that may selectively benefit from RT + immunotherapy. The study will provide novel 
insights into the effects of immunotherapy on both tumor and the immune system in this 
unique population, and provide an initial evaluation of the comparative impact of 
immunotherapy versus EGF-R inhibition on toxicity. PFS is known to be a good 
surrogate endpoint for overall survival in HNC (Michiels 2009), and the high rate of 
events in this population leads to a fast readout of trial results. Heterogeneity in this 
population is an issue, as variation in medical comorbidities, p16 status, smoking history, 
and other known prognostic factors differentially affect treatment outcomes. The trial 
results may help identify subgroups that derive a selective benefit (e.g., patients with PD-

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L1 overexpressing tumors, p16-negative tumors), for which a phase III study could be 
specifically tailored. Collection of blood samples will allow us to examine the effects of 
tumor biomarkers such as T-cell infiltration and CD8 expression on the therapeutic effect 
in an elderly population.  
 
Multiple studies, including RTOG studies, have established that p16 is a prognostic 
biomarker in non-oropharyngeal HNSCC (Chung 2014, Alsidawi 2017, Wookey 2017). 
However, other studies have not found HPV status to be correlated with outcomes in 
HNSCC (Fakhry 2017). Therefore, the prognostic role of p16/HPV status in non-
oropharyngeal cancer is unclear. This study will be among the first NRG Oncology head 
and neck cancer trials to collect p16 status systematically on patients with both 
oropharyngeal and nonoropharyngeal tumors and will lend further insight into the 
prognostic role of p16 status in this population. 
 
Competing Risks 
Competing events such as cancer recurrence and mortality, treatment-related morbidity 
and mortality, and intercurrent non-cancer mortality are well-known to complicate the 
interpretation of treatment effects. Carmona et al. (2016) showed that GCE models 
significantly improve the ability to risk-stratify elderly patients at risk for competing 
events and better identify sub-populations who are likely to selectively benefit from 
treatment intensification. Essentially, the GCE approach identifies subsets of patients 
who are more likely to experience a cancer event (e.g. recurrence or mortality) than a 
competing event (e.g., non-cancer death). By definition, a patient with a ω  ratio < 0.5 has 
a greater hazard for non-cancer mortality than for cancer mortality. A review of RTOG 
trials 9003, 0522, and 0129 shows that GCE is effective in stratifying patients age 65 
years or older into competing event strata (Figure 1). In particular, studies have found 
that patients with a predicted ω ratio (i.e., ω score) ≥ 0.80 selectively benefit from 
intensive treatment (Mell 2019, Zakeri 2018). Various modeling approaches and 
nomograms have been used to develop ω scores. The model used in this trial is based on 
a nomogram developed from the updated MARCH meta-analysis (Lacas 2017). Data 
from the current trial will provide the first opportunity to test the GCE approach 
prospectively within a cooperative group trial.  
 
 

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Figure 1. Stratification of patients older than 65 from RTOG 9003, 0522, and 0129 using a 
Generalized Competing Event (GCE) model. Solid lines represent cancer mortality, and dotted 
lines represent competing causes of mortality. “Low-risk” patients (blue) have comparatively 
lower incidence of cancer mortality relative to competing mortality versus that for the 
“intermediate-risk” (red) and “high-risk” (green) patients. 
 
Supportive Care 
The trial will also collect further evidence to support the use of nomograms to predict toxicity, 
and could validate the use of such tools in the community. 
 
Quality of Life  
Health-related quality of life (HR-QOL) is a complex multidimensional concept describing the 
patient’s perception of the effects of disease and treatment on their physical, functional, 
psychological, emotional, and social well-being, in context of their culture and environment. It is 
an important endpoint on clinical trials to compare treatment arms and understand its effects 
from the patient’s perspective. While physician-reported toxicity may detect and grade adverse 
clinical events, it fails to provide the patient’s perspective on how a treatment affects the patient. 
When comparing different treatments with potentially contrasting toxicity profiles, patient 
reported outcomes (PROs) may be invaluable in determining the best treatment arm combined 
with disease control, and survival endpoints.  
 
Evaluation of HR-QOL in Elderly Patients with Multiple Co-Morbidities 
Evaluation of HR-QOL in locally advanced HNSCC patients who are not candidates for cisplatin 
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elderly vulnerable patients. Since the effects of MEDI4736 (durvalumab) immunotherapy 
combined RT in patients with HNSCC who have a contraindication to cisplatin on HR-QOL are 
currently unknown, this study will provide a unique and critical opportunity to characterize the 
effects of this novel combination treatment on HR-QOL.   
The primary QOL endpoint, the null hypothesis (H0) states that there is no difference in mean 
change in QOL physical function domain of EORTC QLQ from baseline to 1 year (from end of 
RT) between MEDI4736-RT and cetuximab-RT arms. Alternative hypothesis (HA) states that 
there is a clinically meaningful difference in QOL physical function domain of EORTC QLQ 
(change from baseline) between MEDI4736-RT and cetuximab-RT arm, whereby MEDI4736 
will have a less decline in QOL compared to the cetuximab arm at one year (from end of RT).  A 
greater than 10-point difference in mean change in score between arms is considered a minimum 
important change. A 10-point change on a 0-100 points scale in physical functioning QOL 
domain of the EORTC QLQ 30 is considered clinically meaningful. Exploratory analyses also 
will evaluate other domains of the EORTC QLQ/HN35 in the short term (end of RT-8 months) 
and long term (12-24 months) between arms.  
Specific to HNSCC, patients undergoing chemoradiation experience significant distress from a 
constellation of symptoms including acute nausea, alterations in taste and smell, mucositis 
leading to significant oral pain, odynophagia, and malnutrition and in the long term, 
consequential late sequelae, such as xerostomia and dysphagia, may have functional 
consequences for dental health, normalcy of diet and nutrition, and ability to socialize and eat in 
public (List et al., 1997; List et al., 1999). It is important to recognize that symptoms from cancer 
therapy are often found in clusters, and measuring a symptom in isolation may not provide the 
full picture of the burden of treatment or disease on the patient. Studies have shown that CRT for 
patients with HNC have been found to be associated with two stable symptom clusters: head and 
neck-specific symptoms (radiodermatitis, dysphagia, radiomucositis, dry mouth, pain, taste 
disturbance, and fatigue), and a second cluster including gastrointestinal side effects (nausea, 
vomiting, and dehydration) (Xiao 2013). In a National Cancer Institute Symptom Management 
and QOL Clinical Trials Planning Meeting, investigators identified ten HNC-specific core 
symptoms and two HR-QOL domains, including swallowing, oral pain, skin changes, dry mouth, 
dental health, opening mouth/trismus, taste, excess/thick mucus/saliva, shoulder 
disability/motion, voice/hoarseness, social domain, and functional domain which were deemed 
important for evaluation on future clinical HNC trials (Chera 2014). Based on these 
recommendations we will evaluate the HNC specific core symptoms using the HN specific items 
in the EORTC H&N35 module, as well as evaluating symptom specific instruments, including 
the MDADI (MD Anderson Dysphagia Inventory), to evaluate swallowing-related QOL, which 
are important core symptoms in HNC treatment.  
 
Fatigue in HNSCC Related to IMRT and MEDI4736 (durvalumab) 
In head and neck cancer, fatigue is one of the most common and distressing symptoms affecting 
up to 75% of patients, where the majority of patients’ experience fatigue usually peaking during 
the first and second weeks after completion of CRT and that can remain higher than baseline in 
approximately half of these patients long term (Spratt 2012). The underlying etiology of fatigue 
in head and neck cancer patients is thought to be multifactorial. Dosimetric factors have been 
implicated in patients undergoing IMRT due to increase mean and maximum doses to central 
nervous system structures. The PARSPORT (CRUK/03/005) trial demonstrated a statistically 
significant increase in acute clinician-graded fatigue in patients who were treated with IMRT as 

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compared to 3DCRT. The investigators attributed this finding to dosimetric central nervous 
system (CNS) factors. Doses to the posterior fossa, brainstem, and cerebellum have been 
correlated to grade 2 or higher acute fatigue (Gulliford, 2012. Another study identified 
dosimetric variables to the brainstem, cerebellum, pituitary gland, pineal gland, hypothalamus, 
hippocampus, and basal ganglia being associated with increased grade 2 or higher fatigue, 
hypothesizing that the possible radiation-induced fatigue may be caused by pituitary-related 
hormonal function or disruption of connections between these critical CNS structures (Powell, 
2014). Patient reported fatigue has been demonstrated in up to 75% of patients receiving 
radiation for HNC (Niska et al., 2017). More recent datasets have shown that using PROs for 
measuring fatigue may have greater predictive accuracy than clinician scores alone (Quinten et 
al., 2011). Furthermore, fatigue is one of the frequently reported (10% of patients) treatment-
emergent adverse event (TEAE)s from MEDI4736 (durvalumab). Hence, the combined effect of 
IMRT and MEDI4736 (durvalumab) on patient-reported fatigue warrants study. Hence an 
exploratory objective is to evaluate patient reported fatigue using the fatigue items in the EORTC 
QLQ and fatigue item in the PRO-CTCAE in patients receiving MEDI4736 (durvalumab)+ RT 
using IMRT for HNSCC. The hypothesis is that short term fatigue up to 4 months in HNSCC 
patients receiving MEDI4736 (durvalumab) + RT is caused by immune mediated effects 
combined with RT dose volume factors to the CNS organs at risk (OARs). A reduction of 
incidence/severity of fatigue is achieved by optimal dosing of MEDI4736 (durvalumab) with 
optimal IMRT by reduced dose/volume to CNS OARs.  
 
Swallowing-Related QOL with MEDI4736 (Durvalumab) + RT 
Oropharyngeal dysphagia after HNC radiotherapy is a major treatment related morbidity, which 
may have devastating consequences on function and QOL in HNC survivors. Furthermore, the 
functional morbidity of dysphagia after multimodality treatment may contribute to non-cancer 
deaths, such as complications from malnutrition and aspiration, which may offset any survival 
gains from treatment intensification (Cooper 2012; Forastiere 2013). Multiple factors are thought 
to contribute to the severity of oropharyngeal dysphagia including radiation dosimetric factors 
(such as the mean dose and volume to the larynx and pharyngeal constrictors), and the addition 
of concurrent chemotherapy or biologic therapy. Poor swallowing outcomes after HNC 
radiotherapy have been attributed to higher mean radiation dose to the swallowing muscles 
including the pharyngeal constrictors, glottis, supraglottic larynx, and esophagus (Feng et al., 
2007). Swallowing outcomes have been assessed by patient reported measures, clinician graded 
toxicity, percutaneous endoscopic gastrostomy tube rates, and objective measures such as 
videofluoroscopy (Eisbruch et al., 2011; Vainshtein et al., 2015). Using IMRT to spare the 
pharyngeal constrictors, larynx, cervical esophagus, and parotid glands have resulted in 
improved objective and patient reported swallowing in single institutional series (Vainshtein et 
al., 2015). HR-QOL after IMRT is generally stable or improved at two years, and new late 
toxicities beyond two years are uncommon. Eleven percent and 14% of patients reported 
‘moderate’ or ‘severe’ long-term worsening in HNQOL pain and overall bother domains, 
respectively, which were shown to be associated with higher mean radiation dose to the cervical 
esophagus, larynx, and pharyngeal constrictors (Vainshtein et al., 2015). Bhide et al. 
retrospectively evaluated superior, middle, and inferior pharyngeal constrictor, and supra-hyoid 
muscle radiation dose in 50 patients with HNC treated with induction chemotherapy followed by 
CRT (Bhide 2009). One-year clinician graded swallowing toxicity and swallowing PROs using 
the MDADI was available for 37 patients. There was a significant correlation between observer-
rated RTOG graded dysphagia and all MDADI parameters. Levendag et al. examined the 

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relationship between pharyngeal constrictor radiation dose, observer reported dysphagia, and 
patient reported swallowing using the EORTC-QLQ/H&N35 and MDADI, in 81 patients with 
OPC treated with CRT using both IMRT and 3DCRT (Levendag et al., 2007). A dose-effect 
relationship was found with an increase in the probability of clinician graded dysphagia of 19% 
for every 10 Gy increase in mean radiation dose above 55 Gy to the superior and middle 
pharyngeal constrictors. At a mean follow-up of 18 months, RTOG Grade 3 and 4 dysphagia 
(determined from chart review) was found in 23% of patients, and poor swallowing outcomes 
reflected by a total MDADI score of ≤ 50 was found in 26% of patients. A significant correlation 
was also noted between observer-rated grade 3 and 4 dysphagia and MDADI total scores, such 
that MDADI scores of ≤ 50 were considered equivalent to clinician graded 3 or 4 dysphagia. In 
addition, the scores of several EORTC-QLQ/H&N35 items (question 35=swallowing liquids, 36 
=pureed, 37=solids) and the general MDADI was found to be associated with the superior and 
middle constrictor radiation dose, and the scores of EORTC-QLQ/H&N35 questions 
37=swallowing solids and 38=aspiration were associated with radiation dose to the inferior 
constrictor. The most commonly used validated PRO swallowing instrument is the MD 
Anderson Dysphagia Inventory (MDADI), a 20-item self-administered patient reported 
dysphagia-specific instrument consisting of global, emotional, functional, and physical 
subscales. The MDADI has been validated in patients with HNC in single institution series 
(Chen 2001), and is currently being used on several prospective multicenter randomized clinical 
trials. The MDADI total score for clinically acceptable swallowing is defined as mean total 
MDADI score ≥ 60. The secondary QOL objective is to compare swallowing related QOL 
between arms and it is hypothesized that the MEDI4736-RT will have less swallowing QOL 
decline at 1-year (from end of RT) swallowing QOL (mean change from baseline) compared to 
the cetuximab arm. The Null Hypothesis states that is that there is no difference in swallowing 
related QOL decline between arms. The swallowing QOL endpoint will measure the mean 
individual change in total composite MDADI score at 1 year (from end of RT) from baseline in 
each arm. One of the arms will be deemed inferior to the other if there is a mean change score of 
≥ 10 points from baseline for that arm and there is a ≥ 10 point difference between the 2 arms 
that is statistically significant. The minimum important difference (MID) is defined as the 
smallest difference in score in the domain of interest that patients perceive as important, that 
would lead to consider a change in the patient’s management (King 2011). The MID should be 
within 5 to 10% of the instrument range (Ringash 2007). Since the MDADI score ranges from 0-
100, a change of 5- 10% (ie. 5-10 points) in the score may be considered meaningful. Hutcheson 
recently published proposed MID for the MDADI to be 10 points (Hutcheson 2016). Exploratory 
analyses will evaluate the percentage of patients in each arm with poor swallowing QOL, defined 
as an individual patient MDADI score of < 60 at 1 year from the end of RT and will also 
evaluate the subscale scores of the MDADI inventory, particularly the physical and functional 
subscales at 1 year (end of RT) and the EORTC HN35 swallowing domain. 
 
The effects of MEDI4736 (durvalumab) immunotherapy combined with IMRT in HNSCC on 
swallowing-related QOL are unknown. Particularly in this trial which includes laryngeal and 
hypopharyngeal HNSCC patients, patients with multiple co-morbidities who are at greater risk 
for dysphagia, understanding the impact dysphagia on long term swallowing-related QOL and 
survival in this patient population will be important understand on this trial.  
 
QOL and PRO-CTCAE will be measured during the phase II and III portion of the study. 
 

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3. PATIENT SELECTION, 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 
Patient Selection Guidelines 
3.1.1 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
3.1.2 Women of childbearing potential and men who are sexually active should be willing and 
able to use medically acceptable forms of contraception during therapy and for 6 months 
following the last dose of cetuximab or MEDI14736 (durvalumab). 
3.1.3 Submission of H&E stained slides and formalin-fixed and paraffin-embedded (FFPE) 
tissue block (or punch biopsy of FFPE block) to the Biospecimen Bank at UCSF for 
central review for oropharyngeal and unknown primaries and for p16 analysis for all 
other non-oropharyngeal primaries is mandatory for all patients. Investigators should 
check with their pathology department regarding release of biospecimens before 
approaching patients about participation in the trial. (See details in Sections 3.2 and 10) 
 
3.2 
Eligibility Criteria (04-OCT-2019) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
Prior to Step 1 Registration  
3.2.1    Patients must have pathologically confirmed, previously untreated, unresected squamous 
cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or carcinoma of 
unknown head/neck primary prior to Step 1 registration. Submission of H&E stained 
slides and formalin-fixed and paraffin-embedded (FFPE) tissue block (or punch biopsy of 
FFPE block) to the Biospecimen Bank at UCSF for central review for oropharyngeal and 
unknown primaries and for p16 analysis for all other non- oropharyngeal primaries is 
mandatory for all patients. For oropharyngeal and unknown primaries, submission of 
H&E and p16 stained slides (with the required block for PD-L1) to the Biospecimen 
Bank at UCSF for central review is also required prior to Step 2 registration (See Section 
10 for further criteria for central pathology review).  
 
Note: Fine needle aspirates (FNA) samples are not acceptable since they do not provide enough 
material for PD-L1 and p16 testing. However, if a cell block derived from the FNA is 
available, it is allowable if there are sufficient cells present in the block for PD-L1 
testing. Dr. Jordan will determine this upon receipt. For sites submitting FNA cell blocks 
for ALL patients they must do so within 7-10 business days from registering the patient. 
Sites must confirm with their cytology/pathology labs to make sure they can provide the 
required material as the bank must be able to retain these samples for the mandatory 
testing. 

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3.2.2 Patients must have locoregionally advanced HNSCC (see table below) 
- for p16-positive oropharyngeal/unknown primaries, AJCC 8th edition stage III and 
selected stage I-II based on smoking status in pack-years 
 
- for laryngeal, hypopharyngeal, and oral cavity primaries and p16-negative 
oropharyngeal/unknown primaries, AJCC 8th edition stage III-IVB  
 
Based on the following minimum diagnostic workup within 60 days prior to Step 1 
registration:  
• General history and physical examination by a Radiation Oncologist or Medical 
Oncologist or ENT Physician or Head & Neck Surgeon 
• For larynx, hypopharynx, and base of tongue primaries, a laryngopharyngoscopy 
(mirror or fiberoptic or direct procedure) is required, unless the patient cannot tolerate 
or refuses 
• Imaging of the head and neck with a neck CT or MRI (with contrast, unless 
contraindicated) or PET/CT. Note that the CT portion of the PET/CT must be of 
diagnostic quality, including contrast administration unless contraindicated. If the CT 
portion of the PET/CT study is low-dose (non-diagnostic), then an additional CT or 
MRI study with contrast (unless contraindicated) is required.  
• Chest imaging: Chest CT with or without contrast (unless contraindicated) or PET/CT 
 
p16-Positive Oropharyngeal or Unknown Primaries 
AJCC 8th Edition TNM 
AJCC 8th Edition Stage 
Pack-Years* 
T0-2 N1 M0 
I 
> 10 
T0-2 N2 M0 
II 
Any 
T3 N0-1 M0 
II 
> 10 
T3 N2 M0 
II 
Any 
T0-3 N3 M0 
III 
Any 
T4 N0-3 M0 
III 
Any 
 
 
 
Laryngeal, Hypopharyngeal, Oral Cavity, and p16-Negative Oropharyngeal or Unknown 
Primaries 
AJCC 8th Edition TNM 
AJCC 8th Edition Stage 
T3-4b N0 M0 
III-IVB 
T0-4b N1-3 M0 
III-IVB 
*Note: Twenty cigarettes is considered equivalent to one pack.  
 
 
 
 
 
 

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3.2.3 Patients must have a contraindication to cisplatin as defined in the following bullet 
points. Sites must complete the online tool at comogram.org prior to Step 1 registration to 
determine if the patient is eligible. The scores must be recorded on a CRF. (Refer to data 
submission table on the NRG-HN004 protocol page on the CTSU website). 
 
 
 
 
 
• Age ≥ 70 with moderate to severe comorbidity or vulnerability to cisplatin, defined as 
having one or more of the following conditions within 30 days prior to Step 1 
registration: 
o Modified Charlson Comorbidity Index ≥ 1 
o ACE-27 Index ≥ 1 
o ω score < 0.80  
o G-8 score ≤ 14 
o CARG Toxicity Score ≥ 30% 
o CIRS-G Score ≥ 4 
 
—OR—  
 
• Age < 70 with severe comorbidity or vulnerability to cisplatin, defined as having two 
or more of the following conditions within 30 days prior to Step 1 registration  
o Modified Charlson Comorbidity Index ≥ 1 
o ACE-27 Index ≥ 1 
o ω score < 0.80  
o G-8 score ≤ 14 
o CARG Toxicity Score ≥ 30% 
o CIRS-G Score ≥ 4 
 
—OR— 
 
• Age ≥ 18  with an absolute or relative contraindication to cisplatin, defined as one or 
more of the following within 30 days prior to Step 1 registration: 
o Creatinine clearance (CC) > 30 and < 60 cc/min  
For this calculation, use the Cockroft-Gault formula:  
CC = 0.85 (if female)* ((140–Age) / (Serum Creatinine)) * (Weight in kg / 72) 
Patient must be greater than 18 years old  
o Zubrod performance status 2 prior to Step 1 registration 
o Pre-existing peripheral neuropathy grade ≥ 1 
o History of hearing loss, defined as either:  
▪ Existing need of a hearing aid OR  
▪ ≥ 25 decibel shift over 2 contiguous frequencies on a pretreatment hearing 
test as clinically indicated  
3.2.4 Adequate hematologic function within 14 days prior to Step 1 registration defined as 
follows:  
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 
• Platelets ≥ 100,000 cells/mm3 
• Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve 
Hgb ≥ 9.0 g/dl is acceptable). 

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3.2.5 Adequate hepatic and renal function within 14 days prior to Step 1 registration defined as 
follows: 
• AST or ALT ≤ 2.5 times institutional upper limit of normal  
• Serum bilirubin ≤ 1.5 x institutional upper limit of normal 
• Measured creatinine clearance (CL) > 30 mL/min or Calculated creatinine CL > 30 
mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour 
urine collection for determination of creatinine clearance 
Cockcroft-Gault formula:  
CC = 0.85 (if female)* ((140–Age) / (Serum Creatinine)) * (Weight in kg / 72) 
 
3.2.6 For women of childbearing potential, a negative serum or urine pregnancy test within 14 
days prior to Step 1 registration. 
Note: Women will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause. The following age-specific requirements 
apply:  
• Women < 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
• Women ≥ 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 year 
ago, had chemotherapy-induced menopause with last menses >1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
3.2.7 The patient or a legally authorized representative must provide study-specific informed 
consent prior to Step 1 registration. 
 
Prior to Step 2 Registration (for patients with oropharyngeal and unknown primaries)  
3.2.8 For patients with oropharyngeal or unknown primaries: p16 determination by 
immunohistochemistry (defined as greater than 70% strong nuclear or nuclear and 
cytoplasmic staining of tumor cells), confirmed by central pathology review; (see Section 
10.1 for details).  
 
Note: For patients with oral cavity, laryngeal, and hypopharyngeal primaries, analysis of 
p16 status prior to Step 2 registration/randomization is not required (p16 status will be 
analyzed centrally post-hoc). Step 2 registration for these patients can be completed after 
Step 1 registration. 
 
 
 
 
 
 
 
 

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3.3 
Ineligibility Criteria (13-JAN-2021) 
Patients with any of the following conditions are NOT eligible for this study. 
 
Prior to Step 1 Registration 
3.3.1 Prior invasive malignancy within the past 3 years (except for non-melanomatous skin 
cancer, and early stage treated prostate cancer); synchronous head and neck primaries are 
ineligible  
3.3.2 Prior radiotherapy to the region of the study cancer that would result in overlap of radiation 
therapy fields 
 
Note: Prior external beam radiotherapy is excluded, but Iodine 131 is allowed.  
3.3.3 Prior immunotherapy 
3.3.4 Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or 
immune therapy for the study cancer 
3.3.5 Major surgery within 28 days prior to Step 1 registration 
3.3.6 Proven evidence of distant metastases 
3.3.7 If both of the following conditions are present, the patient is ineligible: 
• ≤ 10 pack-year smoking history  
• p16-positive carcinoma of the oropharynx or unknown primary that are T0-3, N0-
1 (AJCC 8th Edition) 
Note: In the event that a registered patient with ≤ 10 pack-years has a p16-positive result 
on central review with the tumor and nodal stage T0-3, N0-1 (AJCC 8th Edition), then the 
site will be notified that the patient is ineligible.  
3.3.8 Age < 18 years 
3.3.9 Zubrod performance status ≥ 3 
3.3.10 Body weight ≤ 30 kg 
3.3.11 Patients with oral cavity cancer are excluded from participation if the patient is medically 
operable and resection of the primary tumor is considered technically feasible by an oral 
or head and neck cancers surgical subspecialist. (Please consult the Surgical Oncology Co-
PI, Steven Chang, MD, if clarification is needed on an individual case.)  
3.3.12 Any of the following severe laboratory abnormalities within 14 days of Step 1 
registration, unless corrected prior to Step 1 registration: 
• Sodium < 130 mmol/L or > 155 mmol/L  
• Potassium < 3.5 mmol/L or > 6 mmol/L  
• Fasting glucose < 40 mg/dl or > 400 mg/dl 
• Serum calcium (ionized or adjusted for albumin) < 7 mg/dl or > 12.5 mg/dl  
• Magnesium < 0.9 mg/dl or > 3 mg/dl  
3.3.13 Unstable angina and/or congestive heart failure requiring hospitalization within 3 months 
prior to Step 1 registration 
3.3.14 Transmural myocardial infarction within 3 months prior to Step 1 registration 
3.3.15 Respiratory illness requiring hospitalization at the time of Step 1 registration 
 
Note: If the respiratory illness is resolved and the patient meets the eligibility status 
above, then the patient can be considered for the trial. 
3.3.16 Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen 
therapy or is thought to require oxygen therapy within 1 year prior to Step 1 registration 
3.3.17  History of (non-infectious) pneumonitis that required steroids or current pneumonitis 
3.3.18 Clinically apparent jaundice and/or known coagulation defects 

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3.3.19 Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc.).   
 
The following are exceptions to this criterion: 
• Patients with vitiligo or alopecia; 
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement; 
• Any chronic skin condition that does not require systemic therapy; 
• Patients without active disease in the last 5 years may be included but only after 
consultation with the medical oncology study chair; 
• Patients with celiac disease controlled by diet alone. 
 
3.3.20 History of active primary immunodeficiency including, but not limited to Acquired 
Immune Deficiency Syndrome (AIDS) based upon current CDC definition; Note: HIV 
testing is not required for entry into this protocol. The need to exclude patients with 
AIDS from this protocol is necessary because the treatment involved in this protocol may 
be immunosuppressive. Patients with known HIV, CD4 counts ≥ 200/μL, and 
undetectable viral loads who are stable on an antiretroviral regimen may be included.  
3.3.21 Current or prior use of immunosuppressive medication within 14 days before Step 1 
registration, with the exceptions of intranasal and inhaled corticosteroids or systemic 
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, 
or an equivalent corticosteroid 
3.3.22 Receipt of live attenuated vaccination within 30 days prior to Step 1 registration  
3.3.23 Medical or psychiatric illness which would compromise the patient's ability to tolerate 
treatment or limit compliance with study requirements  
3.3.24 Pregnancy or women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception during treatment and for 
6 months after the last dose of cetuximab or MEDI14736 (durvalumab); this exclusion is 
necessary because the treatment involved in this study may be significantly teratogenic. 
Women who are breastfeeding are also excluded. 
3.3.25 Prior allergic reaction or hypersensitivity to cetuximab or MEDI4736 (durvalumab) or 
any of study drug excipients. 
3.3.26 History of allogenic organ transplantation 
3.3.27 Uncontrolled hypertension 
3.3.28  Uncontrolled cardiac arrhythmia 
3.3.29 Uncontrolled serious chronic gastrointestinal condition associated with diarrhea 
3.3.30 Active infection including tuberculosis (clinical evaluation that includes clinical history, 
physical examination and radiographic findings, and TB testing in line with local 
practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C.  
Patients with a past or resolved HBV infection (defined as the presence of hepatitis B 
core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for 
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for 
HCV RNA. 

NRG-HN004 
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4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP  
  (13-JAN-2021) 
PRE-TREATMENT ASSESSMENTS  
 
 
Assessments 
Calendar Days  
Prior to Step 1 Registration  
Calendar Days  
Prior to Treatment, 
inclusive of  
Treatment Day 1 
 
≤60 
≤30 
≤14 
 
Pathologic confirmation of 
previously untreated, unresected 
squamous cell carcinoma of larynx, 
hypopharynx, oropharynx, oral 
cavity, or carcinoma of unknown 
head/neck primary 
X 
 
 
 
 
General history and physical 
examination by a Radiation 
Oncologist or Medical Oncologist 
or ENT Physician or Head & Neck 
Surgeon; evaluation must include a 
listing of concomitant medications. 
 
X 
 
 
≤14 
For larynx, hypopharynx, and base 
of tongue primaries, a 
laryngopharyngoscopy (mirror or 
fiberoptic or direct procedure)  
 
X* 
 
 
 
Imaging of the head and neck with 
a neck CT or MRI (with contrast, 
unless contraindicated) or PET/CT 
(CT portion of the PET/CT must be 
of diagnostic quality with contrast, 
unless contraindicated. See section 
3.2.2 for details.) 
 
X 
 
 
 
Chest imaging with CT (with or 
without contrast, unless 
contraindicated) or PET/CT 
 
X 
 
 
 
Charlson Comorbidity Index 
 
 
X 
 
 
ACE-27 Index 
 
 
X 
 
 
ω-Score  
 
 
X 
 
 
G-8 Score (QoL) 
 
 
X 
 
 
CARG Toxicity Score 
 
 
X 
 
 
CIRS-G Score 
 
 
X 
 
 
Zubrod performance status 
 
 
X 
 
 
Pre-existing peripheral neuropathy 
grade ≥ 1 
 
 
X 
 
 
History of hearing loss (use of 
hearing aid or ≥ 25 decibel shift 
 
 
X 
 
 

NRG-HN004 
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over 2 contiguous frequencies on a 
pretreatment hearing test as 
clinically indicated)  
Tissue sample for correlative 
research (baseline) (mandatory) 
 
 
 
 
≤90 
Complete Blood Count with 
Differential (CBCD), including 
Absolute Neutrophil Count (ANC) 
 
 
 
X 
 
Complete Metabolic Panel 
(fasting), Magnesium, 
AST or ALT, 
Total bilirubin 
 
 
 
X 
 
EKG, troponin 
 
 
 
 
≤72 hours of 1st 
MEDI14736 
(durvalumab) infusion 
Pregnancy test, serum or urine (for 
women of childbearing potential)  
 
 
 
X 
 
Informed consent 
 
X 
 
 
 
PSS-HN (Phase II/III patients only; 
clinician graded 
performance/function) 
 
 
 
 
≤28 
PRO-CTCAE Assessment (Phase 
II/III patients only)** 
 
 
 
 
≤28 
 
Quality of Life Assessments*** 
(Phase II/III patients only) 
• 
EORTC QLQ-C30 and 
H&N35 
• 
MDADI 
• 
EQ-5D-5L 
 
 
 
 
 
≤28 
 
Blood specimen collection for 
Banking (for patients who consent 
to biobanking) 
 
 
 
 
≤14 
Blood specimen collection for 
Peripheral Blood Analysis (for 
phase II/III patients who consent to 
blood laboratory study) 
 
 
 
 
≤14 
Mandatory pre-hoc central 
confirmation of p16 status 
(oropharyngeal and unknown 
primary cases only)  
 
 
After Step 1 registration and 
before Step 2 registration 
*Unless patient refuses or cannot tolerate. 
**The specific PRO-CTCAE items for this protocol can be found on the forms section of the CTSU 
protocol webpage and is titled “NRG-HN004 NCI PRO-CTCAE Item Library”. Baseline PRO-CTCAE 
will be completed on paper. 
***Baseline Quality of Life questionnaires will be completed on paper. 
 

NRG-HN004 
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ASSESSMENTS DURING RADIATION THERAPY 
(Day -7 [7 days prior to any treatment] to 4 weeks after RT + Systemic Therapy) 
Assessments 
Within 7 
Days Prior to 
Any Systemic 
Therapy 
Weekly  
(± 2 days)  
during RT, 
or as 
specified 
End of 
RT 
 (± 2 
days) 
1 mo. 
(± 7 days) 
after end of 
RT 
Complete Blood Count with 
Differential (CBCD), including 
Absolute Neutrophil Count (ANC) 
X 
X 
 
 
Creatinine Clearance  
X 
X 
 
 
Complete Metabolic Panel, 
Magnesium 
X 
X 
 
 
TSH* 
 
Note: Thyroid function tests are not 
needed for patients randomized to 
the cetuximab arm. 
 
X 
 
●Week 2 of 
RT  
●Week 6 of 
RT 
 
 
Physical examination by Radiation 
Oncologist or Medical Oncologist 
or ENT Physician or Head & Neck 
Surgeon; evaluation must include a 
listing of concomitant medications 
 
X 
 
 
Troponin** 
X [for 
MEDI4736 
(durvalumab) 
arm only] 
 
 
 
Adverse event evaluation 
X 
X 
X 
 
PSS-HN (Phase II/III patients only; 
clinician graded 
performance/function) 
 
 
X 
 
PRO-CTCAE 
(Phase II/III patients only)*** 
 
●After the 
first dose of 
drug and 
prior to 
starting RT 
●Week 2 of 
RT  
●Week 6 of 
RT 
X 
 
Quality of Life  
(Phase II/III patients only) 
 
 
X 
 
 

NRG-HN004 
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• EORTC QLQ-C30 and H&N35 
• EQ5D-5L 
• MDADI 
Blood specimen collection for 
Banking (for patients who consent 
to biobanking) 
 
≤ 7 days 
prior to 
starting RT 
 
 
 
X 
 
 
Blood specimen collection for 
Peripheral Blood Analysis (for 
phase II/III patients who consent to 
blood laboratory study) 
 
≤ 7 days 
prior to 
starting RT 
(and after 
starting 
systemic 
therapy) 
 
 
X 
*With reflex to free T4; T3 only if clinically indicated afterwards. 
**For all patients in safety run-in component, troponin must be tested prior to each dose of MEDI14736 
(durvalumab) and any additional cardiac testing should be performed as clinically indicated.  During the 
phase II/III component, EKG and troponin (and other cardiac tests such as CK and echocardiogram) 
should be performed as clinically indicated. 
***The specific PRO-CTCAE items for this protocol can be found on the forms section of the CTSU 
protocol webpage and is titled “NRG-HN004 NCI PRO-CTCAE Item Library”. A 7-day window will be 
allowed for collection of PRO-CTCAE. 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 III.   
 
 
 
 

NRG-HN004 
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ASSESSMENTS DURING ADJUVANT THERAPY  
4-16 weeks after RT+ MEDI4736 (Durvalumab), for patients on investigational therapy 
only 
 
 
Assessments 
  
Within 3 Days 
Prior to  
Beginning 
Adjuvant 
Therapy  
Q 4 weeks  
(± 7 days) 
During 
Adjuvant 
Therapy  
Complete Blood Count with Differential (CBCD), 
including Absolute Neutrophil Count (ANC) 
X 
X 
Creatinine Clearance 
X 
X 
Complete Metabolic Panel, Magnesium 
X 
X 
TSH*, amylase, lipase 
X 
X 
Troponin** 
 
X 
Physical examination by Radiation Oncologist or 
Medical Oncologist or ENT Physician or Head & Neck 
Surgeon; evaluation must include a listing of 
concomitant medications 
 
X 
Adverse Event evaluation 
X 
X 
*With reflex to free T4; T3 only if clinically indicated afterwards 
**For all patients in safety run-in component, troponin must be tested prior to each dose of MEDI14736 
(durvalumab) and any additional cardiac testing should be performed as clinically indicated.  During the 
phase II/III component, EKG and troponin (and other cardiac tests such as CK and echocardiogram) 
should be performed as clinically indicated. 
 
 
 
 
 
 

NRG-HN004 
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ASSESSMENTS IN FOLLOW UP  
 
Assessments 
 
1 mo. (± 7 
days) after 
last dose of 
systemic 
therapy 
For cetuximab  
arm only:  
2 and 3 mos. (± 
7 days) after 
last dose of 
systemic 
therapy 
Q 4 mos. (± 28 
days) from end 
of RT for 1 year, 
then Q 6 mos. (± 
28 days) for 2 
years, then 
annually****** 
Complete Blood Count with 
Differential (CBCD), including 
Absolute Neutrophil Count 
(ANC) 
X 
 
 
Creatinine Clearance 
X 
 
 
TSH, amylase, lipase* 
X 
 
 
Complete Metabolic Panel, 
Magnesium 
X 
 
 
Physical examination by 
Radiation Oncologist or 
Medical Oncologist or ENT 
Physician or Head & Neck 
Surgeon; evaluation must 
include a listing of medications  
X 
 
X 
Performance Status evaluation , 
including PSS-HN (Phase II/III 
patients only) 
 
 
X  
(4, 8, 12, 18, 24  
months only) 
Evaluation for presence of a 
feeding tube 
X 
 
X 
Adverse event evaluation 
X 
X† 
X 
Whole body 18-F-FDG-
PET/CT 
 
 
 4 months, then as 
clinically 
indicated** 
Chest CT (with or without 
contrast) 
 
 
As clinically 
indicated 
Diagnostic CT or MRI of neck, 
with contrast  
 
 
 
4 months, then as 
clinically 
indicated*** 
 
Troponin**** 
X [for 
MEDI4736 
(durvalumab) 
arm only] 
 
 
Quality of Life Assessments 
 (Phase II/III patients only) 
• EORTC QLQ-C30 and 
 
 
X 
(4, 8, 12, 18, 24  
months from end 

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Version Date: March 09, 2022 
 
H&N35  
• MDADI 
• EQ5D-5L 
of RT only) 
PRO-CTCAE Assessment 
(Phase II/III patients only)***** 
 
 
X 
(4 months from 
end of RT only) 
Blood specimen collection for 
banking (for patients who 
consent to biobanking) 
X (for 
durvalumab 
arm only) 
 
X 
(4 months from 
end of RT for 
cetuximab arm 
only) 
Blood specimen collection for 
Peripheral Blood Analysis (for 
phase II/III patients who 
consent to blood laboratory 
study) 
X (for 
durvalumab 
arm only) 
 
X 
(4 months from 
end of RT for 
cetuximab arm 
only) 
*TSH, amylase, lipase for patients in the MEDI4736 (durvalumab) arm.  For TSH, with reflex to free 
T4; T3 only if clinically indicated afterwards.  
**Both whole body 18-F-FDG-PET/CT and diagnostic CT or MRI of the neck are strongly encouraged 
4 months following completion of RT +/- 2 weeks, but are not mandatory. For patients in the 
MEDI4736 (durvalumab) arm, this imaging should be done after the last dose of adjuvant MEDI4736 
(durvalumab). If a PET/CT is acquired at any other time in follow-up then additional CT or MRI of the 
neck and chest CT are not required at the same time point. 
***CT (with contrast) and/or MRI (with contrast) of the head and neck is highly recommended at the 
indicated time points, particularly in the presence of persistent symptoms or abnormal/equivocal 
clinical examination findings. 
****For all patients in safety run-in component, troponin must be tested at 1 month after last 
MEDI14736 (durvalumab) infusion and any additional cardiac testing should be performed as 
clinically indicated.  During the phase II/III component, EKG and troponin (and other cardiac tests such 
as CK and echocardiogram) should be performed only as clinically indicated 
*****The specific PRO-CTCAE items for this protocol can be found on the forms section of the CTSU 
protocol webpage and is titled “NRG-HN004 NCI PRO-CTCAE Item Library”. A 7-day window will 
be allowed for collection of PRO-CTCAE. 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 III.   
****** Patients enrolled to the safety-lead in portion are followed for a total of 2 years.  
† Patients randomized to Cetuximab: Adverse event evaluation is required at Month 2 and 3 
after the last dose of systemic therapy. The patient can be seen by the Radiation or Medical 
Oncologist or the adverse event evaluation can be done over the phone by a physician or 
designee (i.e. physician assistant, nurse or nurse practitioner). 
 
Note: For patients with local or regional neck failure, post-treatment imaging showing the 
failure at any time post-treatment must be submitted in DICOM format via TRIAD. The report 
is to be uploaded into Rave. 
 
 
 
 

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Definition of Disease Assessments  
Progression of head and neck cancer will be assessed at defined time points by radiological 
imaging as indicated in the Assessment Tables above. Additionally, any clinical evidence of 
disease progression as determined by the treating physician outside of these defined time points 
during treatment and in follow up should trigger confirmation by radiological imaging and 
biopsy, if clinically feasible and associated with acceptable risk to the patient. The window for 
confirmation is at least 4 weeks after the scan showing progressive disease. 
 
The protocol will utilize RECIST, v. 1.1 for the purposes of evaluating response and progression.  
 
As described in RECIST, v. 1.1, it is strongly recommended that the imaging studies performed 
at baseline be performed in follow up on the same equipment with the same techniques as noted 
above in Recommendations for Imaging. CT neck and chest with contrast of diagnostic quality 
(slice thickness no greater than 3 mm in the head/neck and 5 mm in the chest) is preferred, with 
CT head, abdomen/pelvis added if clinically indicated. 18-F-FDG-PET/CT (inclusive of the 
chest) may be used as radiographic evaluation for overall cancer status.  
 
Progressive disease will be defined as follows: 
 
1. Clinical evidence of disease progression in a radiated field that is confirmed by cytology 
or histopathology (see Note) 
 
—OR— 
 
2. Progressive disease as defined by RECIST, v. 1.1 criteria (Eisenhauer 2009) 
a) At least a 20% increase in the sum of the diameters of target lesions; the sum also 
must demonstrate an absolute increase of at least 5 mm OR 
b) unequivocal progression of non-target lesions OR 
c) the appearance of one or more new lesions 
 
Note: A positive biopsy at the primary site or involved nodes that occurs < 4 months from the 
end of RT will be categorized as disease persistence and ≥ 4 months as progression.  
 
Immediate adjuvant neck dissection is not indicated in this population and should not be 
performed. Pathologic confirmation of persistent disease at the time of a salvage neck dissection 
(performed, say, for persistent adenopathy on imaging ≥ 4 months post-treatment, or for 
clinical/radiographic evidence of progression of adenopathy < 4 months post-treatment) would 
be considered a progression event. An adjuvant neck dissection performed in deviation of the 
protocol that indicates pathologic persistent disease will not be considered a progression event. 
Pathologic confirmation of disease is required to consider a neck dissection as a progression 
event. If a progression occurs at a site of previous gross disease, this is considered a local failure; 
if progression occurs in the elective neck, this is considered a regional failure.  
 
It is anticipated that measurable, target lesions by RECIST, v. 1.1 for head and neck cancer 
would include the primary tumor and up to 2 measurable cervical lymph nodes with a short axis 
of ≥ 15 mm. Non-target lesions would include cervical lymph nodes > 10 mm and < 15 mm. 
Lymph nodes will be considered a single “organ” for the purpose of analyzing response by 

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RECIST v. 1.1.  
 
Local or regional progression during primary treatment for head and neck cancer is unusual; 
however, it may occur and would be defined by meeting RECIST, v. 1.1 criteria in comparison 
to the imaging studies performed at baseline/enrollment. Per RECIST, v. 1.1. progressive disease 
is defined by at least a 20% increase in the sum of the diameters of target lesions, taking as a 
reference the smallest sum on study. It is anticipated that the first required imaging time point 
after completion of radiotherapy (4 months after RT) will be the reference scan for defining 
progression. However, further decline in measurement of target lesions may occur beyond the 4-
month post RT evaluation time point. In that instance, the reference scan containing the smallest 
sum may occur beyond the 4-month post-RT time point.  
 
RECIST, v. 1.1 recognizes that it can be difficult to determine progressive disease in a 
previously irradiated or previously treated area (e.g. after neck dissection). In the event of 
clinical suspicion of progressive disease within an irradiated field in the absence of meeting 
formal RECIST definition, investigators are strongly encouraged to perform further 
investigation, including: 
a) Repeat CT imaging at a short interval (e.g. six weeks). If short interval imaging results in 
confirmation of progressive disease by RECIST, v. 1.1 definition, the date of progression 
will be defined by the first scan.  
b) 18-F-FDG-PET/CT: Per RECIST, progressive disease would be indicated on 18-F-FDG-
PET/CT if a previously negative 18-F-FDG-PET/CT becomes positive at a new lesion. For 
this protocol, a previously negative measurable lesion that becomes positive by FDG-PET 
also would be considered progression. Biopsy confirmation, however, is still strongly 
recommended.  
c) Biopsy  
 
In addition to formal evaluation of progressive disease by RECIST, v. 1.1, investigators will be 
asked at the time of first progression to report whether progressive disease was local (at the 
primary tumor), regional (within the head and neck, including cervical lymph nodes) or distant 
(inclusive of brain and below the clavicles). Sites of distant disease progression should be noted. 
This will accommodate analysis of patterns of failure. 
 
All images should be reviewed and reported by the local study investigators by RECIST, 
version 1.1.  
 
Case-report forms for investigator interpretation of progressive disease by RECIST, v. 1.1 are 
available in Medidata Rave. All imaging studies performed at baseline and 4 months post-RT or 
in response to clinical concern for progression are required to be submitted for a potential 
centralized review by RECIST, version 1.1. 
 
 
 
 
 

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5.  TREATMENT PLAN/REGIMEN DESCRIPTION 
5.1 
Systemic Therapy (15-JAN-2019) 
 
Protocol treatment must begin within 10 days after Step 2 Registration. 
 
 
5.1.1 MEDI4736 (Durvalumab)  
Cycle 1 of MEDI4736 (durvalumab) will be administered as a 1500 mg fixed dose 
starting 2 weeks prior to RT. A variance of 2 days is acceptable for scheduling conflicts 
such as vacation or holidays. Please refer to the dosing table in 5.1 for further schedule 
details. The infusion rate for MEDI4736 (durvalumab) will be approximately 60 minutes.  
 
TABLE 1 
Lead-In Dose Levels 
 
 
Dose Level 
 
MEDI4736 (Durvalumab) 
 
IMRT 
 
Dose level 1  
 
Initial Dose: 1500 mg IV Week -2 
 
Concurrent: 1500 mg IV Weeks 2, 6 of IMRT 
 
Maintenance: 1500 mg IV, q4 weeks for 4 
doses  
(Weeks 10, 14, 18, 22) 
 
70 Gy in 7 weeks 
(conventional 
fractionation) 
Arm 1 
 
Week of IMRT 
 
-1 
1 
2 
3 
4 
5 
6 
7 
IMRT (2 Gy/fx, 5 days/week) 
 
X 
X 
X 
X 
X 
X 
X 
Cetuximab 
400 mg/m2 loading dose 
X 
 
 
 
 
 
 
 
Cetuximab* 
250 mg/m2  
 
X 
X 
X 
X 
X 
X 
X 
*Refer to section 5.1.2 for acceptable variance +/- 1 day for weekly cetuximab. 
Arm 2 
 
Week of IMRT 
 
-2* 1** 
2* 
3 
4 
5 
6 
7 
10 
14 
18 
22 
IMRT (70 Gy- 2 
Gy/fx) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
MEDI4736 
(Durvalumab) 
1500 mg IV  
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
*NOTE: Time between the first and second doses of MEDI4736 (durvalumab) is 3 weeks. 
All remaining doses are every 4 weeks. Refer to section 5.1.1 for acceptable variance +/- 2 
days. 
**RT will start 2 weeks (+/- 1 day) after the first dose of MEDI4736 (durvalumab). 

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Dose level -1;  
if necessary 
 
Initial Dose: 1500 mg IV Week -2 
 
Concurrent: 1500 mg IV  
Week 6 of IMRT 
 
Maintenance: 1500 mg IV, q4 weeks for 5 
doses  
(Weeks 10, 14, 18, 22, 26) 
 
70 Gy in 7 weeks 
(conventional 
fractionation) 
 
Dose level -2;  
if necessary 
 
Initial Dose: 1500 mg IV Week -2 
 
Concurrent: None 
 
Maintenance: 1500 mg IV, q4 weeks for 6 
doses  
(Weeks 10, 14, 18, 22, 26, 30) 
 
70 Gy in 7 weeks 
(conventional 
fractionation) 
 
TABLE 2 
Lead-In Treatment Plan by Dose Level 
 
 
[Dose Level -1 and Dose Level -2 were not used for the Lead-In Treatment Plan] 
Dose Level 1 
 
Week of IMRT 
 
-2* 1** 
2* 
3 
4 
5 
6 
7 
10 
14 
18 
22 
IMRT (2 Gy/fx) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
MEDI4736 
(Durvalumab) 
1500 mg IV  
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
*NOTE: Time between the first and second doses of durvalumab is 3 weeks. 
**RT will start 2 weeks (+/- 1 day) after the first dose of durvalumab. 
(Dose Level -1;  
if necessary 
 
Week of IMRT 
 
-2* 
1 
2 
3 
4 
5 
6* 
7 
10 
14 
18 
22 
26 
IMRT (2 Gy/fx) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
MEDI4736 
(Durvalumab) 
1500 mg IV 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
*NOTE: Time between the first and second doses of durvalumab is 7 weeks. 

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5.1.2 Cetuximab 
For the phase II/III regimen in Arm 1, cetuximab will be administered as 400 mg/m2 
loading dose prior to RT then 250 mg/m2 weekly x 7 cycles concurrent with RT.  
 
Note: Actual body weight should be use for all calculations of BSA. 
 
Cetuximab Loading Dose: Patients on Arm 1 will receive an initial dose of cetuximab, 
400 mg/m2, intravenously (IV) over 120 minutes (maximum infusion rate 10 mg/min). 
No radiation will be given this day. 
The loading dose of cetuximab will precede the first 250 mg/m2 dose of concurrent 
cetuximab and the first radiation treatment by at least 5, but no more than 7, days (the day 
of the loading dose is not included in these 5 days). 
 
Cetuximab Concurrent Dose: Subsequent doses will be given at 250 mg/m2 intravenously 
(IV) over 60 minutes (maximum infusion rate 10 mg/min). A variance of 1 day is 
acceptable for scheduling conflicts such as vacation or holidays.  
 
Note: Patients receive a total of 8 doses of cetuximab over 8 weeks, including the initial 
loading dose, 7 doses concurrent with radiation therapy. If a dose of cetuximab is 
omitted, it will not be made up or added to the end of treatment. The omitted dose and the 
reason for the omission should be recorded in the site’s source documentation. 
 
Hypersensitivity Prophylaxis: Infusion reactions may occur during or following 
cetuximab administration. Most infusion reactions occur with the first infusion of 
cetuximab, but some patients’ first infusion reactions have been reported following 
subsequent doses (a severe reaction occurred in one patient following the 8th dose). The 
infusion reaction may occur during the infusion or be delayed until any time after the 
infusion.  
• Loading Dose Prophylaxis: All patients will be premedicated with diphenhydramine 
hydrochloride, 50 mg, (or an equivalent antihistamine) by IV 30-60 minutes prior to 
the first dose of cetuximab in an effort to prevent an infusion reaction. At the 
discretion of the treating physician, dexamethasone, 20 mg, and an H2 blocker also 
may be administered IV.  
• Subsequent Dose Prophylaxis: Premedications are recommended prior to subsequent 
doses, but at the Investigator’s discretion, the dose of diphenhydramine or 
dexamethasone may be reduced.  
• Monitoring Loading Dose: The medical staff should closely observe patients for 
Dose Level -2;  
if necessary 
 
Week of IMRT 
 
-2* 
1 
2 
3 
4 
5 
6 
7 
10* 
14 
18 
22 
26 
30 
IMRT (2 Gy/Fx) 
 
X 
X X 
X 
X 
X 
X 
 
 
 
 
 
 
MEDI4736 
(Durvalumab) 
1500 mg IV 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
*NOTE: Time between the first and second doses of durvalumab is 11 weeks. 

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treatment-related adverse events, especially infusion reactions (see Section 6.2 for 
management) during the cetuximab infusion and during a post-infusion observation 
period, per their institutional guidelines. For the initial cetuximab infusion, vital signs 
(blood pressure, heart rate, respiratory rate, and temperature) should be monitored 
before, during, and after administration of cetuximab according to institutional 
guidelines, preferably in an area with resuscitation equipment and other agents 
(epinephrine, prednisone equivalents, etc.) available, and with a nurse and physician 
present in close proximity to the treatment area throughout the infusion and 
observation period. In the event that a patient experiences an infusion reaction, the 
site should follow institutional guidelines for proper management.  
• Monitoring Subsequent Doses: For subsequent infusions, vital signs should be taken 
pre- and post-infusion; however, it is recommended that the patient be observed for 1 
hour post-infusion. For the duration that patients are on study therapy, adverse event 
monitoring will be done continuously. Patients will be evaluated for adverse events at 
each visit and are to be instructed to call their physician to report any clinically 
significant adverse events between visits. Patients should be instructed to report any 
delayed reactions to the investigator immediately. 
 
5.2 
Radiation Therapy (13-JAN-2021) 
Protocol treatment must begin within 10 days after Step 2 Registration.  
 
Note: All participating institutions must be credentialed for head and neck IMRT 
and IGRT prior to registering patients to the study (see Section 8.3 for details). 
 
Intensity Modulated Radiation Therapy (IMRT) and Image-Guided Radiation Therapy 
(IGRT) are mandatory for this study. Proton therapy is not permitted. 
 
IMRT (70 Gy) will be given in 35 fractions over 7 weeks, 5 fractions per week. Missed 
treatments due to holidays or logistical reasons can be compensated by delivering 
additional BID fractions, with a minimum inter-fraction interval of 6 hours, or by treating 
on Saturday or Sunday. 
 
5.2.1 Treatment Technology 
Megavoltage energy photon beam irradiation with a photon beam of ≥ 4 MV is required.  
Note:  
• VMAT is allowed.  
• Matched conventional anterior low neck field is allowed. 
• Cyberknife is not allowed. 
 
5.2.2 Immobilization and Simulation (04-OCT-2019) 
 
Immobilization 
Immobilization with a thermoplastic mask is mandatory for head and neck IMRT. 
Patients will be planned in the supine position with their arms at their sides, ensuring the 
shoulders are situated as far inferior as possible to avoid entry and exit through the 
shoulders. Additional immobilization devices such as a bite block are permitted. 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. 

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Simulation Imaging 
The treatment planning CT scan is mandatory for defining target volumes and normal 
organ at risk. The planning CT scan should be done with intravenous contrast (unless 
contraindicated). CT scan thickness should be a maximum of 0.3 cm, and the CT scan 
should be acquired with the patient in the same position and using the same 
immobilization device as for treatment. 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. 
 
5.2.3 Imaging for Structure Definition, Image Registration/Fusion and Follow up 
A diagnostic CT or MRI for structure delineation is recommended. These may be fused 
to the planning CT scans to facilitate target and structure definition. When available  
FDG PET/CT images may also be fused to the planning CT data set. All image sets used 
for structure delineation must be submitted with the RT digital data. 
 
5.2.4 Definition of Dose Prescriptions, 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 name listed. Capital letters, spacing and use of underscores must be 
applied exactly as indicated. 
 
Standard Name 
Description 
Validation  
Required/Required When 
Applicable/Optional 
GTV_7000 
Primary tumor and involved nodes 
 
Required 
CTV_7000 
GTV + 5-10mm margin, excluding 
anatomic boundaries to tumor spread 
Required  
PTV_7000 
 
CTV-to-PTV 5mm margin that can be 
reduced to 3mm in some situations 
Required 
PTV_Eval_7000 
PTV minus OARs, subtract 8 mm from the 
skin when needed  
Required when applicable 
CTV_5600 
CTV_7000 + 1cm margin (excluding 
anatomic boundaries to tumor spread), plus 
elective nodal regions 
Required 

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PTV_5600 
 
CTV-to-PTV 3mm margin  
Required 
CTV_6125 
CTV_7000 plus regions at high-risk for 
subclinical disease 
Required when applicable 
PTV_6125 
CTV-to-PTV 3mm margin  
Required when applicable 
 
General 
The primary tumor and involved nodes will be encompassed by PTV_7000 and will 
receive 2 Gy per fraction x 35 fractions, while subclinical disease sites will be 
encompassed by PTV_5600 which will receive 1.6 Gy per fraction x 35 fractions. 
Treatment of both volumes will occur at the same time using a simultaneous integrated 
boost (SIB) technique delivered at 5 fractions per week over 7 weeks. For regions 
considered to be at high risk for microscopic disease, PTV_6125 may be treated to a dose 
of 61.25 Gy at 1.75 Gy per fraction x 35 fractions. The treatment plan used for each 
patient will be based on an analysis of the volumetric dose, including dose-volume 
histogram (DVH) analyses of the PTVs and critical normal structures. Inverse planning 
with computerized optimization should be used. The density corrected dose distributions 
shall be calculated, and the dose prescription is to be based on a dose distribution 
corrected for heterogeneities. 
 
Gross Tumor Volume (GTV) represents the region judged to contain gross primary 
tumor or grossly involved node(s) based on clinical and endoscopic examinations, CT 
scan, and, when applicable, other imaging techniques. Grossly positive lymph nodes are 
defined as any lymph nodes > 1 cm or nodes with a necrotic center. 
 
Clinical Target Volume (CTV) is defined as the GTV plus areas considered at risk for 
containing microscopic disease delineated by the treating physician. CTV_7000 
represents GTV plus a margin of generally 5-10 mm, and CTV_5600 represents 
CTV_7000 with a margin of 10 mm, plus nodal regions to receive elective irradiation. 
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_6125) that is slightly larger 
than CTV_7000. 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. 
 
Planning Target Volume (PTV) represents an additional margin around CTV to 

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compensate for the variability of treatment set-up and internal organ motion. A minimum 
margin of 3mm 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.  
 
PTV_Eval_7000: PTV volume minus impinging high priority OARs for dosimetric 
evaluation. For some patients, a PTV will overlap critical organs, such as the brainstem, 
spinal cord, optic structures, and brachial plexus. When a PTV overlaps a critical OAR 
(spinal cord and/or brainstem) and its associated PRV, the PTV should be modified to 
exclude the OAR so as to limit the dose delivered to the OAR. 8 mm can be subtracted 
from the skin when needed. 
 
When expansion of a 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. 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 forward for review. 
 
Note. PTV _7000 and PTV_Eval_7000 (Required When Applicable) must be sent for 
review. 
 
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. 
 
Standard Name 
Description 
Validation 
(Required/Required when 
applicable/Optional) 
SpinalCord  
Spinal Cord 
Required 
SpinalCord_PRV05 
Planning Risk Volume of 5mm margin 
around Spinal Cord 
Required 
BrainStem 
Brain Stem 
Required 
BrainStem_PRV05 
Planning Risk Volume of 5mm margin 
around Brain Stem 
Required 

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Lobe_Temporal_L 
Left Temporal Lobe 
Required 
Lobe_Temporal_R 
Right Temporal Lobe 
Required 
OpticNrv_L 
Left Optic Nerve 
Required 
OpticNrv_R 
Right Optic Nerve 
Required 
OpticChiasm 
Optic Chiasm 
Required 
Parotid_L 
Left Parotid 
Required 
Parotid_R 
Right Parotid 
Required 
Cavity_Oral  
Oral Cavity 
Required 
Lips 
Lips 
Required 
Bone_Mandible  
Mandible 
Required 
Joint_TM_L 
Left Temporomandibular Joint 
Required 
Joint_TM_R 
Right Temporomandibular Joint 
Required 
Pharynx 
Uninvolved posterior pharyngeal wall 
plus adjacent constrictor muscles  
Required 
Esophagus_S 
Upper Cervical Esophagus 
Required 
Larynx_SG 
Supra Glottic Larynx 
Required 
Glnd_Submand_L 
Left Submandibular Salivary Gland 
Required 
Glnd_Submand_R 
Right Submandibular Salivary Gland 
Required 
External 
Patient contour encompassing all patient 
anatomy with a single contour on each 
slice 
Required 
E-PTV 
All tissue excluding the PTVs 
Required 
 
Detailed Specifications 
 
Spinal Cord: The spinal cord begins at the cranial-cervical junction (i.e. the top of the C1 
vertebral body). The last slice of the contouring of the spinal cord should be at T3-T4. 
The spinal cord shall be defined based on the treatment planning CT scan. In addition, 
however, a Planning Risk Volume (PRV) spinal cord shall be defined. The PRV cord = 
spinal cord + 5 mm in each dimension. This is irrespective of the use of IGRT for margin 
reduction. 

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Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction 
where it meets the spinal cord. For the purposes of this study, the superior most portion of 
the brainstem is approximately at the level of the top of the posterior clinoid process. The 
brainstem shall be defined based on the treatment planning CT scan. In addition, 
however, a Planning Risk Volume (PRV) brainstem shall be defined. The PRV brainstem 
= brainstem + 5 mm in each dimension. This is irrespective of the use IGRT for margin 
reduction. 
 
Lips and Oral Cavity: These should be contoured as 2 separate structures as the goal is to 
keep the lip dose much lower than the oral cavity dose. The definition of lips is self-
explanatory. The oral cavity will be defined as a composite structure consisting of the 
anterior one half to two thirds of the oral tongue/floor of mouth, buccal mucosa, and 
palate. 
 
Parotid Glands: Parotid glands are defined based on the treatment planning CT scan. 
 
Pharynx: This is defined as the “uninvolved” posterior pharyngeal wall plus adjacent 
constrictor muscles. This extends from the superior constrictor region (the inferior 
pterygoid plates level) to the cricopharyngeal inlet (posterior cricoid cartilage level). 
 
Cervical Esophagus (Esophagus_S): This is defined as a tubular structure that starts at the 
bottom of pharynx and extends to the thoracic inlet. 
 
Larynx (GSL) (Larynx_SG): The GSL begins just inferior to the hyoid bone and extends 
to the cricoid cartilage inferiorly and extends from the anterior commissure to include the 
arytenoids. This includes the infrahyoid but not suprahyoid epiglottis. 
 
Mandible (Bone_Mandible): The mandible includes the entire bony structure from TMJ 
through the symphysis. It is recognized that for oral cavity cancers, this may overlap with 
CTVs and PTVs. 
 
Unspecified Tissue outside of the Targets: This will be defined as all tissue located 
between the skull base and thoracic inlet excluding all PTVs and defined normal 
structures within the external contour of the patient. 
 
 
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.  
Target 
Standard 
Name 
Dose 
(Gy) 
Fraction 
Size (Gy) 
# of 
fractions  
Frequency 
Dose 
specification 
technique 
PTV_7000 
70 
2.0 
35 
Daily 
Covering 95% 
of PTV 

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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 %] 
Dxcc[Gy], Dxcc[%], Dx%[Gy], Dx%[%]: Dose [Gy or %] to 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 volume 
receives prescription dose of 70 Gy. 
 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are 
not met 
 
Target Volume and OAR Constraints 
 
Name of Structure 
Dosimetric 
Parameter 
Per  
Protocol 
Variation 
Acceptable 
PTV_7000 
 
D95%[Gy] 
>=70 
>=69 
V95%[%] 
>99 
>=90 
D99%[Gy] 
>=66.5 
>=63 
D0.03cc[Gy] 
<=77 
<= 82 
PTV_Eval_7000 
D99%[Gy] 
>=66.5 
> 63 
PTV_6125 
D95%[Gy] 
>=61.25 
>=58 
PTV_5600 
D95%[Gy] 
>=56 
>=50.4 
SpinalCord_PRV05 
D0.03cc[Gy] 
<= 50  
<= 52 
BrainStem_PRV05 
D0.03cc[Gy] 
<= 54 
<=56 

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OpticNrv_L or  
OpticNrv_R  
D0.03cc[Gy] 
<= 54 
<=56 
OpticChiasm 
D0.03cc[Gy] 
<=54 
<=56 
Bone_Mandible 
D0.03cc[Gy] 
<=70 
<=75 
Joint_TM_L or  
Joint_TM_R 
D0.03cc[Gy] 
<=70 
<=75 
 
Lobe_Temporal_L or 
Lobe_Temporal_R 
 
D0.03cc[Gy] 
<=70 
<=72 
 
Per Protocol range is excluded from Variation Acceptable range. 
 
It is recognized that portions of PTVs close to the skin or critical PRVs (spinal cord and 
brainstem) may receive significantly less than the prescription doses. This is acceptable 
in these regions as long as cold spots within these PTVs do not exist within the GTV. In 
cases of PTVs close to skin, tissue equivalent bolus must be utilized to ensure adequate 
dose. 
 
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. 
 
Recommended dose acceptance criteria for other normal tissue but not to be used for plan 
score 
 
Name of Structure 
 
Recommended dose acceptance criteria 
Parotid_L or Parotid_R 
Mean[Gy] <26 (for at least one parotid) 
Lips 
Mean[Gy] <20 
Larynx_SG 
Mean[Gy] <20 
Pharynx 
Mean[Gy] <45 
Glnd_Submand_L or 
Glnd_Submand_R (contralateral) 
Mean[Gy] <39 
Cavity_Oral (non-involved oral cavity) 
Mean[Gy] <30 
D0.03cc[Gy] <60 
Esophagus_S 
Mean[Gy] <30 
D0.03cc[Gy] <60 
E-PTV 
D1cc[Gy] <74 
 
 
 

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Delivery Compliance Criteria 
 
 
Per 
Protocol 
Variation Acceptable 
Deviation Unacceptable 
Overall Treatment 
time 
< 50 days 
50-54 days (without a 
medically appropriate 
indication for delay 
> 54 days (without a 
medically appropriate 
indication for delay) 
Interruptions 
0-2 days 
3-4 days 
> 4 days 
 
5.2.8 Treatment Planning Priorities and Instructions 
Prioritization of IMRT Planning 
1.  SpinalCord 
2.  BrainStem 
3.  PTV_7000 
4.  PTV_6125 (if applicable) 
5.  PTV_5600 
6.  a. Pharynx 
 
b. Parotid gland contralateral to primary tumor site 
7.  a. Larynx_SG 
  
b. Esophagus_S 
8.  a. Lips 
  
b. Cavity_Oral 
9.  a. Parotid gland ipsilateral to primary tumor site 
  
b. Bone_Mandible 
10. Unspecified tissue outside the targets 
 
Acceptable choices of algorithm are listed at: 
http://rpc.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TPS%20-
%20algorithm%20list%20updated.pdf. Any algorithm used for this study must be 
credentialed by IROC Houston. 
 
All doses should be reported in terms of dose-to-water and not in terms of dose-to-
medium. 
 
An algorithm that is not included in this list must be credentialed by IROC Houston. 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. 
 
Primary dataset for dose calculation 
In the case in which contrast is present during the treatment planning CT, whether the 

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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. In 
some instances plastic surgical shuts may appear radio-opaque and require appropriate 
HU override. 
 
Dose matrix resolution 
Dose grid size should be ≤ 3 mm in all directions. 
 
Adaptive Planning  
Patients may experience weight change or the target size may change during treatment. 
Due to the sensitive nature of the dose distribution to anatomical change, adaptive 
planning may be required to maintain protocol dose coverage to the PTV and OARs. All 
adaptive plans and final plan sum dose statistics should be submitted at the end of 
treatment.  
 
5.2.9 Patient-Specific QA 
For IMRT/VMAT plans, patient specific QA is highly recommended. Any patient-
specific QA performed should follow your institutional and AAPM guidelines. The 
recommended patient specific QA criteria is for 90% of the comparison points to pass a 
±3%/3mm Gamma Index analysis.  
 
5.2.10 Treatment Localization/IGRT 
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate 
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 shifts and rotations (if available) must be 
determined with computer assistance. 
 
IGRT Instructions 
Bony anatomy IGRT credentialing is required (see Section 8.3). Daily image guidance of 
IMRT may be achieved using any one or more of the following techniques: 
• Orthogonal kilovoltage (KV) images; 
• Linear-accelerator mounted kV and MV cone beam CT images; 
• Linear-accelerator mounted MV CT images. 
 
The institution’s procedure for registering daily treatment imaging datasets with a 
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 supraclavicular region is a part of the target 
volume the ROI should extend to the C6 level; 
• If the fusion software allows the user to create an irregular ROI, treatment room 
objects seen on in-room x-rays should be excluded from the registration; 
• Both manual (e.g. drag-and-drop system based on bony anatomy matching) and 

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automatic (e.g. based on mutual information) types of registration can be used; the 
result of the fusion must be visually 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 < 2.5 mm (this typically corresponds to one half of the usual PRV 
margin), 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 to 5 mm, adjustment is necessary prior to treatment; however, 
reimaging is not mandatory. If one or more of the corrections are > 5 mm, the 
imaging must be repeated in addition to performing table/positioning adjustments. 
However, the use of numerous repeat IGRT studies should be avoided; 
• Imaging dose to the patient may become significant if repeated studies are performed 
for patients with severe set up problems (e.g., requiring frequent corrections of more 
than 5 mm). It is recommended that patients demonstrating severe set up problems 
during the first 7 calendar days of treatment be re-simulated or 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. Please see 
Section 6.1/Supportive Care Guidelines for details. 
 
5.3.2 Prohibited Therapies 
• The use of amifostine or palifermin as a radioprotectant is not allowed. The use of 
granulocyte colony stimulating factor or erythropoietin is not allowed. Transfusion is 
to be performed at the discretion of the treating physician.  
• Any exceptions must be approved by the Principal Investigator, Dr. Mell. An e-mail 
must be sent to Dr. Mell for the approval and NRG Oncology Headquarters Data 
Managers must be copied on that e-mail. 
• Immunosuppressive medications, including, but not limited to, systemic 
corticosteroids at doses exceeding 10 mg/day or prednisone or equivalent, 
methotrexate, azathioprine and tumor necrosis factor-a blockers. These should not be 
given concomitantly or used for premedication prior to the MEDI4736 (durvalumab) 
infusions.  Exceptions include: the use of immunosuppressive medications for the 
management of IP-related AEs, use in patients with contrast allergies. A temporary 
period of steroids will be allowed if clinically indicated and considered to be essential 
for the management of non-immunotherapy related events experienced by the patients 
(e.g. chronic obstructive pulmonary disease, radiation, nausea, etc.) 
 
5.3.3 Participation in Other Trials  
Patients may not participate in other clinical trials that are intended to treat the diagnosed 
head and neck cancer or intended to reduce toxicity of therapy.  

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5.3.4 Blood Donation and Vaccination 
• Patients should not donate blood while participating in this study, or for at least 90 days 
after receipt of the final dose of MEDI4736 (durvalumab).  
• Live attenuated vaccines should not be administered whilst receiving MEDI4736 
(durvalumab) and for 30 days after the last dose of MEDI4736 (durvalumab). 
 
5.4 
Duration of Therapy (15-JAN-2019) 
Patients assigned to MEDI4736 (durvalumab) plus RT will receive 7 doses of MEDI4736 
(durvalumab). Patients assigned to cetuximab plus RT will receive 8 doses of cetuximab.  
 
In the absence of treatment delays due to adverse event(s), treatment will 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); 
• Patient decides to withdraw consent for participation in the study;  
• General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator; 
• New data related to the experimental agent which would suggest that continuing 
treatment on protocol would impose unwarranted potential risks beyond what was 
known at the time of treatment initiation. 
 
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 Guidelines for Immune-Mediated, 
Infusion-Related, and Non-Immune Mediated Reactions for MEDI4736 
(Durvalumab) (15-JAN-2019) 
 
 
Dose modifications, per the tables below, are based upon CTCAE v5.0 adverse event 
assessment. 
 
6.1.1 Dose Modifications 
There are no dose reductions for MEDI4736 (durvalumab). If the patient meets 
retreatment criteria, the full dose of 1500 mg will be administered. If the patient does not 
meet retreatment criteria before the next scheduled dose, if/when the toxicity resolves to 
the point where treatment is possible, the doses of MEDI4736 (durvalumab) are applied 
off schedule q 4 weeks.  
 
Adverse events (both non-serious and serious) associated with MEDI4736 (durvalumab) 
exposure may represent an immunologic etiology. These adverse events may occur 
shortly after the first dose or several months after the last dose of treatment. MEDI4736 
(durvalumab) must be withheld for drug-related toxicities and severe or life-threatening 

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AEs as per the table below. 
 
Note: If in the judgment of the investigator an event is considered clinically unrelated or 
unlikely to be related to MEDI4736 (durvalumab), and an alternate clinical explanation 
is likely, probable, or definite (for example, attributable to prerenal azotemia in the 
setting of nausea, and responding to hydration), then corticosteroids may be omitted and 
MEDI4736 (durvalumab) may be administered. However, even the unrelated event 
should be treated appropriately and resolved prior to continuing treatment. 
 
 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study 
regimen will be made to manage potential immune-related 
AEs based on severity of treatment-emergent toxicities 
graded per NCI CTCAE v5.0. 
In addition to the criteria for permanent discontinuation of 
study drug/study regimen based on CTC grade/severity (table 
below), permanently discontinue study drug/study regimen 
for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of 
≤10 mg of prednisone per day (or equivalent) 
within 12 weeks after last dose of study drug/study 
regimen 
• 
Recurrence of a previously experienced Grade 3 
treatment-related AE following resumption of 
dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or 
Grade 4. 
Study drug/study regimen can be resumed 
once event stabilizes to Grade ≤1 after 
completion of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study 
regimen 
on 
the 
following 
conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per 
Investigator 
or 
treating 
physician’s 
clinical judgement. 
3. 
Doses of prednisone are at ≤10 mg/day or 
equivalent. 
It is recommended that management of immune-mediated 
adverse events (imAEs) follows the guidelines presented in 
this table: 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
concomitant medications, and infections). 
− 
In the absence of a clear alternative etiology, all 
events should be considered potentially immune 
related. 
− 
Symptomatic and topical therapy should be 
considered for low-grade (Grade 1 or 2, unless 
otherwise specified) events. 
− 
For persistent (>3 to 5 days) low-grade (Grade 2) or 
severe (Grade ≥3) events, promptly start prednisone 
1 to 2 mg/kg/day PO or IV equivalent. 
− 
If symptoms recur or worsen during corticosteroid 
tapering (28 days of taper), increase the 
corticosteroid dose (prednisone dose [e.g., up to 2 to 
4 mg/kg/day PO or IV equivalent]) until 
stabilization or improvement of symptoms, then 
resume corticosteroid tapering at a slower rate 
(>28 days of taper). 
− 
More potent immunosuppressives such as TNF 
inhibitors (e.g., infliximab) (also refer to the 
individual sections of the imAE for specific type of 
immunosuppressive) should be considered for 
events not responding to systemic steroids. 
− 
Discontinuation of study drug/study regimen is not 
mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic 
disease and lymph nodes). Continuation of study 
drug/study regimen in this situation should be based 
upon a benefit-risk analysis for that patient. 

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Dose Modifications 
Toxicity Management 
Grade 3 
Depending on the individual toxicity, study 
drug/study regimen may be permanently 
discontinued. Please refer to guidelines 
below. 
Grade 4 
Permanently discontinue study drug/study 
regimen. 
Note: There are some exceptions to permanent 
discontinuation of study drug for Grade 4 events (i.e., 
hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).  
 
 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE 
Immune-mediated adverse event; IV intravenous; NCI National Cancer Institute; PO By mouth. 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and 
symptoms of pneumonitis or ILD 
(new onset or worsening shortness of 
breath or cough). Patients should be 
evaluated with imaging and 
pulmonary function tests, including 
other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical 
evaluation, monitoring of 
oxygenation via pulse oximetry 
(resting and exertion), laboratory 
work-up, and high- resolution CT 
scan. 
Grade 1 
 
No dose modifications 
required. However, 
consider holding study 
drug/study regimen dose 
as clinically appropriate 
and during diagnostic 
work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 
4 days for clinical symptoms, pulse 
oximetry (resting and exertion), and 
laboratory work-up and then as 
clinically indicated. 
− 
Consider Pulmonary and Infectious 
disease consult. 
Grade 2 
 
Hold study drug/study 
regimen dose until Grade 
2 resolution to Grade ≤1. 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves 
to Grade ≤1, then the 
decision to reinitiate 
study drug/study 
regimen will be based 
upon treating 
physician’s clinical 
judgment and after 
For Grade 2 (mild to moderate new 
symptoms): 
− 
Monitor symptoms daily and 
consider hospitalization. 
− 
Promptly start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or 
IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 
days, additional workup should be 
considered and prompt treatment 
with IV methylprednisolone 2 to 
4 mg/kg/day started 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
completion of steroid 
taper. 
− 
If still no improvement within 3 to 5 
days despite IV methylprednisolone 
at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 
5 mg/kg every 2 weeks). Caution: It 
is important to rule out sepsis and 
refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-PCP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections (Category 2B 
recommendation)a 
− 
Consider Pulmonary and Infectious 
disease consult. 
− 
Consider, as necessary, discussing 
with study physician. 
Grade 3 or 4 
 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life-threatening): 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day 
or equivalent. 
− 
Obtain Pulmonary and Infectious 
disease consult; consider, as 
necessary, discussing with study 
physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 
days, additional workup should be 
considered and prompt treatment 
with additional immunosuppressive 
therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
weeks’ dose) started. Caution: rule 
out sepsis and refer to infliximab 
label for general guidance before 
using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and, in 
particular, anti-PCP treatment (refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
(Category 2B recommendation).a 
Diarrhea/Colitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be 
related to diarrhea/enterocolitis 
(abdominal pain, cramping, or 
changes in bowel habits such as 
increased frequency over baseline or 
blood in stool) or related to bowel 
perforation (such as sepsis, peritoneal 
signs, and ileus). 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, 
other medications, or infections), 
including testing for clostridium 
difficile toxin, etc. 
− 
Steroids should be considered in the 
absence of clear alternative etiology, 
even for low-grade events, in order to 
prevent potential progression to 
higher grade event. 
− 
Use analgesics carefully; they can 
mask symptoms of perforation and 
peritonitis. 
Grade 1 
 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening 
symptoms. 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), and loperamide. Use probiotics 
as per treating physician’s clinical 
judgment. 
Grade 2 
 
Hold study drug/study 
regimen until resolution to 
Grade ≤1 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves 
to Grade ≤1, then 
study drug/study 
regimen can be 
resumed after 
completion of steroid 
taper. 
For Grade 2: 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 
5 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, GI consult should be 
obtained for consideration of further 
workup, such as imaging and/or 
colonoscopy, to confirm colitis and 
rule out perforation, and prompt 
treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
started. 
− 
If still no improvement within 3 to 5 
days despite 2 to 4 mg/kg IV 
methylprednisolone, promptly start 
immunosuppressives such as 
infliximab at 5 mg/kg once every 2 
weeksa. Caution: it is important to 
rule out bowel perforation and refer 
to infliximab label for general 
guidance before using infliximab. 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
− 
Consider, as necessary, discussing 
with study physician if no resolution 
to Grade ≤1 in 3 to 4 days. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
 
Grade 3 
Permanently discontinue 
study drug/study regimen  
for Grade 3 if toxicity 
does not improve to Grade 
≤1 within 14 days; study 
drug/study regimen can be 
resumed after completion 
of steroid taper. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen. 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone 2 to 4 mg/kg/day 
or equivalent. 
− 
Monitor stool frequency and volume 
and maintain hydration. 
− 
Urgent GI consult and imaging 
and/or colonoscopy as appropriate. 
− 
If still no improvement within 3 to 5 
days of IV methylprednisolone 2 to 4 
mg/kg/day or equivalent, promptly 
start further immunosuppressives 
(e.g., infliximab at 5 mg/kg once 
every 2 weeks). Caution: Ensure GI 
consult to rule out bowel perforation 
and refer to infliximab label for 
general guidance before using 
infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
Any Grade 
General Guidance 
For Any Grade: 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
Hepatitis (elevated 
LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
− 
Monitor and evaluate liver function 
test: AST, ALT, ALP, and TB. 
− 
Evaluate for alternative etiologies 
(e.g., viral hepatitis, disease 
progression, concomitant 
medications). 
Grade 1 (Based 
on ULN 
regardless of 
baseline LFT) 
 
No dose modifications. 
• 
If it worsens, then 
treat as Grade 2 event. 
For Grade 1: 
− 
Continue LFT monitoring per 
protocol. 
Grade 2 (Based 
on ULN 
regardless of 
baseline LFT) 
 
 
Hold study drug/study 
regimen dose until Grade 
2 resolution to Grade ≤1. 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
• 
If toxicity improves to 
Grade ≤1 or baseline, 
resume study 
drug/study regimen 
after completion of 
steroid taper. 
For Grade 2: 
− 
Regular and frequent checking of 
LFTs (e.g., every 1 to 2 days) until 
elevations of these are improving or 
resolved. 
− 
If no resolution to Grade ≤1 in 1 to 2 
days, consider, as necessary, 
discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or 
worsens, promptly start prednisone 1 
to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 
days despite 1 to 2 mg/kg/day of 
prednisone PO or IV equivalent, 
consider additional work up and start 
prompt treatment with IV 
methylprednisolone 2 to 
4 mg/kg/day. 
− 
If still no improvement within 3 to 5 
days despite 2 to 4 mg/kg/day of IV 
methylprednisolone, promptly start 
immunosuppressives (mycophenolate 
mofetil).a Discuss with study 
physician if mycophenolate mofetil 
is not available. Infliximab should 
NOT be used. 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Based on ULN 
regardless of 
baseline LFT) 
 
 
For Grade 3: 
For elevations in 
transaminases ≤8 × ULN, 
or elevations in bilirubin 
≤5 × ULN: 
• Hold study drug/study 
regimen dose until 
resolution to Grade ≤1 
or baseline 
• Resume study 
drug/study regimen if 
elevations downgrade 
to Grade ≤1 or 
baseline within 
14 days and after 
completion of steroid 
taper. 
• Permanently 
discontinue study 
drug/study regimen if 
the elevations do not 
downgrade to Grade 
≤1 or baseline within 
14 days 
For elevations in 
transaminases >8 × ULN 
or elevations in bilirubin 
>5 × ULN, discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 
days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, 
promptly start treatment with 
immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss 
with study physician if 
mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Perform hepatology consult, 
abdominal workup, and imaging as 
appropriate. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 

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Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
Permanently discontinue 
study drug/study regimen 
for any case meeting Hy’s 
law criteria (AST and/or 
ALT >3 × ULN + 
bilirubin >2 × ULN 
without initial findings of 
cholestasis (i.e., elevated 
alkaline P04) and in the 
absence of any alternative 
cause.b 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that 
may be related to changes in renal 
function (e.g., routine urinalysis, 
elevated serum BUN and creatinine, 
decreased creatinine clearance, 
electrolyte imbalance, decrease in 
urine output, or proteinuria). 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression or 
infections). 
− 
Steroids should be considered in the 
absence of clear alternative etiology 
even for low-grade events (Grade 2), 
in order to prevent potential 
progression to higher grade event. 
Grade 1 
 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and 
any accompanying symptoms. 

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Adverse Events 
Severity Grade 
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(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
• 
If creatinine returns to 
baseline, resume its regular 
monitoring per study 
protocol. 
• 
If creatinine worsens, 
depending on the severity, 
treat as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics. 
Grade 2 
 
Hold study drug/study 
regimen until resolution to 
Grade ≤1 or baseline.  
• 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
• 
If toxicity improves to 
Grade ≤1 or baseline, 
then resume study 
drug/study regimen 
after completion of 
steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics. 
− 
Carefully monitor serum creatinine 
every 2 to 3 days and as clinically 
warranted. 
− 
Consult nephrologist and consider 
renal biopsy if clinically indicated. 
− 
If event is persistent (>3 to 5 days) or 
worsens, promptly start prednisone 1 
to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 
5 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should 
be considered and prompt treatment 
with IV methylprednisolone at 2 to 
4 mg/kg/day started. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 

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Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
− 
When event returns to baseline, 
resume study drug/study regimen and 
routine serum creatinine monitoring 
per study protocol. 
Grade 3 or 4 
 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine 
on daily basis. 
− 
Consult nephrologist and consider 
renal biopsy if clinically indicated. 
− 
Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 
5 days or worsens despite prednisone 
at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should 
be considered and prompt treatment 
with IV methylprednisolone 2 to 
4 mg/kg/day started. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI 
CTCAE v5.0 for 
definition of 
severity/grade 
depending on 
type of skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of 
dermatitis (rash and pruritus). 
− 
IF THERE IS ANY BULLOUS 
FORMATION, THE STUDY 
PHYSICIAN SHOULD BE 
CONTACTED AND STUDY 
DRUG DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 

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version v5.0) 
Dose Modifications 
Toxicity Management 
diphenhydramine or hydroxyzine) 
and topical therapy (e.g., urea 
cream). 
Grade 2 
For persistent (>1 to 2 
weeks) Grade 2 events, 
hold scheduled study 
drug/study regimen until 
resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, 
then treat as Grade 3. 
• 
If toxicity improves 
to Grade ≤1 or 
baseline, then 
resume drug/study 
regimen after 
completion of 
steroid taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) 
and topical therapy (e.g., urea 
cream). 
− 
Consider moderate-strength topical 
steroid. 
− 
If no improvement of rash/skin 
lesions occurs within 3 to 5 days or is 
worsening despite symptomatic 
treatment and/or use of moderate 
strength topical steroid,  consider, as 
necessary, discussing with study 
physician and promptly start 
systemic steroids such as prednisone 
1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
Consider skin biopsy if the event is 
persistent for >1 to 2 weeks or 
recurs. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen until resolution to 
Grade ≤1 or baseline. 
If temporarily holding the 
study drug/study regimen 
does not provide 
improvement of the Grade 
3 skin rash to Grade ≤1 or 
baseline within 30 days, 
then permanently 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day 
or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of 
Nines]. 
− 
Consider skin biopsy (preferably 
more than 1) as clinically feasible. 

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Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
discontinue study 
drug/study regimen. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
− 
consider, as necessary, discussing 
with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
hypothyroidism,  Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
Any Grade 
(depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE v5.0 for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an 
endocrinologist for endocrine events. 
− 
Consider, as necessary, discussing 
with study physician. 
− 
Monitor patients for signs and 
symptoms of endocrinopathies. Non-
specific symptoms include headache, 
fatigue, behavior changes, changed 
mental status, vertigo, abdominal 
pain, unusual bowel habits,  
polydipsia, polyuria, hypotension, 
and weakness. 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression 
including brain metastases, or 
infections). 
− 
Depending on the suspected 
endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, 
free T3 and free T4 and other 
relevant endocrine and related labs 
(e.g., blood glucose and ketone 
levels, HgA1c). 
− 
For modest asymptomatic elevations 
in serum amylase and lipase, 
corticosteroid treatment is not 
indicated as long as there are no 

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version v5.0) 
Dose Modifications 
Toxicity Management 
other signs or symptoms of 
pancreatic inflammation. 
− 
If a patient experiences an AE that is 
thought to be possibly of 
autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, or diabetes 
insipidus), the investigator should 
send a blood sample for appropriate 
autoimmune antibody testing. 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with 
asymptomatic TSH elevation): 
− 
Monitor patient with appropriate 
endocrine function tests. 
− 
For suspected 
hypophysitis/hypopituitarism, 
consider consultation of an 
endocrinologist to guide assessment 
of early-morning ACTH, cortisol, 
TSH and free T4; also consider 
gonadotropins, sex hormones, and 
prolactin levels, as well as 
cosyntropin stimulation test (though 
it may not be useful in diagnosing 
early secondary adrenal 
insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 × 
ULN or consistently out of range in 2 
subsequent measurements, include 
free T4 at subsequent cycles as 
clinically indicated and consider  
consultation of an endocrinologist . 
Grade 2 
For Grade 2 
endocrinopathy  and Type 
1 diabetes mellitus other 
than hypothyroidism, hold 
study drug/study regimen 
dose until patient is 
clinically stable. 
For Grade 2 (including those with 
symptomatic endocrinopathy): 
− 
Consult endocrinologist to guide 
evaluation of endocrine function and, 
as indicated by suspected 
endocrinopathy and as clinically 
indicated, consider pituitary scan. 
− 
For all patients with abnormal 
endocrine work up, except those with 

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Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
Study drug/study regimen 
can be resumed once event 
stabilizes and after 
completion of steroid 
taper. 
Patients with 
endocrinopathies who may 
require prolonged or 
continued steroid 
replacement (e.g., adrenal 
insufficiency) can be 
retreated with study 
drug/study regimen on the 
following conditions: 
1. 
The event stabilizes 
and is controlled. 
2. 
The patient is 
clinically stable as 
per investigator or 
treating physician’s 
clinical judgement. 
3. 
Doses of prednisone 
are ≤10 mg/day or 
equivalent. 
isolated hypothyroidism or Type 1 
DM, and as guided by an  
endocrinologist, consider short-term 
corticosteroids (e.g., 1 to 
2 mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation 
of treatment with relevant hormone 
replacement (e.g., hydrocortisone, 
sex hormones). 
− 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus 
(DM) may be treated with 
appropriate diabetic therapy, without 
study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Once  patients on steroids are 
improving, gradually taper  
immunosuppressive steroids (as 
appropriate and with guidance of 
endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines 
for treatment of cancer-related 
infections [Category 2B 
recommendation]).a 
− 
For patients with normal endocrine 
workup (laboratory assessment or 
MRI scans), repeat laboratory 
assessments/MRI as clinically 
indicated. 
Grade 3 or 4 
For Grade 3 or 4 
endocrinopathy other than 
hypothyroidism and Type 
1 diabetes mellitus, hold 
study drug/study regimen 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide 
evaluation of endocrine function and, 
as indicated by suspected 
endocrinopathy and as clinically 
indicated, consider pituitary scan. 
Hospitalization recommended. 

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Toxicity Management 
dose until endocrinopathy 
symptom(s) are controlled.  
Study drug/study regimen 
can be resumed once event 
stabilizes and after 
completion of steroid 
taper. 
Patients with 
endocrinopathies who may 
require prolonged or 
continued steroid 
replacement (e.g., adrenal 
insufficiency) can be 
retreated with study 
drug/study regimen on the 
following conditions: 
1. 
The event stabilizes 
and is controlled. 
2. 
The patient is 
clinically stable as 
per investigator or 
treating physician’s 
clinical judgement. 
3. 
Doses of prednisone 
are ≤10 mg/day or 
equivalent. 
 
− 
 For all patients with abnormal 
endocrine work up, except those with 
isolated hypothyroidism or Type I 
DM, and as guided by an 
endocrinologist, promptly initiate 
empiric IV  methylprednisolone 1 to 
2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., 
hydrocortisone, sex hormones). 
 
− 
For adrenal crisis, severe 
dehydration, hypotension, or shock, 
immediately initiate IV 
corticosteroids with 
mineralocorticoid activity. 
− 
Isolated hypothyroidism may be 
treated with replacement therapy, 
without study drug/study regimen 
interruption, and without 
corticosteroids. 
− 
Isolated Type 1 diabetes mellitus 
may be treated with appropriate 
diabetic therapy, without study 
drug/study regimen interruption, and 
without corticosteroids. 
− 
Once  patients on steroids are 
improving, gradually taper 
immunosuppressive steroids (as 
appropriate and with guidance of 
endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines 
for treatment of cancer-related 
infections [Category 2B 
recommendation]).a 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
Any Grade 
(depending on 
the type of 
neurotoxicity, 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule 
out any alternative etiology (e.g., 
disease progression, infections, 

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(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
refer to NCI 
CTCAE v5.0 for 
defining the CTC 
grade/severity) 
metabolic syndromes, or 
medications). 
− 
Monitor patient for general 
symptoms (headache, nausea, 
vertigo, behavior change, or 
weakness). 
− 
Consider appropriate diagnostic 
testing (e.g., electromyogram and 
nerve conduction investigations). 
− 
Perform symptomatic treatment with 
neurological consult as appropriate. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations 
above. 
Grade 2 
For acute motor 
neuropathies or 
neurotoxicity, hold study 
drug/study regimen dose 
until resolution to Grade 
≤1. 
For sensory 
neuropathy/neuropathic 
pain, consider holding 
study drug/study regimen 
dose until resolution to 
Grade ≤1. 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
Study drug/study regimen 
can be resumed once event 
improves to Grade ≤1 and 
after completion of steroid 
taper. 
For Grade 2: 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (e.g., gabapentin or 
duloxetine). 
− 
Promptly start systemic steroids 
prednisone 1 to 2 mg/kg/day PO or 
IV equivalent. 
− 
If no improvement within 3 to 5 days 
despite 1 to 2 mg/kg/day prednisone 
PO or IV equivalent, consider 
additional workup and promptly treat 
with additional immunosuppressive 
therapy (e.g., IV IG). 
Grade 3 or 4 
For Grade 3: 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing 
with study physician. 

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Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 within 
30 days. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day 
or equivalent. 
− 
If no improvement within 3 to 5 days 
despite IV corticosteroids, consider 
additional workup and promptly treat 
with additional immunosuppressants 
(e.g., IV IG). 
− 
Once stable, gradually taper steroids 
over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Permanently discontinue  MEDI4736 
(durvalumab) following the diagnosis 
of Guillain Barre or myasthenia 
gravis for any grade 
− 
The prompt diagnosis of immune-
mediated peripheral neuromotor 
syndromes is important, since certain 
patients may unpredictably 
experience acute decompensations 
that can result in substantial 
morbidity or in the worst case, death. 
Special care should be taken for 
certain sentinel symptoms that may 
predict a more severe outcome, such 
as prominent dysphagia, rapidly 
progressive weakness, and signs of 
respiratory insufficiency or 
autonomic instability. 
− 
Patients should be evaluated to rule 
out any alternative etiology (e.g., 
disease progression, infections, 
metabolic syndromes or 
medications). It should be noted that 
the diagnosis of immune-mediated 
peripheral neuromotor syndromes 

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Toxicity Management 
can be particularly challenging in 
patients with underlying cancer, due 
to the multiple potential confounding 
effects of cancer (and its treatments) 
throughout the neuraxis. Given the 
importance of prompt and accurate 
diagnosis, it is essential to have a low 
threshold to obtain a neurological 
consult. 
− 
Neurophysiologic diagnostic testing 
(e.g., electromyogram and nerve 
conduction investigations, and 
“repetitive stimulation” if myasthenia 
is suspected) are routinely indicated 
upon suspicion of such conditions 
and may be best facilitated by means 
of a neurology consultation. 
− 
It is important to consider that the 
use of steroids as the primary 
treatment of Guillain-Barre is not 
typically considered effective. 
Patients requiring treatment should 
be started with IV IG and followed 
by plasmapheresis if not responsive 
to IV IG. 
Grade 1 
No dose modifications.  
Permanently discontinue  
MEDI4736 (durvalumab) 
following the diagnosis of 
any grade of Guillain 
Barre or myasthenia gravis  
For Grade 1: 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of a 
potential decompensation as 
described above. 
− 
Obtain a neurology consult. 
Grade 2 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
For Grade 2: 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Care should be taken to monitor 
patients for sentinel symptoms of a 

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version v5.0) 
Dose Modifications 
Toxicity Management 
if it does not resolve to 
Grade ≤1 within 30 days 
or if there are signs of 
respiratory insufficiency 
or autonomic instability.  
Permanently discontinue  
MEDI4736 (durvalumab) 
following the diagnosis of 
any grade of Guillain 
Barre or myasthenia gravis 
potential decompensation as 
described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (e.g., gabapentin or 
duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to treat 
myasthenia gravis. It is 
important to consider that 
steroid therapy (especially 
with high doses) may result 
in transient worsening of 
myasthenia and should 
typically be administered 
in a monitored setting 
under supervision of a 
consulting neurologist. 
o 
Patients unable to tolerate 
steroids may be candidates 
for treatment with 
plasmapheresis or IV IG. 
Such decisions are best 
made in consultation with a 
neurologist, taking into 
account the unique needs 
of each patient. 
o 
If myasthenia gravis-like 
neurotoxicity is present, 
consider starting AChE 
inhibitor therapy in 
addition to steroids. Such 
therapy, if successful, can 
also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 

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Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
o 
It is important to consider 
here that the use of steroids 
as the primary treatment of 
Guillain-Barre is not 
typically considered 
effective. 
o 
Patients requiring 
treatment should be started 
with IV IG and followed 
by plasmapheresis if not 
responsive to IV IG. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 within 
30 days or if there are 
signs of respiratory 
insufficiency or autonomic 
instability.  Permanently 
discontinue  MEDI4736 
(durvalumab) following 
the diagnosis of any grade 
of Guillain Barre or 
myasthenia gravis 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Consider, as necessary, discussing 
with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain 
neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be 
successfully used to treat 
myasthenia gravis. They 
should typically be 
administered in a 
monitored setting under 
supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate 
steroids may be candidates 
for treatment with 
plasmapheresis or IV IG. 
o 
If myasthenia gravis-like 
neurotoxicity present, 
consider starting AChE 
inhibitor therapy in 
addition to steroids. Such 
therapy, if successful, can 
also serve to reinforce the 

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version v5.0) 
Dose Modifications 
Toxicity Management 
diagnosis. 
 
GUILLAIN-BARRE: 
o 
It is important to consider 
here that the use of steroids 
as the primary treatment of 
Guillain-Barre is not 
typically considered 
effective. 
o 
Patients requiring 
treatment should be started 
with IV IG and followed 
by plasmapheresis if not 
responsive to IV IG. 
Cardiac toxicities  
(including arrhythmia, 
conduction disorder 
heart failure, LV 
dysfunction, 
Myocarditis) 
Any Grade 
General Guidance 
Discontinue drug 
permanently upon 
diagnosis of myocarditis, 
regardless of grade. 
For Any Grade: 
− 
The prompt diagnosis of immune-
mediated myocarditis is important, 
particularly in patients with baseline 
cardiopulmonary disease and reduced 
cardiac function.  
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Monitor patients for signs and 
symptoms of myocarditis (new onset 
or worsening chest pain, arrhythmia, 
shortness of breath, peripheral 
edema). As some symptoms can 
overlap with lung toxicities, 
simultaneously evaluate for and rule 
out pulmonary toxicity as well as 
other causes (e.g., pulmonary 
embolism, congestive heart failure, 
malignant pericardial effusion). A 
Cardiology consultation should be 
obtained early, with prompt 
assessment of whether and when to 
complete a cardiac biopsy, including 
any other diagnostic procedures. 
− 
Initial work-up should include 
clinical evaluation, BNP, cardiac 
enzymes, ECG, echocardiogram 
(ECHO), monitoring of oxygenation 
via pulse oximetry (resting and 
exertion), and additional laboratory 
work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO 

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Dose Modifications 
Toxicity Management 
to assess wall motion abnormalities 
when needed. 
− 
Patients should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, 
other medications, or infections) 
 
 
Grade 1 
 
- No dose modifications 
required unless clinical 
suspicion for myocarditis 
is high, in which case 
suspected, hold  
durvalumab during work-
up.  
- If myocarditis is 
excluded, resume after 
complete resolution to 
Grade 0.  
- If myocarditis is 
diagnosed, permanently 
discontinue durvalumab. 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 
4 days for clinical symptoms, BNP, 
cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and 
laboratory work-up as clinically 
indicated. 
- 
Consider using steroids if clinical 
suspicion is high. 
 
 
Grade 2, 3 or 4 
 
- If Grade 2 -- Hold 
study drug/study 
regimen. If toxicity 
rapidly improves to 
Grade 0 AND 
myocarditis is 
excluded, then the 
decision to reinitiate 
study drug/study 
regimen will be based 
upon treating 
physician’s clinical 
judgment and after 
completion of steroid 
taper.  
- If toxicity does not 
rapidly improve, 
permanently. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV 
methylprednisolone 2 to 4 mg/kg/day 
or equivalent after Cardiology 
consultation has determined whether 
and when to complete diagnostic 
procedures including a cardiac 
biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days 
despite IV methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 
5 mg/kg every 2 weeks). Caution: It 
is important to rule out sepsis and 
refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-PJP 
treatment (refer to current NCCN 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
discontinue study 
drug/study regimen.  
- If myocarditis is 
diagnosed, permanently 
discontinue 
durvalumab. 
- If Grade 3-4, 
permanently 
discontinue study 
drug/study regimen. 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and 
symptoms of poly/myositis. 
Typically, muscle weakness/pain 
occurs in proximal muscles including 
upper arms, thighs, shoulders, hips, 
neck and back, but rarely affects the 
extremities including hands and 
fingers; also difficulty breathing 
and/or trouble swallowing can occur 
and progress rapidly. Increased 
general feelings of tiredness and 
fatigue may occur, and there can be 
new-onset falling, difficulty getting 
up from a fall, and trouble climbing 
stairs, standing up from a seated 
position, and/or reaching up. 
− 
If poly/myositis is suspected, a 
Neurology consultation should be 
obtained early, with prompt guidance 
on diagnostic procedures. 
Myocarditis may co-occur with 
poly/myositis; refer to guidance 
under Myocarditis. Given breathing 
complications, refer to guidance 
under Pneumonitis/ILD.  
Given possibility of an existent (but 
previously unknown) autoimmune 
disorder, consider Rheumatology 
consultation. 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Initial work-up should include 
clinical evaluation, creatine kinase, 
aldolase, LDH, BUN/creatinine, 
erythrocyte sedimentation rate or C-
reactive protein level, urine 
myoglobin, and additional laboratory 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
work-up as indicated, including a 
number of possible 
rheumatological/antibody tests (i.e., 
consider whether a rheumatologist 
consultation is indicated and could 
guide need for rheumatoid factor, 
antinuclear antibody, anti-smooth 
muscle, antisynthetase [such as anti-
Jo-1], and/or signal-recognition 
particle antibodies). Confirmatory 
testing may include 
electromyography, nerve conduction 
studies, MRI of the muscles, and/or a 
muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia 
or dysphonia. 
Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression, other medications, or infections). 
 
Grade 1 
 
- No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 
4 days for clinical symptoms and 
initiate evaluation as clinically 
indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing 
with the study physician. 
 
Grade 2 
 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
- Permanently 
discontinue study 
drug/study regimen if it 
does not resolve to 
Grade ≤1 within 30 
days or if there are 
signs of respiratory 
insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and 
consider hospitalization. 
− 
Obtain Neurology consult, and 
initiate evaluation. 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
If clinical course is rapidly 
progressive (particularly if difficulty 
breathing and/or trouble 
swallowing), promptly start IV 
methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with 
receiving input from Neurology 
consultant  
− 
If clinical course is not rapidly 
progressive, start systemic steroids 
(e.g., prednisone 1 to 2 mg/kg/day 
PO or IV equivalent); if no 
improvement within 3 to 5 days, 
continue additional work up and start 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV 
methylprednisolone at 2 to 
4 mg/kg/day there is no improvement 
within 3 to 5 days, consider start of 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 
5 mg/kg every 2 weeks). Caution: It 
is important to rule out sepsis and 
refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-PJP 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
 
 
Grade 3 or 4 
 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue 
study drug/study regimen 
if Grade 3 imAE does not 
resolve to Grade ≤1 within 
30 days or if there are 
signs of respiratory 
insufficiency. 
 
For Grade 4: 
- Permanently 
discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Monitor symptoms closely; 
recommend hospitalization. 
− 
Obtain Neurology consult, and 
complete full evaluation. 
− 
Consider, as necessary, discussing 
with the study physician. 
− 
Promptly start IV 
methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with 
receiving input from Neurology 
consultant. 
− 
If after start of IV 
methylprednisolone at 2 to 
4 mg/kg/day there is no improvement 
within 3 to 5 days, consider start of 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 
5 mg/kg every 2 weeks). Caution: It 
is important to rule out sepsis and 
refer to infliximab label for general 
guidance before using infliximab. 
− 
Consider whether patient may 
require IV IG, plasmapheresis. 
− 
Once the patient is improving, 
gradually taper steroids over ≥28 
days and consider prophylactic 
antibiotics, antifungals, or anti-PJP 

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aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine 
aminotransferase; AST Aspartate aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common 
Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated adverse event; IG 
Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic 
resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer Network; PCP ; PO  By mouth; 
T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN 
Upper limit of normal. 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event 
(NCI CTCAE 
version v5.0) 
Dose Modifications 
Toxicity Management 
treatment (refer to current NCCN 
guidelines for treatment of cancer-
related infections [Category 2B 
recommendation]).a 
 

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Infusion-Related Reactions 
Severity Grade of 
the Event (NCI 
CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the 
discretion of investigator. 
− 
Monitor patients for signs and symptoms of 
infusion-related reactions (e.g., fever and/or 
shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, 
dyspnea or chest discomfort, or skin rashes) 
and anaphylaxis (e.g., generalized urticaria, 
angioedema, wheezing, hypotension, or 
tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study 
regimen may be decreased by 50% or 
temporarily interrupted until resolution of 
the event. 
 
For Grade 2: 
The infusion rate of study drug/study 
regimen may be decreased 50% or 
temporarily interrupted until resolution of 
the event. 
Subsequent infusions may be given at 50% 
of the initial infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be 
administered per institutional standard at the 
discretion of the investigator. 
− 
Consider premedication per institutional 
standard prior to subsequent doses. 
− 
Steroids should not be used for routine 
premedication of Grade ≤2 infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per 
institutional standards (e.g., IM epinephrine, 
followed by IV diphenhydramine and 
ranitidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 

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Non–Immune-Mediated Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for 
AEs not deemed to be related to study 
treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not 
deemed to be clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution 
to ≤Grade 1 or baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution 
to ≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 2 within 7 
days or resolve to ≤Grade 1 or baseline within 
14 days, resume study drug/study regimen 
administration. Otherwise, discontinue study 
drug/study regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue 
should be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the Sponsor.). 
Treat accordingly, as per institutional standard. 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 
 
 
6.2 
Dose Modification for Cetuximab (15-JAN-2019) 
 
6.2.1 Cetuximab Dose Levels 
 
 
Starting Dose  
Dose Level –1  
Dose Level –2 
Cetuximab loading 
dose 
400 mg/m2  
Not applicable 
Not applicable 
Cetuximab 
250 mg/m2 (weekly) 
200 mg/m2 (weekly) 
150 mg/m2 (weekly) 
 
 
6.2.2 Cetuximab Dose Modifications for Hematologic Adverse Events 
Cetuximab will not be dose reduced or held for hematologic adverse events, such as 
neutropenia, neutropenic fever, or thrombocytopenia. 
 
 
 

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6.2.3 Cetuximab Dose Modifications for Non-Hematologic Adverse Events 
 
Toxicity Grade (CTCAE, v5.0) 
Cetuximab Dose a 
Renal-Calculated 
Creatinine Clearance (Cockroft-Gault 
Formula, see Section 3.2.3 for formula) 
Maintain dose level 
≥ 50 mL/min 
Maintain dose level 
< 50 mL/min 
Maintain dose level 
Nausea/Vomiting 
≤ Grade 2 with maximal medical management 
≥ Grade 3 with maximal medical management 
 
Maintain dose level 
Hold drug until ≤ grade 2, then resume at 
same dose level 
Other Non-hematologic 
Adverse Events b, c 
 
Grade 3- 4, if possibly related to cetuximab, 
or likely to be exacerbated by continuation of 
cetuximab, e.g. diarrhea, except for weight 
loss or mucositis 
Hold drug until < grade 3, then resume at 1 
dose level reduction 
Any grade 1-2 
Maintain dose level 
 
aDose levels are relative to the previous dose. Dose reductions of cetuximab below the –2 dose 
level will not be allowed. If a dose reduction below the -2 dose is mandated by the toxicity grade, 
cetuximab will be permanently discontinued. In any case of cetuximab treatment delay, there 
will be no re-loading infusion, and all subsequent treatment will be at the assigned dose level. 
bWith the exception of infusion reaction; 
cFor depressed K or Mg, administer replacement therapy. Chemotherapy should continue at the 
discretion of the treating physician (see table below for management of hypomagnesemia). 
 
Hypomagnesemia 
Electrolyte repletion, principally magnesium, was necessary in some patients treated with 
cetuximab and in severe cases, intravenous replacement was required. The time to resolution of 
electrolyte abnormalities is not well known, hence monitoring during and after cetuximab 
treatment is recommended. 
 
CTCAE, 
v5.0 
Grade 
Serum Magnesium 
Guidelines for 
management 
Action 
mg/dL 
mmol/L 
1 
< LLN - 1.2  
 
< LLN - 0.5  
 
Consider replacement with 
IV magnesium sulfate 2-5 g 
in normal saline or D5W. 
Infusion schedule based on 
institutional guidelines. 
Maintain dose 
and schedule 
2 
< 1.2 - 0.9  
 
< 0.5 - 0.4  
 
As above for grade 1 and 
consider prophylactic 
weekly infusion of 
magnesium and/or oral 
Maintain dose 
and schedule 

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magnesium 
supplementation (e.g. 
magnesium oxide) if grade 
2 of higher 
hypomagnesemia persists. 
3 
< 0.9 - 0.7  
 
< 0.4 - 0.3  
 
As above for grades 1 and 2 
Hold cetuximab 
until recovery 
to ≤ grade 2, 
then resume at 
same dose level 
4 
< 0.7  
 
< 0.3 
 
As above for grades 1 and 2 
Hold cetuximab 
until recovery 
to ≤ grade 2, 
then reduce by 
1 dose level 
 
 
6.2.4 Cetuximab Infusion Related Reaction Management 
 
CTCAE, v5.0 Adverse Event Grade 
Treatment Guidelines a 
Grade 1: 
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated 
For mild infusion reactions manifesting only 
as delayed drug fever, consider administering 
prophylactic antihistamine medications for 
subsequent doses. Maintain the cetuximab 
dose. Acetaminophen or a non-steroidal anti-
inflammatory drug (NSAID) may be 
administered prior to subsequent cetuximab 
infusions, if not otherwise contraindicated in 
subjects. 
Grade 2: 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDS, narcotics, IV 
fluids); prophylactic medications indicated for 
≤ 24 hrs 
For moderate infusion reactions, slow the 
infusion rate for cetuximab by 50% when the 
drug is restarted and consider administering 
antihistamine medications and/or steroidal 
medications. Maintain the cetuximab dose. 
Acetaminophen or a non-steroidal anti-
inflammatory drug (NSAID) may be 
administered prior to subsequent cetuximab 
infusions, if not otherwise contraindicated in 
subjects. 
Grade 3: 
Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae 
NO FURTHER CETUXIMAB . Severe 
infusion reactions require immediate 
interruption of cetuximab infusion and 
permanent discontinuation from further 
treatment with cetuximab. Appropriate 
medical therapy including epinephrine, 
corticosteroids, diphenhydramine 

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bronchodilators, and oxygen should be 
available for use in the treatment of such 
reactions. Subjects should be carefully 
observed until the complete resolution of all 
signs 
and symptoms. 
Grade 4: 
Life-threatening consequences; urgent 
intervention indicated 
NO FURTHER CETUXIMAB. Life 
threatening infusion reactions require 
immediate interruption of cetuximab 
infusion and permanent discontinuation 
from further treatment with cetuximab. 
Appropriate medical therapy including 
epinephrine, corticosteroids, 
diphenhydramine, bronchodilators, and 
oxygen should be available for use in the 
treatment of such reactions. Subjects should 
be carefully observed until the complete 
resolution of all signs and symptoms. 
 
 
aStudy Therapy Retreatment Following Infusion Reactions: Once a cetuximab infusion rate has 
been decreased due to an infusion reaction, it will remain decreased for all subsequent infusions. 
If the subject has a second infusion reaction > grade 2 with the slower infusion rate, the infusion 
should be stopped, and the subject should receive no further cetuximab treatment. If a subject 
experiences a Grade 3 or 4 infusion reaction at any time, the subject should receive no further 
cetuximab treatment. If there is any question as to whether an observed reaction is an infusion 
reaction of Grades 1-4, the Study Chair or Medical Oncology Co-Chair should be contacted 
immediately to discuss and grade the reaction. 
 
6.2.5 Cetuximab Special Instructions 
Weekly cetuximab will continue if radiation therapy is being held. If cetuximab is 
omitted for more than four consecutive infusions for adverse events due to cetuximab, or 
for an intercurrent illness (e.g., infection) requiring interruption of therapy, the subject 
should be discontinued from further cetuximab therapy. If adverse events prevent the 
administration of cetuximab, the subject may continue to receive radiation therapy. 
 
If a dose of cetuximab is omitted, it will not be made up or added to the end of treatment. 
The omitted dose and the reason for the omission should be recorded in the site’s source 
documentation. 
 
Treatment of Isolated Drug Fever 
In the event of isolated drug fever, the investigator must use clinical judgment to 
determine if the fever is related to the study drug or to an infectious etiology. If a patient 
experiences isolated drug fever, for the next dose, pre-treat with acetaminophen or non-
steroidal anti-inflammatory agent (investigator discretion), repeat antipyretic dose 6 and 
12 hours after cetuximab infusion. The infusion rate will remain unchanged for future 
doses 

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If a patient experiences recurrent isolated drug fever following pre-medication and post-
dosing with an appropriate antipyretic, the infusion rate for subsequent dosing should be 
50% of previous rate. If fever recurs following infusion rate change, the investigator 
should assess the patient’s level of discomfort with the event and use clinical judgment to 
determine if the patient should receive further cetuximab. 
 
Cetuximab-related Rash 
Manifestations 
Rash associated with EGFR-inhibitors is a relatively new dermatologic condition. It 
appears to be “acneiform” but it is NOT considered a form of acne; rather, it is a form of 
folliculitis. Skin changes may be manifested in a number of ways: erythema; follicle 
based papules, which may ulcerate; pain; itching; cosmetic disturbance; and/or nail 
disorders. The rash may become infected and transform into cellulitis. 
 
Grading of Cetuximab-induced Rash 
According to physician judgment, if a patient experiences ≥ grade 3 rash (according to 
either the “outside of the radiation field” or the “inside of the radiation field” definitions 
below), cetuximab treatment adjustments should be made according to the Cetuximab 
Dose Modification table that follows. In patients with mild and moderate skin adverse 
events, cetuximab should continue without adjustment. 
 
NOTE: Rash intensity (i.e., the size and number of papules or the level of discomfort and 
extent of erythema) may be an important consideration. However, the absolute number of 
lesions, without associated physical discomfort, does not necessarily constitute a basis 
for a dose reduction or delay. Rash considered “intolerable” (because of pain, itching, or 
appearance) or that has failed to respond to symptomatic management may be considered 
grade 3 and thus prompt dose reduction or delay of cetuximab. The clinical judgment of 
the treating physician is critical to grading and will ultimately dictate dose 
modification. 
 
Acute Skin Changes 
Rash Occurring Outside of the Radiation Field: Should be graded using CTCAE, v5.0 
terms; common skin toxicities include the following: pruritus, rash/acneiform, 
paronychia. A rash complicated by secondary infection or cellulitis should be graded per 
additional CTCAE, v5.0 terms. 
 
Onset of grade 3 will require modification. See the table below, “Cetuximab Dose 
Modification Guidelines for Dermatologic Changes”. 
 
 
1 
2 
3 
4 
Pruritus 
Mild or 
localized; 
topical 
intervention 
indicated  
 
Widespread and 
intermittent; skin 
changes from 
scratching (e.g., 
edema, 
papulation, 
excoriations, 
Widespread and 
constant; limiting 
self care ADL or 
sleep; systemic 
corticosteroid or 
immunosuppressive 
therapy indicated  
- 

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lichenification, 
oozing/crusts); 
oral intervention 
indicated; 
limiting 
instrumental 
ADL  
 
 
Rash/acneiform Papules and/or 
pustules 
covering <10% 
BSA, which 
may or may not 
be associated 
with symptoms 
of pruritus or 
tenderness  
 
Papules and/or 
pustules 
covering 10 - 
30% BSA, which 
may or may not 
be associated 
with symptoms 
of pruritus or 
tenderness; 
associated with 
psychosocial 
impact; limiting 
instrumental 
ADL; papules 
and/or pustules 
covering > 30% 
BSA with or 
without mild 
symptoms  
 
Papules and/or 
pustules covering 
>30% BSA with 
moderate or severe 
symptoms; limiting 
self-care ADL; 
associated with 
local superinfection 
with oral antibiotics 
indicated  
 
Life-
threatening 
consequences; 
papules and/or 
pustules 
covering any 
% BSA, which 
may or may 
not be 
associated with 
symptoms of 
pruritus or 
tenderness and 
are associated 
with extensive 
superinfection 
with IV 
antibiotics 
indicated  
 
Paronychia 
Nail fold edema 
or erythema; 
disruption of 
the cuticle  
 
Local 
intervention 
indicated; oral 
intervention 
indicated (e.g., 
antibiotic, 
antifungal, 
antiviral); nail 
fold edema or 
erythema with 
pain; associated 
with discharge or 
nail plate 
separation; 
limiting 
instrumental 
ADL  
 
Operative 
intervention 
indicated; IV 
antibiotics 
indicated; limiting 
self care ADL  
 
 
 

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Rash Occurring Inside the Radiation Field: Acute radiation dermatitis may be 
exacerbated by cetuximab or chemotherapy. The severity of such rash should be graded 
using CTCAE, v5.0 criteria for radiation dermatitis (table below). 
 
 
1 
2 
3 
4 
Radiation 
recall reaction 
(dermatologic); 
Dermatitis 
radiation 
 
Faint erythema 
or dry 
desquamation 
Moderate to brisk 
erythema; patchy 
moist desquamation, 
mostly confined to 
skin folds and 
creases; moderate 
edema 
Moist 
desquamation other 
than skin folds and 
creases; bleeding 
induced by minor 
trauma or abrasion 
Life-threatening 
consequences; 
skin necrosis or 
ulceration of 
full 
thickness 
dermis; 
spontaneous 
bleeding from 
involved site; 
skin 
graft indicated 
 
 
Cetuximab Dose Modification Guidelines for Dermatologic Changes (≥ Grade 3) 
 
Cetuximab 
Outcome 
Cetuximab Dose Modification 
1st 
occurrence 
Delay infusion 1 to 2 
weeks 
Improvement to ≤ 
Grade 2 
Continue at 250 mg/m2 
 
 
No Improvement; 
remains grade 3 
Discontinue cetuximab 
2nd 
occurrence 
Delay infusion 1 to 2 
weeks  
Improvement to ≤ 
Grade 2 
Reduce dose to 200 mg/m2 
 
 
No Improvement; 
remains grade 3 
Discontinue cetuximab 
3rd 
occurrence 
Delay infusion 1 to 2 
weeks 
Improvement to ≤ 
Grade 2 
Reduce dose to 150 mg/m2 
 
 
No Improvement; 
remains grade 3 
Discontinue cetuximab 
4th 
occurrence 
Discontinue 
cetuximab 
 
 
 
Drug-Related Rash Management 
Patients developing dermatologic adverse events while receiving cetuximab should be 
monitored for the development of inflammatory or infectious sequelae, and appropriate 
treatment of these symptoms initiated. Below are suggestions for managing cetuximab-
induced rash*: 

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• Antibiotics: The benefit of routine antibiotics in uncomplicated (uninfected) rash is 
unclear. Some clinicians have used oral minocycline (Minocin), mupirocin 
(Bactroban), or topical clindamycin (Cleocin). Rash complicated by cellulitis should 
be treated with appropriate antibiotics based on clinical judgment or microbial 
sensitivity analysis. 
• Antihistamines: Benadryl or Atarax may be helpful to control itching. 
• Topical Steroids: The benefit of topical steroids is unclear. In general, steroids 
should not be used to treat a rash in the RT field.  
• Retinoids: No data to support use. Use is not advised. 
• Benzoyl peroxide: Should NOT be used—may aggravate rash. 
• Makeup: Rash can be covered with makeup; this should not make it worse (use a 
dermatologist-approved cover-up, e.g., Dermablend, or any other type of foundation). 
Remove makeup with a skin-friendly liquid cleanser, e.g., Neutrogena, Dove, or 
Ivory 
• Skin Cleansing Liqui-Gel. 
• Moisturizers: Use emollients to prevent and alleviate the skin dryness, e.g., 
Neutrogena Norwegian Formula Hand Cream or Vaseline Intensive Care Advanced 
Healing Lotion. 
• Sunlight: It is recommended that patients wear sunscreen and hats and limit sun 
exposure while receiving cetuximab as sunlight can exacerbate any skin reactions that 
may occur. 
• Over-the-counter medications: Over-the-counter acne vulgaris medications (e.g., 
benzoyl peroxide) are not advised. This rash is not like acne vulgaris and these 
treatments could make it worse. 
 
*Adapted from Perez-Soler R, Delord J, Halpern A, et al. HER1/EGFR inhibitor-
associated rash: Future directions for management and investigation outcomes from 
the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10:345-56. 
 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS (15-JAN-2019) 
7.1  
Protocol Agents 
Investigational Agent 
The investigational agent administered in NRG-HN004, MEDI4736 (durvalumab), is 
being made available under an IND sponsored by CTEP. For MEDI4736 (durvalumab) 
and cetuximab, determination of whether an adverse event meets expedited reporting 
criteria, see the reporting table in Section 7.5 of the protocol. 
For Arm 2, MEDI4736 (durvalumab), report all adverse events regardless of 
relationship to protocol treatment during treatment and for 100 days from last dose 
of MEDI4736 (durvalumab). During follow-up, only report adverse events 
reasonably related to protocol treatment.  
 
Commercial Agent 
The commercial agent in NRG-HN004 is cetuximab.  
 

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For Arm 1, cetuximab, report all adverse events regardless of relationship to 
protocol treatment during treatment and for 30 days from end of treatment. During 
follow-up, only report adverse events reasonably related to protocol treatment. 
  
7.2 
Adverse Events and Serious Adverse Events (15-JAN-2019) 
7.2.1 Adverse Event Reporting 
Lead-In Phase: The lead-in phase will utilize CTCAE version 5.0 for CTEP-AERS 
reporting. All study case report forms will continue to use CTCAE version 4.0. 
 
Phase II/III: The randomized phase II/III study will utilize CTCAE v5.0 for both CTEP-
AERS reporting and study case report forms. Note:  for the Phase II/III study, CTEP-
AERS reporting is performed via a deep link in Rave (see Section 7.5). 
 
All appropriate treatment areas should have access to a copy of CTCAE versions 4.0 and 
5.0, which can be downloaded from the CTEP web site 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
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-
HN004 NCI PRO-CTCAE Item Library.” 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. 
NOTE: PRO-CTCAE data should not be used for determining dose delays or dose 
modifications or any other protocol directed action. 
 
 
 

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7.2.3 Solicited Adverse Events and PRO-CTCAE 
PRO-CTCAE 
The PRO-CTCAE instrument will be used to assess patient reported toxicity outcomes.  
The United States National Cancer Institute's Patient-Reported Outcomes version of the 
Common Terminology Criteria for Adverse Events (PRO-CTCAE) has been validated 
and tested for reliability and responsiveness in 975 cancer patients undergoing 
chemotherapy or radiotherapy (Dueck 2015). In the HNC population, a study evaluating 
CRT compared the NCI-CTCAE to the PRO-CTCAE, and found a high concordance 
between patient-reported and practitioner-reported symptom severity at baseline, when 
symptoms were absent, but as toxicity increased during therapy, it was noted that 
clinician reported toxicity was significantly lower than patient reported toxicity. The 
PRO-CTCAE is included to address tolerability of the treatment regimen from the 
patients’ perspective. It was developed in recognition that collecting symptom data 
directly from patients using PRO tools can improve the accuracy and efficiency of 
symptomatic AE data collection. This was based on findings from multiple studies 
demonstrating that physicians and nurses underestimate symptom onset, frequency, and 
severity in comparison with patient ratings (Basch 2009, Litwin 1998, Sprangers and 
Aaronson 1992, Falchook 2016). These symptoms have been converted to patient terms 
(eg, CTCAE term “myalgia” converted to “aching muscles”). For several symptoms, like 
fatigue and pain, additional questions are asked about symptom frequency, severity, and 
interference with usual activities. The items included in the PRO-CTCAE have 
undergone extensive qualitative review among experts and patients. These items have 
been extensively evaluated by patients with cancer to be clear and comprehensible, and to 
measure the symptom of interest. In this study, we have selected 17 of the 78 items, 
which are only items that are considered relevant for the trial based on toxicity profiles of 
cetuximab, MEDI4736 (durvalumab), and radiotherapy for head and neck cancer.   
 
PRO-CTCAE is available in English, French (Canada), and Spanish 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 (Canada) 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. 
 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and for each cycle of 
treatment by CTCAE, PRO-CTCAE (for the phase II/III portion of study only), or both. 
 
Assessments will be collected as specified in the Section 4 assessment tables. 
 
CTCAE 
PRO-CTCAE 
Items 
with 
(Attributes) 
1. Dysphagia  
2. Mucositis (oral) 
3. Anorexia  
4. Nausea  
Oral: 
1. Difficulty swallowing (S) 
2. Mouth/Throat sores (SI) 
Gastrointestinal: 

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5. Vomiting  
6. Diarrhea 
7. Abdominal pain   
8. Dyspnea 
9. Cough  
10. Wheezing  
11. Edema limbs 
12. Rash maculopapular 
13. Rash acneiform  
14. Pruritus  
15. Dermatitis radiation 
16. Myalgia 
17. Fatigue 
 
3. Decrease appetite (SI) 
4. Nausea (FS) 
5. Vomiting (FS) 
6. Diarrhea (F) 
7. Abdominal pain (FSI) 
Respiratory: 
8. Shortness of breath (SI) 
9. Cough (SI) 
10. Wheezing (S) 
Cardiovascular 
11. Arm or leg swelling (FSI) 
Cutaneous: 
12. Rash (P) 
13. Acne (S) 
14. Itching (S) 
15. Radiation skin reaction (S) 
Pain: 
16. Muscle pain (FSI) 
Sleep/wake: 
17. Fatigue (SI) 
 
Attributes: 
F: Frequency 
S: Severity 
I: Interference 
P: Presence/Absence/Amount 
 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for  
MEDI4736 (Durvalumab, NSC 778709) (21-AUG-2019) 
 
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 2833 patients. Below is the CAEPR for 
MEDI4736 (durvalumab). 
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 2.4, April 17, 20191 

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 Adverse Events with Possible  
 Relationship to MEDI4736 (durvalumab) 
 (CTCAE 5.0 Term) 
[n= 2833] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Blood and lymphatic system 
disorders - Other (idiopathic 
thrombocytopenic purpura)2 
  
 
 
Thrombotic thrombocytopenic 
purpura2 
  
CARDIAC DISORDERS 
  
 
 
Myocarditis2 
  
 
 
Pericarditis2 
  
ENDOCRINE DISORDERS 
  
 
 
Adrenal insufficiency2 
  
 
 
Endocrine disorders - Other 
(diabetes insipidus) 
  
 
 
Endocrine disorders - Other 
(diabetes mellitus type 1)2 
  
 
Hyperthyroidism2 
 
  
 
 
Hypopituitarism2 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Keratitis2 
  
 
 
Uveitis2 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colitis2 
  
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
 
Gastrointestinal disorders -
Other - (gastrointestinal 
perforation)2,3 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
 
Pancreatitis2 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Immune system disorders - 
Other (immune related adverse 
events)2 
  
 
 
Immune system disorders - 
Other (sarcoidosis) 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  Infection4 (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Infusion related reaction 
  
INVESTIGATIONS 
  

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 Adverse Events with Possible  
 Relationship to MEDI4736 (durvalumab) 
 (CTCAE 5.0 Term) 
[n= 2833] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Alanine aminotransferase 
increased2 
 
 Alanine aminotransferase 
increased2 (Gr 2) 
 
Aspartate aminotransferase 
increased2 
 
 Aspartate aminotransferase 
increased2 (Gr 2) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthritis2 
 
  
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis)2 
  
 
Myalgia 
  
 Myalgia (Gr 2) 
 
 
Myositis2 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2,5 
  
 
 
Myasthenia gravis2 
  
 
 
Nervous system disorders - 
Other (aseptic meningitis)2 
  
 
 
Peripheral sensory neuropathy   
RENAL AND URINARY DISORDERS 
  
 
Dysuria 
 
 Dysuria (Gr 2) 
 
 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
Cough 
 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Pneumonitis2 
 
  
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(dysphonia) 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 Hyperhidrosis 
 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash2,6  
 
 Rash2,6 (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (scleroderma) 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (severe 
dermatitis)2,7 
  
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
 
NOTE: Cardiomyopathy, and graft versus host disease, while not observed on clinical trials of MEDI4736 
(durvalumab) at this time, are known events with this class of agent (PD-L1 antagonist). 
 
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. 
 

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2Immune-mediated adverse reactions (irAEs) have been reported in patients receiving MEDI4736 
(durvalumab).  irAEs can involve any of the organs or systems in the body.  Most irAEs were reversible 
and managed with interruptions of MEDI4736 (durvalumab), administration of corticosteroids and 
supportive care, however, these events can be serious and fatal. 
 
3Gastrointestinal perforations have been observed only in patients receiving MEDI4736 (durvalumab) in 
combination with tremelimumab (CP-675,206). 
 
4Infections includes infection in the lungs, upper respiratory tract, dental and oral soft tissues and other 
organs under the INFECTIONS AND INFESTATIONS SOC.  Infections generally are mild (Gr 1-2) but 
severe infections including sepsis, necrotizing fasciitis, and osteomyelitis have been reported. 
 
5Guillain-Barre Syndrome has been reported in patients receiving MEDI4736 (durvalumab) in combination 
with tremelimumab (CP-675,206) but can potentially occur after durvalumab monotherapy.  
 
6Rash includes the terms: rash erythematous, rash generalized, rash macular, rash maculopapular, rash 
papular, rash pruritic, rash pustular, erythema, and eczema. 
 
7In rare cases, severe dermatitis has been reported to manifest as Stevens-Johnson syndrome, toxic 
epidermal necrolysis, or rashes complicated by dermal ulceration or necrotic, bullous, or hemorrhagic 
manifectations. 
 
 
Adverse events reported on MEDI4736 (durvalumab) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MEDI4736 (durvalumab) caused 
the adverse event:  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Disseminated intravascular coagulation 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (coronary artery 
disease); Pericardial effusion; Pericardial tamponade; Restrictive cardiomyopathy; Right ventricular 
dysfunction; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Eye disorders - Other (choroidal effusion with shut down of ciliary body) 
GASTROINTESTINAL DISORDERS - Ascites; Constipation; Dental caries; Gastrointestinal disorders - 
Other (gastrointestinal hemorrhage); Mucositis oral; Proctitis; Small intestinal obstruction; Upper 
gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Non-cardiac chest 
pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic hemorrhage 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (drug-induced liver injury); Serum 
sickness 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Wound complication 
INVESTIGATIONS - Blood bilirubin increased; CPK increased; Electrocardiogram T wave abnormal; GGT 
increased; Lipase increased; Lymphocyte count decreased; Neutrophil count decreased; Platelet count 
decreased; Serum amylase increased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypermagnesemia; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; 
Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (brain metastasis swelling); Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (lung cyst); Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (tumor flare, tumor inflammation); Treatment 
related secondary malignancy; Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Dizziness; Edema cerebral; Headache; Nervous system 
disorders - Other (axonal neuropathy); Nervous system disorders - Other (hemiparesis); Paresthesia; 

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Seizure 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Hypoxia; Pleural effusion; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin 
VASCULAR DISORDERS - Hypertension 
 
Note: MEDI4736 (durvalumab) 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 Agents: Cetuximab 
Refer to the package insert for detailed pharmacologic and safety information 
Common adverse events include: infusion reaction; nausea, vomiting, diarrhea; weight; 
loss; abnormal liver function tests; rash acneiform; radiation dermatitis. 
 
7.5 
Expedited Reporting of Adverse Events (21-AUG-2019) 
Lead-In Phase: 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://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Phase II/III: All adverse events are submitted for expedited reporting protocol-specific 
rules evaluation using the Medidata Rave data management system. All AEs must first be 
entered in Rave and will undergo CTEP-AERS rules evaluation to determine whether 
expedited reporting is recommended based on a set of programmed expedited reporting 
rules. AEs identified as meeting the programmed expedited reporting requirements can 
then be submitted in CTEP-AERS. A deep link in Rave will take the user directly to 
CTEP-AERS where the expedited report may be completed and submitted via CTEP-
AERS. 
 
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 link in Rave. CTEP-AERS is also accessed via the CTEP web 
site, but all expedited reports must be initiated in RAVE 
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to 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  
•  “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.  
CTEP-AERS 24-hour notification must be followed by a complete report within 5 
days.  
• Supporting source documentation is requested by CTEP or NRG as needed to 
complete adverse event review. Supporting source documentation should include the 

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protocol number, patient ID number, and CTEP-AERS ticket number on each page. 
Contact NRG Oncology at 1-215-574-3191 for details to submit source 
documentation (CTEP fax: 301-897-7404). 
• 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 CTEP Expedited Reporting Requirements for Adverse Events  
 
 
For the Lead-In and Arms 1 and 2 of the Phase 2/3: Expedited Reporting 
Requirements for Adverse Events that Occur within 30 Days of the Last 
Administration of Cetuximab or RT and within 100 Days of the Last 
Administration of MEDI4736 (durvalumab)1, 2 
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 electronic 
submission 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 submitted electronically 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 electronically within 10 
calendar days of learning of the AE. 

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1Serious adverse events that occur more than 30 days after the last administration of protocol treatment (Arm 1) 
and more than 100 days after the last administration of MEDI4736 (durvalumab) (safety lead-in and Arm 2) 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: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
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 
 
Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements  
Clinician graded CTCAE is the AE 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 study-specific PRO-CTCAE items for this protocol can be found 
on the forms section of the CTSU protocol webpage and is titled “NRG-HN004 NCI PRO-
CTCAE Item Library” 
 
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.  
 
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: 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
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. 
 
 

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7.6 
Routine Reporting Requirements for Adverse Events (15-JAN-2019) 
All Adverse Events must be reported in routine study data submissions. For the Lead-In, 
AEs reported expeditiously through CTEP-AERS must also be reported in routine study 
data submissions. For the Phase II/III, all AEs must first be entered in Rave and will 
undergo CTEP-AERS rules evaluation to determine whether expedited reporting is 
recommended based on a set of programmed expedited reporting rules. AEs identified as 
meeting the programmed expedited reporting requirements can then be submitted in 
CTEP-AERS via a deep link in Rave. 
 
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 (15-JAN-2019) 
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 6 months after the last dose of either cetuximab or 
MEDI4736 (durvalumab) 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 
 
8.1 
CTEP Registration Procedures and Access requirements for OPEN, Medidata 
Rave, and TRIAD (13-JAN-2021) 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.   
 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
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; 

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• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
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) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs 
and NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the 
FDA Form 1572 in RCR to allow the following: 
• Added to a site roster; 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• Act as the site-protocol Protocol Investigator (PI) on the IRB approval; and  
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
In addition, all investigators acting as the site-protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization. 
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
 
 
 
 

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8.2 
CTSU Registration Procedures (09-MAR-2022) 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
8.2.1 IRB Approval  
For 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 after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). 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). 
 
In addition, the site-protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
• Holds an active CTEP status; 
• Active status at the site(s) on the IRB/REB approval (applies to US and Canadian 
sites only) on at least one participating organization’s roster; 
• If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB 
Signatory Institutions(s) record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; 
• Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 
in the RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol. 
 
Additional Requirements for NRG-HN004 Site Registration 
Additional site requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); 
• A valid IRB approval; 
• An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only);  
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site must be aligned to an RTI provider (see further information below).  
• Delegation of Task Log (DTL) – see section 8.2.4 for further instructions. 
• IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC 
to begin the modality credentialing process.   
o Credentialing documentation received from IROC Houston for this trial- 
See Section 8.3 Table for details. 
• Compliance with all protocol specific requirements (PSRs). 
 
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 a treating site roster can update the 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 website. 
 
To complete protocol-specific credentialing the RTI provider or enrolling site should 
follow instructions in the section 8.3 of protocol to submit documentation or other 
materials to the designated IROC Quality Assurance (QA) center. IROC Houston QA 
Center will notify the site that all desired credentialing requirements have been met. 
The site will need to upload a PDF of approval email from IROC Houston to the 
CTSU Regulatory Portal for RSS to be updated. 
 
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 OPEN credentialing screen and may need to answer 
additional questions related to treatment in the eligibility checklist. 
 
8.2.2 Downloading Site Registration Documents:  
Download the site registration forms from the NRG-HN004 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and staff 
on a participating roster. To view/download site registration forms:   
 
• Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• 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 

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protocol number NRG-HN004. 
• 
Click on Documents, Protocol Related Documents, and use the Document Type filter 
and select Site Registration to download and complete the forms provided.  (Note: 
For sites under the CIRB, IRB data will load automatically to the CTSU.) 
 
8.2.3    Submitting Regulatory Documents:  
         Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ 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 Portal should alert the CTSU 
Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org in order to receive further instruction and support. 
 
8.2.4    Delegation of Task Log (DTL) 
Each site must complete a protocol-specific DTL. The Clinical Investigator (CI) is 
required to review and electronically sign the DTL prior to the site receiving an approved 
site registration status and enrolling patients to the study. To maintain an approved site 
registration status the CI must re-sign the DTL at least annually and when a new version 
of the DTL is released; and to activate new task assignments requiring CI sign-off. Any 
individual at the enrolling site on a participating roster may initiate the site DTL. Once 
the DTL is submitted for CI approval, only the designated DTL Administrators or the CI 
may update the DTL. Instructions on completing the DTL are available in the Help 
Topics button in the DTL application and include a Master Task List, which describes 
DTL task assignments, CI signature, and CTEP registration requirements.  
 
Canadian sites participating under the Canadian Cancer Trials Group (CCTG), should 
complete the DTL in CCTG’s Ripple application when CCTG holds the Clinical Trials 
Agreement with Health Canada. Ripple is integrated with the CTSU DTL application for 
this trial.   
 
8.2.5 Checking Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  
• Click on Regulatory at the top of the screen;  
• Click on Site Registration; and  
• 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 outlined within the protocol. It does not reflect compliance with protocol 
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status with NCI or their affiliated networks. 
 
8.3 
RT-Specific Pre-Registration Requirements (09-MAR-2022) 
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, the IROC Houston QA Center 
will notify your institution and NRG Headquarters when all credentialing requirements 
have been met and the institution is RT credentialed to enter patients onto this study.  
 
 
8.3.1 Digital RT Data Submission to NRG Using TRIAD  
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: 
Credentialing 
Requirements 
 
Web Link for Procedures and Instructions: [www.irochouston.meanderson.org 
 
Treatment 
Modality 
Key Information 
 
Photons 
 
Facility 
Questionnaire 
✓
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 
http://irochouston.mdanderson.org to receive your FQ link. 
Credentialing 
Status Inquiry 
Form 
✓
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 ). 
Phantom 
Irradiation 
✓
An IMRT Head and neck phantom irradiation 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). Note that an 
institution, depending on its treatment delivery modalities, may be required to irradiate a 
phantom on different delivery machines such as TomoTherapy. 
IGRT 
Verification 
Study 
✓
Institutions must be credentialed for bony tissue IGRT by IROC Houston. Find details on the 
IROC Houston QA Center website (http://irochouston.mdanderson.org) Institutions that have 
previously been approved for IGRT may not need to repeat credentialing. 
 
Credentialing Issued to: 
Institution 
 
 
IROC Houston QA Center will notify the site that all desired credentialing requirements have 
been met. The site will need to upload a PDF of approval email from IROC Houston to the 
CTSU Regulatory Portal for RSS to be updated. 

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• A valid Cancer Therapy Evaluation Program Identity and Access 
Management (CTEP-IAM) account.  
• 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. 
• TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have 
access to TRIAD and may submit images for credentialing purposes, or for 
enrollments to which the provider is linked in OPEN. 
 
TRIAD Installations: 
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. 
 
8.4  
Patient Enrollment (09-MAR-2022) 
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.  
 
8.4.1 Oncology Patient Enrollment Network (OPEN)  
Patient enrollment for this 2-step (registration and randomization) trial will be 
facilitated using the Oncology Patient Enrollment Network (OPEN). 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:   

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• A valid CTEP-IAM account; 
• To perform enrollments: 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; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrars must 
hold the OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for the protocol prior to patient enrollment. 
To assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR 
only), or investigator receiving a transfer in OPEN, the IVR or NPIVR must list the IRB 
number used on the site’s approval on their Form FDA 1572 in RCR.  If a DTL is 
required for the study, the IVR or NPIVR must be assigned the appropriate OPEN-related 
tasks on the DTL. 
 
Prior to accessing OPEN site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes; and 
• 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 at https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
NOTE: Step 2 registration requires a second web registration for all patients.  
If a patient is not going on to randomization, Step 2 registration must still be completed 
via OPEN and the reason why the patient will not go on study must be provided. 
 
8.4.2 Summary of Registration Procedures 
This is a 2-step registration study.  
• All eligibility criteria (except central p16 review*) must be met prior to Step 1 
registration (*central p16 review applicable to Oropharynx and Unknown primary 
only). 
• All patients will be registered to Step 1.  
o For Oropharynx and Unknown primary patients, tissue submission is 
required for the central p16 review after Step 1 registration has been 
completed and a case number assigned (refer to section 10 for details on 
tissue submission). 
▪ The central review will take approximately 1-2 business days from 
receipt of samples. 
▪ NRG Oncology will notify the sites via an e-mail once the p16 
results have been received. Sites can complete Step 2 registration 
at this time. 

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o For Oral cavity, Hypopharynx, and Larynx primary patients, sites must 
complete step II registration the following day. NRG requires the time to 
calculate the stratification, which is required for randomization.  
8.5 
Medidata Patient Cloud ePRO Registration (13-JAN-2021) 
This study includes the use of Medidata Patient Cloud ePRO (electronic patient-reported 
outcomes). After the patient is registered to the trial via OPEN, and if the patient is 
willing to participate in electronic data collection, the site staff will then complete a 
registration for the patient to the Patient Cloud ePRO through iMedidata. Note: Site staff 
must have already completed required eLearning for the Patient Cloud ePRO application 
to register a patient and information about the training is in the ePRO Appendix. The 
registration to the Patient Cloud ePRO will create a unique patient registration code that 
the site staff will provide to the patient. The patient (with assistance from the site staff) 
should be instructed to download the Patient Cloud ePRO app onto his/her own device 
(IOS, Android, phone or tablet) and use the unique patient registration code to create an 
account. Once the patient's account is set up, the patient will be able to complete the 
submission of patient reported outcomes electronically for the trial. There are multiple 
versions of the app available. The Patient Cloud App will be used on this study. Ensure 
that the patient downloads the correct version of the ePRO app. Note only 1 version of 
the app is active per protocol. 
 
For sites providing a shared institutional device for use by multiple patients on site:  
• The site staff should assist the patient with access and registration to the Patient 
Cloud ePRO app, and the patient can then complete the electronic data submission 
independently.  Site staff may need to assist patients with logging on to the device at 
each visit.  
8.5.1 CRA Patient Registration Instructions for ePRO 
Please visit the CTSU website for reference information.  
i. 
The subject registration process starts in iMedidata.  Begin by selecting the Patient 
Cloud ePRO Registration link for your study 
ii. 
The patient management app will display, select your STUDY and SITE from the 
drop downs and click Launch. 
iii. 
Now you can register your first patient. Create a subject ID and select a Country / 
Language from the drop down, (these are the only required data fields). The subject 
initials are optional, but are helpful in identifying which subject ID maps with which 
activation code. When finished, click Add. 
iv. 
The subject added and will include the date the patient was added, the subject ID, 
subject initials, (if included) and a unique auto-generated activation code. The 
activation code is unique for each patient and linked to the subject ID, it is not 
interchangeable. In addition, there is a status section, which indicates if the patient 
has registered. When the patient has registered the status will change from "invited" 
to "registered". 
Reminder- site staff must have already completed the Medidata Patient Cloud training in 

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order to register study participants. Please visit the CTSU website for reference 
information.  
 
9. 
DRUG INFORMATION  
9.1 
Investigational Study Agent: MEDI4736 (Durvalumab) (NSC 778709) (09-MAR-
2022) 
 
9.1.1 Agent Ordering and Agent Accountability  
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. Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the PMB Online 
Agent Order Processing (OAOP) application. Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of an 
“active” account status and a “current” password. 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. 
 
9.1.2 Subjects must be enrolled and assigned to the MEDI4736 (durvalumab) treatment 
arm prior to submitting the agent request to PMB. 
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  
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)  
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 

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Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
9.1.3 Agent-Specific Information 
  
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 Online 
Agent Order Processing (OAOP) application. Access to OAOP 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. 
Questions about IB access may be directed to the PMB IB Coordinator via email to 
ibcoordinator@mail.nih.gov or the IB Coordinator may be contacted at 240-276-6575. 
 
 
Other Names: IMFINZI™ 
 
Classification: Anti-PD-L1 MAb 
 
Molecular Weight: ~ 149 kDa 
 
Mode of Action: Durvalumab (MEDI4736) inhibits binding of programmed cell death 
ligand 1 (PD-L1) to PD-1 and CD80.  In-vitro studies demonstrate that durvalumab 
(MEDI4736) relieves PD-L1-mediated suppression of human T-cell activation.  
Durvalumab (MEDI4736) does not trigger antibody-dependent cellular cytotoxicity or 
complement-dependent cytotoxicity in cell-based functional assays. 
 
Description: Durvalumab (MEDI4736) is a human immunoglobulin G1 kappa (IgG1κ) 
monoclonal antibody. 
 
How Supplied: Durvalumab (MEDI4736) is supplied by AstraZeneca, and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI.  Durvalumab (MEDI4736) 
injection is a clear to slightly opalescent, colorless to slightly yellow solution for 
intravenous use.  Each vial contains 500 mg of durvalumab (MEDI4736) in 10 mL of 
solution.  Each 1 mL of solution contains 50 mg of durvalumab (MEDI4736) and is 
formulated in: L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), α,α-
trehalose dihydrate (104 mg), polysorbate 80 (0.2 mg), and Water for Injection, USP. 
 
Preparation: Durvalumab (MEDI4736) solution for infusion must be diluted prior to 
administration.  To prepare the infusion solution add the dose volume of durvalumab 
(MEDI4736) to an infusion bag containing 0.9% Sodium Chloride Injection or Dextrose 
5% in Water Injection, USP and mix by gentle inversion to ensure homogeneity of the dose 
in the bag.  The final concentration must be between 1 mg/mL to 15 mg/mL. 
 
Infusion bags must be latex-free and can be made of polypropylene, polyethylene, 
polyolefin copolymers, or polyvinyl chloride. 
 

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Storage: Store intact vials between 2-8°C (36-46°F).  Do not freeze.  Protect from light by 
storing in the original box.   
 
If a storage temperature excursion is identified, promptly return durvalumab (MEDI4736) to 
between 2-8°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: Refer to the package label for expiration. 
 
Total in-use storage time from needle puncture of durvalumab (MEDI4736) vial to start of 
administration should not exceed 8 hours at room temperature or 24 hours at 2-8°C (36-
46°F).  Prior to the start of the infusion, ensure that the bag contents are at room temperature 
(approximately 25°C) to avoid an infusion reaction due to the administration of the solution 
at low temperatures.   
 
Route of Administration: IV infusion 
 
Method of Administration: Infuse over approximately 60 minutes using an infusion set 
containing a 0.22 or 0.2 μm in-line filter.  No incompatibilities between durvalumab 
(MEDI4736) and polyethylene, polypropylene, polyvinylchloride, or polyolefin 
copolymers have been observed.  Flush the IV line with a volume of IV bag diluent equal 
to the priming volume of the infusion set used at the completion of infusion.  Do not co-
administer other drugs through the same infusion line. 
 
Patient Care Implications: Refer to the protocol for information on evaluation and 
management of potential immune-related adverse events. 
 
9.2 
Commercial Agent: Cetuximab NSC# 714692  
Sites must refer to the package insert for detailed pharmacologic and safety information. 
 
9.2.1 Adverse Events 
A list of the adverse events and potential risks associated with cetuximab administered in 
this study can be found in Section 7.4. 
 
9.2.2 Availability/Supply  
 
Cetuximab is available via commercial prescription. 
 
9.2.3 Preparation, Storage and Stability 
  
Refer to the current FDA-approved package insert.  
 
9.2.4 Administration 
Please see Section 5.1.2 for administration instructions.  Administer through a low 
protein-binding 0.22 micrometer in-line filter. 
 
 

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10.  
PATHOLOGY/BIOSPECIMEN  
10.1 
Biospecimen Submissions (04-OCT-2019) 
Note: Investigators should check with their pathology department regarding release of 
biospecimens before approaching patients about participation in the trial. 
 
In this study, submission of H&E stained slides and block (or punch biopsy of paraffin 
block) to the Biospecimen Bank at UCSF for central review is mandatory for all patients, 
for the purpose of analyzing tissue for PD-L1 status. In addition, oral cavity, laryngeal, 
and hypopharyngeal primaries will be tested for p16 at the end of the trial. These 
submissions must be received at the biobank within 7-10 business days from time of 
patient registration. Sites must confirm with their pathology labs to make sure they can 
provide the required material as the bank must be able to retain these samples for the 
mandatory testing. 
 
Note: Fine needle aspirates (FNA) samples are not acceptable since they do not provide 
enough material for PD-L1 and p16 testing. A cell block derived from the FNA is 
allowable if there are sufficient cells present in the block for PD-L1 testing. Dr Jordan 
will determine this upon receipt. For sites submitting FNA cellblocks for ALL patients, 
they must do so within 7-10 business days from registering the patient. Sites must 
confirm with their cytology/pathology labs to make sure they can provide the required 
material as the bank must be able to retain these samples for the mandatory testing. 
 
Sites can obtain a new biopsy to get sufficient tissue if needed (prior to Step 1 
registration). An additional biopsy is NOT required, but if there is not enough tissue to 
verify p16 status from the standard of care pre-registration biopsy, patients with 
oropharyngeal and unknown primaries will be ineligible for the study and will not receive 
study treatment (see details below).  
 
For oropharyngeal and unknown primaries, submission of H&E and p16 stained slides 
(with the required block for PD-L1) to the Biospecimen Bank at UCSF is required prior 
to Step 2 registration.  
 
It is also highly recommended (but optional for the patient) that serum and peripheral 
blood specimens be submitted for banking for future translational research.  

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10.2   Pre-hoc Central Review of Oropharyngeal and Unknown Primaries (04-OCT-2019) 
 
Pre-hoc central review mandatory for oropharyngeal and unknown primaries to confirm 
p16 status prior to Step 2 registration. Institutions must test for p16 status by 
immunohistochemistry (IHC) using a Clinical Laboratory Improvement Amendments 
(CLIA)-certified laboratory. Note: 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. 
 
 
Pre-hoc central review will be conducted with rapid turnaround (1-2 business days from 
receipt of the slides) coordinated by Dr. Richard Jordan at the NRG Oncology 
Biospecimen Bank–San Francisco. Specifics of type and source of p16 antibody and 
testing method will be requested (although not required) at the time of specimen 
submission. Every effort should be made to obtain and submit this information at the time 
of specimen transmission, in order to ensure the fastest possible resolution should there 
be any questions about staining technique. 
 
H&E stained slides will be submitted for oropharyngeal and unknown primaries used to 
confirm presence of tumor in the sample and to aid in assay interpretation. These slides 
must be submitted with blocks. The primary reviewer will be the Pathology Co-Chair, 
Richard Jordan, DDS, PhD. Interpretation of each p16 immunostained slide will be 
performed using the H-score method described by Jordan et al. (2012) that has been 
validated as a reliable, reproducible, and accurate method to score p16 in squamous cell 
carcinoma of the head and neck.  
 
The p16 IHC will be scored as evaluable if strong and diffuse positivity was observed in 
the tissue mounted on each slide. The highest intensity of p16 staining present in the 
tumor will be scored on an ordinal score of 0-3, relative to the intensity of the positive 
(score 3) and negative (score 0). The percent of tumor staining at the highest intensity 
also will be estimated within 5% increments. The H score is derived from the cross 
product of the intensity score (0 to 3), and the percent of tumor staining at the highest 
intensity (0-100%). An optimal H-score cut-point of 60 on a scale of 0-300 yields an 
average sensitivity of 91.6% and specificity of 90.4% for HR-HPV oncogene expression 
and thus an H-score cut-point of 60 indicates that a tumor with diffuse low-intensity 
nuclear and cytoplasmic p16 staining in the majority of the tumor is a true positive 
(Jordan 2012). High agreement on inter-rater interpretation has been reported (Schlecht 
2011, Thavaraj 2011), indicating the familiarity of pathologists with interpretation of IHC 
assays. Similarly, comparable assay performance for p16 to that observed here has also 
been previously reported (Schlecht 2011, Thavaraj 2011). The most common p16 
monoclonal antibody in use is E6H4 (CINtec). Other acceptable p16 antibody types 
include 16P04 and JC8. If a different p16 antibody is used, discussion with the Pathology 
Co-Chairs is strongly encouraged. 
 
 
 
 
 

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 Mandatory: Specimen Collection for Central p16 Confirmation of  
Oropharyngeal and Unknown Primary Tumors 
 
 
• H&E and p16 stained slides must be submitted for oropharyngeal and unknown 
primary tumors.  
• For patients with oropharyngeal or unknown primary cases, rapid central review of 
p16 slides will be performed within 1-2 business days from receipt of samples and 
paperwork. H&E slide will be used to confirm presence of tumor. 
• P16 staining will be performed at UCSF for oral cavity, laryngeal, and 
hypopharyngeal primaries cases at the end of the trial. 
• Required Forms: ST form and pathology reports with study and case number date of 
procedure, pathology accession number and p16 staining result; any other personal 
health information (PHI) should be redacted by sites before sending. 
• Shipping costs: Submitting site pays cost of shipping FFPE samples and returns. 
• Residual Material: p16 slides will be retained unless return is requested by the 
submitting site. H&E slides and blocks will be retained at the bank. 
 
Ship all biospecimens for central review for this trial by courier (Fed Ex/UPS) 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 
For oropharyngeal and 
unknown primary 
tumors: 
 
-One H&E slide 
-One p16 stained IHC 
slide from primary tumor 
 
H&E slides can be 
duplicate cut slides, they 
do not have to be the 
diagnostic slide 
Pre-Treatment 
H&E and p16 slide 
must be made from the 
same pathology block. 
Enrolling institution, 
using a CLIA certified 
laboratory, screens 
patient with p16 testing 
by IHC. Then 
Biospecimen Bank 
does central review 
prior to randomization. 
Slides shipped 
ambient to NRG 
Biospecimen Bank 
San Francisco 
 
 
 
 
 

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10.3 
Tissue Blocks for Central Review of PD-L1 and p16 status (13-JAN-2021) 
All tissue specimens will be analyzed for PD-L1 status at the end of the trial. Tissue 
specimens for oral cavity, laryngeal, and hypopharyngeal primaries will also be analyzed 
for p16 status at the end of the trial. 
 
PD-L1 testing will be performed at QualTek Molecular Laboratories Clinical 
Laboratories (215-504-7402) at the end of the trial. QualTek has two fully equipped 
Laboratory locations in Santa Barbara, CA (CAP/CLIA accredited) and Newtown, PA 
(GLP capable). We will use the Ventana SP263 rabbit polyclonal antibody, with a 
positive result considered as >25% expressing tumor cells of any intensity.  
 
Tumor p16 expression will be evaluated by immunohistochemical analysis with a mouse 
monoclonal antibody (MTM Laboratories) visualized with use of an autostainer (Ventana 
XT, Ventana) and a one-view secondary detection kit (Ventana). Positive p16 expression 
will be defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of 
the tumor cells (Ang 2010).  
 
Mandatory: Specimen Collection for PD-L1 and p16 Expression 
 
• Submission of H&E stained slides and block (or punch biopsy of paraffin block) to 
the Biospecimen Bank at UCSF for central review is mandatory for all patients. 
• For oropharyngeal or unknown primary patients, the block must be submitted at the 
same time as the H&E and p16 slide.  
• For all other patients, the slides and block must be submitted within 14 days from date 
patient was enrolled on study. 
• Required Forms: ST form and pathology reports with date of procedure, pathology 
accession number; any other personal health information (PHI) should be redacted by 
sites before sending. 
• FFPE Punch Kits should be requested from the Biospecimen Bank when requesting 
Frozen specimen kits. 
• Shipping costs: Submitting site pays cost of shipping FFPE samples and returns. 
• PD-L1 testing will be performed on all cases when study closes to accrual by QualTek 
Molecular Laboratories Clinical Laboratories  
Results: QualTek Molecular Laboratories Clinical Laboratories will report to NRG 
Oncology when study closes to accrual.  
• Residual Material: FFPE specimens will be retained at the Biospecimen Bank unless 
needed for 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  

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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 
 
Baseline tumor 
specimen 
H&E stained slide; can 
be the same as 
submitted for central 
review or additional 
slides can be submitted 
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 
Corresponding FFPE 
Block or one to two 3-
mm punches from the 
same block as the 
H&E slide that is being 
submitted 
(embedded*) 
Shipped ambient or 
with cold pack to 
the NRG 
Biospecimen Bank 
San Francisco 
 
*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 new H&E slide must then be submitted to 
the NRG Oncology Biospecimen Bank in San Francisco. 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 punches to the bank to be 
embedded by the Biospecimen Bank. 
 
10.4 
Optional Specimen Submissions (13-JAN-2021) 
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. 
 
 
Specimen 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 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. 
 
 

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Batch ship frozen serum samples Monday-Wednesday (US sites) and Monday-Tuesday 
(Canadian Sites). 
 
Processing Instructions: Located on the CTSU website protocol specific documents. 
NOTE: If sites missed collecting serum samples at baseline, they should not collect serum at 
future time points. 
 
Ship all serum specimens 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 
 
Serum: One 10 
mL red top (clot) 
tube 
● Baseline (within 14 
days prior to starting 
systemic therapy) 
● Within 7 days prior 
to starting RT (after 
starting systemic 
therapy) 
● 1 month after end 
of RT (± 7 days)  
● 1 month (± 14 
days) after last dose 
of systemic therapy 
(durvalumab arm) 
OR 4 months (± 14 
days) after RT 
(cetuximab arm) 
 
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).  
 
Samples should be frozen 
and stored at -80⁰C until 
ready to batch ship. 
 
If sites missed collecting 
serum samples at baseline, 
they should not collect 
serum at future time points. 
 
 
Serum sent frozen on 
dry ice via overnight 
carrier to the NRG 
Biospecimen Bank- 
San Francisco 
 
Batch shipping of 
multiple cases/time 
points in one 
shipment is 
encouraged.  
 
Tumor tissue (for patients who consent to optional biobanking) 
Residual tissue from mandatory pre-treatment tissue studies will be retained at the NRG 
Oncology Biospecimen Bank–San Francisco, if the patient consents to optional biobanking. 
 
 
 

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Analysis of Peripheral Blood Specimens (to be offered to Phase II/III patients only) 
 
 
Peripheral Blood Specimens 
Peripheral blood specimens will be collected at baseline and longitudinally. Specimens will be 
banked and analyzed at the Moores Cancer Center (MCC) biorepository at University of 
California San Diego. 
 
NOTE: If sites missed collecting peripheral blood samples at baseline, they should not collect 
peripheral blood samples at future time points. For baseline samples collected but determined 
non-viable by the MCC lab, sites will be notified to not collect future time points.  
 
After adequate samples for all time points have been collected for 100 patients, we will contact 
sites to stop sample collection. 
 
Required Form: Study Specific Specimen Transmittal (ST) form  
Biospecimen Kits: Can be requested from the NRG Biobank at NRGBB@ucsf.edu. Allow 5-10 
business days for kits. Sites must have IRB approval before requesting kits.  
Shipping days: Monday- Wednesday (U.S. sites).  
 
Shipping labels will be provided with kits for peripheral blood.  
 
Ship specimens for this peripheral blood specimen study to:  
Attn.: Sharmeela Kaushal 
Assistant Director, MCC Biorepository  
UCSD Moores Cancer Center Biorepository 
3855 Health Sciences Dr, Room 3331 OR Room 3345-G 
La Jolla, CA 92093-0819 
Email: skaushal@ucsd.edu   
Phone: 858-534-7302 
Fax: 858-822-5380 
  
NOTE: Samples MUST be overnighted within 12 hours of collection.  
 
NOTE: Do NOT collect and/or ship samples on Friday, Saturday, or Sunday.  
 
NOTE: The coordinator or personnel collecting the sample MUST send a notification by email to 
Sharmeela Kaushal (skaushal@ucsd.edu) and Mason Kyle (mkyle@ucsd.edu) in advance and 
provide the tracking information. 
 
NOTE: Do NOT ship peripheral blood to NRG Oncology Biospecimen Bank. 
 
For additional questions, contact:  
Dr. Mell: 858-246-2174 (lmell@ucsd.edu) or Alfredo Molinolo (amolinolo@ucsd.edu) 
 

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Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
 
Draw blood in five (5) 10 
ml green top (heparin) 
tubes. Collect at least 8 ml 
per tube. 
● Baseline (within 
14 days prior to 
starting systemic 
therapy) 
● Within 7 days 
prior to starting RT 
(after starting 
systemic therapy) 
● 1 month after end 
of RT (± 7 days)  
● 1 month (± 14 
days) after last dose 
of systemic therapy 
(durvalumab arm) 
OR 4 months (± 14 
days) after RT 
(cetuximab arm) 
 
See Appendix II for 
processing and 
shipping 
information. 
 
If sites missed 
collecting peripheral 
blood at baseline, 
they should not 
collect future time 
points. 
Ship fresh at room 
temperature 
overnight for 
morning delivery to 
the UCSD MCC 
Biorepository 
 
Peripheral blood (for patients who consent to optional biobanking) 
Residual blood or derivatives from optional studies will be shipped to the NRG Oncology 
Biospecimen Bank–San Francisco from the UCSD MCC Biorepository for biobanking, if the 
patient consents to optional biobanking. Based on the usability of the specimen and at the 
discretion of the NRG Biospecimen Bank Director (Dr. Richard Jordan) these will be retained or 
destroyed. 
 
 
11. SPECIAL STUDIES (NON-TISSUE) 
All participating centers will be required to participate in the quality of life and patient 
reported outcome assessments. 
 
11.1 Quality of Life Instruments Description (15-JAN-2019) 
           See Section 4 for time points. 
 
EORTC QLQ-C30 / EORTC QLQ-H&N35 
The European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC 
QLQ-C30 Version 3.0) and the Head-and-Neck module (EORTC QLQ-H&N35 Version 1.0) 
(Aaronson NK, 2012, Sherman AC, 2000) 
 
The EORTC QLQ-C30 / EORTC QLQ-H&N35 (Version 1) consists of a 30-item self-reporting 
questionnaire developed to assess overall QOL of patients with cancer and a 35-item head and 
neck cancer specific module. 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 

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cancer patients, and two questions assessing overall QOL. This copyrighted instrument is 
validated and can be found on the NRG-HN004 protocol page of the CTSU website. The 
EORTC QLQ-H&N35 module is specific for multi-modality HNC therapy and contains an 
additional 35 questions. Both of the scales and single-item measures range in score from 0 to 
100; a high scale score represents a higher response/functioning level (better QOL). The time for 
administration is about 7-10 minutes for each instrument. While social and emotional well-being 
are important to QOL, they are not as likely to change as quickly or dramatically over time or in 
response to therapy. Furthermore, in a pooled analysis of RTOG 90-03 and RTOG 91-11, the 
emotional well-being subscale was not shown to be predictive of survival in cancer patients 
(Coyne et al., 2007). Therefore we will evaluate the individual subscales of the EORTC QLQ, in 
particular the role and physical functioning between arms. The minimum important difference 
(MID), which is defined as the smallest difference in score that a patient perceives as important, 
that may lead to a change in the patient’s management (King, 2011). The clinically meaningful 
MID of a QOL instrument is often estimated as being at least 5-10% of the instrument range. 
Cella et al. found that clinical meaningful group score changes in global QOL are often small for 
QOL improvements from baseline, whereas worsening global QOL is often associated with 
much larger negative score changes (Cella 2002).  
 
NRG Oncology has obtained permission to use the EORTC QLQ-C30 and H&N35 for this study 
in English, Spanish, and French. If a site would like access to another language, please contact 
NRG Oncology to discuss.  
 
MD Anderson Dysphagia Inventory (MDADI) 
Swallowing will be evaluated using the validated PRO swallowing instrument is the MD 
Anderson Dysphagia Inventory (MDADI), 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. Hutcheson et al. evaluated the MD Anderson Dysphagia Inventory 
(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). The difference in the mean MD 
Anderson Dysphagia Inventory (MDADI) composite score, measured at one year after radiation 
between arms will be compared. In this study, because it is expected that patients will be older or 
have more medical comorbidities with contraindication to cisplatin, and include laryngeal and 
hypopharyngeal patients, swallowing QOL may be worse in this patient cohort compared 
patients participating in other ongoing NRG oncology studies. The effects of durvalumab 
immunotherapy combined with IMRT in HNSCC on swallowing-related QOL are unknown. It 
will be important to evaluate long term swallowing in this patient cohort particularly if the 
functional morbidity of dysphagia after multimodality treatment potentially contributes to non-
cancer deaths secondary to complications from malnutrition and aspiration, which could 
potentially offset any survival gains from combined modality therapy (Cooper 2012; Forastiere 
2013).  
 
NRG Oncology has obtained permission to use the MDADI for this study in English, Spanish, 
and French. If a site would like access to another language, please contact NRG Oncology to 
discuss.  
 

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Charlson Comorbidity Index (CCI) and Demographic and Health Status Markers  
Multiple studies have shown that in addition to classic prognostic markers such as age, race, 
performance status, and smoking and alcohol use, many demographic and health status markers, 
including body mass index, socioeconomic status (and proxy instruments, such as distance 
traveled), marital status, and comorbidity, have additive prognostic value and explain a 
considerable proportion of the variation in outcomes for head/neck cancer patients (Mell 2010; 
Rose 2011). In addition, it is known that models accounting for such factors outperform standard 
prognostic methods (Carmona 2016) and that failing to account for them can bias or confound 
results of phase III trials (Zakeri 2013; Mell 2014). The current study affords a unique 
opportunity to gather detailed baseline and demographic health variables in a clinical trial 
population to compare and contrast with results from population studies. 
 
In this study, research associates will gather information on Charlson Comorbidity Index 
(Charlson 1987), body mass index ((mass in kg) / (height in m2)), patient and treatment center 
zip code, and marital status. These are not PRO instruments, and the data will be collected only 
at baseline by extracting information from the patient’s history and/or chart. These are simple 
metrics to collect, posing no significant additional burden to the patient or study team. The 
metrics are not used to determine eligibility and will be used only to characterize the sample and 
assess comparability between the treatment arms. 
 
Geriatric-8 Questionnaire (G-8) 
Routine serial implementation of the comprehensive geriatric assessment (CGA) is challenging 
due the comprehensive length of the tool and resources required to complete the full assessment. 
Hence a screening tool to evaluate QOL and patient vulnerability (defined as impairment of 2 or 
more domains within the CGA) will be evaluated using the G-8. The G-8 tool has been validated 
in the elderly vulnerable population (Liuu 2014). The G-8 is a seven-item clinician-administered 
questionnaire which includes, age, Mini Nutritional Assessment (MNA), Activities Daily Living 
(ADL), Instrumental ADL, Mini-Mental State Exam, Geriatric Depression Scale, Cumulative 
Illness Rating Scale-Geriatrics, and Timed Get Up and Go. When considering the presence of at 
least one questionnaire with an impaired score as an abnormal reference exam, the prevalence of 
being at risk varied from 60% to 94% per the various definitions of the reference test. When 
considering the primary reference test, a cut-off value of 14 for the G-8 tool provided a good 
sensitivity estimate (85%) without deteriorating the specificity excessively (65%)(Bellera et al., 
2012). In the head and neck cancer population, the G-8 has been compared to other screening 
tools including the Vulnerable Elders Survey-13 (VES-13), in combination and correlated with 
the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires 
(EORTC QLQ)-C30 and -H&N35 in 100 HNC patients, aged ≥65 years, undergoing curative 
radio(chemo)therapy. Pretreatment, the G-8 defined patients as vulnerable in 69.0% compared to 
71.3% using the CGA, mainly due to the presence of severe grade co-morbidities, difficulties in 
community functioning and nutritional problems. At week 4 of radiation, significantly more 
patients were identified as vulnerable due to nutritional, functional and emotional deterioration. 
Vulnerable patients reported lower function and higher symptom burden on HR-QOL scores as 
compared with “fit” patients. A comparable deterioration in HR-QOL was observed in 
vulnerable and fit patients during treatment. This study demonstrated that the G-8 was the 
screening tool of choice (Pottel 2014) and superior to the VES-13 in identifying vulnerable 
patients. G-8 has also shown to be indicative of quality-adjusted survival in older HNC patients 
(Pottel 2015). 

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Quality-Adjusted Survival, EuroQol (EQ-5D-5L) 
The EQ-5D™ is a trademark of the EuroQol Group, it is a well-accepted instrument to measure 
general QOL and cost-utility analysis (EuroQol Group 1990) and will be used to assess quality-
adjusted survival for this study. It is a 2-part questionnaire that the patient can complete in 
approximately 5 minutes and has been translated into multiple languages. The first part 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. There are 
243 potential health states. The second part is a visual analogue scale (VAS) valuing current 
health state, measured on a 20 cm, 10 point-interval scale. Either the index score or the VAS 
score can be used in the quality-adjusted survival analysis. The benefit of measuring quality-
adjusted survival is that the product, quality-adjusted survival, can be compared to the outcomes 
of other interventions across disease sites and can be used by health policy makers to rank 
interventions. The EQ5D-5L will be used to evaluate the effect of adding MEDI4736 to 
chemoradiation on quality-adjusted survival. The EQ-5D-5L is available in over 125 languages. 
 
NRG Oncology has obtained permission to use the EQ-5D-5L for this study in English, Spanish, 
and French. If a site would like access to another language, please contact NRG Oncology to 
discuss. 
 
Performance Status Scale for Head and Neck Cancer (PSS-HN) 
The Performance Status Scale for Head and Neck Cancer (PSS-HN) and Swallowing Function  
The PSS-HN will be a secondary tool to assess swallowing function in addition to physician 
assessment of nutrition and PEG tube status and has been used on multiple RTOG head and neck 
trials. The PSS-HN is a clinician-rated instrument consisting of 3 subscales: normalcy of diet, 
public eating, and understandability of speech. The PSS-HN has been psychometrically validated 
(List 1997; List 1999) and recommended by the NCCN for measurement of swallowing and 
speech performance in patients with head and neck cancer undergoing primary radiotherapy 
based treatment. PSS-HN scores are an important evaluation of normalcy of diet and ability to 
eat in public. In RTOG 0522, it was found that 38% and 26% of patients at 12 months had 
clinically worsened normalcy of diet and ability to eat in public, respectively, after 
chemoradiation using the PSS-HN. Furthermore, baseline PSS-HN- diet and eating scores in the 
intermediate and high-risk OPC and non-OPC patients were lower compared to the low-risk 
OPC patient population. In RTOG 0522, longitudinal swallowing function demonstrated acute 
deterioration in scores for PSS-HN-diet and eating in both treatment arms in the last 2 weeks of 
treatment to 3 months in all patients receiving CRT. However, p16-negative OPC patients 
demonstrate a slower recovery compared to p16-positive OPC patients (Truong 2017). It is 
hypothesized that MEDI4736 (durvalumab) will have less decline in long-term swallowing 
function with respect to normalcy of diet and ability to eat in public and swallowing-related QOL 
as measured by the EORTC H&N35 subscale items pertaining to eating and swallowing at 12 
months from the end of RT compared to the control arm. 
 
PSS-HN is not a PRO; hence, investigators or research associates can complete it quickly at the 
scheduled visits without adding to patient burden.  
 

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11.1.1  Administration of NRG-HN004 Patient-Completed Questionnaires  
Time points for administration are located in Section 4. 
 
11.1.2 Administration Instructions  
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-HN004 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 III. 
 
12. MODALITY REVIEWS (09-MAR-2022) 
12.1 
Radiation Therapy Quality Assurance Reviews  
Cases for the RT Quality Assurance Reviews will be selected using a sampling scheme. 
The Principal Investigator, Dr. Loren Mell, or NRG Oncology Headquarters approved 
designee will perform an RT Quality Assurance Review for all patients included in the 
sample who receive radiation therapy. Reviews will be performed after NRG Headquarters 
has received complete data for each case enrolled. 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: Per Protocol, Variation Acceptable, Deviation 
Unacceptable, and Not Evaluable. 
 
12.2 
Medical Oncology Modality Quality Assurance Reviews (15-JAN-2019) 
The Medical Oncology Co-Chair, Dr. Stuart Wong, or NRG Oncology Headquarters 
approved designee will perform a Systemic Therapy Assurance Review of all patients who 
receive or are to receive systemic therapy in this trial. The goal of the review is to evaluate 
protocol compliance. The review process is contingent on timely submission of systemic 
therapy data as specified in Section 12.1. The scoring mechanism is: 1) Per Protocol, 2) 
Acceptable Variation, 3) Unacceptable Deviation, and 4) Not Evaluable.  
 
Dr. Wong/designee will perform a Quality Assurance Review after NRG Oncology 
Headquarters has received complete data for each case. The reviews will be ongoing.  

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13.       DATA AND RECORDS 
13.1 
Data Management/Collection (09-MAR-2022) 
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: 
• 
A valid CTEP-IAM account; and  
• 
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: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• 
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. 
 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access 
to Rave must also be assigned the appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation email from iMedidata. 
  
To accept the invitation, site users must either click on the link in the email or log in to 
iMedidata via the CTSU members’ website under Data Management > Rave Home and 
click to accept the invitation in the Tasks pane located in the upper right corner of the 
iMedidata screen. 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 eLearning link 
in the Tasks pane located in the upper right corner of the iMedidata screen. If an 
eLearning is required for a study and has not yet been taken, the link to the eLearning 
will appear under the study name in the Studies pane located in the center of the 
iMedidata screen; 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 replace the 
eLearning link 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 RSS 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 

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(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 at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by email at ctsucontact@westat.com.   
 
13.2     Data Quality Portal (09-MAR-2022) 
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, DQP 
Form Status, and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status, and 
timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules. 
 
13.3     Rave-CTEP-AERS integration (09-MAR-2022) 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) Integration enables evaluation of Adverse Events (AE) entered in 
Rave to determine whether they require expedited reporting and facilitates entry 
in CTEP-AERS for those AEs requiring expedited reporting. Sites must initiate 
all AEs for this study in Medidata Rave.   
 
Pre-treatment AEs: Solicited baseline adverse events that occur prior to start of 
treatment are collected in Medidata Rave on the Protocol Specific Adverse Event 
Baseline form. 
 
Treatment-emergent AEs: All AEs that occur after start of treatment are collected 
in Medidata Rave using the Adverse Event form, which is available for entry at 
each treatment course or reporting period and is used to collect AEs that start 
during the period or persist from the previous reporting period.  AEs that occur 30 
Days after the Last Administration of the Investigational Agent/Intervention are 
collected using the Late Adverse Event form. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify 
the following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct; and 

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• AEs are recorded and complete (no missing fields) and the form is query 
free. 
 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If 
the CRA modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for 
rules evaluation by completing the Expedited Reporting Evaluation form. Both 
NCI and protocol-specific reporting rules evaluate the AEs submitted for 
expedited reporting. A report is initiated in CTEP-AERS using information 
entered in Medidata Rave for AEs that meet reporting requirements. The CRA 
completes the report by accessing CTEP-AERS via a direct link on the Medidata 
Rave Expedited Reporting Evaluation form. Contact the CTSU Help Desk at 1-
888-823-5923 or by email at ctsucontact@westat.com if you have any issues 
submitting an expedited report in CTEP-AERS. 
 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to 
be made to CTEP by telephone at 301-897-7497. Once internet connectivity is 
restored, the 24-hour notification that was phoned in must be entered immediately 
into CTEP-AERS using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the 
CTSU members’ website: 
• Study specific documents: Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting; and   
• Additional resources: Resources > CTSU Operations Information> User 
Guides & Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
• NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf 
 
13.4 
Summary of Data Submission (21-AUG-2019) 
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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Summary of Dosimetry Digital Data Submission (Submit to TRIAD; see Section 8.3.1 for 
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 5.2.3). 
     
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. 
 
13.5 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, 
July 31, and October 31.  Instructions for submitting data using the CDUS can be found 
on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
14.       STATISTICAL CONSIDERATIONS  
14.1 
Study Design (15-JAN-2019) 
Justification of Design 
This is a randomized phase II/III trial of radiotherapy with concurrent MEDI4736 
(durvalumab) vs. radiotherapy with concurrent cetuximab in patients with stage 
locoregionally advanced head and neck cancer with a contradiction to cisplatin. There 
will be a safety lead in to evaluate the dose limiting toxicities for radiotherapy with 
concurrent MEDI4736 (durvalumab). If proved to be safe, patients will be randomized 
between the two arms for a comparison of PFS in the phase II component, these patients 
will be included in the phase III final analysis if there is a statistically significant 

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difference in PFS in the phase II. 
Randomization 
The stratified permuted block randomization treatment allocation scheme described by 
Zelen (1974) will be used as it balances patient factors other than the treating institution. 
The randomization ratio between the two arms will be 2 (RT + MEDI4736):1 (RT + 
cetuximab).  
 
Stratification 
Patients will be stratified by the following factors: 
• Stage (T0-3 and N0-2 vs. T4 and/or N3) 
• Performance status/comorbidity (PS=0 and modified CCI=0 vs. PS=1-2 and/or 
modified CCI>0) 
• Primary site (p16+ OPX/CUP vs. Other [Larynx, HPX, Oral Cavity, or p16- 
OPX/CUP])   
 
Total Accrual 
Lead-In: 8-30 evaluable patients (depending on required dose levels) 
Phase II: 234 randomized patients (projecting 260 enrolled to reach 234 randomized)  
Phase III:  444 randomized patients, including the 234 randomized in Phase II (projecting  
493 enrolled to reach 444 randomized) 
 
14.2 
Study Endpoints (15-JAN-2019) 
14.2.1  Primary Endpoints 
Lead-In: 
Dose-limiting toxicity (DLT) 
Phase II: 
Progression-free survival (PFS) 
Phase III: 
Overall survival (OS) 
 
14.2.3 Secondary Endpoints 
• Locoregional failure (LRF) 
• Distant metastasis (DM) 
• Competing mortality 
• Response on 4-month FDG-PET/CT, measured by RECIST 
• Adverse events measured by CTCAE and PRO-CTCAE 
• QOL endpoints including functional domain of the EORTC QLQ and swallowing 
QOL using total composite MDADI score at 1 year from end of RT change from 
baseline 
• Performance status per PSS-HN 
• Translational research, including PD-L1 and p16 
 
14.2.4 Exploratory Endpoints 
• Secondary biomarkers 
• PRO-CTCAE 
• QOL endpoints using other items in EORTC QLQ/HN35, EQ5D and MDADI 
subscales in the short term (end of RT to 8 months) and long term (12-24 months 
from end of RT) 
 

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14.3 
Primary Objectives Study Design (09-MAR-2022) 
14.3.1  Primary Hypotheses and Endpoint Definitions 
Lead-In 
It is hypothesized that MEDI4736 (durvalumab) can be safely delivered, per the DLT 
definition, when given concurrently with radiation for patients with locoregionally 
advanced HNC who have a contraindication to cisplatin. 
 
DLT for radiotherapy with concurrent MEDI4736 (durvalumab), as defined below 
(please see section 5.1 for dose level guidelines). 
 
▪ DLT Observation Period: The DLT observation period will start at the first dose of 
MEDI4736 (durvalumab) and extend for 4 weeks after the completion of radiation 
therapy.  
 
▪ DLT Definition: DLT is defined as the occurrence of an adverse event (AE) listed 
below that is definitely or probably related to MEDI4736 (durvalumab) irrespective 
of relationship to radiation therapy and occurs during the specified observation 
window. AEs will be graded according to NCI CTCAE version 4.0. 
 
The following criteria will be used to define DLT: 
• Any ≥ Grade 3 non-hematologic toxicity except: 
➢ Grade 3 or 4 in-field radiation dermatitis for which RT is held ≤ 1 week (5 
fractions); 
➢ Grade 3 or 4 mucositis for which RT is held ≤ 1 week (5 fractions); 
➢ Grade 3 or 4 hypomagnesemia, hypokalemia, or hypophosphatemia without life-
threatening consequences, which corrects to Grade ≤ 2 with observation or 
replacement therapy; 
➢ Grade 3 pain, dysphagia, weight loss, or fatigue which are expected toxicities for 
chemoradiation of HNSCC and will be managed aggressively by treating 
investigators per standards of care; 
➢ Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy and the patient is asymptomatic; 
➢ Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.); 
➢ Grade 3 or 4 concurrent vitiligo or alopecia; 
➢ Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management; 
➢ Isolated Grade 3 electrolyte abnormalities that are not associated with clinical 
signs or symptoms and are reversed with appropriate maximal medical 
intervention within 3 days; 
➢ Grade 3 AST/ALT elevation ≤ 8 x ULN; 
➢ Grade 3 bilirubin elevation ≤ 5 x ULN.  
• Any Grade 3 or 4 immune-related adverse event, excluding colitis or pneumonitis, 
that does not downgrade to Grade 2 within 3 days despite optimal medical 
management including systemic corticosteroids or does not downgrade to ≤ Grade 1 
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• Delay in completion of RT > 2 weeks (10 fractions), or inability to complete 
prescribed RT course, due to immune toxicity definitely or probably related to 
MEDI4736; 
• Grade 3 or 4 neutropenia with fever (oral temperature > 39°C); 
• Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
does not improve by at least 1 grade within 3 days; 
• Grade 3 or 4 thrombocytopenia with bleeding; 
• Grade 3 or 4 thrombocytopenia that is not associated with clinically significant 
bleeding that requires medical intervention that does not improve by at least 1 grade 
within 3 days; 
• Grade 3 AST/ALT elevation > 8 × ULN; 
• Grade 3 bilirubin elevation > 5 × ULN; 
• Any Grade 5 toxicity. 
 
Phase II 
It is hypothesized that MEDI4736 (durvalumab) given concurrently with radiation for 
patients with locoregionally advanced HNC who have a contraindication to cisplatin will 
show a signal for improved PFS, compared to patients treated with concurrent radiation 
and cetuximab. 
 
Progression-free survival is defined as time from randomization until first evidence of 
local, regional, or distant disease progression or recurrence, or death from any cause. 
(Note: PFS factors in effects of therapies on both cancer events and competing mortality 
events. Both are important to assess the net benefit of therapies in this population. There 
is reason to believe that MEDI4736 (durvalumab) will have a beneficial effect on both 
cancer events and competing events relative to cetuximab. Endpoints like local-regional 
control or time to progression would not be sensitive to a beneficial effect on competing 
mortality. PFS is thus the best phase II primary endpoint to assess effectiveness). 
 
Phase III 
It is hypothesized that MEDI4736 (durvalumab) given concurrently with radiation for 
patients with locoregionally advanced HNC who have a contraindication to cisplatin will 
improve OS, compared to patients treated with radiation and cetuximab. 
 
Overall survival is defined as time from randomization until death from any cause. 
 
14.3.2 How Primary Endpoints Will Be Analyzed 
 
Lead-In 
All patients who receive at least one dose of MEDI4736 (durvalumab) are considered 
evaluable for DLT, should a DLT occur. In the absence of DLT, patients must have 
received at least one dose of MEDI4736 (durvalumab) and one fraction of radiation 
therapy and have completed the DLT observation period to be evaluable for DLT. 
Patients considered inevaluable may be replaced to ensure the required number of 
evaluable patients per arm.  
 
For the first dose level, 8 patients will be evaluated.  It is projected that 10 patients will 

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be entered to reach the required 8 evaluable patients. If more than 8 patients are 
evaluable, data from the first 8 patients will be analyzed for the DLT endpoint. In the 
event of 0-2 DLT events, the experimental therapy is considered safe and the study will 
proceed to phase II.  Otherwise, the MEDI4736 (durvalumab) dose will be de-escalated. 
Should dose de-escalation be necessary, then a second (and, if necessary, third) dose level 
will be evaluated with 8 patients each. It is projected that 10 patients will be entered to 
reach the required 8 evaluable patients.  If more than 8 patients are evaluable, data from 
the first 8 patients will be analyzed for the DLT endpoint. For a given de-escalated dose, 
in the event of 0-2 DLT events, the experimental therapy is considered safe and the study 
will proceed to phase II. The treatment plans for dose de-escalation (if necessary) appear 
in Tables 1 and 2 in Section 5.  
 
 
Phase II 
The intention-to-treat (ITT) population (all randomized patients) will be used for the 
primary analysis of PFS. PFS will be estimated using the Kaplan-Meier method (1958). 
The difference in PFS between the two arms will be tested using a log-rank test. If the 
PFS endpoint is met in Phase II, then the study will continue. 
 
If the PFS endpoint is not met, the study will be reported, including exploratory analysis 
adjusting for important factors such as age, site, Zubrod performance status, and clinical 
stages will be conducted using Cox models, otherwise, multivariable analyses for PFS 
will be done at the end of the Phase III portion of the study. 
 
 
Phase III 
The intention-to-treat (ITT) population (all randomized patients) will be used for the 
primary analysis of OS. OS will be estimated using the Kaplan-Meier method (1958). 
The difference in OS between the two arms will be tested using a log-rank test. 
Exploratory analysis adjusting for important factors such as age, site, Zubrod 
performance status, and clinical stages will be conducted using Cox models. 
 
14.3.3 Sample Size and Power Calculations 
Lead-In 
The lead-in will test a fixed-dose in a cohort of 8 evaluable patients for a given dose 
level. In the event of 0-2 DLT events, the experimental therapy is considered safe and the 
study will proceed to phase II. With a cohort of 8 patients, the probability of the 
experimental arm being judged to be too toxic when the true toxicity rate is 45% or 
higher is at least 78%. If the true toxicity rate is 20% or lower, the probability that the 
therapy will be safe is 80%. Should dose de-escalation be necessary, then a second (and, 
if necessary, third) dose level will include 8 analyzable patients each (expecting to enroll 
10 patients accrued to get 8 analyzable).  
 
Phase II  
A sample size of 234 randomized patients is required, assuming an accrual rate of 10 
patients per month, total accrual time of 2.2 years, 2:1 distribution of patients in the 
experimental and control arms, a hazard ratio (HR) of 0.65 for the experimental arm 
relative to control, a 2-year PFS of 40.3% in the control arm (median PFS 1.53 years for 
the control arm, 2.35 years for the experimental arm), one-sided alpha of 0.20, and power 

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0.80. A total of 69 PFS events will be needed to achieve the statistical power. Accounting 
for 10% non-randomization, we expect to enroll 260 patients in order to obtain the 
required 234 randomized patients. When we randomize 234 patients, we expect to 
observe the total number of events needed for the phase II final analysis. If so, there will 
be no or minimal time needed for the analysis. On the other hand, if we still need time to 
observe certain number of events before reaching the total required for the final analysis, 
accrual will be suspended temporarily to observe any remaining events. 
 
Revised Phase II Sample Size: The accrual to the phase II portion stopped with 186 
randomized patients following an interim futility analysis and toxicity monitoring results. 
The phase II primary endpoint analysis will be done once 69 PFS events have been 
observed in the 186-patient ITT population using the design parameters specified in 
Section 14.4.2. Phase III target accrual remains unchanged. 
 
Phase III  
An additional 210 randomized patients will be required, assuming an accrual rate of 10 
patients per month, total additional accrual time of 4.1 years, 2:1 distribution of patients 
in the experimental and control arms, a hazard ratio (HR) of 0.73 for the experimental 
arm relative to control, a 2-year OS of 46.6% in the control arm (median OS 1.82 years 
for the control arm, 2.49 years for the experimental arm), two-sided alpha of 0.05, and 
power 0.80. A total of 364 OS events will be needed to achieve the statistical power. 
Accounting for 10% non-randomization, we expect to enroll an additional 233 patients. 
In total (excluding lead-in), we expect to enroll 493 patients in order to obtain the 
required 444 randomized patients. The exact timing of the analysis for OS will be based 
on the required total number of events. 
 
14.4     Study Monitoring of Primary Objectives (09-MAR-2022) 
14.4.1 Interim Reports to Monitor the Study Progress   
Interim reports with will be prepared twice per year until the initial treatment results have 
been presented/published. In general, the interim reports will contain the following 
information: 
▪ patient accrual rate with a projected completion date (while the study is still accruing) 
▪ total patients accrued  
▪ distributions of important pre-treatment and prognostic baseline variables  
▪ the frequencies and severity of adverse events by treatment arm 
 
The interim reports will not contain the results from the primary endpoints (DLTs, PFS, 
OS) or any secondary endpoints, with the exception of routine reporting of adverse 
events. 
 
14.4.2 Significance Testing for Early Stopping and/or Reporting 
Phase II 
In phase II, the primary endpoint PFS will be tested for the interim analysis when there 
are 35 events. If the observed hazard ratio is ≥ 1.0 favoring control arm, then early 
stopping will be considered, with the conclusion being that this regimen would not be a 
candidate for further evaluation in phase III. The interim results will be reported to the 
NRG Oncology DMC for its review and recommendation regarding next steps of the 

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trial.  
 
At the phase II final analysis, a log-rank test will be used for the comparison of the two 
treatment arms; the total required PFS events is 69 at 2.2 years from accrual start. If the 
hazard ratio is ≤ 0.806, we will reject the null hypothesis and continue to phase III. This 
analysis will be performed within 6 weeks from the date the required number of events 
are observed.  
 
Key Sensitivity Analysis to the Phase II Primary Endpoint: When phase II accrual 
was halted, some patients that were still under RT+durvalumab treatment were allowed to 
switch to off-protocol treatment after the release of the Dear Investigator Letter/Dear 
Patient Letter. Therefore, a key sensitivity analysis to the protocol-specified phase II 
primary analysis will be performed to inform the decision-making regarding continuing 
to the phase III portion using the following approach: patients randomized to the 
RT+durvalumab arm eight weeks or less prior to the date of release of the DP/DI letters 
(8/9/2021) will be censored at the release time. All the remaining patients receiving 
RT+durvalumab at the release time will be included in the final analysis without this 
censoring type.  
 
If at the time of phase II primary endpoint analysis the study statistician recommends 
reopening the trial based on the protocol-specified design, all relevant outcome and 
toxicity information supporting the reopening recommendation will be provided to CTEP 
in a confidential manner to get approval before this recommendation is presented to the 
NRG DMC.  
 
The NRG DMC will be notified regarding the Go/No Go decision in phase II. 
 
Phase III 
There will be two interim analyses on OS when 182 (50%), and 273 (75%) deaths are 
observed for the two arms combined. The results will be reported to the NRG Oncology 
DMC with recommendations based on the results. An O’Brien-Fleming boundary will be 
utilized for efficacy monitoring. The stopping hazard ratio (HR) boundary and 
cumulative alpha spent are shown in the table below: 
 
# Events 
Hazard ratio 
One-sided 
significance level 
Cumulative alpha 
spent 
182 
0.627 
0.002 
0.002 
273 
0.739 
0.008 
0.010 
 
For futility, the statistical monitoring boundary will be based on the LIB20 method at the 
same analysis times, as recommended by Freidlin (2010).  
 
If the study is not stopped at an interim analysis, the final analysis will occur when 364 
total deaths are observed and tested at a 1-sided significance level of 0.021, for a 
cumulative alpha level of 0.025. 
 
14.4.3 Data Monitoring Reviews 

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Lead-In 
The study data, especially adverse events, will be closely monitored by the study team 
including but not limited to the study PI, co-PIs, and statistician, as listed on the protocol 
cover page. Given the projected monthly accrual and required data submission, a 
minimum of monthly conference calls will be held with the full study team (as described 
above) to review the study data, especially SAEs and DLTs. More frequent calls will be 
held as needed. Information will be disseminated to institutional PIs per standard practice 
of NRG Oncology. The study chair will follow up any report of DLT with individual 
investigators. 
 
Phase II/III 
The NRG Oncology Data Monitoring Committee (DMC) will review the randomized 
portion of the study twice a year with respect to patient accrual and morbidity. The DMC 
also will review the study for protocol-specified primary endpoint interim analyses, as 
well as on an “as needed” basis for any other issues.  
 
14.5 Accrual/Study Duration Considerations (09-MAR-2022) 
14.5.1  Lead-In 
The accrual rate will be 5 patients per month in the lead in phase. During the first three 
months after study activation, minimal accrual is expected. So the duration from start of 
accrual to primary endpoint reporting is 8-9 months for the initial dose of the lead-in, 
including accrual ramp-up time.  If de-escalation is required, the duration from start of 
accrual to primary endpoint reporting for each additional dose level is approximately 8 
months. The lead in accrual will be monitored according to the CTEP early phase slow 
accrual guidelines.  
 
14.5.2  Phase II and Phase III 
The monthly accrual will be 10 patients per month for the phase II/III component, with 
minimal accrual is expected during the first three months after the Phase II begins. The 
accrual will be monitored according to the CTEP late phase slow accrual guidelines.   
 
Accrual Goal and Duration 
Phase II:  234 randomized patients (projecting 260 enrolled to reach 234 randomized) 
accrued over 2.2 years. 
 
Actual Phase II Accrual (Revised):  186 randomized patients and 190 enrolled patients. 
 
Phase III:  444 randomized patients, including the 234 randomized in Phase II (projecting  
493 enrolled to reach 444 randomized), accrued over 4.1 years (including the Phase II 
accrual time) 
 
Estimated Duration for Completion of Primary Endpoint 
Phase II  
It is projected that the 69 PFS events required for the PFS primary endpoint analysis will 
occur approximately 2.2 years after the Phase II study activation, depending on the length 
of the safety lead-in portion, and approximately 3 years (assuming one cohort for the 
lead-in) after the randomized accrual begins. 

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Phase III  
It is projected that the 364 deaths required for the OS primary endpoint analysis will 
occur approximately 8.1 years after study activation, depending on the length of the 
safety lead-in portion, and approximately 6.5 years after the randomized accrual begins. 
 
14.6 Secondary Endpoints (15-JAN-2019) 
14.6.1  Response  
The 4-month response by FDG-PET/CT will be measured by RECIST.  Response rates 
between the two arms will be compared using Fisher’s exact test. 
 
14.6.2  Local-Regional Failure and Distant Metastases 
The intention-to-treat (ITT) population (all randomized patients) will be used for LRF 
and DM analyses. LRF is defined as time from randomization until first evidence of 
local, regional disease progression or recurrence, or death from study cancer or unknown 
causes. DM is defined as time from randomization until first evidence of distant 
metastasis. The table below shows the failures and competing risks for each of the three 
endpoints. LRF and DM will be estimated by cumulative incidence methods and 
compared using a cause-specific log-rank test. All failure times will be measured from 
the date of study randomization to the date of failure or last follow up.  
 
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 from 
unknown causes 
Failure 
Failure 
Competing risk 
Death due to any other reason 
Failure 
Competing risk Competing risk 
 
14.6.3 Toxicity 
 
CTCAE 
For toxicity analysis, all treated patients will be included in the analysis. The rates of 
adverse events will be estimated using a binomial distribution along with their associated 
95% confidence intervals and will be compared using Fisher’s exact test. 
 
PRO-CTCAE 
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. Once a patient submits the responses, 
the data goes directly from the device into the Rave database.  There are no documents to 
audit.  The electronic responses are the source documentation. 
 
14.6.4 Competing Mortality 

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Competing mortality for PFS and OS is defined as deaths due to other causes. This will 
be estimated by cumulative incidence methods and the effects of other covariates will be 
assessed using the GCE model.  
 
14.6.5 Quality of Life Analysis 
            EORTC QLQ-C30/HN35 
The focus of the quality of life (QOL) analysis is the EORTC QLQ-C30/H&N35 change 
in score from baseline to 12 months from the end of RT. The null hypothesis (H0) states 
that there is no difference in mean change in QOL physical function domain of EORTC 
QLQ between the MEDI4736-RT and cetuximab-RT arms. The alternative hypothesis 
(HA) states that there is a clinically meaningful difference in this mean change, whereby 
MEDI4736 will have a less decline in QOL compared to the cetuximab arm at one year 
from end of RT. A ≥ 10-point difference in mean change in score between arms is 
considered a minimum important change. A 10-point change on a 0-100 points scale in 
physical functioning QOL domain of the EORTC QLQ 30 is considered clinically 
meaningful. The intention-to-treat (ITT) population (all randomized patients) will be used 
for QOL analyses. Sensitivity analyses limited to patients that started protocol treatment 
may also be done.   
 
Based on prior trials in head and neck cancers, assuming the attrition rate is 35% at 12 
months, it is projected that 289 randomized patients will be evaluable for this analysis. To 
be conservative in power estimation, a standard deviation of 26.7 for the physical 
function domain of the EORTC QLQ mean change score is assumed. With a two-sided 
test at an alpha of 0.05, there will be 80% statistical power to detect a difference between 
treatment arms in mean change scores of 0.35 standard deviations. 
 
Overall, the mean individual domain scores of the EORTC QLQ/H&N35, overall 
summary score of the EQ5D and MDADI, and the subscales will be determined. The 
mean change from baseline at each time point will be summarized using mean and 
standard deviations for each arm. Mean change from baseline will be compared between 
the arms using a two sample t test. If data normality assumptions are not met, the 
Wilcoxon rank sum test will be used to test the hypothesis 
 
In addition to the primary hypothesis, exploratory analyses will evaluate change from 
baseline to other time points, as well as other domains of the EORTC QLQ/HN35. 
 
MDADI 
The MDADI will measure swallowing related QOL. Two summary scores can be 
obtained from the MDADI: 1) global and 2) composite. The global scale is a single 
question “my swallowing impacts my day-to-day life”. The composite MDADI score 
summarizes overall performance on remaining 19-items of the MDADI, as a weighted 
average of the physical, emotional, and functional subscale questions. Summary and 
subscale MDADI scores are normalized to range from 20 (extremely low functioning) to 
100 (high functioning). The composite MDADI score will be chosen as the primary 
swallowing endpoint as it reflects overall performance on 19-items (Hutcheson, 2016). 
The MDADI total composite score for clinically acceptable swallowing is defined as total 
composite MDADI score ≥ 60. A secondary QOL objective is to compare swallowing 

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related QOL between arms and it is hypothesized that the MEDI4736-RT will have less 
swallowing QOL decline, based on the change in score from baseline to 12 months from 
end of RT, compared to the cetuximab arm. The Null Hypothesis states that is that there 
is no difference in swallowing related QOL decline between arms. The swallowing QOL 
endpoint will measure the mean individual change in total composite MDADI score at 1 
year (from end of RT) from baseline in each arm. One of the arms will be deemed 
inferior to the other if there is a mean change score of ≥ 10 points from baseline for that 
arm and there is a ≥ 10 point difference between the 2 arms that is statistically significant 
at a 2-sided alpha of 0.05. Exploratory analyses will evaluate the percentage of patients in 
each arm with poor swallowing QOL, defined as an individual patient total composite 
MDADI score of < 60 at 12 months from end of RT and will also evaluate the subscale 
scores (global, physical, emotional, functional) of the MDADI inventory, with particular 
focus on the physical and functional subscales at 12 months from end of RT and the 
EORTC HN35 swallowing domain. 
 
QOL will be measured during the phase II and III portion of the study.  In addition to 
comparing the change scores at end of RT and at 4, 8, 12, 18, and 24 months from end of 
RT to baseline, overall trends in these QOL tools, and subscale scores will be modeled 
using the general linear mixed-effect model. This model will be used to compare the 
differences of scores over time between the two arms and to compute least squares mean 
and SEs, while adjusting for clinical variables and treatment by visit interaction terms. 
The model also allows for adjustments using stratification variables and other covariates 
of interest. The use of general linear mixed modeling allows flexibility in analyzing data 
with missing responses. For QOL endpoints, based on results from 175 patients enrolled 
on RTOG 0522 and Ringash (2004), the mean change score is approximately half of the 
standard deviation. Also, from the results of Curran (2007), we expect a meaningful 
between group change from baseline of 10 points on the EORTC QLQ/H&N35.  
 
Based on prior trials in head and neck cancers, assuming the attrition rate is 35% at 12 
months, we expect 289 patients will be randomized for the evaluation at 1 year. To be 
conservative in power estimation, we assume a standard deviation of 26.7 for physical 
function domain of the EORTC QLQ change score and MDADI at 12 months (from end 
of RT) from baseline. With a two-sided test of 5%, even if the change from baseline were 
as small as 0.375 of the standard deviation, the statistical power would be 88%. 
 
PSS-HN 
The PSS-HN is a clinician-rated instrument consisting of 3 subscales: normalcy of diet, 
public eating, and understandability of speech, each of which is rated from 0 to 100, with 
higher scores indicating better performance. In this study it is hypothesized that 
MEDI4736 (durvalumab) will have less decline in long-term swallowing function with 
respect to normalcy of diet and public eating from baseline to 12 months from the end of 
RT compared to the control arm. The mean score change for each of these subscales 
between arms will be compared using a two-sample independent t-test with a two-sided 
significance level of 0.05. A Wilcoxon test will be used if normality assumption does not 
hold. Temporal trends and differences between arms at other time points will be assessed 
using mixed models with the following covariates: time, treatment arm and its 
interaction. 

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Addressing Missing Data 
To handle poor compliance and missing data, efforts will be made to minimize attrition 
due to avoidable factors. To assess the missing data mechanism, we will compare 
possible differences between patients who dropped out of the study against those who 
remained in the study with respect to imbalance factors such as treatment, baseline 
scores, clinical and demographic data. We will undertake sensitivity analyses to 
investigate reasons for missingness (e.g. by drop-out), considering various factors as 
mentioned earlier. A logistic regression model will be used to summarize number of 
missing data and to test if the dropout process is missing completely at random (MCAR). 
Analysis of complete cases and cases with multiple imputations for missing observations 
(before death) will be done to check robustness of the main results. A pattern mixed 
model or selection model will be used to assess treatment effect to see if it is dropout 
dependent. Cox proportional hazard models will be used to determine the prognostic 
effects of baseline QOL on overall survival after adjusting for RT level, MEDI4736 
(durvalumab) or cetuximab usage and other potential factors.  
 
14.6.6  Correlative Biomarkers 
The primary correlative hypotheses are that PD-L1 and p16 are prognostic and possibly 
predictive for OS. To test these hypotheses, analyses of interaction between treatment 
arm and marker status will be done. Additionally toxicity for the two arms by marker 
status will be compared. Although both analyses are exploratory, we provide power for 
the prognostic effects on OS as shown in the following table. For dichotomized variables, 
the statistical power can be calculated by the method of Schoenfeld (1981). The table 
below shows statistical power to detect hazard ratios of 1.25, 1.50, 1.75, 2.00, 2.25, and 
2.50 for prevalence rates of 10%, or 20%, or 30%, etc. Statistical power will be the same 
if prevalence rate is 1-prevalence. The significance level was set at 0.05. As seen in the 
table, there will be > 87% power (given prevalence of >10% of the factor of interest in 
the study population) to detect a hazard ratio of 1.50 or greater for two arms combined. 
 
Overall Survival 
Statistical Power to Detect Various Hazard Ratios with 2-Sided 0.05 
 
 
Hazard Ratio 
Proportion Marker+ 
Events 
1.25 
1.50 
1.75 
2.00 
2.25 
2.50 
0.90 or 0.10 
364 
0.24 
0.64 
0.89 
0.97 
0.99 
0.99 
0.80 or 0.20 
364 
0.39 
0.87 
0.98 
0.99 
0.99 
0.99 
0.70 or 0.30 
364 
0.49 
0.94 
0.99 
0.99 
0.99 
0.99 
0.60 or 0.40 
364 
0.55 
0.96 
0.99 
0.99 
0.99 
0.99 
0.50 
364 
0.56 
0.97 
0.99 
0.99 
0.99 
0.99 
 
Univariable and multivariable analysis will be performed using the Cox proportional 
hazards model for OS. Potential covariates evaluated for the multivariate models would 
be assigned treatment, age, Zubrod performance status, T-stage, N-stage, primary site, 
smoking history, other risk factors, as well as p16 and/PD-L1. 
 

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14.6.7  Gastrostomy Tube Retention Rates  
Gastrostomy tube retention rates between arms at 1 year from the end of the RT will be 
compared using a Chi-square test with a two-sided alpha level of 0.05. Comparison of 
rates between arms at other time-points will be done if it is deemed necessary.  
 
14.7     Exploratory Analyses (21-AUG-2019) 
Translational (Exploratory) Analyses on Peripheral Blood Specimens  
The exploratory analyses in this section will be performed conditional on sufficient 
funding. Samples from the first 100 randomized patients at the different time points will 
be collected. We will test the hypothesis that MEDI4736 (durvalumab) combined with 
radiation enhances the adaptive immune response compared to cetuximab plus radiation. 
We will interrogate this hypothesis using three distinct methods of Immunophenotyping. 
Blood samples will be collected from patients into sodium heparin coated vacutainers 
(BD Vacutainer® Green BD Hemogard™) at time points specified under the study 
protocol: 1) Baseline (within 14 days prior to starting immunotherapy), 2) within 7 days 
prior to starting RT (and after starting systemic therapy), 3) 1 month after end of RT, 4) 
1 month after last dose of systemic therapy (durvalumab arm) or 4 months after RT 
(cetuximab arm).  
 
We will perform Multiparametric Flow cytometry on peripheral mononuclear cells 
(PBMC) from patient-derived blood samples to quantify changes in immune cell 
frequency and activation status before, during and after radiation combined with 
cetuximab or radiation combined with MEDI4736 (durvalumab) including: T-cell 
subsets (CD3, CD4, CD8, CD25, FOXP3, CD45RA, CD62L, CD127, CD278, PD-1, 
IFN-gamma, TNF-alpha), B cells (CD19, CD20), Macrophage I/II and myeloid-derived 
suppressor cells (MDSC) (CD16, CD68, CD206) and Natural killer cells (CD56, CD16, 
KIR, CD117, CD94). 
1) We will perform Next generation T-cell receptor sequencing (ImmunoSeq), using 
TCR-Beta CDR3 Kit (Adaptive Biotechnologies). TCR-β CDR3 regions will be 
amplified and sequenced using the survey ImmunoSeq assay in a multiplexed PCR 
method with reads obtained using an Illumina HiSeq System. 
2) Assessment of plasma IgG anti-tumor antibody responses will be performed using 
high-content protein microarray. IgGs levels against candidate antigens will validated 
uses multiplexed antigen-conjugated, spectrally distinguishable, fluorescent 
proprietary microspheres. 
3) For TCR ImmunoSeq Analysis: Shannon entropy will be calculated on the clonal 
abundance of all productive TCR sequences in the data set. Shannon entropy will be 
normalized to the range by dividing Shannon entropy by the logarithm of the number 
of unique productive TCR or BCR sequences in the data set. This normalized entropy 
value will then inverted (1 − normalized entropy) to produce the clonality metric. 
 
For analytical assessment of three phenotype changes such as plasma IgG anti-tumor 
antibody responses: changes in plasma IgG levels will be reported relative to pretreatment. 
To assess the statistical significance of pre- to post-treatment changes in levels of IgGs as 
well as other markers, normalized signal intensities (log2) will be tested using a paired t 
test within an arm and two sample t test between the two arms. If the distribution 

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assumption is violated for the t tests, nonparametric tests, such as the Wilcoxon signed-
rank test will be considered. IgG response will also be defined as ≥2-fold increase in signal 
intensity at 3 months post-treatment compared with pre-treatment and compared by a chi-
square test. The Benjamini and Hochberg procedure will be used to perform multiple 
testing adjustment of P values and obtain estimated false discovery rates (FDR). 
 
Lastly, the association between PFS and OS and post-treatment changes in frequency and 
activation state of T-cells, clonality and diversity of TCR, and IgG levels will be evaluated 
using a two-sided Wald test at 0.05 level on the basis of Cox models. 
 
From this analysis we will determine:  
1) Whether there is any statistically significant difference in the frequency and activation 
state of T-cells, memory T-cell precursors, B-cells, Macrophages, and NK cells in 
peripheral blood during or after treatment with radiation combined with cetuximab 
versus radiation combined with MEDI4736 (durvalumab);  
2) Whether there is a statistically significant changes in clonality and diversity of T-cell 
receptors in the peripheral blood during or after treatment with radiation combined with 
cetuximab versus radiation combined with MEDI4736 (durvalumab). Additionally the 
ImmunoSeq analysis will allow us to determine whether there is any statistically 
significant difference in the magnitude and diversity of adaptive immune responses 
after the combined treatment.  
3) From the IgG analysis, whether there is any statistically significant difference in 
development of humoral B-cell mediated antibody responses in patients during or 
after radiation combined with cetuximab versus radiation combined with MEDI4736 
(durvalumab). 
 
Patient-Reported Fatigue  
Patient reported fatigue is measured using the fatigue items 10, 12, and 18 in the EORTC 
QLQ-C30. The range of the PR fatigue scores is 0-100, where a high score represents a 
high level of fatigue. The change in EORTC QLQ fatigue scores from baseline to 4 
months from the end of RT between the MEDI4736-RT and cetuximab-RT arms will be 
compared using a two-sample t-test with a two-sided alpha level of 0.05. If the normality 
assumption does not hold, a Wilcoxon test will be used. Data analyses of change from 
baseline to the other collected time points will also be analyzed. A dichotomized version 
of the EORTC QLQ-C30 raw fatigue scores may be considered. A comparison of 
severity and interference (attributes a and b in Item 53) of PRO-CTCAE fatigue from 
baseline to 4 months from the end of RT between arms will be done using a chi-squared 
test with an alpha level of 0.05. For each patient a new outcome with three categories is 
defined: improved, stable (no change) and worsened. A patient is labeled as ‘improved’ if 
the PRO-CTCAE fatigue score at the baseline is greater than that at 4 months from the 
end of RT. Conversely, a patient is labeled as ‘worsened’ if the PRO-CTCAE fatigue 
score at the baseline is smaller than that at 4 months from the end of RT. Otherwise, the 
patient is being classified as ‘stable (no change)’. The distribution of the new outcome 
will be compared between the two arms using the chi-square statistics. 
 
Clinician and PRO Toxicity 
 

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Grades 1 to 5 in the CTCAE refers to the severity of the AEs, while the AE scores in 
PRO-CTCAE use a 5-point Likert scale for each attribute of an AE (frequency, severity, 
amount, interference and presence/absence). PRO-CTCAE scores with an attribute of 
severity (none, mild, moderate, severe or very severe with scores from 0 to 4, 
respectively) will be compared to AE scores graded by based on the CTCAE (none, mild, 
moderate, severe, life threating and death with scores from 0 to 5). The agreement 
between clinician and PRO toxicity will be assessed using the Pearson correlation 
between scores and the independence between scores will the tested using the Mantel-
Haenszel chi-square statistic with a one-sided alpha level of 0.025 (Agresti, 2002).  
 
Health Utilities Using the EQ5D-5L 
Quality adjusted survival or quality adjusted life years (QAYL) will be compared between 
“fit” and “vulnerable” patients as classified by the G-8 and EQ5D (Pottel 2015). Quality 
adjusted survival is calculated as the weighted sum of different time in different health 
states added up to a total quality adjusted survival time (Glasziou, 1990).  
 
The visual analog scale (VAS) and index scores from the EQ-5D-5L will be calculated at 
each time point (baseline, end of RT, and at 4, 8, 12, 18 and 24 months after RT ends) and 
compared between treatment arms using a t-test with a 2-sided significance level of 0.05.    
 
 
 
 
 
 
14.8  Gender/Ethnicity/Race Distribution (15-JAN-2019) 
 
Lead-In 
 
 
Racial Categories 
DOMESTIC 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 
4 
0 
0 
5 
White  
4 
14 
1 
2 
21 
More Than One Race 
0 
0 
0 
0 
0 
Total 
5 
18 
1 
2 
26 
 
 
 
INTERNATIONAL (including Canadian participants) 

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Racial Categories 
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 
0 
0 
0 
0 
0 
White  
1 
3 
0 
0 
4 
More Than One Race 
0 
0 
0 
0 
0 
Total 
1 
3 
0 
0 
4 
 
 
 
 
 
 
 
 
Phase II/III 
 
 
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 
3 
0 
0 
4 
Asian 
1 
3 
0 
0 
4 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
14 
58 
1 
5 
78 
White  
57 
228 
4 
17 
306 
More Than One Race 
0 
0 
0 
0 
0 

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Total 
73 
292 
5 
22 
392 
 
 
 
 
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 
1 
0 
0 
1 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
2 
7 
0 
1 
10 
White  
7 
30 
1 
2 
40 
More Than One Race 
0 
0 
0 
0 
0 
Total 
9 
39 
1 
3 
52 
 
 
 
 
 
 
 
 
 
 
 
REFERENCES (21-AUG-2019) 
Adelstein DJ, Lavertu P, Saxton JP, et al. Mature results of a phase III randomized trial 
comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III 
and IV squamous cell carcinoma of the head and neck. Cancer. 2000;88:876-83. PMID: 
10679658. 
Agresti, A. Categorical Data Analysis. Wiley Series in Probability and Statistics, 2002.  
Ahn MJ, D'Cruz A, Vermorken JB, et al. Clinical recommendations for defining platinum 
unsuitable head and neck cancer patient populations on chemoradiotherapy: A literature review. 
Oral Oncol. 2016 Feb;53:10-6. 
Alongi F, Bignardi M, Garassino I, et al. Prospective phase II trial of cetuximab plus VMAT-SIB 
in locally advanced head and neck squamous cell carcinoma. Feasibility and tolerability in 
elderly and chemotherapy-ineligible patients. Strahlenther Onkol. 2012;188(1):49-55.  

NRG-HN004 
145  
Version Date: March 09, 2022 
 
Alsidawi S, Westin G, Chintakuntlawar AV, Okuno SH, Price K. The impact of HPV infection 
on survival of patients with non-oropharyngeal head and neck cancer (abstr.) Proc Amer Soc 
Clin Oncol; J Clin Oncol. 2017;35(suppl; abstr 6048). 
Ang KK, Chen A, Curran WJ Jr, et al. Head and neck carcinoma in the United States: First 
comprehensive report of the Longitudinal Oncology Registry of Head and Neck Carcinoma 
(LORHAN). Cancer. 2012;118(23):5783-92.  
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with 
oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35. PMID: 20530316. 
Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial of concurrent accelerated 
radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: 
RTOG 0522. J Clin Oncol. 2014;32(27):2940-50. PMID: 25154822. 
Baxi SS, O'Neill C, Sherman EJ, Atoria CL, Lee NY, Pfister DG, Elkin EB. Trends in 
chemoradiation use in elderly patients with head and neck cancer: Changing treatment patterns 
with cetuximab. Head Neck. 2016 Apr;38(suppl 1): E165-71. PMID: 25535104. 
Bellera CA, Rainfray M, Mathoulin-Pelissier S, et al. Screening older cancer patients: first 
evaluation of the G-8 geriatric screening tool. Ann Oncol. 2012;23(8):2166-72. 
Bernard DL, Loeffler DR, Rothrock NE, et al. 2017. The challenge of measuring intra-individual 
change in fatigue during cancer treatment. Qual Life Res. 2017;26(2):259-271. 
Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant 
chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945-52. 
PMID: 15128894. 
 
Bhide, S. A, Gulliford, S, Kazi, R, et al. Correlation between dose to the pharyngeal constrictors 
and patient quality of life and late dysphagia following chemo-IMRT for head and neck cancer. 
Radiother Oncol. 2009;93(3):539-44. 
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced 
head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between 
cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21-8. PMID: 19897418. 
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma 
of the head and neck. N Engl J Med. 2006;354:567-78. PMID: 16467544. 
Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without 
concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med. 
1998;338:1798-804. PMID: 9632446. 
Carmona R, Zakeri K, Green G, et al. Improved method to stratify elderly cancer patients at risk 
for competing events. J Clin Oncol. 2016;34(11):1270-7. 
Cella D, Hahn EA, Dineen, K. Meaningful change in cancer-specific quality of life scores: 

NRG-HN004 
146  
Version Date: March 09, 2022 
 
differences between improvement and worsening. Qual Life Res. 2002;11(3):207-21. 
 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic 
comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-
383. 
 
Chen AY, Frankowski R, Bishop-Leone J, et al. The development and validation of a dysphagia-
specific quality-of-life questionnaire for patients with head and neck cancer: The M. D. 
Anderson Dysphagia Inventory. Arch Otolaryngol Head Neck Surg. 2001;127(7):870-76. 
Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive 
B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19:3462-73. 
Chera BS, Eisbruch A, Murphy BA, et al. Recommended patient-reported core set of symptoms 
to measure in head and neck cancer treatment trials. J Natl Cancer Inst. 2014;106(7). PMID: 
25006189. 
 
Chung CH, Zhang Q, Kong CS, et al. p16 protein expression and human papillomavirus status as 
prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin 
Oncol 2014;32:3930-8. 
Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and 
chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 
2004;350:1937-44. PMID: 15128893. 
Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase 
III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell 
carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012;84(5):1198-1205. 
Coyne JC, Pajak, T. F, Harris, J, Konski, A, Movsas, B, Ang, K, Watkins Bruner, D. Emotional 
well-being does not predict survival in head and neck cancer patients: A Radiation Therapy 
Oncology Group study. Cancer. 2007;110(11):2568-75. 
Dansky Ullmann C, Harlan LC, Shavers VL, Stevens JL. A population-based study of therapy 
and survival for patients with head and neck cancer treated in the community. Cancer. 
2012;118(18):4452-61. 
Eisbruch A, Kim HM, Feng FY, et al. Chemo-IMRT of oropharyngeal cancer aiming to reduce 
dysphagia: swallowing organs late complication probabilities and dosimetric correlates. Int J 
Radiat Oncol Biol Phys. 2011;81(3):e93-9. 
 
Fairman D, Narwal R, Liang M, et al. Pharmacokinetics of MEDI4736, a fully human anti-PDL1 
monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol. 2014;32(15): 2602.  
 
Fakhry C, Westra WH, Wang SJ, et al. The prognostic role of sex, race, and human 
papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. 
Cancer. 2017;123(9):1566-75. 

NRG-HN004 
147  
Version Date: March 09, 2022 
 
 
Falchook AD, Green R, Knowles ME, et al. Comparison of patient- and practitioner-reported 
toxic effects associated with chemoradiotherapy for head and neck cancer. JAMA Otolaryngol 
Head Neck Surg. 2016;142(6):517-23.  
 
Feng FY, Kim HM, Lyden, TH, et al. Intensity-modulated radiotherapy of head and neck cancer 
aiming to reduce dysphagia: early dose-effect relationships for the swallowing structures. Int J 
Radiat Oncol Biol Phys. 2007;68(5):1289-98. 
Ferris RL, Blumenschein GR, Fayette J, et al. Further evaluations of nivolumab (nivo) versus 
investigator’s choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell 
carcinoma of the head and neck (SCCHN): CheckMate 141 (abstr.) J Clin Oncol 2016;34(suppl; 
abstr 6009). 
Firat S, Byhardt RW, Gore E. Comorbidity and Karnofksy performance score are independent 
prognostic factors in stage III non-small-cell lung cancer: an institutional analysis of patients 
treated on four RTOG studies. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 
2002;54(2):357-64. 
Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of 
three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced 
larynx cancer. J Clin Oncol. 2013;31(7): 845-52. 
Freidlin B., Korn E.L., Gray R., (2010), A general inefficacy interim monitoring rule for 
randomized clinical trials. Clinical Trials 7, 197-208. 
Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III 
randomized study to compare hyperfractionation and two variants of accelerated fractionation to 
standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of 
RTOG 9003. Int J Radiat Oncol Biol Phys. 2000;48(1):7-16. 
Glasziou, P. P., Simes, R. J., Gelber, R. D. Quality adjusted survival analysis. Stat Med. 
1990;9(11):1259-1276. 
Gottesman SR, Walford RL, Thorbecke GJ. Proliferative and cytotoxic immune functions in 
aging mice. II. Decreased generation of specific suppressor cells in alloreactive cultures. J 
Immunol. 1984;133(4):1782-7. 
Grégoire V, Ang K, Budach W, et al. Delineation of the neck node levels for head and neck 
tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG 
consensus guidelines. Radiother Oncol. 2014;110(1):172–81. 
 
Gulliford SL, Miah AB, Brennan S, et al. Dosimetric explanations of fatigue in head and neck 
radiotherapy: an analysis from the PARSPORT Phase III trial. Radiother Oncol. 
2012;104(2):205-12. 
Haynes L, Maue AC. Effects of aging on T cell function. Curr Opin Immunol. 2009;21(4):414-7. 

NRG-HN004 
148  
Version Date: March 09, 2022 
 
PMID: 19500967. 
Haynes L, Eaton, SM. The effect of age on the cognate function of CD4+ T cells. Immunol Rev 
2005;205:220-8; PMID: 15882356. 
Hurria A, Cirrincione, CT, Muss, HB, et al. Implementing a geriatric assessment in cooperative 
group clinical cancer trials: CALGB 360401 J Clin Oncol. 2011;29(10):1290–96. 
Hurria A, Gupta S, Zauderer M, et al. Developing a cancer-specific geriatric assessment: A 
feasibility study. Cancer. 2005;104(9): 1998-2005. PMID: 16206252. 
Hutcheson KA, Barrow MP, Lisec A, Barringer DA, Gries K, Lewin JS. What is a clinically 
relevant difference in MDADI scores between groups of head and neck cancer patients? 
Laryngoscope. 2016;126(5):1108-13. 
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J Clin. 2010;60(5):277-300.  
Jensen AD, Bergmann ZP, Garcia-Huttenlocher H, et al. Cetuximab and radiation for primary 
and recurrent squamous cell carcinoma of the head and neck (SCCHN) in the elderly and multi-
morbid patient: a single-centre experience. Head Neck Oncol. 2010;2:34. 
Kallogjeri D, Gaynor SM, Piccirillo ML, Jean RA, Spitznagel EL Jr, Piccirillo JF. Comparison 
of comorbidity collection methods. J Am Coll Surg. 2014;219(2):245-55.  
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat 
Assoc. 1958;53:457-81. 
King MT. 2011. A point of minimal important difference (MID): A critique of terminology and 
methods. Expert Rev Pharmacoecon Outcomes Res. 2011;11 (2):171-184.  
 
Kirilovsky A, Marliot F, El Sissy C, Haicheur N, Galon J, Pagès F. Rational bases for the use of 
the Immunoscore in routine clinical settings as a prognostic and predictive biomarker in cancer 
patients. Int Immunol. 2016;28(8):373-82.  
Kish JA, Zhang Q, Langer CJ, et al. The effect of age on outcome in prospective, phase III NRG 
Oncology/RTOG trials of radiotherapy (XRT) +/- chemotherapy in locally advanced (LA) head 
and neck cancer (HNC) [abstract]. J Clin Oncol. 2015;33 (suppl; abstr 6003). 
Lacas B, Bourhis J, Overgaard J, Zhang Q, Grégoire V, Nankivell M, Zackrisson B, Szutkowski 
Z, Suwiński R, Poulsen M, O'Sullivan B, Corvò R, Laskar SG, Fallai C, Yamazaki H, 
Dobrowsky W, Cho KH, Beadle B, Langendijk JA, Viegas CMP, Hay J, Lotayef M, Parmar 
MKB, Aupérin A, van Herpen C, Maingon P, Trotti AM, Grau C, Pignon JP, Blanchard P; 
MARCH Collaborative Group. Role of radiotherapy fractionation in head and neck cancers 
(MARCH): an updated meta-analysis. Lancet Oncol. 2017 Sep;18(9):1221-1237. 
 
Levendag PC, Teguh DN, Voet P, et al. Dysphagia disorders in patients with cancer of the 

NRG-HN004 
149  
Version Date: March 09, 2022 
 
oropharynx are significantly affected by the radiation therapy dose to the superior and middle 
constrictor muscle: A dose-effect relationship. Radiother Oncol. 2007;85(1):64-73. 
Liang H, Deng L, Burnette B, Weichselbaum RR, Fu YX. Radiation-induced tumor dormancy 
reflects an equilibrium between the proliferation and T lymphocyte-mediated death of malignant 
cells. Oncoimmunology. 2013;2(9): e25668. PMID: 24319637. 
List MA, Mumby, P, Haraf D, et al. Performance and quality of life outcome in patients 
completing concomitant chemoradiotherapy protocols for head and neck cancer. Qual Life Res. 
1997;6(3): 274-284. 
 
List MA, Siston A, Haraf D, et al. Quality of life and performance in advanced head and neck 
cancer patients on concomitant chemoradiotherapy: A prospective examination. J Clin Oncol. 
1999;17(3):1020-28.  
 
Liuu E, Canoui-Poitrine F, Tournigand C, et al. Accuracy of the G-8 geriatric-oncology 
screening tool for identifying vulnerable elderly patients with cancer according to tumour site: 
the ELCAPA-02 study. J Geriatr Oncol. 2014;5(1):11-19. 
Lustgarten J, Dominguez AL, Thoman M. Aged mice develop protective antitumor immune 
responses with appropriate costimulation. J Immunol. 2004;173:4510-5. 
Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1: PD-L1 pathway in 
immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 
2013;73(6):1733-41. PMID: 23288508. 
MacFarlane AW, Jillab M, Plimack ER, et al. PD-1 expression on peripheral blood cells 
increases with stage in renal cell carcinoma patients and is rapidly reduced after surgical tumor 
resection. Cancer Immunol Res. 2014;2:320-31.  
Magrini SM, Buglione M, Corvò R, et al. Cetuximab and radiotherapy versus cisplatin and 
radiotherapy for locally advanced head and neck cancer: A randomized phase II trial. J Clin 
Oncol. 2016;34(5):427-35. 
Mell LK, Dignam JJ, Salama JK, et al. Predictors of competing mortality in advanced head and 
neck cancer. J Clin Oncol. 2010;28(1):15-20. PMID: 19933920. 
Mell LK, Zakeri K, Rose BS. On lumping, splitting, and the nosology of clinical trial populations 
and end points. J Clin Oncol. 2014;32(10):1089-90. PMID: 24550413. 
Mell LK, Shen H, Nguyen-Tan PF, et al. Nomogram to predict the benefit of intensive treatment 
for locoregionally advanced head and neck cancer. Clinical Cancer Research 2019; in press. 
Michiels S, Le Maître A, Buyse M, et al. Surrogate endpoints for overall survival in locally 
advanced head and neck cancer: meta-analyses of individual patient data. Lancet Oncol. 
2009;10(4):341-50. 

NRG-HN004 
150  
Version Date: March 09, 2022 
 
Miller MD, Paradis CF, Houck PR, et al. Rating chronic medical illness burden in 
geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. 
Psychiatry Res. 1992;41:237-48. 
Mosley RL, Koker MM, Miller RA. Idiosyncratic alterations of TCR size distributions affecting 
both CD4 and CD8 T cell subsets in aging mice. Cell Immunol. 1998;189(1):10-8. 
Movsas B, Hunt D, Watkins-Bruner D, et al. Can electronic web-based technology improve 
quality of life data collection? Analysis of Radiation Therapy Oncology Group 0828. Pract 
Radiat Oncol. 2014;4(3):187-91. 
Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune 
checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and meta-
analysis. Cancer Treat Rev. 2016;45:30-7.  
Niska JR, Halyard, MY, Tan AD., Atherton PJ, Patel SH, & Sloan JA. Electronic patient-
reported outcomes and toxicities during radiotherapy for head-and-neck cancer. Qual Life Res. 
2017, Feb in press. 
 
Perez-Soler R, Delord J, Halpern A, et al. HER1/EGFR inhibitor-associated 
rash: Future directions for management and investigation outcomes from the HER1/EGFR 
Inhibitor Rash Management Forum. Oncologist. 2005;10:345-56,. 
Pfister DG, Spencer S, Brizel DM, et al. Head and neck cancers, Version 1. J Natl Compr Canc 
Netw. 2015;13(7):847-55.  
Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Meta-analysis 
of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 
17,346 patients. Radiother Oncol. 2009;92(1):4-14. 
Pottel L, Lycke M, Boterberg T, et al. G-8 indicates overall and quality-adjusted survival in older 
head and neck cancer patients treated with curative radiochemotherapy. BMC Cancer. 
2015;15:875.  
Pottel L, Lycke M, Boterberg T, et al. Serial comprehensive geriatric assessment in elderly head 
and neck cancer patients undergoing curative radiotherapy identifies evolution of 
multidimensional health problems and is indicative of quality of life. Eur J Cancer Care 
2014;23(3):401-412. 
 
Powell C, Schick U, Morden JP, et al. 2014. Fatigue during chemoradiotherapy for 
nasopharyngeal cancer and its relationship to radiation dose distribution in the brain. Radiother 
Oncol. 2014;110(3) 416-421. 
Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity 
in metastatic bladder cancer. Nature. 2014;515(7528): 558-62. PMID: 25428503 
Quinten C, Maringwa J, Gotay CC, et al. Patient self-reports of symptoms and clinician ratings 

NRG-HN004 
151  
Version Date: March 09, 2022 
 
as predictors of overall cancer survival. J Natl Cancer Inst. 2011;103(24):1851-1858. 
Rades D, Seidl D, Janssen S, Bajrovic A, Karner K, Strojan P, Schild SE. Comparison of weekly 
administration of cisplatin versus three courses of cisplatin 100 mg/m(2) for definitive 
radiochemotherapy of locally advanced head-and-neck cancers. BMC Cancer. 2016;16:437. 
Ringash, J., O'Sullivan, B., Bezjak, A., Redelmeier, D. A. Interpreting clinically significant 
changes in patient-reported outcomes. Cancer. 2007;110(1):196-202. 
Rose BS, Jeong JH, Nath SK, Lu SM, Mell LK. Population-based study of competing mortality 
in head and neck cancer. J Clin Oncol. 2011;29(26): 3503-9. PMID: 21844503 
Rubinstein L, Crowley J, Ivy P, Leblanc M, Sargent D. Randomized phase II designs. Clin 
Cancer Res. 2009;15(6):1883-90. PMID:1927627 
Sarris EG, Harrington KJ, Saif MW, Syrigos KN. Multimodal treatment strategies for elderly 
patients with head and neck cancer. Cancer Treat Rev. 2014;40(3):465-75. PMID: 24238923 
Segal NH, Ou SH, Balmanoukian AS, et al. Safety and efficacy of MEDI4736, an anti-PD-L1 
antibody, in patients from a squamous cell carcinoma of the head and neck (SCCHN) expansion 
cohort (Abstr.) J Clin Oncol. 2015;33:15 (suppl; abstr 3011). 
Seiwert TY, Burtness B, Weiss J, et al. A phase Ib study of MK-3475 in patients with human 
papillomavirus (HPV)-associated and non-HPV–associated head and neck (H/N) cancer. J Clin 
Oncol. 2014;32:5s (suppl; abstr 6011). 
Seiwert TY, Weiss J, Baxi SS, et al. A phase 3, randomized, open-label study of first-line 
durvalumab (MEDI4736) ± tremelimumab versus standard of care (SoC; EXTREME regimen) 
in recurrent/metastatic (R/M) SCCHN: KESTREL (Abstr.) J Clin Oncol. 2016;34(15), (suppl; 
abstr TPS6101). 
Sharabi AB, Nirschl CJ, Kochel CM, et al. Stereotactic radiation therapy augments antigen-
specific PD-1 mediated anti-tumor immune responses via cross-presentation of tumor antigen. 
Cancer Immunol Res. 2015;3(4):345-55. PMID: 25527358 
Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade 
immunotherapy: Radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 
2015;16(13):e498-509.  
Siddiqui F, Gwede CK. Head and neck cancer in the elderly population. Semin Radiat Oncol. 
2012;22(4):321-33. PMID: 22985815 
Sprecher E, Becker Y, Kraal G, Hall E, Harrison D, Shultz LD. Effect of aging on epidermal 
dendritic cell populations in C57BL/6J mice. J Invest Dermatol. 1990:94;247-53. PMID 
2299200 
Strom TJ, Trotti AM, Kish J, Russell JS, Rao NG, McCaffrey J, Padhya TA, Otto KJ, Caudell JJ. 

NRG-HN004 
152  
Version Date: March 09, 2022 
 
Comparison of every 3 week cisplatin or weekly cetuximab with concurrent radiotherapy for 
locally advanced head and neck cancer. Oral Oncol. 2015;51:704-8. 
Thoman ML, Ernst DN, Hobbs MV, Weigle WO. T cell differentiation and functional 
maturation in aging mice. Adv Exp Med Biol. 1993;330:93-106. 
Truong MT, Zhang Q, Rosenthal DI, et al. 2017. Quality of life and performance status from a 
substudy conducted within a prospective phase 3 randomized trial of concurrent accelerated 
radiation plus cisplatin with or without cetuximab for locally advanced head and neck 
carcinoma: NRG Oncology Radiation Therapy Oncology Group 0522. Int J Radiat Oncol Biol 
Phys. 2016;97(4):687-99. 
Twyman-Saint V, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-
redundant immune mechanisms in cancer. Nature. 2015;520(7547):373-7. 
Vainshtein JM, Moon DH, Feng FY, Chepeha DB, Eisbruch A, Stenmark MH. 2015. Long-term 
quality of life after swallowing and salivary-sparing chemo-intensity modulated radiation therapy 
in survivors of human papillomavirus-related oropharyngeal cancer. Int J Radiat Oncol Biol 
Phys. 2015;91(5): 925-933. 
VanderWalde NA, Meyer AM, Deal AM, et al. Effectiveness of chemoradiation for head and 
neck cancer in an older patient population. Int J Radiat Oncol Biol Phys. 2014;89:30-7.  
Wildiers H, Mauer M, Pallis A, et al. End points and trial design in geriatric oncology research: 
A joint European organisation for research and treatment of cancer—Alliance for Clinical Trials 
in Oncology–International Society of Geriatric Oncology position article. J Clin Oncol. 
2013;31(29): 3711-8. PMID: 24019549 
WHO GLOBOCAN database: <http://www-dep.iarc.fr> accessed January 31, 2015. 
Wong SJ, Harari PM, Garden AS, et al. Longitudinal Oncology Registry of Head and Neck 
Carcinoma (LORHAN): Analysis of chemoradiation treatment approaches in the United States. 
Cancer. 2011;117(8): 1679-86.  
Wookey V, Appiah AK, Kallam A, Ernani V, Smith L, Ganti AK. HPV status and survival in 
non-oropharyngeal squamous cell carcinoma of the head and neck (abstr.) Proc Amer Soc Clin 
Oncol; J Clin Oncol 35, 2017 (suppl; abstr 6046). 
 
Xiao, C., Hanlon, A., Zhang, Q, et al. 2013. Symptom clusters in patients with head and neck 
cancer receiving concurrent chemoradiotherapy. Oral Oncol. 49(4): 360-66. 
 
Yost KJ, Eton DT, Garcia, SF, Cella D. 2011. Minimally important differences were estimated 
for six Patient-Reported Outcomes Measurement Information System-Cancer scales in 
advanced-stage cancer patients. J Clin Epidemiol. 64(5): 507-16. 
 
Zakeri K, Rotolo F, Lacas B, Vitzthum LK, Le QT, Gregoire V, Overgaard J, Tobias J, 
Zackrisson B, Parmar MK, Burtness BA, Ghi MG, Sanguineti G, O’Sullivan B, Fortpied C, 

NRG-HN004 
153  
Version Date: March 09, 2022 
 
Bourhis J, Shen H, Harris J, Pignon J, Mell LK. Predictor of Effectiveness of Treatment 
Intensification on Overall Survival in Head and Neck Cancer (HNC). Ann Oncol (abstr.) 2018; 
29 (suppl 8): viii372-viii399. 
Zandberg DP, Strome SE. The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of 
the head and neck. Oral Oncol. 2014 Jul;50(7):627-32. 
Zavala WD, Cavicchia JC. Deterioration of the Langerhans cell network of the human gingival 
epithelium with aging. Arch Oral Biol. 2006;51:1150-5. 
Zelen M. The randomization and stratification of patients to clinical trials. J Chron Dis. 1974;27: 
365-75. 
Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-
term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2): 343-9.  
Zhang Q, Freidlin B, Korn E, Halabi S, Mandrekar S, Dignam JJ. Comparison of futility 
monitoring guidelines using completed phase III oncology trials, Clinical Trials. 2017;14(1):48-
58. 
 
Zumsteg ZS, Cook-Wiens G, Yoshida E, et al. Incidence of oropharyngeal cancer among elderly 
patients in the United States. JAMA Oncol. 2016;2(12):1617-23. 
  
 
 

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APPENDIX I: CTEP COLLABORATIVE AGREEMENTS LANGUAGE 
 
The agent supplied by CTEP, DCTD, NCI used in this protocol is 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 

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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. 
 
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: 
 
E-mail: 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 II: PREPARATION, PROCESSING,  
AND SHIPPING OF PERIPHERAL BLOOD (21-AUG-2019) 
 
To be offered to Phase II/III Patients only 
 
The Biospecimen Kit (described below) is available from the UCSF Biobank (Contact 
NRGBB@ucsf.edu). 
 
Kit Contents (per time point): 
• Five (5) 10 ml Heparin Blood (green top) draw tubes  
• Styrofoam tube holder 
• Outer box for tube holder with plastic bag 
• Study-specific specimen Transmittal (ST) Form 
• Fed Ex Clinical Pak with label 
 
Processing: 
1. Sites should only draw blood samples on Monday-Wednesday (U.S. Sites).  
2. Draw blood in five (5) 10 ml green top (heparin) tubes. Collect at least 8 ml per tube. 
3. Mix gently. 
4. Place tubes in tube holder and outer box provided with Kit. 
5. Seal up tube holder box and place in Fed Ex Clinical Pak provided. 
6. Ship the blood ambient for overnight morning delivery to the Mell Laboratory. The 
shipping label is provided with the Clinical Pak. 
7. During cold weather months, protect green top tubes from freezing, which will cause 
hemolysis and render the tubes unusable. A room-temperature gel pack is advised. 
8. If sites draw the blood sample late in the day, the site should maintain the sample at room 
temperature until it is shipped and note this on the ST form. 
 
NOTE: Samples MUST be overnighted within 12 hours of collection.  
 
NOTE: Do NOT collect and/or ship samples on Friday, Saturday, or Sunday.  
 
NOTE: The coordinator or personnel collecting the sample MUST send a notification by email 
to Sharmeela Kaushal (skaushal@ucsd.edu) and Mason Kyle (mkyle@ucsd.edu) in advance and 
provide the tracking information. 
 
NOTE: Do NOT ship peripheral blood to NRG Oncology Biospecimen Bank. 
 
Ship specimens for this peripheral blood specimen study to:  
Attn.: Sharmeela Kaushal 
Assistant Director, MCC Biorepository 
UCSD Moores Cancer Center Biorepository 
3855 Health Sciences Dr, Room 3331 OR Room 3345-G  
La Jolla, CA 92093-0819 
Email: skaushal@ucsd.edu   
Phone: 858-534-7302 

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Fax: 858-822-5380 
 
For questions, contact:  
• Sharmeela Kaushal, skaushal@ucsd.edu  
• Mason Kyle (mkyle@ucsd.edu) 
• Loren Mell, lmell@ucsd.edu 
• Alfredo Molinolo, amolinolo@ucsd.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX III (13-JAN-2021) 
Medidata Patient Cloud Operational Instructions 
 
Introduction 
Electronic collection of patient-reported outcomes (ePRO) through Medidata Patient Cloud 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 with their passwords or their PIN codes on the same device.  
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 
 
 
 
 
The following Patient Cloud App is used on this study: 
Patient Cloud 
 
 
 
 
CRA Site Users 
Site users of Patient Cloud require the same access as Rave. Access to the trial in the Patient 
Cloud is granted through the iMedidata. Site users will receive an invitation to Patient Cloud 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 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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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. 
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. 
Patient Users 
To use the Patient Cloud, 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 with their passwords or their PIN codes on the 
same device. Refer to the paragraph above on Setting the Patient Cloud App to Multi-User 
Mode.   
Patient Instructions for Accessing the Patient Cloud Using Your Personal Device 
Downloading the Patient Cloud 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. 
 
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 Medidata Patient Cloud 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 Medidata Patient Cloud 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 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 
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. 

NRG-HN004 
161  
Version Date: March 09, 2022 
 
 
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: 
• 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. 
• Anytime Forms (with a 
 icon): These forms have "Last Completed Time" 
indicator on them which tells the most recent date or time when you 

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