Conditions: Metastatic Nasopharyngeal Carcinoma Metastatic Nasopharyngeal Keratinizing Squamous Cell Carcinoma Metastatic Nasopharyngeal Nonkeratinizing Carcinoma Metastatic Nasopharyngeal Undifferentiated Carcinoma Nasopharyngeal Nonkeratinizing Carcinoma Recurrent Nasopharyngeal Carcinoma Recurrent Nasopharyngeal Keratinizing Squamous Cell Carcinoma Recurrent Nasopharyngeal Undifferentiated Carcinoma Stage IV Nasopharyngeal Carcinoma AJCC v8 Stage IVA Nasopharyngeal Carcinoma AJCC v8 Stage IVB Nasopharyngeal Carcinoma AJCC v8
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
This phase III trial compares the effect of adding nivolumab to the usual chemotherapy (cisplatin or carboplatin with gemcitabine) versus standard chemotherapy alone in treating patients with nasopharyngeal cancer that has come back (recurrent) or spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as cisplatin, carboplatin, and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab with the usual chemotherapy may work better than the standard chemotherapy alone in treating patients with nasopharyngeal cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine if adding nivolumab to platinum-gemcitabine as first-line treatment improves overall survival (OS) for patients with recurrent and/or metastatic nasopharyngeal carcinoma (NPC).

SECONDARY OBJECTIVES:

I. To compare patterns of failure (local-regional relapse and distant metastasis) between treatment arms.

II. To determine if adding nivolumab to platinum-gemcitabine as first-line treatment improves the objective tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

III. To determine if adding nivolumab to platinum-gemcitabine as first-line treatment improves progression free survival (PFS) for patients with recurrent and/or metastatic NPC.

IV. To evaluate the toxicity based on the Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.

V. To characterize patient-reported symptomatic toxicities measured by Patient-Reported Outcomes (PRO)-CTCAE.

VI. To assess the quality of life (QOL), as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core (C)30, between the two arms (primary PRO).

VII. To assess fatigue, as measured by Multidimensional Fatigue Inventory (MFI-20), between the two arms (secondary PRO).

VIII. To determine if a subset of patients based on an optimal cutoff point of Programmed Death Receptor Ligand-1 (PD-L1) Combined Positive Score (CPS)/Tumor Proportion Score (TPS) is more likely to benefit in terms of PFS from adding nivolumab to platinum-gemcitabine as first-line treatment.

EXPLORATORY OBJECTIVES:

I. To determine if a subset of patients based on an optimal cutoff point of PD-L1 CPS/TPS is more likely to benefit in terms of overall survival (OS) from adding nivolumab to platinum-gemcitabine as first-line treatment.

II. To determine changes in QOL as measured by EORTC QLQ-C30 and in fatigue as measured by MFI-20, between and within arms over time (exploratory PRO).

III. To collect blood and tissue specimens for future translational research.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1, gemcitabine IV over 30 minutes on days 1 and 8, and cisplatin IV over 30-60 minutes or carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After 4 weeks, patients then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive gemcitabine and cisplatin or carboplatin as in Arm I.

After completion of study treatment, patients are followed up every 4 months for 2 years, every 6 months for 3 years, and then annually.

Arms:
arm 1: Patients receive nivolumab IV over 30 minutes on day 1, gemcitabine IV over 30 minutes on days 1 and 8, and cisplatin IV over 30-60 minutes or carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After 4 weeks, patients then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive gemcitabine and cisplatin or carboplatin as in Arm I.

Interventions: intervention 1: Carboplatin intervention 2: Cisplatin intervention 3: Gemcitabine intervention 4: Nivolumab intervention 5: Questionnaire Administration
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
i 
 
For Protocol Amendment 1 to: NRG-HN007, An Open-Label, Phase III Study of Platinum-Gemcitabine 
With or Without Nivolumab in the First-Line Treatment of Recurrent or Metastatic Nasopharyngeal 
Carcinoma 
 
NCI/Local Protocol #: NRG-HN007 
 
NCI Protocol Version Date: February 16, 2021 
 
Request for Rapid Amendment (RRA) for studies using nivolumab: 
7.3 
In response to a CTEP Request for Rapid Amendment (RRA) for studies using 
nivolumab, the CAEPR for nivolumab (Version 2.4, December 2, 2020) was revised 
as follows: 
 
• The SPEER grades have been updated. 
• Added New Risk: 
• Less Likely: CD4 lymphocytes decreased 
• Rare: Enterocolitis; Eye disorders - Other (Vogt-Koyanagi-Harada); 
Hepatobiliary disorders - Other (immune-mediated hepatitis); Renal and 
urinary disorders - Other (immune-mediated nephritis) 
• Modified Specific Protocol Exceptions to Expedited Reporting (SPEER) 
reporting requirements:  
• Added: CD4 lymphocytes decreased 
• Provided Further Clarification: 
• Immune system disorders - Other (sarcoid granuloma) is now reported as 
Immune system disorders - Other (sarcoidosis). 
 
 
Other changes: 
Global 
• The protocol version date was updated in the document footer.  
• Formatting and typographical errors were corrected as needed. 
Cover page 
• Contact information for the Quality of Life Co-Chair was updated. 
• This amendment was added to the Document History table.  
3.1.11 
“Arm 2” was corrected to “Arm 1”.  
3.1.12 
The weblink was updated. 
4.1 
• “Urine analysis” was revised to “Urinalysis (to include protein)” for 
clarification. 
• In footnote number 3, “free” was added before “T4” and “T3” for clarification. 
5.1.5 
The infusion time was corrected from 60 to 30 minutes to align with section 9.2 as 
referenced in NRG’s December 02, 2020 broadcasted study memo.  
5.2.2 
“5.4.2” was inadvertently referenced in the 3rd bullet and was removed.  
7.5.2 
The first paragraph under “Additional Protocol-Specific Instructions or Exceptions 
to Expedited Reporting Requirements” was removed as this text was inadvertently 
added.   
8.1 
8.3.1 
 These sections were updated per current CTSU logistics. 
10.1.3 
10.3.1 
These sections were updated per NRG Biobank logistics and to clarify ctDNA 
collection for Asian sites.  


NRG-HN007 
1  
Version Date: February 16, 2021 
 
      NRG ONCOLOGY 
 
                                                      NRG-HN007  
(ClinicalTrials.gov NCT #04458909) 
 
AN OPEN-LABEL, PHASE III STUDY OF PLATINUM-GEMCITABINE WITH OR 
WITHOUT NIVOLUMAB IN THE FIRST-LINE TREATMENT OF RECURRENT 
OR METASTATIC NASOPHARYNGEAL CARCINOMA 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the 
participation of the network of NCTN organizations: the Alliance for Clinical Trials in 
Oncology; ECOG-ACRIN Medical Group; and SWOG. 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team (16-FEB-2021) 
 
Principal Investigator/Medical Oncology  
Brigette B. Y. Ma, MD 
The Chinese University of Hong Kong 
Department of Clinical Oncology 
Prince of Wales Hospital, Shatin 
30-32 Ngan Shing Street 
New Territories, Hong Kong  
852-3505-2118/FAX 852-2648-7097 
brigette@clo.cuhk.edu.hk 
 
Medical Oncology Co-Chairs 
A. Dimitrios Colevas, MD 
Stanford University 
875 Blake Wilbur Drive, CC-2228 
Stanford, CA 94305 
650-724-9707/FAX 650-498-5800 
colevas@stanford.edu  
 
Lillian L. Siu, MD 
University Health Network - Princess Margaret 
Hospital 
700 University Avenue 
Hydro Building, 7-624 
Toronto, ON M5G 1Z5 CA 
416-946-2911 
lillian.siu@uhn.ca  
Translational Research Co-Chairs 
Allen K. C. Chan, FRCPA 
The Chinese University of Hong Kong 
Department of Chemical Pathology 
Prince of Wales Hospital, Shatin 
1/F, Lui Che Woo Clinical Sciences Building 
New Territories, Hong Kong 
852-3505-3589/FAX 852-2636-5090 
allen@cuhk.edu.hk  
 
Boon Cher Goh, MBBS, MRCP 
National University Cancer Institute, Singapore 
Department of Hematology-Oncology 
1E Kent Ridge Rd 
Singapore, 119228 
65-6773-7888 
boon_cher_goh@nuhs.edu.sg  
 
Kwok Wai Lo, BSc, MPhil, PhD 
The Chinese University of Hong Kong 
Department of Anatomical and Cellular Pathology 
Prince of Wales Hospital, Shatin 
30-32 Ngan Shing Street 
New Territories, Hong Kong  
852-3505-2178/FAX 852-2637-6274 
kwlo@cuhk.edu.hk  


NRG-HN007 
2  
Version Date: February 16, 2021 
 
Wan Teck Darren Lim, MBBS, MRCP 
National Cancer Centre Singapore – Sing Health 
Division of Medical Oncology 
11 Hospital Drive 
Singapore, 169610  
65-6436-8174 
darren.lim.w.t@singhealth.com.sg     
 
 
Danny Rischin, MD, MBBS, FRACP 
Peter MacCallum Cancer Centre 
305 Grattan St 
Melbourne, VC 3000 
Australia 
03-8559-5000  
danny.rischin@petermac.org  
 
Bhumsuk Keam, MD, PhD 
Seoul National University Hospital 
101 Daehak-ro  
Jongno-gu, Seoul 
South Korea 
82-10-3231-2208/FAX 82-2-3668-7059 
bhumsuk@snu.ac.kr  
 
Quality of Life Co-Chair 
Canhua Xiao, PhD, RN, FAAN 
Emory University 
1520 Clifton RoadAtlanta, GA 30322404-712-
9633 
canhua.xiao@emory.edu  
Pathology Co-Chair 
Sara M. Calkins, MD 
University of California San Francisco  –  Mt. Zion 
1600 Divisadero Street 
San Francisco, CA 94143 
415-353-7650/FAX 415-353-7676 
sarah.calkins@ucsf.edu  
 
Co-Chair 
Yun-Fei Xia, MD 
Sun Yat-Sen University Cancer Center 
Department of Radiation Oncology 
651 Dongfeng Road East 
Guangzhou 510060, China 
86-20-8734-3373 
xiayf@sysucc.org.cn  
 
Senior Statistician 
Pedro Torres-Saavedra, PhD 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-0851/FAX 215-928-0153 
torresp@nrgoncology.org  
 
 
 
The following NCTN Group Study Champion has been added to this trial: 
Alliance for Clinical Trials in Oncology  
Alan L. Ho, MD, PhD 
Memorial Sloan Kettering Cancer Center 
300 East 66th Street 
New York, NY 10065 US 
646-888-4235 
hoa@mskcc.org   
 
 
 
NRG Oncology Contact Information 


NRG-HN007 
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Version Date: February 16, 2021 
 
Data Management 
For questions concerning eligibility or 
data submission 
Vanita Patel, MS 
Lisa Abate 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102  
215-574-3170 (Patel) 
215-574-3178 (Abate) 
FAX 215-940-8830 
patelv@nrgoncology.org 
abatel@nrgoncology.org  
 
Protocol Development: 
For questions concerning protocol and 
informed consent versions & 
amendments 
Thien Nu Do 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3174  
dot@nrgoncology.org  
 
Head and Neck Committee Chair 
Quynh-Thu Le, MD, FACR, FASTRO 
Stanford University 
875 Blake Wilbur Drive, MC 5847 
Stanford, CA 94305 
650-498-5032/FAX 650-725-8231 
qle@stanford.edu  
 
 
 


NRG-HN007 
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Version Date: February 16, 2021 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Nivolumab 
CTEP/PMB 
748726 
 
DCTD, NCI 
Carboplatin 
Commercial 
241240 
Cisplatin 
Commercial 
119875 
Gemcitabine 
Commercial 
613327 
 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
 
Document History 
 
Version Date 
Amendment 1 
February 16, 2021 
Initial 
 August 31, 2020 
 
 
 
 
  
 
 
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. 


NRG-HN007 
5  
Version Date: February 16, 2021 
 
                                                    NRG ONCOLOGY  
 
                                                         NRG-HN007  
 
AN OPEN-LABEL, PHASE III STUDY OF PLATINUM-GEMCITABINE WITH OR 
WITHOUT NIVOLUMAB IN THE FIRST-LINE TREATMENT OF RECURRENT OR 
METASTATIC NASOPHARYNGEAL CARCINOMA 
 
CONTACT INFORMATION 
 
For regulatory 
requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
Regulatory Submission 
Portal: (Sign in at 
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 at 1-866-651-
2878 to receive further 
instruction and support. 
 
Contact the CTSU 
Regulatory Help Desk at 1-
866-651-2878 for regulatory 
assistance. 
Please 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_S
YSTEM/ 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 members’ 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.  
For clinical questions (i.e. patient eligibility or treatment-related)  
Contact the Study Data Managers of the Lead Protocol Organization.  


NRG-HN007 
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Version Date: February 16, 2021 
 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission)  
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
 


NRG-HN007 
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Version Date: February 16, 2021 
 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................9 
1. 
OBJECTIVES ....................................................................................................................11 
1.1       Primary Objective ..................................................................................................11 
1.2 
Secondary Objectives .............................................................................................11 
1.3 
Exploratory Objectives ..........................................................................................11 
2 
BACKGROUND ...............................................................................................................11 
2.1 
Epidemiology and Natural History of Endemic Nasopharyngeal 
Carcinoma (NPC)...................................................................................................11 
2.2 
Current Standard of Care for Metastatic or Incurable Recurrent NPC ..................11 
2.3 
Prognostic Factors in Metastatic NPC That Should Be Considered for 
Patient Stratification ...............................................................................................12 
2.4 
Preclinical Data on Targeting Immune-Checkpoint Signaling in NPC .................12 
2.5 
Clinical Data: The Development of Immunotherapy in 
Recurrent/Metastatic NPC .....................................................................................12 
2.6 
Clinical Data on Combining PD-1 Inhibitor and Chemotherapy in NPC 
and Other Cancers ..................................................................................................13 
2.7 
Impact of KEYNOTE-048 on the Design of This Study .......................................14 
2.8 
Prognostic and Predictive Biomarkers in NPC ......................................................14 
2.9       Quality of Life and Other Patient-Reported Outcomes in Patients with 
NPC Receiving Immunotherapy and Chemotherapy .............................................15 
3 
ELIGIBILITY AND INELIGIBILITY CRITERIA ..........................................................16 
3.1 
Inclusion Criteria ...................................................................................................16 
3.2 
Exclusion Criteria ..................................................................................................18 
4 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........21 
4.1 
Study Calendar for Treatment Arm 1 (Experimental) ...........................................21 
4.2 
Study Calendar for Treatment Arm 2 (Control) ....................................................23 
4.3 
Objective Tumor Response ....................................................................................25 
4.4 
Tumor Imaging During the Study ..........................................................................25 
5. TREATMENT PLAN/REGIMEN DESCRIPTION..................................................................26 
5.1 
Systemic Therapy - Summary ................................................................................26 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................29 
5.3 
Participation in Other Trials ...................................................................................31 
5.4 
Duration of Therapy ...............................................................................................31 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT .....................................................31 
6.1 
Dose Modifications and Toxicity Management for Cisplatin-Gemcitabine ..........32 
6.2       Dose Modifications and Toxicity Management for Carboplatin ...........................34 
6.3 
Dose Modifications and Toxicity Management for Nivolumab-related 
Adverse Events ......................................................................................................35 


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7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................43 
7.1      Protocol Agents .......................................................................................................43 
7.2      Adverse Events and Serious Adverse Events .........................................................43 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for 
CTEP Study Agent: Nivolumab.............................................................................44 
7.4 
Adverse Events for Commercial Study Agents: Cisplatin, Carboplatin, and 
Gemcitabine ...........................................................................................................48 
7.5 
Expedited Reporting of Adverse Events ................................................................49 
7.6 
Routine Reporting Requirements for Adverse Events ...........................................53 
7.7 
Pregnancy ...............................................................................................................53 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES .............................................53 
8.1 
Cancer Trials Support Unit Registration Procedures .............................................54 
8.2 
Patient Enrollment .................................................................................................58 
8.3 
Medidata Patient Cloud ePRO Registration ..........................................................59 
9.0 
DRUG INFORMATION ...................................................................................................60 
9.1 
Agent Ordering and Agent Accountability ............................................................60 
9.2 
Investigational Study Agent: Nivolumab (NSC 748726) ......................................60 
9.3 
Commercial Agent: Cisplatin ................................................................................62 
9.4 
Commercial Agent:  Carboplatin ...........................................................................63 
9.5 
Commercial Agent:  Gemcitabine .........................................................................63 
10. 
PATHOLOGY/BIOSPECIMEN .......................................................................................64 
10.1 
Optional Tumor Tissue Collection and Correlative Studies Blood 
Sampling ................................................................................................................64 
10.2 
Tissue Selection for Integrated Marker Testing .....................................................66 
10.3 
Biospecimen Submission Tables ...........................................................................67 
11. 
SPECIAL STUDIES (NON-TISSUE) ...............................................................................72 
11.1    Description of QOL/PRO Instruments ....................................................................72 
11.2    Administration of Patient-Completed Questionnaires ............................................73 
12. 
MODALITY REVIEWS ...................................................................................................74 
12.1     Medical Oncology Modality Quality Assurance Reviews .....................................74 
13. 
DATA AND RECORDS ...................................................................................................74 
13.1     Data Management/Collection ................................................................................74 
13.2 
Summary of Data Submission ...............................................................................75 
13.3 
Data Quality Portal ................................................................................................75 
13.4 
Rave-CTEP-AERS integration ..............................................................................76 
13.5 
Global Reporting/Monitoring ................................................................................77 
14. 
STATISTICAL CONSIDERATIONS...............................................................................77 
14.1 
Study Design ..........................................................................................................77 
14.2 
Study Endpoints .....................................................................................................77 
14.3 
Primary Objectives Study Design ..........................................................................78 


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14.4    Study Monitoring of Primary Objectives ................................................................79 
14.5 
Accrual/Study Duration Considerations ................................................................80 
14.6 
Alternative Design if Accrual is Higher than Projected ........................................80 
14.7 
Secondary/Exploratory Hypothesis and Endpoints (including correlative 
science aims) ..........................................................................................................82 
14.8 
Gender/Ethnicity/Race Distribution .......................................................................91 
REFERENCES ..............................................................................................................................92 
APPENDIX I: NIVOLUMAB TOXICITY MANAGEMENT ALGORITHMS ..........................98 
APPENDIX II: MEDIDATA PATIENT CLOUD EPRO OPERATIONAL INSTRUCTIONS 106 
APPENDIX III: CARBOPLATIN DOSE CALCULATION INSTRUCTIONS ........................112 
APPENDIX IV: COLLABORATIVE AGREEMENTS .............................................................114 
APPENDIX V: PATIENT CLINICAL TRIAL WALLET CARD .............................................116 
 
 
 
 
 
 
 
 
 
 
 
 
NRG-HN007 
 
SCHEMA 
 
 
STRATIFY 
 
• Disease (locoregional only vs. lung metastases vs. other distant metastases) 
• Zubrod/ECOG performance status (0 vs. 1) 
• Prior platinum-gemcitabine therapy (Yes vs. No)* 
 
RANDOMIZE (1:1) 
↓                                                                   ↓                
Arm 1 (Experimental)** 
 
Arm 2 (Control)** 


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Platinum (Cisplatin or Carboplatin) 
+ 
Gemcitabine 
+ 
Nivolumab 
 
 
Platinum (Cisplatin or Carboplatin) 
+ 
Gemcitabine 
 
 
*See section 3.2.2 and 14.1 for more details. 
**See Section 5 for systemic therapy treatment details. 
 
 
 
 
 
 


NRG-HN007 
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1. OBJECTIVES 
1.1 Primary Objective 
To determine if adding nivolumab to platinum-gemcitabine as first-line treatment improves 
overall survival (OS) for patients with recurrent and/or metastatic nasopharyngeal carcinoma 
(NPC). 
 
1.2 Secondary Objectives 
1.2.1 To compare patterns of failure (local-regional relapse and distant metastasis) between 
treatment arms. 
1.2.2 To determine if adding nivolumab to platinum-gemcitabine as first-line treatment 
improves the objective tumor response based on RECIST 1.1. 
1.2.3 To determine if adding nivolumab to platinum-gemcitabine as first-line treatment 
improves progression free survival (PFS) for patients with recurrent and/or metastatic 
NPC. 
1.2.4 To evaluate the toxicity based on CTCAE v5.0. 
1.2.5 To characterize patient-reported symptomatic toxicities measured by PRO-CTCAE. 
1.2.6 To assess quality of life (QOL), as measured by EORTC QLQ-C30, between the two 
arms (primary PRO). 
1.2.7 To assess fatigue, as measured by Multidimensional Fatigue Inventory (MFI-20), 
between the two arms (secondary PRO). 
1.2.8 To determine if a subset of patients based on an optimal cutoff point of PD-L1 CPS/TPS 
is more likely to benefit in terms of PFS from adding nivolumab to platinum-gemcitabine 
as first-line treatment. 
 
1.3 Exploratory Objectives 
1.3.1 To determine if a subset of patients based on an optimal cutoff point of PD-L1 CPS/TPS 
is more likely to benefit in terms of OS from adding nivolumab to platinum-gemcitabine 
as first-line treatment. 
1.3.2 To determine changes in QOL as measured by EORTC QLQ-C30, and in fatigue as 
measured by MFI-20, between and within arms over time (exploratory PRO). 
1.3.3 To collect blood and tissue specimens for future translational research. 
 
2 BACKGROUND 
2.1 Epidemiology and Natural History of Endemic Nasopharyngeal Carcinoma (NPC)  
NPC is endemic to Southern China and Southeast Asia where 129,079 new cases and 72,987 
NPC-related deaths were reported worldwide in 2018 (Globocan 2018). Approximately 5% 
to30% of patient presented with metastatic NPC at diagnosis, while 30% of patients will 
recur at distant sites (and less commonly at locoregional sites) despite radiotherapy (Chua 
2016).  
 
2.2 Current Standard of Care for Metastatic or Incurable Recurrent NPC 
Platinum-based chemotherapy is the standard first-line therapy for the treatment of recurrent 
or metastatic NPC. Historic data from single-armed studies have reported the median OS of 
metastatic NPC to be 12 to 15 months following first-line chemotherapy (Lee 2015). Based 
on the phase III study by Zhang et al, which compared 6 cycles of cisplatin-gemcitabine 
(GC) with cisplatin-5-fluorouracil in the first-line treatment of metastatic NPC in 362 


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patients, GC was superior in terms of objective response rate (ORR) (64% vs 46%), median 
PFS (7.0 vs 5.6 months; hazard ratio, HR=0.55; 95% CI: 0.44-0.68; p<0.0001), and median 
OS (29.1 vs 20.9 months; HR=0.62; 95% CI: 0.45-0.84; p=0.0025) (Zhang 2016). However, 
most patients will progress within 5 to 7 months. A Canadian retrospective cohort containing 
patients with non-keratinizing and keratinizing NPC has shown that GC is active as well in 
the palliative setting (Ma 2002). A recent study by Zhang et al has shown that GC is effective 
as an induction regimen prior to radical chemoradiotherapy (CRT) for non-metastatic, locally 
advanced NPC (Zhang 2019). Therefore, in planning this study, one has to account for the 
probability that some patients who recur following CRT will have exposure to GC in the 
induction portion of their treatment.   
 
2.3 Prognostic Factors in Metastatic NPC That Should Be Considered for Patient 
Stratification 
There are several important prognostic factors in patients with metastatic NPC. These include 
(1) the site of metastasis – patients with metastases limited to the lung live longer than others; 
(2) the number of metastases – solitary versus multiple; and (3) synchronous or 
metachronous metastases (Chua 2016).  
 
2.4 Preclinical Data on Targeting Immune-Checkpoint Signaling in NPC 
NPC is often regarded as an “immune-hot” tumor with overexpression of the programmed 
death receptor ligand-1 (PD-L1) found in over 40% of NPC (Ma 2018). However, its 
prognostic significance remains inconsistent (Ma 2018; Fang 2014; Chan 2017). The 
principal investigators’ collaborations have unraveled some characteristics of NPC, which 
may render it more susceptible to immune checkpoint inhibitors (Li 2017). For instance, the 
tumor mutational burden (TMB) of NPC is higher than previously described; also the 
expression of PD-L1 in immune cells and tumor cells is prevalent in NPC models and tumor 
samples which suggests that upregulation of PD-L1 is one of the immune-evading 
mechanisms of NPC. Other research has found that latent membrane protein (LMP)-1 can be 
up-regulated by PD-L1 in NPC cell lines (Fang 2014).        
         
2.5 Clinical Data: The Development of Immunotherapy in Recurrent/Metastatic NPC 
EBV is ubiquitous in endemic NPC. Strategies such as cytotoxic T-cell therapy directed 
against EBV infected cells and EBV vaccines have been evaluated in NPC (Chua 2016). 
However, clinical response was modest. Hsu et al reported a NPC expansion cohort of a 
phase 1 study of pembrolizumab in 27 patients with PD-L1 positive NPC (Hsu 2017), with 
ORR of 26.3% reported. In an NCI-sponsored study of 45 patients treated with nivolumab, 
the ORR was 20.5% and the 1-year OS rate was 59% (95% CI: 44.3-78.5%) (Ma 2018). 
Among the 41% of tumors expressing PD-L1, a higher proportion of responders was found in 
the group with higher PD-L1 expression – for PD-L1 expression at < 1%, ≥ 1% and ≥ 10%, 
the respective response rates to nivolumab were 13%, 29%, and 33% (non-statistical 
comparison). Two randomized studies comparing PD-1 inhibitors and chemotherapy in 
subsequent line in metastatic NPC have completed accrual (KEYNOTE-122 and 
NCT02605967).   
 


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2.6 Clinical Data on Combining PD-1 Inhibitor and Chemotherapy in NPC and Other 
Cancers 
The positive result of the KEYNOTE-189 study has provided the scientific proof that 
addition of pembrolizumab can improve the efficacy of platinum-based chemotherapy 
(Gandhi 2018, Langer 2018). In the study by Gandhi et al, the 1-year OS was 69.2% in the 
pembrolizumab-chemotherapy group versus 49.4% in the placebo-chemotherapy group 
(HR=0.49; 95% CI: 0.38-0.64; p<0.001 for non-squamous lung cancer). With respect to 
nivolumab specifically, the safety of nivolumab with platinum-based chemotherapy has been 
evaluated in phase 1 studies of patients with solid cancers (Weiss 2017; Rizvi 2016). In the 
study by Rizvi et al (Checkmate 012), the combination of nivolumab (nivolumab at 10 
mg/kg, D1), cisplatin (C, D1) gemcitabine (G, D1 & D8) on a 21-day cycle for 4 cycles, 
followed by nivolumab monotherapy every 3 weeks at the same dose as maintenance, was 
well tolerated in a cohort of 12 patients with advanced lung cancer. The incidence of 
treatment-related grade 3-4 toxicities reported in ≥ 10% of patients was 25% (any event) in 
patients who received GC+nivolumab, which was numerically lower than that reported with 
cisplatin-pemetrexed-nivolumab (47%, n = 15) or carboplatin-paclitaxel-nivolumab (73%, n 
= 15). In the GC+nivolumab arm, the most common grade 3-4 toxicities were anemia, 
pneumonitis, thrombocytopenia, and neutropenia (1 patient per toxicity). Other immune-
related toxicities such as skin rash, diarrhea (no colitis), and thyroid function disturbances 
were only grade 1-2 in severity. Notably, there were no reports of renal failure or ALT/AST 
increase. Only 8% of patients (1 of 12 patients) in the GC+nivolumab arm discontinued study 
treatment due to treatment-related toxicities, the lowest rate compared with cisplatin-
pemetrexed-nivolumab (33%). Importantly, Rivzi et al found that pharmacokinetic modeling 
suggested that nivolumab 5 mg/kg every 3 weeks results in sustained exposure between 
treatments, equivalent to nivolumab 3 mg/kg every 2 weeks. The authors concluded that the 
combination of nivolumab (5 mg/kg) and platinum doublet-chemotherapy at an every 3 week 
schedule should be the regimen for phase III evaluation.   
 
Regarding the use of nivolumab at an every 3 week schedule (360 mg flat dose), the 
Checkmate 227 study is an ongoing 4-arm study comparing standard chemotherapy with 
nivolumab alone, nivolumab+ipilumab, or nivolumab+chemotherapy (Borghaei 2018). The 
nivolumab+chemotherapy arm uses a flat dose of nivolumab 360 mg every 3 weeks and 
platinum-doublet chemotherapy (choices included cisplatin or carboplatin, together with 
gemcitabine, pemetrexed, or paclitaxel). An interim report found that the nivolumab-
chemotherapy arm (n = 177) improves PFS and is well tolerated (with only 13% 
discontinuation rate). Enrollment is ongoing.  
 
Ueno et al recently published a phase I study of an every 2 week regimen of GC+nivolumab 
in patients with recurrent biliary cancer and found that the regimen is active with manageable 
toxicities (Ueno 2019). Gupta et al reported their interim experience with a 3-weekly 
schedule of cisplatin (70 mg/m2 on D1), gemcitabine (1000 mg/m2 on D1 & D8) and 
nivolumab (360 mg flat dose) IV on D8 every 21 days, in the neoadjuvant treatment of 
patients with muscle-invasive bladder cancer (Gupta 2019). Of the 12 (out of 41 planned 
total) patients treated to date, the combination has not resulted in any added toxicities or 
immune-related AEs.   
Fang et al from China reported a phase I/II study of an IgG4 against PD-1, camrelizumab 


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(Hengrui Medicine Co., China) as monotherapy and in combination with GC in the treatment 
of recurrent/metastatic NPC (Fang 2018). The 1-yr PFS of 61% compares favorably with the 
historic PFS of 20% with GC alone in a similar setting (Zhang 2016).  
Ma et al recently published a phase I trial of nivolumab at 240 mg every 2 weeks or 360 mg 
every 3 weeks flat dosing of nivolumab in patients with NPC (Ma 2019). Nivolumab 
monotherapy at 3 mg/kg and flat doses of 240 mg and 360 mg were well tolerated in this 
Chinese patient population, with PK profiles at 3 mg/kg being similar to those of patients 
treated in Korean patients, in which PK data were shown to be comparable to United States 
and Japanese populations treated in previous reports.  
 
2.7 Impact of KEYNOTE-048 on the Design of This Study 
Reported in late October 2018 and again in 2019 (Burtness 2018, Rischin 2019), this 3-arm 
trial compared pembrolizumab alone with pembrolizumab and platinum-5FU and the 
“EXTREME” regimen in recurrent head and neck squamous cancer (HNSC). Patients with 
tumors with a CPS ≥ 1% and ≥ 20% benefited more from having pembrolizumab alone or 
together with chemotherapy. We analyzed a cohort of 98 IO-naïve patients with NPC 
(unpublished data, Prof KW Lo). The percentage of tumors with CPS of ≥ 1% or ≥ 20% are 
91.8% and 37.7%, while the percentages of TPS of ≥ 1% or ≥ 20% are 55.1% and 25.5%, 
respectively. A non-statistical trend favoring better RECIST response was observed in a 
nivolumab-treated cohort with a TPS or CPS ≥ 1% (Ma 2018). Therefore, we hypothesize 
that CPS or TPS may be useful in selecting patients for nivolumab-chemotherapy in NPC.  
 
2.8 Prognostic and Predictive Biomarkers in NPC 
Plasma EBV DNA as a prognostic biomarker for NPC: EBV infection is ubiquitous in non-
keratinizing NPC and plasma EBV DNA can be detected in over 96% of NPC patients using 
real time PCR, a technique pioneered by the team led by Dennis Lo and Allen Chan at the 
Chinese University of Hong Kong. Plasma EBV DNA clearance during the early phase of 
treatment has been shown to correlate with survival in patients undergoing first-line 
chemotherapy for metastatic NPC (Wang 2010, Chua 2016). This marker has also been 
shown to closely reflect tumor burden. The role of this marker in patients undergoing 
combined chemotherapy and immune-checkpoint inhibitor in metastatic NPC warrants 
investigation.  
 
Programmed death receptor ligand-1 as biomarker of response to immune-checkpoint 
inhibitors: PD-L1 expression in tumor has been evaluated extensively as a predictive 
biomarker of response to PD1/L1 inhibitor in different solid tumors. Different commercial 
companion diagnostic assays for PD-L1 are now available, each assay using a different 
method of scoring PD-L1 expression with different clinical cut-off values. The “Blueprint 
PD-L1 IHC Assay Comparison Project” revealed that the 22C3, 28-8, and SP263 PD-L1 
assays are closely aligned on tumor cell staining whereas the SP142 assay showed 
consistently fewer tumor cells stained (Hirsch 2017). The PD-L1 CPS and TPS scoring 
system have been prospectively evaluated together with the 22C3 assay for selecting patients 
with lung, cervical, urothelial and non-NPC HNSC for PD1 inhibitor therapy. In KEYNOTE- 
048, over 800 patients with metastatic or recurrent HNSC were randomized to 1 of 3 arms: 
(1) pembrolizumab alone if the PD-L1 CPS was ≥ 20%; (2) EXTREME regimen 
(chemotherapy and cetuximab); or (3) pembrolizumab and chemotherapy. In this study, an 


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OS advantage was seen in patients with PD-L1 CPS “≥ 20%” (HR=0.61; 95% CI 0.45-0.83; 
p = 0.0007) or “≥ 1%” (HR=0.78; 95% CI: 0.64-0.96; p=0.0086) who received 
pembrolizumab alone compared with the EXTREME regimen (Burtness 2018). For patients 
randomized to the two chemotherapy-based arms, the subgroup analysis based on PD-L1 
status has not been reported to date. There is no reported information about the clinical 
significance of CPS and TPS for NPC. In a single-arm phase II study of nivolumab in 
recurrent/metastatic NPC led by the principal investigator of this current study, there was a 
non-statistically higher proportion of responders among those with tumors expressing PD-L1 
(22C3 assay) > 1% and > 10% (Ma 2018). But the study was underpowered to detect any 
survival difference. No other trials reported to date on PD-1 inhibitor in NPC have 
investigated the significance of PD-L1 expression using the 22C3 assay.   
 
2.9 Quality of Life and Other Patient-Reported Outcomes in Patients with NPC Receiving 
Immunotherapy and Chemotherapy 
Quality of life (QOL) is an important endpoint in phase III clinical trials to assess treatment 
effects from patients’ perspectives. Findings from QOL or other patient-reported outcomes 
(PROs) can be used to inform and guide clinical practice changes suggested by the clinical 
trials. The effect of nivolumab combined with chemotherapy on QOL is unclear for patients 
with recurrent/metastatic NPC. Data from a phase III randomized trial for patients with 
recurrent/metastatic HNSC did show significant and clinically meaningful differences in 
favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite 
loss measured by the European Organisation for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30, Harrington 2017). The 
beneficial effect of nivolumab on QOL was also demonstrated in phase III clinical trials for 
other cancers, such as advanced renal cell carcinoma (Cella 2019). Additionally, another PD-
1 checkpoint inhibitor, pembrolizumab, has been shown to generate favourable results on 
QOL for patients with recurrent/metastatic HNSC (Cohen 2019) or with advanced non-small-
cell lung cancer (Brahmer 2017).  
 
Fatigue is among the most common and distressing side effects of cancer and its treatment; 
recent studies on immunotherapy have further shown that fatigue is one of the most 
prominent side effects of immune checkpoint inhibitors. The incidence rate of all-grade 
fatigue in patients receiving nivolumab ranged from 16% to 33% among various cancer 
diagnoses (Abdel-Rahman 2016). In patients with recurrent/metastatic NPC, a phase II 
single-arm trial showed that fatigue was the most common side effect of nivolumab, and was 
present in 22% of patients (Ma 2018). Similarly, fatigue was the second most common side 
effect for patients with recurrent/metastatic HNSC receiving pembrolizumab (Cohen 2019). 
Although the mechanisms of a high rate of fatigue among patients receiving immunotherapy 
are unclear, it is possible that other toxicities of immune checkpoint inhibitors may contribute 
to or present with nonspecific symptoms such as fatigue. These immunologic mediated 
toxicities from immunotherapy include pneumonitis and endocrinopathies (pituitary, 
hypothalamus, thyroid, and adrenal disease). Since the effects of nivolumab on patient-
reported fatigue have not been well documented in patients with recurrent/metastatic NPC, 
further large studies are warranted.  
 


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3 ELIGIBILITY AND INELIGIBILITY CRITERIA 
3.1 
Inclusion Criteria (16-FEB-2021) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
3.1.1 Pathologically (histologically or cytologically) proven diagnosis of NPC that has recurred 
at locoregional and/or distant sites. For locoregional recurrence, the disease must not be 
amenable to potentially curative surgery or re-irradiation. The following histological types 
are accepted: (a) Keratinizing – squamous cell carcinoma; (b) Non-keratinizing – 
undifferentiated or poorly differentiated; 
3.1.2 Measurable disease by the RECIST 1.1 criteria. Lesion(s) that have been irradiated 
previously can be counted as measurable as long as radiological progression has been 
demonstrated prior to enrollment;  
3.1.3 Age ≥ 18;  
3.1.4    History/Physical examination by Medical Oncologist or Clinical Oncologist within 14 days 
prior to registration; 
3.1.5 Zubrod/ECOG Performance Status of 0-1 within 14 days prior to registration; 
3.1.6    Contrast enhanced MRI or CT of the nasopharynx and neck within 30 days prior to 
registration; 
3.1.7   Contrast enhanced CT scan of the chest, abdomen and pelvis within 30 days prior to 
registration; 
3.1.8 Adequate organ function within 14 days prior to registration defined as follows: 
 
Adequate Organ Function Laboratory Values 
 
Organ Function 
Laboratory value 
Hematological 
 
Absolute neutrophil count 
(ANC) 
≥ 1500 cells/mm3 
Platelets 
≥ 100,000 cells/mm3 
Hemoglobin 
≥ 9.0 g/dL (Transfusion is accepted. Erythropoietin 
dependency not accepted.) 
Hepatic 
 
Total bilirubin 
≤ 1.5 × ULN OR direct bilirubin ≤ ULN for patients 
with total bilirubin levels >1.5 × ULN. Patients with 
known Gilbert’s syndrome are not excluded. 
ALT (SGPT) 
≤ 2.5 × ULN (≤ 3 × ULN for patients with 
liver metastases) 
Renal  
 
Serum creatinine 
OR 
Calculated creatinine clearance 
(CrCl) based on Cockcroft-
Gault equation 
≤ 1.5× ULN 
OR 
> 30 mL/min for patients with serum creatinine levels 
> 1.5 × ULN. In this protocol, cisplatin or carboplatin 
may be used at the discretion of the investigator – 


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except for patients with CrCl between 30-50 mL/min, 
for whom carboplatin should be used instead of 
cisplatin.  
 
Legend:  
• ULN = upper limit of normal based on institutional standard  
• ALT (SGPT) = alanine aminotransferase 
3.1.9 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load 
must be undetectable and patients must be receiving anti-viral therapy at enrollment. 
Patients must agree to continue anti-viral therapy throughout the study period as directed 
by their treating physicians.  
• Known positive test for hepatitis B virus surface antigen (HBsAg) indicating acute or 
chronic infection would make the patient ineligible unless the viral load becomes 
undetectable on anti-viral therapy.  
• Patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) 
are eligible (i.e., patients immunized against hepatitis B).  
• In some centers, hepatitis B core antibody (anti-HBc) are done routinely before 
chemotherapy for some cancer patients. This is because patients who are HBsAg-
negative but positive for anti-HBc should have undetectable HBV viral load at 
enrollment and receive prophylactic anti-viral therapy throughout the study 
(American Society of Clinical Oncology 2015 guideline, Hwang 2015). In this 
protocol anti-HBc should be performed based on institutional standards.   
3.1.10 Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured. For patients with HCV infection who are currently on treatment, they are eligible if 
they have an undetectable HCV viral load; 
Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating 
acute or chronic infection would make the patient ineligible unless the viral load becomes 
undetectable on suppressive therapy;  
3.1.11 For women of childbearing potential (WOCBP), negative serum or urine pregnancy test 
within 14 days prior to registration. For WOCBP randomized to Arm 1, an additional 
negative serum or urine pregnancy is required within 24 hours prior to starting nivolumab 
treatment. 
• Women of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization (hysterectomy 
or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined 
clinically as 12 months of amenorrhea in a woman over 45 in the absence of other 
biological or physiological causes.    
3.1.12 Women of childbearing potential (WOCBP) and men who are sexually active with 
WOCBP must be willing to use an adequate method of contraception (As a reference 
only for sites in the United States: 
https://www.cdc.gov/reproductivehealth/contraception/index.htm; for other sites, women 
must use an effective oral contraception and the male partner must use condom) during 
and after treatment (see Section 9.2);  


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3.1.13 The patient or a legally authorized representative must provide written informed consent 
prior to study entry. 
 
3.2 
Exclusion Criteria 
Patients with any of the following conditions are NOT eligible for this study. 
3.2.1 Diagnosed with another invasive malignancy (except non-melanomatous skin cancer) 
unless disease free for more than 3 years. Note: Patients with basal cell carcinoma of the 
skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, 
cervical cancer in situ) who have undergone potentially curative therapy are not excluded); 
3.2.2 Any prior systemic anti-cancer agents (including chemotherapy and investigational agents) 
for the purpose of treating locoregional and/or distant recurrence of NPC.  
3.2.3  Patients who have received neoadjuvant (induction) and/or adjuvant chemotherapy for 
primary NPC with chemotherapy (any drug regimens including those containing platinum 
and/or gemcitabine) at or within 6 months prior to registration are excluded (counting from 
the last day of the chemotherapy for the primary NPC, prior to enrolling into the current 
study). The following subgroups of patients are NOT excluded:  
• Patients who have received neoadjuvant (induction) and/or adjuvant chemotherapy for 
primary (non-metastatic/non-recurrent) NPC more than 6 months prior to registration, 
counting from the last day of the chemoradiotherapy for the primary NPC, prior to 
enrolling into the current study.  
• For prior RT with radical intent: Patients who have prior radiotherapy (RT) to the 
primary and locoregional disease (i.e. non-recurrent disease) with or without 
concurrent cisplatin or carboplatin monotherapy are not excluded as long as they have 
not received any neoadjuvant/adjuvant chemotherapy within 6 months prior to 
registration (counting from the last day of the chemotherapy), and that the last RT 
fraction (with radical intent) has been given more than 3 months prior to registration.    
• For RT with palliative intent: Prior radiotherapy (RT) at or within 30 days prior to 
registration, this includes RT given with palliative intent (with or without concurrent 
cisplatin or carboplatin alone) to recurrent/ metastatic sites in patients with 
recurrent/metastatic NPC. The re-irradiated sites must not be the only sites of 
measurable recurrent disease;    
• Prior chemotherapy for cancers other than NPC is allowed as long as the last course of 
chemotherapy was administered more than 3 years prior to registration and the patient 
has remained disease-free for more than 3 years;    
 
3.2.4 Prior therapy for any indication, with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-
4, OX-40, CD137);  
3.2.5 History of severe (grade 3-4) hypersensitivity reaction to any monoclonal antibody 
including nivolumab and/or any of its excipients; 
 
 


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3.2.6 Severe, active co-morbidity defined as follows: 
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 
6 months. 
• Myocardial infarction within the last 6 months. 
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration. 
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy within 30 days of registration. 
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects. 
• History of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis requiring steroids and/or immunosuppressive therapy. 
• History of active TB (Bacillus Tuberculosis, not known to be multi-drug resistant) as 
defined by the need to receive systemic treatment within the last 2 years or any known 
history of multi-drug resistant TB. Note: Patients who had a distant history of treated 
TB (not known to be multi-drug resistant) at 5 or more years from enrollment and have 
no current symptoms suggestive of active TB, are not excluded from this study. Note: 
Testing for prior exposure to TB is not required in this study since TB is endemic in 
parts of Asia.   
• Prior solid organ transplant or bone marrow transplant. 
 
• 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.  
• Condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone or equivalents) or other immunosuppressive medications within 14 days of 
registration. Inhaled or topical steroids and adrenal replacement doses < 10 mg daily 
prednisone equivalents are permitted in the absence of active autoimmune disease. 
Steroid premedication for the prophylaxis of CT contrast-related allergies is allowed. 
The use of dexamethasone as an anti-emetic premedication prior to chemotherapy is 
also allowed.  
• Active autoimmune disease requiring systemic treatment (i.e. disease modifying 
agents, corticosteroids, or immunosuppressive drugs) within the past 2 years. These 
include but are not limited to patients with a history of immune-related neurologic 
disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre 
syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, rheumatoid 
arthritis, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), 
Crohn’s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal 
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be 
excluded because of the risk of recurrence or exacerbation of disease.  
 


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Note: Patients are permitted to enroll if they have vitiligo; type I diabetes mellitus; 
hypothyroidism, pituitary or adrenal insufficiency requiring only hormone 
replacement; psoriasis not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger (precipitating event); 
3.2.7  Patients who are pregnant or breastfeeding and unwilling to discontinue breastfeeding. 
3.2.8  Known history of grade 3-4 allergic reaction and/or hepatic toxicity to cisplatin, 
carboplatin, or gemcitabine.  
NOTE: For patients with known history of grade 3-4 renal toxicity to cisplatin or known 
history of clinically significant hearing loss (grade 2 or above) attributed to cisplatin, or 
other intolerances to cisplatin that are of clinical significance, carboplatin can be used in 
this study and therefore these patients are NOT excluded from enrollment.     
3.2.9  Known CNS metastases and/or carcinomatous meningitis. Patients with base of  skull 
involvement by NPC are not excluded unless their disease is directly invading the brain 
parenchyma and is associated with clinical symptoms (headaches, nausea and vomiting, 
neurological abnormalities on physical examination) and/or cerebral edema on radiological 
imaging; 
3.2.10 Patients who have received a live vaccine within 30 days prior to the first dose of study 
treatment.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed. 
3.2.11 History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject’s participation for the 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
 
3.3     Inclusion of Women and Minorities 
NIH policy requires that women and members of minority groups and their subpopulations 
be included in all NIH-supported biomedical and behavioral research projects involving 
NIH-defined clinical research unless a clear and compelling rationale and justification 
establishes to the satisfaction of the funding Institute & Center (IC) Director that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of the research.  
Exclusion under other circumstances must be designated by the Director, NIH, upon the 
recommendation of an IC Director based on a compelling rationale and justification.  Cost 
is not an acceptable reason for exclusion except when the study would duplicate data from 
other sources.  Women of childbearing potential should not be routinely excluded from 
participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 


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4 REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
4.1 Study Calendar for Treatment Arm 1 (Experimental): Chemotherapy & Nivolumab (See section 3.1 for details) (16-FEB-
2021) 
 
Prior to 
Registration 
Prior to 
Treatment 
Concurrent platinum, gemcitabine, and nivolumab 
(Q 21 days)  
Nivolumab 
Maintenance 
(Q 28 days) 
 
Starts within 
4 weeks (± 7 
days) from 
end of last 
cycle of 
chemo  
End of 
Treatment  
± 30 Days   
Follow-up 
from end of 
concurrent 
chemotherapy: 
q4 months for 
2 yrs, q6 
months for 3 
yrs and then 
annually  
 
Cyc 1 
± 3 
Days 
Cyc 2 
 ± 3 Days 
Cyc 3 
± 3 
Days 
Cyc 4 
± 3 
Days 
Cyc 5 
± 3 
Days 
Cyc 6 
± 3 
Days 
Q 28 days (± 
3 days) up to 
24 cycles (2 
years) 
 
 
Pathologically (histologically or 
cytologically) proven diagnosis of NPC 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination by Medical 
Oncologist or Clinical Oncologist 1  
Within 14 
days 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 7 
Concomitant medication 
 
X 
 
 
 
 
 
 
 
 
 
Zubrod/ECOG Performance Status 
Within 14 
days 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC + Diff (including include ANC, platelets, 
Hgb)  
Within 14 
days 
 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1 
 
 
CMP (total bilirubin, ALT (SGPT), serum 
creatinine, fasting glucose 2), calculated CrCl 
Within 14 
days 
 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1 
 
 
Serum or urine pregnancy test for women 
of childbearing potential 
Within 14 
days 
Within 24 
hours 
 
 
 
 
 
 
 
 
 
Thyroid function tests, fasting glucose 3 
 
 
X 
 
 
X 
 
 
X 
 
 
Urinalysis (to include protein) 
 
X 
 
 
 
 
 
 
D1 of Cyc 1 
only 
 
 
HBsAg, Anti-HCV 4 
X 
 
 
 
 
 
 
 
 
 
 
Contrast enhanced CT chest (include 
abdomen and pelvis if clinically indicated) 5 
Within 30 
days 
 
 
 
X 
 
 
X 
X 
 
 
Contrast enhanced CT or MRI NP+N 5 
Within 30 
days 
 
 
 
 
 
 
 
 
 
 
Adverse Events Evaluation 
 
 X 
D1+D8 
D1+D8 
D1+D8  D1+D8  D1+D8  D1+D8  
X 
X 
X 7 


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Prior to 
Registration 
Prior to 
Treatment 
Concurrent platinum, gemcitabine, and nivolumab 
(Q 21 days)  
Nivolumab 
Maintenance 
(Q 28 days) 
 
Starts within 
4 weeks (± 7 
days) from 
end of last 
cycle of 
chemo  
End of 
Treatment  
± 30 Days   
Follow-up 
from end of 
concurrent 
chemotherapy: 
q4 months for 
2 yrs, q6 
months for 3 
yrs and then 
annually  
 
Cyc 1 
± 3 
Days 
Cyc 2 
 ± 3 Days 
Cyc 3 
± 3 
Days 
Cyc 4 
± 3 
Days 
Cyc 5 
± 3 
Days 
Cyc 6 
± 3 
Days 
Q 28 days (± 
3 days) up to 
24 cycles (2 
years) 
 
 
PRO-CTCAE 6 
 
X 
 
 
 
 
 
X 
X (Year 1, 
Year 2) 
 
 
QOL 6 
▪ EORTC QLQ-C30 
▪ MFI-20 
 
X 
 
 
 
 
 
X 
X (Year 1, 
Year 2) 
 
 
Patient History form (patient reported): 
Optional 
 
X 
 
 
 
 
 
 
 
 
 
Specimen submissions for biobanking 
(Optional, but highly recommended - See 
section 10.3 for details):  
• Archival or Newly Obtained Tissue 
• ctDNA blood (for participating sites only) 
 
X 
 
 
 
 
 
 
 
 
 
Specimen submissions for biobanking 
(Optional, but highly recommended - See 
section 10.3.1 for details):  
Plasma EBV DNA blood (for non-
keratinizing NPC only)  
 
X (Within 
7 days of 
cycle 1, 
D1) 
D8, 
D15 
D1, D8 
 
 
 
 
 
 
 
1 For patients with evidence of CHF, MI, cardiomyopathy, or myositis, a cardiac evaluation including lab tests and cardiology consultations as clinically indicated including EKG, CPK, troponin, ECHO 
cardiogram. 
2 Fasting glucose needs to be performed within 14 days prior to starting treatment. 
3 Thyroid function test (TSH with reflex to free T4; free T3 if clinically indicated) and fasting glucose should be done at each new cycle of NIVOLUMAB for at least 6 months, and then at every 3 cycles of 
nivolumab thereafter until end of treatment (i.e., every 11-12 weeks). 
4 Patients who are HBsAg positive (or HbsAg-ve, but anti-HB core +ve) should have HBV DNA performed at registration to ensure that the level is undetectable to become eligible for the study. These 
patients should undergo HBV DNA monitoring according to institutional guideline/practice.   
5 Imaging: See Section 4.3 for details.  
6 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 II. Baseline questionnaires 
will be completed on paper. Patients that consent to Medidata Patient Cloud ePRO will complete all questionnaires electronically using personal electronic device except baseline. The study-specific PRO-
CTCAE items for this protocol can be found on the forms section of the CTSU protocol webpage and is titled “NRG-HN007 NCI PRO-CTCAE Item Library”. 
7 Follow-up may coincide with the nivolumab cycle. 


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4.2 Study Calendar for Treatment Arm 2 (Control): Chemotherapy alone (See section 3.1 for details) 
 
 
Prior to 
Registration 
Prior to 
Treatment 
Concurrent platinum, gemcitabine  
(Q 21 days)  
End of 
Treatment  
± 30 Days   
Follow-up from 
end of 
concurrent 
chemotherapy: 
q4 months for 2 
yrs, q6 months 
for 3 yrs and 
then annually 
Cyc 1 ± 
3 Days 
Cyc 2 ± 
3 Days 
Cyc 3 ± 
3 Days 
Cyc 4 ± 
3 Days 
Cyc 5 ± 
3 Days 
Cyc 6 ± 
3 Days 
 
Until PD 
Pathologically (histologically or 
cytologically) proven diagnosis 
of NPC 
X 
 
 
 
 
 
 
 
 
 
Physical examination by 
Medical Oncologist or Clinical 
Oncologist 1  
Within 14 days 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
 
X 
 
 
 
 
 
 
 
 
Zubrod/ECOG Performance 
Status 
Within 14 days 
 
X 
X 
X 
X 
X 
X 
X 
 
CBC + Diff (including include 
ANC, platelets, Hgb) 
Within 14 days 
 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
X 
 
CMP (total bilirubin, ALT 
(SGPT), serum creatinine, fasting 
glucose 2), calculated CrCl 
Within 14 days 
 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
X 
 
Serum or urine pregnancy test 
for women of childbearing 
potential 
Within 14 days 
 
 
 
 
 
 
 
 
 
HBsAg, Anti-HCV 3 
X 
 
 
 
 
 
 
 
 
 
Contrast enhanced CT chest 
(include abdomen and pelvis if 
clinically indicated) 4 
Within 30 days 
 
 
 
X 
 
 
X 
 
X 6 
Contrast enhanced CT or MRI 
NP+N 4 
Within 30 days 
 
 
 
 
 
 
 
 
 
Adverse Events Evaluation 
 
X 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1+D8 
D1+D8  
X 
X 
PRO-CTCAE 5 
 
X 
 
 
 
 
 
X 
 
Year 1 & 2 
QOL 5  
▪ EORTC QLQ-C30 
 
X 
 
 
 
 
 
X 
 
Year 1 & 2 


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Prior to 
Registration 
Prior to 
Treatment 
Concurrent platinum, gemcitabine  
(Q 21 days)  
End of 
Treatment  
± 30 Days   
Follow-up from 
end of 
concurrent 
chemotherapy: 
q4 months for 2 
yrs, q6 months 
for 3 yrs and 
then annually 
Cyc 1 ± 
3 Days 
Cyc 2 ± 
3 Days 
Cyc 3 ± 
3 Days 
Cyc 4 ± 
3 Days 
Cyc 5 ± 
3 Days 
Cyc 6 ± 
3 Days 
 
Until PD 
▪ MFI-20 
Patient History form (patient 
reported)- optional 
 
X 
 
 
 
 
 
 
 
 
Specimen submissions for 
biobanking (Optional, but 
highly recommended - See 
section 10.3.1 for details) 
• 
Archival or Newly 
Obtained Tissue  
• 
ctDNA blood (for 
participating sites 
only)  
 
X 
 
 
 
 
 
 
 
 
Specimen submissions for 
biobanking (Optional, but 
highly recommended - See 
section 10.3.1 for details):  
Plasma EBV DNA blood (for 
non-keratinizing NPC only)    
 
X (Within 
7 days of 
cycle 1, 
D1) 
D8, 
D15 
D1, D8 
 
 
 
 
 
 
1 For patients with evidence of CHF, MI, cardiomyopathy, or myositis, a cardiac evaluation including lab tests and cardiology consultations as clinically indicated including EKG, CPK, 
troponin, ECHO cardiogram. 
2 Fasting glucose needs to be performed within 14 days prior to starting treatment. 
3 Patients who are HBsAg positive (or HbsAg-ve, but anti-HB core +ve) should have HBV DNA performed at registration to ensure that the level is undetectable to become eligible for 
the study. These patients should undergo HBV DNA monitoring according to institutional guideline/practice.   
4 Imaging: See Section 4.3 for details. 
5 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 II. 
Baseline questionnaires will be completed on paper. Patients that consent to Medidata Patient Cloud ePRO will complete all questionnaires electronically using personal electronic 
device except baseline. The study-specific PRO-CTCAE items for this protocol can be found on the forms section of the CTSU protocol webpage and is titled “NRG-HN007 NCI PRO-
CTCAE Item Library”. 
6 See section 4.4 for details. 


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4.3 Objective Tumor Response 
The protocol will utilize RECIST, v1.1 for the purposes of evaluating response and progression 
(Eisenhauer 2009).  
• Progressive Disease (PD) (per RECIST v1.1): At least a 20% increase in the sum of 
diameters of target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
one or more new lesions is also considered progression). 
• Second Primary Neoplasm: Tumor reappearing within the initial and immediate adjoining 
anatomical region of the primary will be considered local recurrence. Multiple lung 
nodules/masses are considered distant metastases from the index cancer unless proven 
otherwise. 
• Local or Regional Relapse: Relapse is defined as reappearance of tumor after complete 
response. If possible, relapse should be confirmed by 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, regional or 
distant. Sites of distant disease progression should be noted. This will accommodate analysis of 
patterns of failure. 
 
4.4 Tumor Imaging During the Study 
Tumor imaging during concurrent chemotherapy phase:  
Post-treatment scan after cycle 3 +/- 7 days and after cycle 6 (+/-7 days). The result of the post-
cycle 6 imaging must be available for assessing best response to chemotherapy (or concurrent 
chemotherapy-nivolumab) before starting the maintenance.  
 
Tumor imaging after concurrent chemotherapy phase (maintenance or observation phase):  
(a) Arm 1 (experimental): Tumor imaging should be performed every 12 weeks (+/-7 days) 
during the nivolumab maintenance therapy. If the patient discontinues nivolumab then the 
imaging should continue until disease progression. The modality of tumor imaging could be 
decided at the physician’s discretion based on local standards.   
(b) Arm 2 (Control): Tumor imaging is recommended within 6 months, and more frequently as 
clinically indicated such as every 12 weeks until disease progression. The modality of tumor 
imaging could be decided at the physician’s discretion based on local standards.  
 
More frequent imaging may be performed if clinically indicated.   
 
Tumor imaging after maintenance or observation phase:  
In patients who complete the maintenance (Arm 1) or observation (Arm 2) phase without 
documented disease progression, the imaging interval will be at the physician’s discretion.  
 
 
 
 
 


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5. TREATMENT PLAN/REGIMEN DESCRIPTION 
    Protocol treatment must begin within 14 days after randomization. 
 
5.1 
Systemic Therapy - Summary (16-FEB-2021) 
Trial treatment should begin within 14 days of randomization. The treatment to be used in this 
trial is outlined below in tables 5.1A and 5.1B. 
 
Trial treatment should be administered on Day 1 of each 21 day cycle after all 
procedures/assessments have been completed as detailed on the Study Calendars in sections 4.2 
and 4.3.  Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons. For patients randomized to either treatment arms, 
carboplatin or cisplatin can be used at the investigator’s discretion from cycle 1 onwards, except 
for patients with CrCl < 50 mL/min in whom carboplatin should be used instead of cisplatin – see 
section 5.1.1 Criteria for starting a new cycle of chemotherapy with or without nivolumab. 
 
Table 5.1A 
Arm 1 (Experimental): Nivolumab-gemcitabine-platinum for 6 cycles + Maintenance 
nivolumab monotherapy  
 
Weeks (Cycle) 
 
1-3 
4-6 
7-9 
10-12 
13-15 
16-18 
Maintenance Phase 
Nivolumab a 
Day 1 of each 21 day cycle 
 
X 
X 
X 
X 
X 
X 
 Nivolumab 480 mg Q 
28 days until a 
maximum number of 24 
cycles  c 
Gemcitabine  
Days 1 and 8 per 21 day cycle 
 
X 
X 
X 
X 
X 
X 
 
Cisplatin/Carboplatin b 
Day 1 of each 21 day cycle 
 
X 
X 
X 
X 
X 
X 
 
a Nivolumab will be administered prior to chemotherapy when agents are delivered on the same day.  
b Carboplatin or cisplatin can be used at the investigator’s discretion from cycle 1 onwards, except for 
patients as noted in section 5.1.1. 
c Nivolumab should be started 4 weeks (+/- 7 days) from the last cycle of chemotherapy (cycle 6). See 
section 5.1.1 Criteria for starting maintenance nivolumab.  
 
Table 5.1B 
Arm 2 (Control): Gemcitabine-platinum for 6 cycles    
 
Weeks (Cycle) 
 
1-3 
4-6 
7-9 
10-12 
13-15 
16-18 
Gemcitabine 
Days 1 and 8 per 21 day cycle 
 
X 
X 
X 
X 
X 
X 
Cisplatin/Carboplatin a 
Day 1 of each 21 day cycle 
 
X 
X 
X 
X 
X 
X 
a Carboplatin or cisplatin can be used at the investigator’s discretion from cycle 1 onwards, except for 
patients as noted in section 5.1.1. 


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5.1.1 Criteria for starting a new cycle of treatment:  
Criteria for starting a new cycle (day 1) of chemotherapy with or without nivolumab:  
 
• Zubrod/ECOG Performance status ≤ 1; 
• CBC/differential and chemistries obtained on day 1 (+/- 2 days) of each new cycle of 
chemotherapy, with adequate bone marrow function defined as follows: Absolute 
Neutrophil Count (ANC) ≥ 1,500 cells/mm3 and Platelets ≥ 100,000 cells/mm3; 
• Total bilirubin < Grade 2 (CTCAE, v5.0); 
• ALT ≤ 2.5 × ULN (≤ 3 × ULN for patients with liver metastases) 
• Serum creatinine < Grade 2 (CTCAE, v5.0). For patients on cisplatin, the calculated CrCl 
should be > 50 mL/min (by Cockcroft-Gault formula) – switch to carboplatin is allowed 
during treatment with cisplatin – see section 6.2.1; 
• All non-hematological AEs that are deemed related to the study drugs, and/or are 
clinically significant must be < Grade 3 (CTCAE, v5.0). Non-clinically significant AEs 
are those which are deemed unrelated to the study drugs, or biochemical abnormalities 
that are not worsening and are not accompanied by any clinical symptoms. 
 
 
Criteria for starting a new cycle of maintenance nivolumab (for patients randomized to Arm 1): 
 
Some patients may continue to benefit from treatment, maintaining or improving responses after 
progression including those treated with steroids.  
Restarting applies only to grade 2 events and some grade 3 events (skin rash and thyroiditis).  
For non-autoimmune or non-inflammatory events patients may resume treatment with study drug 
when the drug-related AE(s) resolve to Grade ≤ 1 or baseline value, with the following 
exceptions:  
• Patients may resume treatment in the presence of Grade 2 fatigue  
• Evaluation to exclude any additional immune mediated events endocrine, GI, and 
liver/pancreas function as clinically indicated must be made prior to restarting.  
• Non-drug-related toxicity including hepatic, pulmonary toxicity, diarrhea, or colitis, must 
have resolved to baseline before treatment is resumed.  
 
If the criteria to resume treatment are met, the patient should restart treatment no sooner than the 
next scheduled time point per protocol. However, if the treatment is delayed past the next 
scheduled time point per protocol the treatment should resume at the earliest convenient point 
that is within the six week delay period.  
 
If treatment is delayed for > 6 weeks, (> 8 weeks for patients on a steroid taper), the patient must 
be permanently discontinued from study therapy, except as specified in Section 5.4 (Study 
withdrawal or discontinuation, duration of treatment, follow-up). It should be emphasized that if 
adverse event occurs which requires treatment with steroids, it is preferable to withhold 
nivolumab and start steroids earlier to obtain resolution with the possibility for restarting 
nivolumab, rather than just waiting for higher grade events. 
 
 
 
 


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5.1.2 Cisplatin 
Administration Guidelines  
Cisplatin infusion:  80 mg/m2 intravenously over 30-60 minutes on day 1 of a 21 day cycle for 6 
cycles. Infusion rate should not exceed 2 mg/min. See section 6.1 for dose modifications. 
 
High-dose cisplatin is highly emetogenic and can cause both acute and delayed nausea 
(occurring > 24 hours after chemotherapy administration). Investigators should be prepared to 
use aggressive prophylactic antiemetics and hydration. Many institutions will have standard 
guidelines for the administration of cisplatin at the doses used in this study. For purposes of this 
protocol, individual investigators may use their local guidelines for cisplatin 
administration. The anti-emetic regimen is to be determined by the local investigator. The 
following represent some suggested anti-emetic regimens:  
 
• All patients receiving cisplatin chemotherapy should be offered a combination of anti-
emetics based on institutional standards. Examples of appropriate anti-emetic choices are 
provided. 
o Neurokinin 1 (NK1) receptor antagonist 
▪ Aprepitant 125 mg PO on day of cisplatin and 80 mg PO on days 2 and 3, 
or 
▪ Fosaprepitant 150 mg IV on day of cisplatin 
o Serotonin (5-HT3) receptor antagonist 
▪ Granisetron 1 mg IV on day of cisplatin, or 
▪ Ondansetron up to 16 mg IV on day of cisplatin, or 
▪ Palonosetron 0.25 mg IV on day of cisplatin 
o Steroid 
▪ Dexamethasone up to 20 mg IV on day of cisplatin 
o Olanzapine  
▪ 10 mg PO on day of cisplatin 
• Dexamethasone (up to 8 mg PO daily) and olanzapine may be continued on days 2 to 4 of 
cisplatin administration to prevent delayed nausea. 
• A 5-HT3 receptor antagonist may also be used as needed for delayed nausea. 
• Cisplatin pre-hydration guidelines (for reference only, physician should follow 
institutional standard of care): 1 liter D5 ½ NS and 40 meq KCL/ liter x 1 liter prior to 
cisplatin. Mannitol 12.5 gm IV immediately prior to cisplatin.  
• Cisplatin post-hydration guidelines (for reference only, physician should follow 
institutional standard of care): Following the end of the cisplatin administration, an 
additional liter of ½ NS with 10 meq KCL/L, 8 meq MgSO4/L, and 25 g mannitol should 
be infused over 2 hours. On the second and third day following cisplatin, patient should 
be encouraged to take at least 2 liters of fluid per day orally. Patients unable to orally 
self-hydrate should be considered for additional IV hydration on these days with normal 
saline.  
 
5.1.3 Carboplatin  
Carboplatin should be dosed at AUC of 5 using the Calvert formula: dose (mg) = AUC (mg/mL - 
1 min) x [GFR (mL/min) + 25 (mL/min)]. It should be infused in 250 to 500 mL of NS or 5% DW 
on day 1 over 30 to 60 minutes IV.  


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5.1.4 Gemcitabine  
Gemcitabine infusion: 1000 mg/m2 in 250 mL NS over 30 minutes on days 1 and 8 of a 21 day 
cycle. Note: The final concentration of the prepared drug should be in the range of 38 mg/mL to 
0.1 mg/mL. 
The preparation and administration of gemcitabine should follow local treatment guidelines. Pre-
medication with steroids prior to IV infusion is permitted as per local standard of care.  
 
5.1.5   Nivolumab 
Nivolumab 360 mg fixed dose administered as a 30-minute IV infusion will be given every three 
weeks (± 3 days) when given concurrently with platinum-gemcitabine. Maintenance nivolumab 
will be given at 480 mg dose every 4 weeks as a 30-minute IV infusion (+/- 3 days). 
Patients may be dosed no less than 18 days from the previous dose of drug. There will be no dose 
modifications allowed, although delayed doses are allowed to be made up.  
 
When nivolumab is to be given together with platinum-gemcitabine on the same day, the 
nivolumab should be given before giving the chemotherapy.  
 
During the nivolumab maintenance period, concomitant use of other systemic anti-cancer 
therapy is not allowed, and these include but not limited to maintenance chemotherapy, 
immunotherapy (including vaccines, cell therapy, antibodies) and any investigational therapy. 
 
At disease progression (clinical and/or radiological), subsequent treatment will be decided at the 
physician’s discretion. The type of systemic therapy to be given at disease progression will need 
to be recorded. For patients randomized to the control arm (Arm 2), the follow-up frequency is 
around 4 – 8 weeks at the discretion of the investigator to allow some flexibility.   
 
5.2 
General Concomitant Medication and Supportive Care Guidelines (16-FEB-2021) 
5.2.1 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.  
▪ Anticonvulsants 
▪ Antiemetics 
▪ Anticoagulants 
▪ Antidiarrheals 
▪ Analgesics 
▪ Myeloid stimulating growth factors such as Pegfilgrastim or Filgrastim may be used  
▪ Highly active antiretroviral therapy (HAART) 
 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.   
Herbal and Nutritional Supplement 
The concomitant use of herbal therapies is generally not recommended, as their pharmacokinetics, 
safety profiles, and potential drug-drug interactions are generally unknown. However the use of 
general nutritional foundation supplements will be allowed including: calcium with vitamin D 


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and/or minerals, Omega3s (fish oil), Vitamin B6, Vitamin B12,  basic multivitamins , L-glutamine, 
or probiotics oral supplements will be permitted either at or below the recommended dosing by a 
healthcare provider.  Herbal-based multivitamins are not allowed.  
 
5.2.2 Radiotherapy, surgery and local ablative therapy:  
• External radiotherapy with palliative intent for the treatment of symptomatic bone metastases 
are permitted in this study. All study drugs must be withheld during radiotherapy and be 
resumed as soon as the patient has recovered from any acute toxicities (if any) of the 
radiotherapy. The maximum period of withholding study drugs is 8 weeks.    
• External radiotherapy (e.g. SBRT), surgery and/or local ablative therapy (including but not 
limited to radiofrequency ablation, cryosurgery, percutaneous ethanol injection) for the 
treatment of any non-osseous metastases that are new or progressing on clinical and/or 
radiological assessment, are not permitted in this study. Such patients are considered to have 
progressive disease and will need to be taken off protocol treatment before undergoing any 
radiotherapy to such lesions. Such local therapies that are used at first disease progression 
will be recorded in the CRF.  
• For patients on maintenance nivolumab who have developed oligoprogression in a single site 
of disease, but are otherwise stable, please refer to section on continuation of nivolumab 
beyond progression. The use of local therapy such as radiotherapy, surgery or local ablation 
are not permitted. If such local therapies are considered necessary for the patient’s 
oncological care, the patient will need to be taken off protocol treatment.  
 
5.2.3 Prohibited Therapies 
Participants are prohibited from receiving the following therapies during protocol treatment: 
Anti-cancer systemic chemotherapy, biological therapy (including tyrosine kinase inhibitors, 
gene therapy, any immunotherapy such as but not limited to vaccines, cell-based therapy, any 
antibodies, CAR-T therapy) that not specified in this protocol are not permitted. In particular:    
 
• For patients randomized to Arm 2, the use of chemotherapy or any systemic anti-cancer 
therapy(s) as listed above with a “maintenance” intent is NOT permitted.  For such patients, 
if they experience disease progression, they will need to be taken off protocol treatment 
first before starting any other anti-cancer systemic therapies.  
• Investigational agents other than nivolumab. 
• Live vaccines within 30 days prior to the first dose of study treatment and while on 
treatment.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids for patients with adrenal and/or pituitary insufficiency are permitted. Use 
of prophylactic corticosteroids to avoid allergic reactions (e.g. IV contrast dye) or for anti-


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emetic premedication prior to chemotherapy is permitted. Intranasal steroid for the 
treatment of allergic rhinitis, and inhaled steroids for the treatment of stable asthma are 
permitted.  
5.3 
Participation in Other Trials 
Patients are not to participate in other therapeutic trials that involve study interventions 
including systemic experimental agents including cytotoxic chemotherapy, herbal and/or 
alternative medicine, local ablative therapy, radiotherapy and surgery. However, non-
interventional, observational studies are allowed (e.g. imaging trials, quality of life, 
blood-sampling, endoscopic biopsy of the primary nasopharyngeal tumor).  
 
5.4 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
▪ 
Any progression or recurrence of NPC, or any occurrence of another malignancy 
(diagnosed since enrollment) that requires active treatment, 
▪ 
Intercurrent illness that prevents further administration of treatment, 
▪ 
Unacceptable or intolerable adverse event(s), as described in Section 6 (see also 
specific nivolumab algorithms in the Investigator’s Brochure) 
▪ 
For patients receiving platinum-gemcitabine with or without nivolumab, and for 
patients on maintenance nivolumab: Any dosing interruption lasting > 8 weeks, with 
the following exceptions:  
(a) Dosing interruptions > 8 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Study Chair or designate.  
(b) Dose interruptions > 8 weeks due to drug-related adverse events should result in 
permanent study therapy discontinuation, unless the study doctor thinks that it is 
in the patient’s best interest to remain on the study treatment. The study doctor 
should consult the Study Chair or designate before continuing study treatment. 
(c) For patients with nivolumab-related immune toxicities that require systemic 
steroids, a maximum dose interruption of 8 weeks is allowed in order for the 
steroids to be weaned off completely. See section 6.3.  
 
Note: Tumor assessments should continue as per protocol even if dosing is 
interrupted. 
▪ 
Patient or legally acceptable representative decides to withdraw consent for 
participation in the study, or 
▪ 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
▪ 
Patient’s repeated non-compliance with study procedures and/or requirement, which 
in the opinion of the investigator, result in an increased risk to the patient  
▪ 
The patient has a confirmed positive serum pregnancy test. 
 
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. 


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6.1 
Dose Modifications and Toxicity Management for Cisplatin-Gemcitabine 
 
Dose Modification levels for platinum-gemcitabine 
 
Cisplatin Dose Levels During Cisplatin-Gemcitabine 
Starting Dose 
Dose Level -1 
Dose Level -2 
80 mg/m2 
60 mg/m2 
45 mg/m2 
 
Gemcitabine Dose Levels During Cisplatin-Gemcitabine 
Starting Dose 
Dose Level -1 
Dose Level -2 
1000 mg/m2 
750 mg/m2 
500 mg/m2 
 
Carboplatin Dose Levels During Carboplatin-Gemcitabine 
Starting Dose 
Dose Level -1 
Dose Level -2 
AUC = 5 
AUC = 4 
AUC = 3 
 
6.1.1    Cisplatin Dose Modifications for Hematologic Adverse Events  
Below are recommendations for cisplatin dose modifications. For purposes of this protocol, 
individual investigators may use their local institutional guidelines. 
 
Chemotherapy should not be administered until blood count recovery (i.e., ANC is at least 1500 
cells/mm3 and the platelet count is at least 100,000 cells/mm3 - see section 5.1.1 Criteria for starting 
a new cycle of chemotherapy with or without nivolumab. If these parameters are not met, then 
treatment should be delayed in weekly increments until they have recovered to this level, but no 
more than an 8 week delay is permitted.   
Dose reductions for ANC and platelets based on counts at anticipated day of treatment, ONCE 
RECOVERY TO THE ABOVE LEVELS ARE ACHIEVED: 
For patients on cisplatin-gemcitabine with or without nivolumab 
ANC at day of treatment 
(day 1 of each cycle) 
 
Platelets at day of 
treatment 
(day 1 of each cycle) 
Cisplatin dose Reduction 
≥ 1500 cells/mm3  
and 
≥ 100,000 cells/mm3 
None 
< 1500 cells/mm3 
or 
< 100,000 cells/mm3 
At count recovery, resume 
at one lower dose level of 
BOTH cisplatin and 
gemcitabine 
 
6.1.2  Cisplatin Dose Modifications for Cisplatin-Related Non-Hematologic Adverse Events  
• In this study, cisplatin or carboplatin may be used at the discretion of the investigator, except 
for those patients with CrCl of < 50 mL/min in whom carboplatin should be used instead of 
cisplatin. The following treatment modification applies to patients who have been 
commenced on cisplatin in cycle 1 onwards.   
• If any one or more of the following cisplatin-related adverse events occur during treatment, 
carboplatin may be used to substitute cisplatin at the investigator’s discretion:  


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o Neurological Events Attributable to Cisplatin (i.e., peripheral neuropathy): Grade 2, 
decrease cisplatin by one dose level OR switch to carboplatin. For ≥ Grade 3, hold 
cisplatin and switch to carboplatin. 
o Ototoxicity:  Should patients develop any grade of ototoxicity, cisplatin should be 
substituted by carboplatin.  
o Renal Adverse Events: Dose will be modified based on the calculated CrCl (Cockcroft-
Gault formula) prior to each cisplatin dose. If the calculated CrCl is < 50 mL/min, 
cisplatin should be substituted by carboplatin and continued on carboplatin. For patients 
receiving concurrent nivolumab-cisplatin-gemcitabine, if the CrCl has stabilized after a 
dose interruption of a maximum of 3 weeks, AND the cause of the creatinine rise is 
considered unrelated to nivolumab, may substitute cisplatin with carboplatin in 
subsequent cycles.  
o All Other Non-Hematologic and non-renal Adverse Events Attributable to Cisplatin: For 
all other non-hematologic adverse events in which toxicity is ≥ grade 2 (CTCAE v5.0), 
investigators are advised to evaluate and manage correctable issues promptly to prevent 
worsening of toxicity. Then switching to carboplatin is advised in subsequent cycles.  
o Once a patient has been switched from cisplatin to carboplatin, he/her should stay on 
carboplatin for all subsequent cycles and not switched back to cisplatin.  
 
6.1.3 Dose Modification Guidelines for Gemcitabine Hematologic Drug-Related Events  
For day 1 gemcitabine: please refer to “Criteria for starting a new cycle of chemotherapy” in 
section 5.1.1 and Table 5.1A: Trial Treatment. For dose modification on day 1 of gemcitabine:  
 
Day 1 of each cycle: For patients on cisplatin-gemcitabine with or without nivolumab 
ANC at day 1 of each new 
cycle 
 
Platelets at day 1 of 
each new cycle 
Gemcitabine dose 
Reduction 
≥ 1500 cells/mm3  
and 
≥ 100,000 cells/mm3 
None 
< 1500 cells/mm3 
or 
< 100,000 cells/mm3 
At count recovery, resume at 
one lower dose level of 
BOTH cisplatin and 
gemcitabine 
 
Dose reduction for day 8 gemcitabine 
                 ANC (cells/mm3)                     Platelets (cells/mm3) 
Gemcitabine Dose 
≥ 1000             and              ≥ 100,000 
1000 mg/m2 
500-999      or              50,000 - 99,999 
750 mg/m2 
< 500             or                 < 50,000 
Hold 
 
Note:  Day 1 of Gemcitabine may be delayed; however, held doses of gemcitabine on day 8 will 
be considered missed doses and will not be delayed or made up. 
 
 
 


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6.1.4 Dose Modification Guidelines for Gemcitabine-specific Non-Hematologic Drug-Related 
Events  
Withhold gemcitabine, then reduce dose to 500 mg/m2 for other severe (Grade 3 or 4) non-
hematologic toxicities until resolved to Grade 0-1. This applies to both day 1 and day 8 of each 
cycle.  
• No dose modifications are recommended for alopecia, nausea, or vomiting. 
• Permanently discontinue gemcitabine for the following: 
o Unexplained dyspnea or other evidence of severe pulmonary toxicity 
o Severe hepatic toxicity 
o Hemolytic-uremic syndrome 
o Capillary leak syndrome 
o Posterior reversible encephalopathy syndrome 
For additional guidance regarding treatment modification of gemcitabine, please refer to the 
United States package insert (or local prescribing information) for dose modifications for 
hematologic and other non-hematologic toxicities 
 
6.1.5 All Other Non-Hematologic Adverse Events During cisplatin-gemcitabine  
For grade 3 or 4 events, drugs should be held until resolution to grade 1 or less, then both drugs 
resumed at dose level -1. Gemcitabine doses on day 8 of each cycle will not be made up but merely 
skipped for grade 3 or greater AEs occurring between days 1 and 8. Chemotherapy should be 
stopped if greater than grade 2 AEs are not resolved to grade 1 within 3 weeks, and patient should 
proceed directly to next cycle of treatment. For specific AEs attributabed exclusively to one or the 
other agent (platinum or gemcitabine), dose reduction only for that agent is required. 
 
6.2   Dose Modifications and Toxicity Management for Carboplatin 
Chemotherapy should not be administered until blood count recovery - i.e. ANC is at least 1500 
cells/mm3 and the platelet count is at least 100,000/mm3.  If these parameters are not met, then 
treatment should be delayed in weekly increments until they have recovered to this level, but no 
more than an 8 week delay is permitted.   
Dose reductions for ANC and platelets based on counts at anticipated day of treatment, ONCE 
RECOVERY TO THE ABOVE LEVELS ARE ACHIEVED: 
Table 6.2A 
For patients on carboplatin-gemcitabine with or without nivolumab 
ANC at day 1 of each new 
cycle 
 
Platelets at day 1 of 
each new cycle 
Carboplatin Dose Reduction 
≥ 1500 cells/mm3  
and 
≥ 100,000 cells/mm3 
None 
< 1500 cells/mm3 
or 
< 100,000 cells/mm3 
At count recovery, resume at 
one lower dose level of BOTH 
carboplatin and gemcitabine 
 
 


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6.3 
Dose Modifications and Toxicity Management for Nivolumab-related Adverse 
Events 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
nivolumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with nivolumab are provided in section 6.3.1.  Please refer to 
Appendix I for nivolumab toxicity management algorithms which include specific treatment 
guidelines.  These guidelines are applicable to patients who are receiving nivolumab with 
chemotherapy and maintenance phase. These algorithms should be followed unless there are 
specific clinical circumstances for which the treating physician decides an alternative treatment 
approach is clinically appropriate.  Dose reduction of nivolumab is not allowed in this study.  
• Nivolumab dose interruption during concurrent phase: if the platinum and/or gemcitabine 
need to be withheld, nivolumab will also need to be withheld (i.e., the entire treatment cycle 
will be interrupted). However if only nivolumab needs to be withheld, platinum-gemcitabine 
can be continued as long as the patient does not need systemic steroids and/or potent 
immunosuppressive, and that it is safe to do so at the discretion of the investigator. If a 
patient needs systemic steroids for nivolumab-related AEs, the chemotherapy should be 
withheld until the nivolumab can be resumed and the steroids weaned off completely within 
6 weeks from the date of dose interruption. If nivolumab cannot be resumed within 8 weeks, 
the patient should discontinue from study protocol treatment permanently.   
• Any Grade 3 or 4 drug-related laboratory abnormality or electrolyte abnormality, that can 
be managed independently from underlying organ pathology with electrolyte replacement, 
hormone replacement, insulin or that does not require treatment does not require 
discontinuation.  The exception is grade 3-4 pancreatitis complicated by diabetes mellitus 
– these patients need to discontinue protocol treatment permanently.  
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued study drug 
dosing should discontinue nivolumab.   
 
Table 6.3A 
ALL NON-
IMMUNOLOGIC 
EVENTS 
Management/Next Dose for Nivolumab  
≤ Grade 1 
Continue nivolumab. 
Grade 2  
Hold until ≤ Grade 1 OR baseline (exceptions as noted below). 
If recurs at resumption, should discontinue nivolumab 
permanently.  
Grade 3  
Hold* until ≤ Grade 1 OR baseline. Resume at investigator’s 
discretion  
Grade 4  
Discontinue nivolumab permanently.   
*Not agent related, OR agent-related but non-immunologically mediated 
Recommended management:  As clinically indicated   
 
 


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ALL IMMUNOLOGIC 
EVENTS 
Management/Next Dose for Nivolumab  
≤ Grade 1 
Continue nivolumab. 
Grade 2  
Hold until ≤ Grade 1 OR baseline (exceptions as noted below). 
If recurs at resumption, discontinue permanently.   
Grade 3  
Hold until ≤ Grade 1 OR baseline and patient has been weaned 
off systemic steroid if it has been initiated (exceptions as noted 
below).  Resume at investigator’s discretion. Permanently 
discontinue for events with a high likelihood of morbidity or 
mortality with recurrent events.  
Grade 4  
Discontinue nivolumab.  
Recommended management:  As clinically indicated   
 
6.3.1 Guideline for Specific Nivolumab-Related Adverse Events 
 
• Prior to starting corticosteroids or hormone replacement for any reason, appropriate 
endocrine testing including cortisol, Cortrosyn® adrenocorticotrophic hormone (ACTH), 
thyroid stimulating hormone (TSH), and thyroxine (T4) must be obtained to document 
baseline.   
• Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and 
continue to taper over at least 4 weeks. 
• For situations where nivolumab has been withheld, nivolumab can be resumed after AE 
has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Nivolumab should 
be permanently discontinued if AE does not resolve within 8 weeks of last dose of 
nivolumab, or corticosteroids cannot be weaned off within 8 weeks.  
• For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed 
by oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be 
controlled by corticosteroids. Any patients receiving nivolumab who require additional 
immune suppressive treatment beyond systemic steroids should discontinue nivolumab. 
Any patient started on systemic corticosteroids empirically for suspected autoimmune 
toxicity, and is subsequently determined to be not requiring steroid treatment, may resume 
nivolumab after a 2-week observation period at the discretion of the PI or investigator. 
• Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment should discontinue nivolumab.   
 
 
Skin Rash and Oral 
Lesions  
  
Management/Next Dose for Nivolumab  
≤ Grade 1  
No change in dose*.  
Grade 2  
Hold* until ≤ Grade 1 or resolved.  Resume at same dose level.   
Grade 3  
Hold* until ≤ Grade 1 or has weaned off systemic steroids if it has 
been initiated. Resume at same level at investigator discretion   


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Grade 4  
Discontinue nivolumab.  
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson 
syndrome, toxic epidermal necrolysis (TEN), and autoimmune bullous disease including oral 
lesions of bullous pemphigus/pemphigoid.  Pruritus may occur with or without skin rash and 
should be treated symptomatically if there is no associated liver or GI toxicity.  Note skin 
rash typically occurs early and may be followed by additional events particularly during 
steroids tapering.    
Recommended management:  AE management guidelines  
 
 
Liver Function  
AST, ALT, Bilirubin 
  
Management/Next Dose for Nivolumab  
Grade 1  
Hold at investigator discretion until ULN or baseline.  Resume at 
same dose level. 
Grade 2  
Grade 2 (3x ULN to 5x ULN): Hold and resume at same dose 
level when return to grade 1 or baseline within 7 days without 
steroids. If systemic steroids are required, resume at same dose 
level when return to baseline or grade 1 and weaned off steroids. 
If grade 2 recurs, then discontinue permanently.   
Grade 3-4  
Permanently discontinue nivolumab.  
Continued treatment of active immune mediated hepatitis may exacerbate ongoing 
inflammation.  Holding drug to evaluate liver function test (LFT) changes and early 
treatment are recommended.  LFT changes may occur during steroid tapers from other events 
and may occur together with other GI events including cholecystitis/pancreatitis.  
Please note:  Grades for liver function follow ULN rather than multiples of baseline. 
Recommended management:  see Hepatic AE management algorithm  
 
Diarrhea/Colitis 
Management/Next Dose for Nivolumab 
Grade 1 
 
Continue at same dose, use anti-diarrheal.   
Grade 2-3 
Hold dose. Consult gastroenterologist. Resume at same dose level 
if resolved to grade 1 within 7 days without steroids and no 
evidence of colitis on endoscopy.  If corticosteroids are needed, 
hold dose until resolution to baseline, and when steroids are 
weaned off within 8 weeks. If grade 2-3 diarrhea/colitis recurs at 
resumption, then discontinue from study treatment permanently.    
Grade 4  
Permanently discontinue nivolumab. 
See GI AE Algorithm for management of symptomatic colitis.   
Patients with Grade 2 symptoms but normal colonoscopy and biopsies may be retreated with 
nivolumab after resolution.  Patients who require systemic steroids and cannot be weaned off,
should be taken off study treatment.   
Recommended management:  see GI AE management Algorithm  
 


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Pancreatitis 
Amylase/Lipase   
Management/Next Dose for Nivolumab  
≤ Grade 1  
Continue nivolumab if asymptomatic at investigator discretion.   
Grade 2  
Continue nivolumab if asymptomatic at investigator discretion.  
If symptomatic, resume nivolumab when resolved.  
Grade 3  
Continue nivolumab if asymptomatic at investigator discretion.  
Patients should have imaging study when clinically indicated 
(grade 3 symptomatic pancreatitis) before resuming treatment.  
Patients who develop grade 3 symptomatic pancreatitis 
complicated by diabetes mellitus should discontinue nivolumab.   
Grade 4  
Hold until grade 2.  Resume at same dose level if asymptomatic.  
Patients who are symptomatic should have imaging study prior 
to resuming treatment and when clinically indicated.  Patients 
who develop grade 4 symptomatic pancreatitis complicated with 
or without diabetes mellitus should be discontinue nivolumab.   
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as diabetes 
mellitus and diabetic ketoacidosis (DKA).  Lipase elevation may occur during the period of 
steroid withdrawal and with other immune-mediated events or associated with colitis, 
hepatitis, and patients who have asymptomatic lipase elevation typically have self-limited 
course and may be retreated with nivolumab. For treatment management of symptomatic 
pancreatitis, please follow the Hepatic AE Management Algorithm.   
  
 
 Pneumonitis  
Management/Next Dose for Nivolumab  
Grade 1  
Hold dose until resolution to baseline including baseline pO2, 
then resume without change in dose. Consultation with 
respiratory team is advisable.  
Grade 2  
Hold dose. Administer corticosteroids (initial dose of 1-2 mg/kg 
prednisone or equivalent) followed by taper. Consultation with 
respiratory team is advisable. Hold dose until resolution to 
baseline including baseline pO2, and when steroids are weaned 
off within 8 weeks, then resume without change in dose. If grade 
2 pneumonitis recurs at resumption of nivolumab, discontinue 
nivolumab permanently.   
Grade 3 or 4  
Permanently discontinue nivolumab.  
Recommended management:  See Pulmonary AE Management Algorithm   
   
 
Other GI  
Nausea, Vomiting   
Management/Next Dose for Nivolumab  
≤ Grade 1  
Continue nivolumab.   
Grade 2  
Hold pending evaluation for gastritis, duodenitis, and other 
immune AEs or other causes.  Resume after resolution to ≤ 
Grade 1.    


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Grade 3  
Hold pending evaluation until ≤ Grade 1, then resume.  If 
symptoms do not resolve within 7 days with symptomatic 
treatment, patients should discontinue nivolumab.  
Grade 4  
Discontinue nivolumab.  
Patients with Grade 2 or 3 N-V should be evaluated for upper GI inflammation and other 
immune related events. 
  
 
 Fatigue 
Management/Next Dose for Nivolumab  
  
Grade 2 
Continue nivolumab. 
Grade 3 
Hold until≤ Grade 2, then resume.  
Fatigue is the most common AE associated with immune checkpoint therapy.  Grade 2 or 3 
fatigue should be evaluated for associated or underlying organ involvement including 
pituitary, thyroid, and hepatic, or muscle (CPK) inflammation.   
   
 
Neurologic Events 
Management/Next Dose for Nivolumab  
≤ Grade 1  
Hold dose pending evaluation and observation.  Resume when 
resolved to baseline.   
Grade 2  
Hold dose pending evaluation and observation.  Hold until ≤ 
Grade 1. Discontinue nivolumab if treatment with steroids is 
required.  Resume at same dose level for peripheral isolated 
cranial nerve VII (Bell’s palsy).   
Grade 3  
Discontinue nivolumab. 
Grade 4  
Discontinue nivolumab.   
Patients with any CNS events including aseptic meningitis, encephalitis, or myopathy, 
peripheral demyelinating neuropathy, cranial neuropathy (other than peripheral n. VII), 
Gullain-Barre syndrome, and myasthenia gravis should discontinue nivolumab permanently.  
Recommended management:  See Neurologic AE Management Algorithm   
  
 
  
Hypophysitis  
Adrenal Insufficiency 
Management/Next Dose for Nivolumab  
≤ Grade 1  
*Hold pending evaluation for evidence of adrenal insufficiency 
or hypophysitis.  Asymptomatic thyroid stimulating hormone 
(TSH) elevation may continue treatment while evaluating the 
need for thyroid replacement.  
Grade 2  
Hold until patients are on a stable replacement hormone 
regimen.  If treated with steroids, patients must be stable off 
steroids for 2 weeks.  Then resume nivolumab.   
Grade 3  
Hold until patients are on a stable replacement hormone 


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regimen.  If treated with steroids, patients must be stable off 
steroids for 2 weeks. Then resume nivolumab.  
Grade 4  
Discontinue nivolumab.  
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, 
but including severe headache or enlarged pituitary on MRI should be considered Grade 3 
events.  Isolated thyroid or testosterone deficiency may be treated as Grade 2 if there are no 
other associated deficiencies and adrenal function is monitored.   
Please evaluate pituitary function before beginning steroid therapy or replacement therapy 
of any kind.  *Note patients with thyroiditis may be retreated on replacement therapy.  
Patients must be evaluated to rule out pituitary disease prior to initiating thyroid 
replacement.  
Recommended management:  See Endocrine Management Algorithm   
  
 
 
Hypothyroidism 
Management/Next Dose for Nivolumab  
Grade 1 
Continue nivolumab.  
Grade 2-3  
Continue nivolumab, initiate thyroid hormone replacement. 
Grade 4  
Hold until patients are clinically stable and on a stable 
replacement hormone regimen, then resume nivolumab at same 
dose. The TSH level does not need to be normalized if the 
patient if clinically stable.  
Recommended management:  See Endocrine Management Algorithm   
 
 
 
Hyperthyroidism 
Management/Next Dose for Nivolumab  
Grade 1 
Continue nivolumab.  
Grade 2  
Continue nivolumab at same dose, treat with non-selective 
beta-blockers (eg, propranolol) or thionamides as appropriate. 
Grade 3-4  
Hold until patients are stable. Resume nivolumab or 
discontinue nivolumab permanently at the investigator’s 
discretion.  
Recommended management:  See Endocrine Management Algorithm   
 
 


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Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
Management/Next Dose for Nivolumab  
Newly onset T1DM or  
Grade 3 or 4 
hyperglycemia  
Hold until patients are stabilized with medical therapy (e.g. 
insulin, or anti-hyperglycemic agents), then resume 
nivolumab.  
 
Recommended management:  See Endocrine Management Algorithm   
 
 
Renal/nephritis 
Management/Next Dose for Nivolumab  
Grade 1  
Monitor closely and continue therapy.  
Grade 2  
Hold until ≤ Grade 1. Resume nivolumab.  
Grade 3-4  
Discontinue nivolumab permanently. Administer systemic 
steroids.    
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over 
the course of 1-2 weeks should be done for other autoimmune events that may present as 
fever. 
  
 
 Infusion Reaction   
Management/Next Dose for Nivolumab  
Grade 1  
Infusion rate may be slowed or interrupted and restarted at 
50% of the original infusion rate when symptoms resolve; if 
no further complications ensue after 30 minutes, the rate may 
be increased to 100% of the original infusion rate. Monitor 
patient closely.   
  
The following prophylactic premedications are recommended 
for future infusions:  diphenhydramine and/or paracetamol (or 
acetaminophen) at least 30 minutes before additional 
nivolumab administrations, slowing infusion rate as above. 
Grade 2: Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hrs 
Stop the nivolumab infusion, give IV fluids, 
diphenhydramine (or equivalent) and/or paracetamol; 
Corticosteroid or bronchodilator therapy may also be 
administered as appropriate.  If the infusion is interrupted, 
then restart the infusion at 50% of the original infusion rate 
when symptoms resolve within 1 hour of stopping nivolumab; 
if no further complications ensue after 30 minutes, the rate 
may be increased to 100% of the original infusion rate.  
Monitor patient closely.  If symptoms recur, re administer 
diphenhydramine 50 mg IV, and stop infusion.   
Hold dose until resolved to baseline. The following 
prophylactic premedications are recommended for future 


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infusions: diphenhydramine and acetaminophen (or 
paracetamol). If necessary, corticosteroids (up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
Grade 3: Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
  
Grade 4: Life-threatening; 
pressor or ventilatory 
support indicated 
Nivolumab will be permanently discontinued. 
Immediately discontinue infusion of nivolumab. Give IV 
fluids, diphenhydramine (or equivalent) and/or paracetamol, 
bronchodilators, epinephrine and/or steroids if indicated. 
Investigators should follow their institutional guidelines for 
the treatment of anaphylaxis.  
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to 
be immunogenic and induce infusion or hypersensitivity reactions.  However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, urticaria, 
angioedema, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience 
isolated fever during infusion reactions or up to several days after infusion.  Evaluation over 
the course of 1-2 weeks should be done for other autoimmune events that may present as 
fever.   
  
 
 
Cardiac *   
Management/Next Dose for Nivolumab Cardiac 
Toxicities 
Less than grade 2 
Hold dose pending evaluation and observation.**  Evaluate 
for signs and symptoms of CHF, ischemia, arrhythmia or 
myositis.  Obtain history EKG, CK (for concomitant 
myositis), CK-MB.  Repeat troponin, CK and EKG 2-3 days.  
If troponin and labs normalize without evidence of 
myocarditis may resume therapy.   If labs worsen or 
symptoms develop then treat as below.   
Grade >2 with suspected 
myocarditis 
Hold dose.**  Admit to hospital.  Cardiology consult.  Rule 
out MI and other causes of cardiac disease.  Cardiac 
Monitoring.  Cardiac Echo.  Consider cardiac MRI and 
cardiac biopsy.  Initiate high dose methylprednisolone and 
immune suppression as clinically indicated. May resume 
therapy if there is a return to baseline and myocarditis is 
excluded or considered unlikely. 


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Cardiac *   
Management/Next Dose for Nivolumab Cardiac 
Toxicities 
Grade >2 with confirmed 
myocarditis   
Discontinue nivolumab permanently.  Consider high dose 
methylprednisolone. Add ATG or tacrolimus if no 
improvement.    
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other 
event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been 
established.  Since this toxicity has caused patient deaths, an aggressive approach is 
recommended.   
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 Protocol Agents 
Investigational Agent 
The investigational agent administered in NRG-HN007, nivolumab, is being made available 
under an IND sponsored by CTEP.   
Commercial Agent 
The commercial agents in NRG-HN007 are cisplatin, carboplatin, and gemcitabine.  
 
 
7.2 Adverse Events and Serious Adverse Events 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
 
PRO-CTCAE is not intended for expedited reporting, real time review, or safety 
reporting. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study patients must be reported via CTEP-AERS in an expedited manner. 


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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-
HN007 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. 
 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for CTEP Study 
Agent: Nivolumab (16-FEB-2021) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Nivolumab (NSC 748726) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2069 patients. Below is the CAEPR for 
Nivolumab. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
     Version 2.4, December 2, 20201 
 
 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2 
  
 
 
Pericarditis 
  


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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency3 
 
  
 
Hyperthyroidism3 
 
  
 
Hypophysitis3 
 
  
 
Hypothyroidism3 
 
  
EYE DISORDERS 
  
 
 
Blurred vision 
  
 
 
Dry eye 
  
 
 
Eye disorders - Other (diplopia)3 
  
 
 
Eye disorders - Other (Graves 
ophthalmopathy)3 
  
 
 
Eye disorders - Other (optic neuritis 
retrobulbar)3 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada) 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis3 
 
  
 
 
Colonic perforation3 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Enterocolitis 
  
 
 
Gastritis 
  
 
 
Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - Other 
(immune-mediated hepatitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release syndrome5 
  
 
 
Immune system disorders - Other 
(GVHD in the setting of 
allotransplant)3,6 
  
 
 
Immune system disorders - Other 
(sarcoidosis)3 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased3 
 
 Alanine aminotransferase 
increased3 (Gr 3) 


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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Aspartate aminotransferase 
increased3 
 
 Aspartate aminotransferase 
increased3 (Gr 3) 
 
Blood bilirubin increased3 
 
 Blood bilirubin increased3 (Gr 2) 
 
CD4 lymphocytes decreased 
 
 CD4 lymphocyte decreased (Gr 4) 
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 
4) 
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
Serum amylase increased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism and nutrition disorders 
- Other (diabetes mellitus with 
ketoacidosis)3 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  
 
 
Guillain-Barre syndrome3 
  
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - Other 
(demyelination myasthenic 
syndrome) 
  
 
 
Nervous system disorders - Other 
(encephalitis)3 
  
 
 
Nervous system disorders - Other 
(meningoencephalitis) 
  
 
 
Nervous system disorders - Other 
(meningoradiculitis)3 
  
 
 
Nervous system disorders - Other 
(myasthenic syndrome) 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  
 
 
Renal and urinary disorders - Other 
(immune-mediated nephritis) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  


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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia)3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  
 
Pruritus3 
 
 Pruritus3 (Gr 2) 
 
Rash maculo-papular3 
 
 Rash maculo-papular3 (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (bullous 
pemphigoid) 
  
 
Skin and subcutaneous tissue 
disorders - Other (Sweet's 
Syndrome)3 
 
  
 
Skin hypopigmentation3 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3Nivolumab being a member of class of agents involved in the inhibition of “immune checkpoints”, may result in 
severe and possibly fatal immune-mediated adverse events probably due to T-cell activation and proliferation.  This 
may result in autoimmune disorders that can include (but are not limited to) autoimmune hemolytic anemia, 
acquired anti-factor VIII immune response, autoimmune aseptic meningitis, autoimmune hepatitis, autoimmune 
nephritis, autoimmune neuropathy, autoimmune thyroiditis, bullous pemphigoid, exacerbation of Churg-Strauss 
Syndrome, drug rash with eosinophilia systemic symptoms [DRESS] syndrome, facial nerve disorder (facial nerve 
paralysis), limbic encephalitis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, 
endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia gravis, 
polymyositis, and Guillain-Barre syndrome. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying fever and 
pancytopenia. 
 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have occurred in patients 
receiving allo stem cell transplant (SCT) after receiving Nivolumab.  These complications may occur despite 
intervening therapy between receiving Nivolumab and allo-SCT. 
 
7Infusion reactions, including high-grade hypersensitivity reactions which have been observed following 
administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, hypertension or hypotension, or 
difficulty breathing during and immediately after administration of nivolumab. 


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Adverse events reported on Nivolumab trials, but for which there is insufficient evidence to suggest that there 
was a reasonable possibility that Nivolumab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; Ventricular 
arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; Gastrointestinal disorders - 
Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; 
Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other (autoimmune thrombotic 
microangiopathy); Immune system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - Other (protein total 
decreased); Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Musculoskeletal and 
connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal and connective tissue disorder - Other 
(polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (Histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other (tubulointerstitial 
nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; Cough; Dyspnea; 
Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain of skin; 
Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other (rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
Note: Nivolumab in combination with other agents could cause an exacerbation of any adverse event currently 
known to be caused by the other agent, or the combination may result in events never previously associated with 
either agent. 
 
 
 
7.4 
Adverse Events for Commercial Study Agents: Cisplatin, Carboplatin, and 
Gemcitabine 
Refer to the package insert for detailed pharmacologic and safety information 
 
7.4.1 Adverse Events and PRO-CTCAE 
PRO-CTCAE  
The PRO-CTCAE instrument will be used to assess patient reported toxicity outcomes.  
 
PRO-CTCAE is a validated instrument developed by the National Cancer Institute to assess 
clinical trial toxicity outcomes by patient report; it complements information collected by 


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physician-reported CTCAE. PRO-CTCAE is available in English, Spanish, French 
(Canada), Chinese (simplified and traditional), and Korean 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 or Chinese (simplified or traditional) language PRO-CTCAE is not currently 
available on the Medidata Patient Cloud ePRO. Collection time points are listed in Section 
4. 
 
Assessments will be collected as specified in the Section 4 assessment tables. 
 
The patient-reported AEs that will be assessed using PRO-CTCAE are listed in the table 
below. These adverse events are considered expected and, if reported, should also be 
clinician graded using CTCAE v5.0. 
 
 
CTCAE v5.0 
PRO-CTCAE Items With Attributes 
1. 
Dry mouth 
Dry mouth (Severity) 
2. 
Esophagitis 
Dysphagia 
Difficulty swallowing (Severity) 
3. 
Voice alteration 
Voice quality changes (Presence) 
4. 
Mucositis oral 
Mouth/throat sore (Severity) 
5. 
Dysgeusia 
Taste changes (Severity) 
6. 
Abdominal pain 
Abdominal pain (Severity) 
7. 
Palpitations 
Heart palpitations (Severity) 
8. 
Rash acneiform  
Rash maculo-papular 
Rash (Presence) 
9. 
Pruritus 
Itching (Severity) 
10. 
Peripheral sensory neuropathy 
Numbness & tingling (Severity) 
11. 
Blurred vision 
Blurred vision (Severity) 
12. 
Tinnitus 
Ringing in ears (Severity) 
13. 
Concentration impairment 
Concentration (Severity) 
14. 
Memory Impairment 
Memory (Severity) 
15. 
Headache 
Headache (Severity) 
16. 
Depression 
Sad (Severity) 
 
7.5 
Expedited Reporting of Adverse Events (16-FEB-2021) 
All adverse events (AEs) are submitted for expedited reporting protocol-specific rules 
evaluation using the Medidata Rave data management system. All AEs will be evaluated 
by the Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) 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-


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AERS, accessed via the link in RAVE. CTEP-AERS is also accessed via the CTEP 
website, but all expedited reports must be initiated in RAVE: https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613. 
 
Submitting a report via Rave-CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 
adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to CTEP by telephone at 301-897-7497 and the NRG Oncology by phone at 1-215-
574-3191. An electronic report must be submitted immediately upon re-establishment of 
the Internet connection. 
 
7.5.1 Expedited Reporting Methods 
• 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. 
• Supporting source documentation is requested by NRG as needed to complete 
adverse event review. Supporting source documentation should include the protocol 
number, patient ID number, and CTEP-AERS ticket number on each page; fax 
supporting documentation to CTEP at 301-897-7404 and contact NRG Oncology at 
1-215-574-3191 for source documentation assistance. 
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
 
7.5.2 Expedited Reporting Requirements for Adverse Events  
Arm 2:  Any Phase Study Utilizing a Commercial Agent1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they are considered 
related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH 
E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 


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Attribution 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
10 day 
10 day 
Possible 
Probable 
Definite 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
Unexpected Grade 4 and all Grade 5 AEs 
 
 
 
Late Phase 2 and Phase 3 Studies: Arm 1: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of Nivolumab1, 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 


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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. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
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-HN007 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 
 


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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 
AE reporting unless otherwise specified. 
 
7.6 
Routine Reporting Requirements for Adverse Events 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
7.6.1    Reporting PRO-CTCAE  
Symptomatic Adverse Events reported by patients through PRO-CTCAE are not safety 
reporting and should also be clinician graded using CTCAE v5.0 and reported as routine 
AE data. 
 
 
7.7 
Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS. In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be 
completed and submitted to CTEP. Any pregnancy occurring in a patient or patient’s 
partner from the time of consent to 5 months or 7 months, respectively, after the last dose 
of nivolumab; or 6 months after the last dose of cisplatin; or 6 months or 3 months 
respectively, after the last dose of gemcitabine 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 
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 at 
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; 


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• 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; 
• 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 Cancer Trials Support Unit (CTSU) websites and applications. In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards 
(IRBs) covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• Addition to a site roster; 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN; 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• Assign 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) or 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. 
 
8.1 
Cancer Trials Support Unit Registration Procedures (16-FEB-2021) 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval  
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 


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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 for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to 
the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 
network or protocol level. Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
• Holds an active CTEP status; 
• Rostered at the site on the IRB/REB approval and on at least one participating 
roster; 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements for Protocol NRG-HN007 Site Registration 
Additional 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); and 
• Compliance with all protocol-specific requirements (PSRs).  
• Delegation Task Log (DTL) – see section 8.1.1 for instructions. 


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• IRB/REB approved consent (International and Canadian sites only: English and 
native language versions* English version must be submitted to NRG Regulatory 
(Regulatory-PHL@nrgoncology.org) for review prior to IRB/REB submission. 
International and Canadian Institutions must provide certification/verification of 
IRB/REB consent translation to NRG Oncology as described below).  
*Translation of documents is critical. The institution is responsible for all translation 
costs. All regulatory documents, including the IRB/REB approved consent, must be 
provided in English and in the native language. Certification of the translation is optimal 
but due to the prohibitive costs involved NRG Oncology will accept, at a minimum, a 
verified translation. A verified translation consists of the actual REB approved consent 
document in English and in the native language, along with a cover letter on 
organizational letterhead/stationery that includes the professional title, credentials, and 
signature of the translator as well as signed documentation of the review and verification 
of the translation by a neutral third party. The professional title and credentials of the 
neutral third party translator must be specified as well. 
Additional Requirements for sites in Canada  
 
Prior to clinical trial commencement, sites in Canada must also complete and submit the 
following documents to CTSU via the Regulatory Submission Portal. 
• Clinical Trial Site Information Form  
• Qualified Investigator Undertaking Form  
• Research Ethics Board Attestation Form 
• Protocol Signature Page  
• Investigator Brochure Signature Page  
• List of Laboratories  
• SIV/Training Confirmation of Completion Form – Research Associate (please 
refer to the activation memo for details)  
• SIV/Training Confirmation of Completion Form – Qualified Investigator (please 
refer to the activation memo for details)  
 
The following items are collected By NRG Oncology Regulatory on a yearly or biyearly 
basis:   
• IRB/REB Membership Roster  
• Laboratory Certificates and Normal Values  
• CVs for Qualified Investigator and Sub-Investigators noted on the DTL 
Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a Protocol Organization (PO) on the protocol. One way to search for a 
protocol is listed below. 


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• 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 
Oncology and protocol number NRG-HN007. 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.)  
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go 
to the → Regulatory section and select → Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in 
order to receive further instruction and support. 
 
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 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
8.1.1    Delegation of Task Log (DTL)  
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the 
DTL application in the Delegation Log section on the CTSU members’ website. 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 activate new task 
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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. 
 
8.2 
Patient Enrollment 
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.   
 
8.2.1 Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
Requirements for OPEN access:   
• A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 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 Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. A DTL is required for the study, and 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 HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 


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8.3 
Medidata Patient Cloud ePRO Registration (16-FEB-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.  
8.3.1    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 
order to register study patients. Please visit the CTSU website for reference information.  
 


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9.0 DRUG INFORMATION  
9.1 
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. 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, a “current” password, and active person registration status. For questions about 
drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the PMB’s 
website for specific policies and guidelines related to agent management. 
 
 
9.1.1 Starter supplies are not being provided. Patients must be registered prior to sites ordering 
study agents.   
Refer to the Policy and Guidelines for Investigational Agent Ordering and the contact 
information below for order processing time and conditions. Normal order processing time is two 
business days. An express courier account number must be provided for next-day delivery.  
 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/    
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov   
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/ 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/    
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov   
PMB email: PMBAfterHours@mail.nih.gov   
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET)  
IB Coordinator: IBCoordinator@mail.nih.gov  
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
9.2 
Investigational Study Agent: Nivolumab (NSC 748726) 
To supplement the toxicity information contained in this document, investigators must obtain the 
current version of the investigator brochure for comprehensive pharmacologic and safety 
information. 


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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. 
 
Amino Acid Sequence:  4 polypeptide chains, which include 2 identical heavy chains with 440 
amino acids and 2 identical light chains. 
 
Other Names: 
BMS-936558, MDX1106 
 
Classification: 
Anti-PD-1MAb 
 
M.W.:  146,221 Daltons 
 
Mode of Action:  Nivolumab targets the programmed death–1 (PD-1, cluster of differentiation 
279 [CD279]) cell surface membrane receptor. PD-1 is a negative regulatory receptor expressed 
by activated T and B lymphocytes. Binding of PD-1 to its ligands, programmed death–ligand 1 
(PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation. Nivolumab 
inhibits the binding of PD-1 to PD-L1 and PD-L2.  Inhibition of the interaction between PD-1 
and its ligands promotes immune responses and antigen-specific T-cell responses to both foreign 
antigens as well as self-antigens. 
 
Description:  Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; light 
(few) particulates may be present. The drug product is a sterile, nonpyrogenic, single-use, 
isotonic aqueous solution formulated in sodium citrate dihydrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), polysorbate 80 (Tween® 80), and water for 
injection.  Dilute solutions of hydrochloric acid and/or sodium hydroxide may be used for pH 
adjustment (pH 5.5-6.5). 
 
How Supplied: Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg vials (10 mg/mL) with a 0.7mL 
overfill.  It is supplied in 10 mL type I flint glass vials, with fluoropolymer film-laminated rubber 
stoppers and aluminum seals. 
 
Preparation:  Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose.  When the dose is based on patient weight (i.e., 
mg/kg), nivolumab injection can be infused undiluted or diluted to protein concentrations as low 
as 0.35 mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab 
injection can be infused undiluted or diluted so as not to exceed a total infusion volume of 160 
mL.  For patients weighing less than 40 kilograms (kg), the total volume of infusion must not 
exceed 4 mL per kg of patient weight. During drug product preparation and handling, vigorous 
mixing or shaking is to be avoided. 
 


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Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles.  
 
Storage: Vials of Nivolumab injection must be stored at 2°- 8°C (36°- 46°F) and protected from 
light and freezing. The unopened vials can be stored at room temperature (up to 25°C, 77°F) and 
room light for up to 48 hours. 
 
If a storage temperature excursion is identified, promptly return Nivolumab to 2°C-8°C and 
quarantine the supplies.  Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability. 
 
Stability:  Shelf-life surveillance of the intact vials is ongoing. 
 
The administration of undiluted and diluted solutions of Nivolumab must be completed within 24 
hours of preparation.  If not used immediately, the infusion solution may be stored up to 24 hours 
in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 8 hours of the total 24 hours can be at 
room temperature (up to 25°C, 77°F) and room light.  The maximum 8-hour period under room 
temperature and room light conditions includes the product administration period. 
 
CAUTION: The single-use dosage form contains no antibacterial preservative or 
bacteriostatic agent.  Therefore, it is advised that the product be discarded 8 hours 
after initial entry. 
 
Route of Administration:  Intravenous infusion over 30 minutes.  Do not administer as an IV 
push or bolus injection. 
 
Method of Administration:  Administer through a 0.2 micron to 1.2 micron pore size, low-
protein binding (polyethersulfone membrane) in-line filter.  
 
Potential Drug Interactions: The indirect drug-drug interaction potential of nivolumab was 
assessed using systemic cytokine modulation data for cytokines known to modulate CYP 
enzymes.  There were no meaningful changes in cytokines known to have indirect effects on 
CYP enzymes across all dose levels of nivolumab. This lack of cytokine modulation suggests 
that nivolumab has no or low potential for modulating CYP enzymes, thereby indicating a low 
risk of therapeutic protein-drug interaction. 
 
Patient Care Implications: Women of childbearing potential (WOCBP) receiving nivolumab 
must continue contraception for a period of 5 months after the last dose of nivolumab. Men 
receiving nivolumab and who are sexually active with WOCBP must continue contraception for a 
period of 7 months after the last dose of nivolumab. 
  
9.3 
Commercial Agent: Cisplatin 
 
 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
9.3.1 Adverse Events 
 
Please refer to the package insert. 


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9.3.2 Availability/Supply  
 
Please see Section 5.1 for administration instructions. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage. 
 
9.3.3 Patient Care Implications  
 
Females of childbearing potential must use adequate contraception during treatment and 
for 6 months after the last dose of cisplatin chemotherapy. Male patients must who are 
sexually active with WOCBP must use highly effective contraception for a total of 6 
months after last dose of cisplatin chemotherapy. 
 
9.4 
Commercial Agent:  Carboplatin  
 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
9.4.1 Adverse Events 
 
Please refer to the package insert. 
 
9.4.2 Availability/Supply  
 
Please see Section 5.1 for administration instructions. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage. 
 
9.4.3 Patient Care Implications  
 
Females of childbearing potential must use adequate contraception during treatment and 
for 6 months after the last dose of carboplatin chemotherapy. Male patients who are 
sexually active with WOCBP must use highly effective contraception for a total of 6 
months after last dose of carboplatin chemotherapy. 
 
9.5 
Commercial Agent:  Gemcitabine  
 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
9.5.1 Adverse Events 
 
Please refer to the package insert. 
 
9.5.2 Availability/Supply  
 
Please see Section 5.1 for administration instructions. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage. 
 
9.4.3 Patient Care Implications  
 
Females of childbearing potential must use adequate contraception during treatment and 
for 6 months after the last dose of gemcitabine chemotherapy. Male patients who are 
sexually active with WOCBP must use highly effective contraception for a total of 3 
months after last dose of gemcitabine chemotherapy. 
  
 


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10. PATHOLOGY/BIOSPECIMEN 
10.1 
Optional Tumor Tissue Collection and Correlative Studies Blood Sampling (16-
FEB-2021) 
Patients must be offered the opportunity to consent to optional specimen collection (highly 
recommended). If the patient consents to participate, the site is required to submit the patient’s 
specimens as specified per protocol. Sites are not permitted to delete the specimen component 
from the protocol or from the sample consent. 
 
See detailed specimen collection/processing/shipping instructions on the protocol-specific 
website, www.ctsu.org. 
 
This study will include collection of biospecimens for future analyses. An amendment for any 
correlative science studies to be performed on biological samples will be submitted to CTEP, 
NCI for review and approval according to NCTN guidelines or via the Navigator portal after the 
trial has been reported. Amendments to the protocol and/or proposals for use of banked tissue or 
blood samples will include the appropriate background, experimental plans with assay details, 
and a detailed statistical section. Samples for testing will not be released for testing until the 
appropriate NCI approvals have been obtained. 
 
10.1.1 Tumor tissue collection for PD-L1 Status 
Background: PD-L1 expression in tumor has been evaluated extensively as a predictive 
biomarker of response to PD1/L1 inhibitor in different solid tumors. Different 
commercial companion diagnostic assays for PD-L1 are now available, each assay using 
a different method of scoring PD-L1 expression with different clinical cut-off values. The 
“Blueprint PD-L1 IHC Assay Comparison Project” revealed that the 22C3, 28-8, and 
SP263 PD-L1 assays are closely aligned on tumor cell staining whereas the SP142 assay 
showed consistently fewer tumor cells stained (Hirsch 2017). The PD-L1 CPS and TPS 
scoring system have been prospectively evaluated together with the 22C3 assay for 
selecting patients with lung, cervical, urothelial and non-NPC HNSC for PD1 inhibitor 
therapy. In the KEYNOTE-048, over 800 patients with metastatic or recurrent HNSC 
were randomized 3 arms: (1) pembrolizumab alone if the PD-L1 CPS was ≥ 20%; (2) 
EXTREME regimen (chemotherapy and cetuximab); (3) or  pembrolizumab and 
chemotherapy. In this study, an OS advantage was seen in patients with PD-L1 CPS “≥ 
20%” (HR=0.61; 95% CI: 0.45-0.83; p=0.0007) or “≥ 1%” (HR=0.78; 95% CI: 0.64-
0.96; p=0.0086) who received pembrolizumab alone compared with the EXTREME 
regimen (Burtness 2018). For patients randomized to the two chemotherapy-based arms, 
the subgroup analysis based on PD-L1 status has not been reported to date. There is no 
reported information about the clinical significance of CPS and TPS for NPC. In the 
single arm phase II study of nivolumab in recurrent/metastatic NPC led by the principal 
investigator of this NCI proposal, there was a non-statistically higher proportion of 
responders among those with tumors expressing PD-L1 (22C3 assay) > 1% and > 10% 
(Ma 2018). But the study was underpowered to detect any survival difference. No other 
trials reported to date on PD-1 inhibitor in NPC have investigated the significance of PD-
L1 expression using the 22C3 assay.   
Rationale and study plan: This study plans to use programmed death receptor ligand-1 
(PD-L1) expression in NPC as an integrated biomarker. PD-L1 expression will be 


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recorded according to the Tumor Proportion Score (TPS) and the Combined Positive 
Score (CPS). The biomarker will be used in to examine the association with overall 
survival and progression-free survival in this study. PD-L1 analysis will be performed on 
archived or fresh tumor biopsies (collected at baseline) toward the end of enrollment. PD-
L1 expression will not be used as an eligibility criterion or used for treatment assignment. 
This study hypothesizes that the use of PD-L1 expression based on the TPS or CPS may 
be useful in identifying those patients who are more likely to benefit from treatment with 
PD-1 inhibitor in combination with chemotherapy. This study will explore a range of 
CPS and TPS scores. 
 
Tissue collection: All subjects who consent should submit either a newly obtained core or 
excisional biopsy or archival tissue (FNA not adequate for both archival and new tissue 
samples). Submission of formalin-fixed paraffin embedded tumor tissue sample blocks is 
preferred. United States and Canadian sites will send their FFPE samples to the NRGBB-
SF. For Asian and Australian sites, FFPE samples will be sent at the end of the study to a 
laboratory affiliated with the Chinese University of Hong Kong (CUHK) for the 
characterization of PD-L1 status. The PD-L1 status will be determined at the end of the 
study, and will not be used to stratify patients prior to randomization. 
 
• Detailed instructions for tissue collection, processing, and shipment are provided in 
section 10.3. 
• If the subject signs the consent for future research, any leftover samples that would 
ordinarily be discarded at the end of the main study will be retained for Future 
Biomedical Research future research.  
 
10.1.2 For patients with non-keratinizing NPC: Plasma Epstein-Barr virus DNA 
• Rationale: We hypothesize that plasma EBV DNA half-life during the first 6 weeks of 
treatment may be associated with subsequent response in patients with non-keratinizing 
NPC. 
• Collection time points: A total of five sampling time points will be used: 5 mL of EDTA 
blood sample (5 mL tube x 1) will be taken at baseline (within 7 days prior to starting the 
first dose of study drug), and then at: cycle 1 day 8 +/-3 days, day 15 +/-3 days; cycle 2 
day 1 +/- 3 days and day 8 +/- 3 days.  
• Detailed instructions for blood sample collection, processing, and shipment are provided 
in section 10.3. 
• All samples from patients who consent are to be submitted for central testing. 
• If the subject signs the Future Biomedical Research consent, any leftover samples that 
would ordinarily be discarded at the end of the main study will be retained for Future 
Biomedical Research. 
10.1.3  For participating sites in Asia only: Circulating Tumor DNA (ctDNA) Analysis 
Background: The team at the Chinese University of Hong Kong led by Dennis Lo and 
Allen Chan has pioneered the real-time PCR technique for detecting plasma EBV DNA. 
Lately, they have developed a second-generation and more accurate way of detecting 
plasma EBV DNA (Lam 2018). Furthermore, they have developed a new ctDNA analysis 
technique called ‘Orientation-aware plasma DNA fragmentation analysis’ (Sun 2019) 


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which may inform the tissue of origin of the ctDNA for various types of cancers. The 
group is able to perform whole genome-wide profiling of copy number aberrations and 
point mutations in the plasma of cancer patients using massively parallel sequencing 
(Chan 2013).   
 
Blood sample collection: Collection of blood sample for ctDNA is optional and patients 
who are enrolled into the study must give separate consent. This sample collection is only 
applicable to selected NRG Oncology sites which are interested in participating. The 
clinical significance of the alteration in ctDNA, including point mutations, copy number 
aberrations and the changes in the tissue contribution, has not been evaluated 
prospectively in NPC patients undergoing chemotherapy +/- nivolumab. In this study, we 
plan to collect a single baseline sample of blood from patients who consent for research 
into the alterations in ctDNA. The decision of whether Streck or EDTA tubes will be 
made following discussion between the study team and the participating site. If EDTA 
tubes are used: Twenty (20) mL of EDTA blood (for those sites which can process the 
samples within 6 hours of collection as outlined in section 10.3) will be collected into 
special tubes for ctDNA analysis at baseline.  
 
Detailed instructions for blood sample collection, processing, and shipment are provided 
in section 10.3. 
10.2 
Tissue Selection for Integrated Marker Testing 
10.2.1  Testing requirements and reporting 
• Testing will be performed in a molecular diagnostics service laboratory at the Department 
of Anatomical and Cellular Pathology, Prince of Wales Hospital, the Chinese University 
of Hong Kong. This laboratory is accredited by the National Testing Authority of 
Australia (NATA). The performance of the 22C3 (DAKO) assay has been well 
characterized as it is a FDA approved assay. Additionally, the pathologists at the 
department have published a comparison of technical performance of 4 different PD-L1 
assays in over 700 lung cancer specimens from Chinese patients (Chan 2018). For 
Mainland China sites: Samples will be shipped to and analysed at a designated laboratory 
affiliated with the Chinese University of Hong Kong within Mainland China, in batches 
towards the end of the study. 
• PD-L1 assay will be performed towards the end of study enrolment.  
 
10.2.2  Method of testing 
• Immunohistochemistry (IHC) using the FDA-approved Dako PD-L1 IHC 22C3 pharmDx 
platform (Agilent, Santa Clara, USA) will be used to analyse PD-L1 expression in 
formalin fixed paraffin embedded (FFPE) tissues.  
• IHC will be performed as previously described (Ma 2018). In brief, all specimens will be 
fixed in 10% buffered formalin and sectioned at a thickness of 4 µm. Paraffin-embedded 
sections will be deparaffinized by dissolving the paraffin in xylene and then rehydration 
with a gradient of ethanol and water. The EnVision Detection Systems Peroxidases/DAB 
(DAKO) will be used according to manufacturer’s instructions. Two experienced 
pathologists who are blinded to the patient’s clinical information will score the PD-L1 
IHC independently using the CPS and TPS according to the DAKO’s manufacturer’s 


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manual.  
• Specimen requirements (tissue/tumor requirements): Corresponding FFPE Block must be 
from the same block as the H&E slide that is being submitted. 
• Invalid test results:  When testing cannot be performed within the validated parameters of 
a test, the result is an “invalid” result. An “invalid” result will be reported when 
inadequate tumor amount, poor quality of the sections, and wrong tumor type/specimen 
were found. Firstly, a new specimen will be requested for the test.  
 
10.2.3 Location of testing 
Molecular Diagnostic Laboratory, Department of Anatomical & Cellular Pathology, The 
Chinese University of Hong Kong; Location: 5/F, Sir YK Pao Centre for Cancer, Prince 
of Wales Hospital, Shatin, N.T., Hong Kong SAR, China; Contact person: Kwok Wai Lo, 
Email: kwlo@cuhk.edu.hk, Tel: 852-35052178 or Chit Chow, Email: chit@cuhk.edu.hk, 
Tel: 853-35051141. 
 
10.2.4 Tissue Submission for testing   
See Biospecimen Submission tables in section 10.3 below. 
 
10.3 
Biospecimen Submission Tables (16-FEB-2021) 
10.3.1  Optional Specimen Submissions  
See detailed specimen collection/processing/shipping instructions on the protocol-
specific website. 
 
Specimen Collection for Biobanking for Potential Future Research (US and Canada Sites) 
(to be offered to all patients) 
 
Forms: ST Form 
 
Kits: Frozen Specimen 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 all frozen 
biospecimens only. Batch shipments can be made once sites have collected the post treatment 
samples or with other cases. Shipping Days: Frozen specimens should be shipped on dry ice by 
priority overnight Monday-Wednesday for US Sites, or Monday-Tuesday for Canadian sites.  
  
Processing: Instructions for processing and shipping are included with the protocol pathology and 
correlatives documents included on the CTSU website, www.ctsu.org.  
 
Ship all specimens to:  
Attn: 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:  


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Email: NRGBB@ucsf.edu 
415-476-7864/Fax 415-476-5271 
 
Specimen Type  
Collection Time Points 
 
Collection Information and 
Requirements/Instructions for 
Site 
Shipping 
 
H&E slide(s) of 
primary or 
recurrent/metastatic 
tumor  
 
Baseline pre-treatment 
 
H&E slide can be duplicate 
cut H&E slide, does not have 
to be diagnostic slide. H&E 
must come from same block 
being submitted. 
 
Note: Unstained slides are not 
allowed. 
Ship ambient to 
NRG BB-SF  
 
 
 
FFPE block of 
primary tumor or 
recurrent/ 
metastatic (same as 
H&E) 
 
Baseline pre-treatment 
Corresponding FFPE block 
(paraffin-embedded) from the 
same block as the H&E slide 
that is being submitted. 
 
Sites unable to submit blocks 
should instead submit one to 
two 3 mm punches from the 
block. 
Ship ambient to 
NRG BB-SF (use 
cold packs during 
warm weather) 
 
 
Plasma for EBV 
DNA analysis  
 
• Baseline pre-
treatment (within 7 
days prior to 
chemotherapy) 
• Cycle 1: day 8 +/-
3 days 
• Cycle 1: day 15 
+/-3 days 
• Cycle 2: day 1 +/- 
3 days 
• Cycle 2: day 8 +/- 
3 days 
 
 
 
The following method is 
preferred. Sites with any 
queries should check with 
study team first:  
 
5 mL of EDTA blood would 
be collected for each time 
point. Blood samples would 
need to be processed within 6 
hours after the sample 
collection.  
 
The whole blood sample is 
centrifuged at 3,000 g for 10 
minutes. The supernatant 
would be harvested carefully 
without disturbing the blood 
cells into 2 mL Eppendorf 
tubes.  
 
The harvested supernatant 
would be re-centrifuged at 
30,000 g for 10 minutes at 4oC 
The harvested 
plasma samples 
can be batch 
shipped to the 
NRG BB-SF on 
dry ice.  


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to remove all remaining cells. 
NOTE: For sites unable to 
spin in Eppendorf tubes at 
30,000 g, they can spin a 
second time at 16,000 g in one 
15 mL tube instead. The 
spinning can also be carried 
out without refrigeration if the 
room temperature is below 
25⁰C. 
 
The plasma is harvested into 
one to two 2.5 mL cryovials 
and stored frozen at -80oC.  
 
 
 
Whole Blood: One 
5-10 mL EDTA 
tube 
 
Baseline pre-treatment 
 
Note: If site missed 
this collection, they 
may collect at any 
other time but must 
note this on the ST 
form when submitting 
Collect blood, mix and aliquot 
1-1.5 mL of whole blood per 
vial into three 2 mL cryovials.   
 
Place into biohazard bag and 
immediately freeze tubes 
upright at -70 to -90ºC. 
 
Samples should be frozen and 
stored at -80⁰C until ready to 
batch ship.  
Batch ship on Dry 
Ice by overnight 
courier to NRG 
BB-SF. 
 
 
 
 
 
Specimen Collection for Biobanking for Potential Future Research (International: Asia and 
Australian Sites) 
(to be offered to all patients) 
 
Processing: Instructions for processing and shipping are included with the protocol documents 
included on the CTSU website, www.ctsu.org.  
 
Ship all specimens to:  
Prof Kwok Wai Lo or Dr. Chit Chow 
5/F, Sir YK Pao Centre for Cancer,  
Prince of Wales Hospital, 
Shatin, N.T.,  
Hong Kong SAR, China  
 
For questions, please contact Kwok Wai Lo at:  
Email: kwlo@cuhk.edu.hk  


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Tel: 852-35052178 
 
For Mainland China sites: Samples will be shipped to a designated laboratory affiliated with the 
Chinese University of Hong Kong in batches towards the end of the study.  
 
For Plasma EBV DNA and ctDNA:  
To Prof. Allen K.C. Chan 
Rm 401, 4/F, Li Ka Shing Medical Sciences Building, Prince of Wales Hospital, Shatin, N.T. Hong 
Kong SAR. 
Email: allen@cuhk.edu.hk or brigette@clo.cuhk.edu.hk 
 
Specimen Type  
Collection Time Points 
 
Collection Information and 
Requirements/Instructions for 
Site 
Shipping 
 
H&E slide(s) of 
primary or 
recurrent/ 
metastatic tumor  
 
Baseline pre-treatment 
 
H&E slide can be duplicate 
cut H&E slide, does not have 
to be diagnostic slide. H&E 
must come from same block 
being submitted. 
Ship ambient to 
Kwok Wai Lo / Chit 
Chow, Hong Kong  
 
 
FFPE block of 
primary or 
recurrent/ 
metastatic tumor 
(same as H&E) 
 
Baseline pre-treatment 
Corresponding FFPE block 
(paraffin-embedded) from the 
same block as the H&E slide 
that is being submitted.  
 
Sites unable to submit blocks 
should instead submit one to 
two 3 mm punches from the 
block. 
 
Ship ambient to 
Kwok Wai Lo / Chit 
Chow, Hong Kong 
 
 
Plasma for EBV 
DNA analysis 
• Baseline pre-
treatment (within 7 
days prior to 
chemotherapy) 
• Cycle 1: day 8 +/- 
3 days 
• Cycle 1: day 15 +/-
3 days 
• Cycle 2: day 1 +/- 
3 days 
• Cycle 2: day 8 +/- 
3 days 
 
 
 
The following method is 
preferred. Sites with any 
queries should check with 
study team first:  
 
5 mL of EDTA blood would 
be collected for each time 
point.  
 
Blood samples would need to 
be processed within 6 hours 
after the sample collection.  
 
The whole blood sample is 
centrifuged at 3,000 g for 10 
minutes. The supernatant 
would be harvested carefully 
without disturbing the blood 
The harvested 
plasma samples will 
be sent to Prof Allen 
Chan’s laboratory 
responsible for the 
plasma EBV DNA 
analysis in dry ice.  
 
The samples will be 
sent in batches. 


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cells into 2 mL Eppendorf 
tubes.  
 
The harvested supernatant 
would be re-centrifuged at 
30,000 g for 10 minutes at 
4oC to remove all remaining 
cells. NOTE: For sites unable 
to spin in Eppendorf tubes at 
30,000 g, they can spin a 
second time at 16,000 g in 
one 15 mL tube instead. The 
spinning can also be carried 
out without refrigeration if the 
room temperature is below 
25⁰C.  
 
The plasma is harvested into 
one to two 2.5 mL cryovials 
and stored frozen at -80oC.  
 
 
 
Plasma for 
ctDNA analysis 
(for 
participating 
sites in Asia 
only) 
Baseline pre-treatment  The site will need to discuss 
with the study team regarding 
whether to use EDTA or 
Streck tubes.  
 
If EDTA tubes are used:  
20 mL of EDTA blood would 
be collected for each time 
point.  
 
Blood samples would need to 
be processed within 6 hours 
after the sample collection.  
 
The whole blood sample is 
centrifuged at 3,000 g for 10 
minutes. The supernatant 
would be harvested carefully 
without disturbing the blood 
cells into 2 mL Eppendorf 
tubes.*  
 
The harvested supernatant 
Plasma samples will 
be sent in dry ice to 
Prof Allen Chan’s 
laboratory for the 
plasma  ctDNA 
analysis. 
 
Whole Blood 
samples in Streck 
tubes need to kept at 
room temperature 
and shipped to Prof 
Allen Chan’s 
laboratory within 7 
days. 
 
The samples will be 
sent in batches. 


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would be recentrifuged at 
30,000 g for 10 minutes at 
4oC to remove all remaining 
cells. NOTE: For sites unable 
to spin in Eppendorf tubes at 
30,000 g, they can spin a 
second time at 16,000 g in 
one 15 mL tube instead. The 
spinning can also be carried 
out without refrigeration if the 
room temperature is below 
25⁰C.  
 
The plasma would be 
harvested into five 2 mL 
cyrovials and stored frozen at 
-80oC. 
 
*For sites that cannot perform 
the above method of sample 
processing, Streck tubes can 
be used for sample collection.  
Whole Blood: 
One 5-10 mL 
EDTA tube 
 
Baseline pre-treatment 
 
Note: If site missed this 
collection, they may 
collect at any other 
time but must note this 
on the ST form when 
submitting 
Collect blood, mix and aliquot 
1-1.5 mL of whole blood per 
vial into three 2 mL cryovials.   
 
Place into biohazard bag and 
immediately freeze tubes 
upright at -70 to -90ºC. 
 
Samples should be frozen and 
stored at -80⁰C until ready to 
batch ship.  
 
 
11. SPECIAL STUDIES (NON-TISSUE) 
All participating centers will be required to participate in the patient-reported outcome and 
quality of life assessments. 
 
11.1   Description of QOL/PRO Instruments 
EORTC QLQ-C30  
The EORTC QLQ-C30 Version 3.0 is a well-established, 30-item self-reporting questionnaire 
developed to assess overall QOL of patients with cancer. The EORTC QLQ-C30 is grouped into 
five functional subscales (role, physical, cognitive, emotional and social functioning), three 
multi-item symptom scales (fatigue, pain, and nausea and vomiting), individual questions 
concerning common symptoms in cancer patients, and two questions assessing overall QOL. The 
subscales and symptom measures range in score from 0 to 100; a high scale score represents 


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better functioning or higher symptom burden (symptom scales will be reversed to facilitate 
presentation). The EORTC QLQ-C30 has been used in clinical trials using nivolumab for 
patients with recurrent/metastatic HNSC (Ferris 2016, Harrington 2017) and using the EORTC 
QLQ-C30 in this trial will provide a reliable comparison among trials. The time for 
administration is about 7-10 minutes. Clinical meaningful changes in the EORTC QLQ-C30 will 
be defined as a 10-point difference (Osoba 1998). 
 
NRG Oncology has obtained permission to use the EORTC QLQ-C30 for this study in English,  
Spanish, French (Canada), Chinese (Mandarin), and Korean. 
 
MFI-20 
Fatigue will be measured by using the Multidimensional Fatigue Inventory (MFI)-20. MFI is a 
20-item self-report instrument with five dimensions: general fatigue, physical fatigue, mental 
fatigue, reduced motivation, and reduced activity (Smets 1995). Each dimension includes four 
items on a 1- to 5-point scale. The total score is the sum of the 20 items or the sum of the 5 
dimensions, and ranged from 20 to 100 with a higher score representing more fatigue. The MFI-
20 has well-established validity and reliability (α=0.84) in use with patients with cancer and is 
available in English, Spanish, French (Canada), Chinese (Hong Kong), traditional Chinese 
(Chuang 2018, Chung 2014), and Korean (Yoon 2020). The MFI-20 can be completed in 5-10 
minutes. A total score of ≥ 43.5 indicates moderate-to-severe fatigue, and a total score of ≥ 52.5 
suggests severe fatigue (Andic 2019). 
 
11.2 Administration of Patient-Completed Questionnaires 
11.2.1   Time Points for Administration:  
All questionnaires will be completed as specified in the Study Assessment Calendars in section 
4.0. 
 
11.2.2     Administration Instructions 
Questionnaires are to be administered per section 4.0.  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-HN007 study therapy or who experience disease progression 
should continue participating in the PRO study.  If a patient does not come in to clinic, the 
questionnaires will either be mailed to the patient or the research assistant will call the patient to 
complete the forms.  If the patient does not return the forms within two weeks the patient will be 
called and either another set will be sent or the patient will complete the questionnaires over the 
phone with the research assistant. 
  
If a patient declines to complete a scheduled PRO forms or if the questionnaire is not completed 
for any other reason (and cannot be completed by phone or mail), the QOL coversheet must be 
completed in Rave.  For patients who agree to use ePRO for PRO collection please refer to 
Appendix II. 


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Patients who speak and understand English or Spanish will have the option to complete the 
PROs using ePRO (see Appendix II for more details). 
 
12. MODALITY REVIEWS 
12.1 Medical Oncology Modality Quality Assurance Reviews 
The Medical Oncology Co-Chair or NRG Oncology Headquarters approved designee(s) will 
perform a Chemotherapy Assurance Review of all patients who receive or are to receive 
chemotherapy in this trial.  The goal of the review is to evaluate protocol compliance.  The review 
process is contingent on timely submission of chemotherapy treatment data. The scoring 
mechanism is: 1) Per Protocol, 2) Variation Acceptable, 3) Deviation Unacceptable, and 4) 
Not Evaluable.   
 
The Medical Oncology Co-Chair or designee will perform a Quality Assurance Review after NRG 
Headquarters has received complete data for each case enrolled. The reviews will be ongoing.  
 
13. DATA AND RECORDS 
13.1 Data Management/Collection 
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: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
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 e-mail 
from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff will not be able 
to access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 


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in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in 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 (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 e-mail at ctsucontact@westat.com.   
 
13.2 
Summary of Data Submission 
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 
Sections 7.5 and 7.6 for information about expedited and routine reporting.   
 
Summary of All Data Submission: Refer to the CTSU website. 
 
13.3 
Data Quality Portal  
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, 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, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on the 
DQP. A protocol must have the Calendar functionality implemented in Rave by the Lead 
Protocol Organization for delinquent form details and reports to be available on the DQP. Site 
staff should contact the LPO Data Manager for their protocol regarding questions about Rave 
Calendaring functionality.   


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13.4 
Rave-CTEP-AERS integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) Integration enables evaluation of post-baseline 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.    
 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period and used to collect 
AEs that start during the period or persist from the previous reporting period. The CRA 
will enter AEs that occur prior to the start of treatment on a baseline form that is not 
included in the Rave-CTEP-AERS integration. AEs that occur prior to enrollment must 
begin and end on the baseline Adverse Events form and should not be included on the 
standard Adverse Events form that is available at treatment unless there has been an 
increase in grade. 
 
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 
• 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. 
 
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 
website: 
• Study specific documents: Protocols > Documents> Education and Promotion; 
and   
• Expedited Safety Reporting Rules Evaluation user guide: 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 


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available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf. 
 
13.5 
Global Reporting/Monitoring 
Data for this study will be submitted via the Data Mapping Utility (DMU).  Cumulative protocol- 
and patient-specific data will be submitted weekly to CTEP electronically via the DMU.  DMU 
Light reporting consists of Patient Demographics, On/Off Treatment Status, Abbreviated 
Treatment and Course information, and Adverse Events as applicable.  Instructions for setting up 
and submitting data via DMU are available on the CTEP Website:  
(https://ctep.cancer.gov/protocolDevelopment/dmu.htm).   
Note:  All adverse events (both routine and serious) that meet the protocol mandatory reporting 
requirements must be reported via DMU in addition to expedited reporting of serious adverse 
events via CTEP-AERS.   
 
14. STATISTICAL CONSIDERATIONS 
14.1 
Study Design 
This is a prospective randomized phase III trial comparing the platinum-gemcitabine-nivolumab 
combination to platinum-gemcitabine in the first-line treatment of recurrent and/or metastatic 
NPC. Patients will be stratified by: 
• Disease: locoregional only vs. lung metastases vs. other distant metastases; 
• Zubrod/ECOG performance status: 0 vs. 1;  
• Prior platinum-gemcitabine neoadjuvant (induction) therapy and/or adjuvant 
chemotherapy for primary non-metastatic/recurrent NPC more than 6 months prior to 
registration: yes vs. no. 
 
After being stratified, patients will be randomized to both arms using a 1:1 ratio.  
 
14.2 
Study Endpoints 
14.2.1 Primary Endpoint 
• Overall survival (OS) (failure – death due to any cause).  
 
14.2.2 Secondary Endpoints  
• Locoregional failure and distant metastases. 
• Progression-free survival (PFS) (failure – progression or death due to any cause). 
• Tumor response according to RECIST 1.1. 
• Toxicity based on CTCAE v5.0.  
• Patient-reported symptomatic toxicities measured by PRO-CTCAE. 
• QOL as measured by EORTC QLQ-C30. 
• Fatigue, as measured by MFI.  
• PFS based on PD-L1 CPS/TPS cut-off. 
 
14.2.3 Exploratory Endpoints  
• OS based on PD-L1 CPS/TPS cut-off. 


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• Changes in QOL as measured by EORTC QLQ-C30, and in fatigue as measured by 
MFI-20, between and within arms over time. 
• Translational research studies. 
 
14.3 
Primary Objectives Study Design 
14.3.1 Primary Hypothesis and Endpoints 
This study hypothesizes that the platinum-gemcitabine-nivolumab combination would result in a 
better OS than platinum-gemcitabine in the first-line treatment of recurrent and/or metastatic 
NPC. 
 
14.3.2 How Primary Endpoints Will Be Analyzed 
Overall survival rates for both treatment arms will be estimated using the Kaplan-Meier method 
(Kaplan 1958). The comparison of OS distributions between treatment arms will be done using a 
logrank test (Mantel 1966). More details on the primary endpoint analysis are given in Section 
14.6.2. Multivariate analysis will be also performed using the Cox proportional hazards model 
evaluating the stratification factors listed in Section 14.1, country (Asian sites vs. Non-Asian 
sites), keratinizing squamous carcinoma, prior definitive RT for NPC, gender, age, and PD-L1 
status (CPS). Variable selection based on BIC and AIC will be performed to determine relevant 
covariates in the multivariate models. Hazard ratios and their respective 95% confidence 
intervals will be provided.  
 
14.3.3 Sample Size and Power Calculations:  
To date, the 1-yr OS rate of cisplatin-gemcitabine has only been formally reported in a phase II 
study to be 62% [16]. In the phase III study by Zhang et al, the 1-yr OS rate can only be 
estimated to be 70-80% from the OS curve (Zhang 2016). Therefore, it is reasonable to assume 
that the 1-yr OS is around 71-75% for this clinical setting. In the KEYNOTE-048 study, HR for 
OS is 0.77 (95% CI: 0.63-0.93; p=0.0034) for unselected patients for pembrolizumab-
chemotherapy relative to the EXTREME regimen, whereas the HR for OS is 0.61 (95% CI: 0.45-
0.83) for patients with PD-L1 CPS score ≥ 20%. Thus, a HR for OS should be somewhere 
between 0.61-0.93 for patients unselected for PD-L1 expression in NPC. In the KEYNOTE-048 
study, patients in the control arm received cetuximab maintenance, but there is no level 1 
evidence on maintenance therapy in NPC. Most centers would give 6 to 8 cycles of 1st line 
chemotherapy followed by observation. The KEYNOTE-189 study met the primary endpoints 
with a 19.8% difference in the 1-yr OS favoring the chemo-PD-1 inhibitor arm (HR=0.49). In the 
study of camrelizumab (Fang 2014), the 1-yr PFS of 61% appears to be more than double of the 
rate reported with cisplatin-gemcitabine by the same group in China (27%). Thus, we speculated 
that the magnitude of benefit of adding nivolumab to chemo should be larger than previously 
estimated.   
   
After being stratified (see Section 14.1), patients will be randomized in a 1:1 ratio to receive 
either platinum-gemcitabine with nivolumab (experimental arm) or without nivolumab (control 
arm). The primary endpoint is OS defined as the time from randomization to death due to any 
cause. It is hypothesized that OS will be superior for patients on platinum-gemcitabine with 
nivolumab (followed by maintenance with nivolumab alone) as compared to patients on the 
platinum-gemcitabine without nivolumab arm. The hypothesized effect size is a HR of 0.67 in 
favor of the nivolumab arm, corresponding to an increase in 1-year OS from 75% to 82.5% under 


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the exponential distribution assumption (i.e. an increase in the median survival time from 28.9 
months to 43.2 months). With a 1-sided type I error rate of 0.025, 80% power, and two interim 
analyses, the log-rank test requires 200 OS events from 300 randomized patients. After an 
adjustment of 5% due to loss to follow-up, the target accrual is 316 randomized patients.  
 
14.4    Study Monitoring of Primary Objectives 
Interim Analysis for the DMC 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a year with 
respect to patient accrual and morbidity. The DMC also will review the study on an “as needed” 
basis in between regularly scheduled meetings.  
 
Interim Analysis to Monitor Study Progress 
Interim reports with statistical analyses 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 pretreatment and prognostic baseline 
variables, and the frequencies and severity of adverse events by treatment arm. The interim 
reports will not contain the results from the treatment comparisons with respect to the primary 
endpoint, OS, or any secondary endpoints, with the exception of reporting of adverse events. 
 
Significance Testing for Early Termination and/or Reporting 
Two interim efficacy analyses based on the O’Brien-Fleming boundary will be performed when 
50% and 75% (100 and 150) of the OS events have occurred. These are projected to occur 
approximately 54 and 69 months from study activation, respectively. The nominal significance 
levels and the corresponding HRs for rejecting the H0 at the interim analyses are shown in the 
table below. If a boundary is crossed, then recommendations will be made to the NRG Oncology 
Data Monitoring Committee (DMC) relative to stopping accrual (if applicable) and/or reporting 
the study results early, otherwise, accrual to the trial and/or follow-up (as applicable) will 
continue until the final analysis. There will be two interim futility analyses at the same time 
points. The statistical monitoring boundaries for futility are based on the LIB20 method at the 
same times as the efficacy analyses (Haybittle 1971, Freidlin 2010). The last column in Table 1 
provides the decision rule for the interim futility analysis. 
 
Table 1. Nominal significance level and HR for interim analyses 
 
 
Efficacy Boundary 
Futility boundary 
(LIB20) 
Interim 
Analysis 
Number of 
Events  
(% Information) 
Reject H0 
if p ≤ 
Reject H0 if 
HR(Exp./Control) 
≤ 
Reject H1 if 
HR(Exp./Control)  ≥ 
#1 
100 (50%) 
0.0015 
0.55 
1.00 
#2 
150 (75%) 
0.0092 
0.68 
0.96 
 
In addition to the routine reporting of accrual, distributions of pretreatment characteristics, and 
frequency/severity of adverse events, the interim efficacy/futility results will be reported to the 
NRG DMC, following the required number of events for the planned interim analyses. 
 


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Analysis for Reporting the Initial Treatment Results  
The primary hypothesis of the study is to determine if adding nivolumab to platinum-
gemcitabine as first-line treatment improves OS for patients with recurrent and/or metastatic 
NPC. The primary analysis will happen when 200 OS events (deaths) have been observed, which 
is projected to require 33 months of follow-up after accrual closure (approx. 92 months from 
study activation). The primary analysis will be done in the intent-to-treat (ITT) population. 
 
The analysis report will include: tabulation of all cases entered and those excluded from the 
analyses with the reasons for exclusion given, distributions of important prognostic baseline 
variables, the frequencies and severity of adverse events by treatment arm, compliance rate of 
treatment delivery, observed results with respect to the primary and secondary endpoints. The 
primary hypothesis of improved OS, assuming the two interim analyses have been carried out, 
will be tested with a 1-sided significance level of 0.022.    
 
 
14.5 
Accrual/Study Duration Considerations 
The expected accrual rate is 6 patients/month, thus around 59 months (4.9 years) are expected for 
the total accrual including a 6-month period of minimal accrual after study activation. The 
follow-up period will take approximately 33 months (2.75 years) after accrual closure to reach 
the required events for primary endpoint analysis. Total study duration is 92 months (~7.7 years) 
from activation.  
 
14.6 
Alternative Design if Accrual is Higher than Projected 
The study team will monitor accrual of this trial to determine the feasibility of increasing the 
sample size based on a slightly higher hazard ratio than the hypothesized value (HR=0.67) used 
in the original design in Sections 14.3-14.5. This increase in HR, or equivalently, a decrease in 
the treatment effect size, is motivated by the possible dilution of the treatment effect given that 
no immune-selection based on PD-L1 expression has been implemented in this trial. The study 
team will examine the monthly accrual rate for quarters 5-6. If the observed accrual rate for 
quarters 5-6 is at least 7 patients/month then a biomarker-guided design will be proposed to 
allow for parallel testing of the treatment effect in the overall population and a biomarker-
defined subgroup. This redesign will imply a change in the PD-L1 expression from an integrated 
to an integral biomarker since the PD-L1 expression will be involved in the primary efficacy 
analysis. If warranted, the protocol amendment process to increase the sample size will be 
initiated once the accrual for quarters 5-6 is available and the protocol amendment will be 
submitted to NCI/CTEP by the end of quarter 8 accrual. 
 
14.6.1 Fully Specified Biomarker-Guided Design 
This section presents the alternative design for this trial if the actual accrual rate for quarters 5-6 
supports changing the accrual parameter to 7 patients/month. Under this scenario and using the 
PD-L1 CPS cutpoint parameter of 20, the protocol will be amended to adopt the design shown in 
this section instead of the current design shown in Sections 14.3-14.5. This alternative design 
will use a parallel testing after allocating a one-sided alpha level of 0.015 for the primary 
efficacy testing in the overall population and 0.010 for the biomarker-defined subgroup analysis, 
as explained later (overall one-sided alpha level of 0.025). This design recognizes the possibility 
of a treatment effect on OS in the overall population while allowing for the testing of the 


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treatment effect on OS in a biomarker-defined subgroup that is likely to show a more profound 
treatment benefit. 
 
Overall population analysis: The hypothesized effect size for the overall population is a HR of 
0.70 in favor of the nivolumab arm, corresponding to an increase in 1-year OS from 75% to 
81.8% under the exponential distribution assumption (i.e. an increase in the median survival time 
from 28.9 months to 41.3 months). Note that the target HR is along the observed HR for the 
pembroluzimab+chemotherapy vs. EXTREME regimen in the overall population in the 
KEYNOTE-048 trial (HR=0.72, 95% IC [0.60, 0.87]) (Burtness et al 2019). With a 1-sided type 
I error rate of 0.015, 80% power, and two interim analyses at 50% of 75% of information, the 
log-rank test requires 290 OS events from 430 randomized patients. After an adjustment of 5% 
due to loss to follow-up, the target accrual is 452 randomized patients. The boundaries for 
rejecting the H0 (efficacy) and H1 (futility) at the interim analyses are shown in the table below. 
The first interim analysis is projected to occur around 60 months into accrual (~80% of accrual 
target), and the second interim look around 76 months from trial activation. 
Nominal significance level and HR for interim analyses 
 
 
Efficacy Boundary 
Futility boundary 
(LIB20) 
Interim 
Analysis 
Number of 
Events  
(% Information) 
Reject H0 
if p ≤ 
Reject H0 if 
HR(Exp./Control) 
≤ 
Reject H1 if 
HR(Exp./Control)  ≥ 
#1 
145 (50%) 
0.0006 
0.58 
0.99 
#2 
218 (75%) 
0.0048 
0.70 
0.96 
 
The primary efficacy analysis for the overall population will be performed when 290 OS events 
(deaths) have been observed, which is projected to occur around 99 months from study 
activation. This analysis will be done in the intent-to-treat (ITT) population. The primary 
hypothesis of improved OS, assuming the two interim analyses have been carried out, will be 
tested with a 1-sided significance level of 0.0134.    
 
Biomarker-defined subgroup analysis: Under this alternative design, a one-sided alpha level of 
0.010 is allocated for the biomarker-subgroup analysis based on OS for patients with CPS ≥ 20, 
which is assumed to be 40% of patients (Burtness et al. 2018). This assumption translates into a 
monthly accrual rate of 2.8 patients for this cohort. The hypothesized effect size for this 
biomarker subgroup is a HR of 0.55 in favor of the nivolumab arm, a reasonable figure according 
to the results from the KEYNOTE-048 trial for chemotherapy plus pembroluzimab vs. the 
EXTREME regimen in recurrent and metastatic HNSCC patients: HR=0.60 (95% CI [0.45, 
0.82]). With a 1-sided type I error rate of 0.010, 80% power, the log-rank test requires 113 OS 
events from 182 randomized patients with CPS ≥ 20. 
 
 
Overall 
Population 
Biomarker-defined subgroup  
CPS ≥ 20* 
Monthly accrual rate 
7 
2.8 
One-sided alpha level 
0.015 
0.010 
Power 
80% 
80% 


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Targeted HR 
(exp./control) 
0.70 
0.55 
# of randomized patients 
452 
182 
# OS events 
290 
113 
*About 40% NPC patients with CPS ≥ 20, according to KEYNOTE-048. 
Under this alternative design, an optimal cut-off point finding algorithm based on OS and the 
Procedure A in Jiang et al (2007) will be also added as an exploratory objective/endpoint. Note 
that this exploratory objective is still reasonable given the current evidence on the role of PD-L1 
expression in NPC. All these details will be added to the amended protocol if this design is 
adopted given the accrual rule specified in this section.  
 
Accrual and Study Duration Considerations for the Biomarker-Guided Design 
The expected accrual rate for this alternative design is 7 patients/month, thus around 70 months 
(~5.8 years) are expected for the total accrual including a 6-month period of minimal accrual 
after study activation. The follow-up period will take approximately 29 months (~2.4 years) after 
accrual closure to reach the required events for primary endpoint analysis. Total study duration is 
99 months (~8.2 years) from activation. The time required to enroll the patients in the biomarker-
defined subgroup and to reach the number of OS events for the primary efficacy analysis in this 
cohort is about the same as for the overall population, as shown in the table below. Adjustments 
to the operating characteristics of this trial could be performed as the result of the actual accrual 
rate for quarters 5-6.  
 
 
Overall 
Population 
Biomarker-defined subgroup  
CPS ≥ 20* 
Monthly accrual rate 
7 
2.8 
Accrual duration 
70 mo. (~5.8 yrs) 
70 mo. (~5.8 yrs) 
Study duration 
99 mo. (~8.2 yrs) 
103 mo. (~8.6 yrs) 
*About 40% NPC patients with CPS ≥ 20, according to KEYNOTE-048. 
 
14.6.2 Further design considerations 
Currently, the PD-L1 (CPS) has been not validated in NPC, unlike recurrent and metastatic 
HNSCC (KEYNOTE-048). The Mainland China study with chemotherapy and chemotherapy 
plus camrelizumab in the first-line of R/M NPC (NCT03707509), and also the KEYNOTE-122 
(NCT02611960), a study with platinum pre-treated R/M NPC, may provide further evidence on 
the utility of PD-L1 CPS in R/M NPC. Therefore, the proposed alternative design in Section 
14.6.1 could be modified after considering the new data evidence on PD-L1 expression from the 
aforementioned trials. If the actual monthly accrual rate for quarters 5-6 is at least 7 and 
discussions are needed about modifications to any of the design parameters in the alternative 
design shown in Section 14.6.1, then the design modification process will be carried out by an 
independent statistician who has no knowledge of the study outcome and biomarker data. The 
decision about any modifications to the alternative design will be made by the study chairs and 
the independent statistician, without any knowledge of outcome data from NRG-HN007. 
 
14.7 
Secondary/Exploratory Hypothesis and Endpoints (including correlative science 
aims) 
14.7.1 Secondary Hypotheses and Endpoints 
• Locoregional failure (LRF) 


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Hypothesis: The platinum-gemcitabine-nivolumab combination would result in lower 
LRF rates. 
• Distant metastasis (DM) 
Hypothesis: The platinum-gemcitabine-nivolumab combination would result in lower 
DM rates. 
• Progression-free survival (PFS)  
Hypothesis: The platinum-gemcitabine-nivolumab combination would result in 
superior PFS. 
• Tumor response according to RECIST 1.1 
Hypothesis: The platinum-gemcitabine-nivolumab combination would result in better 
objective response rate (RECIST 1.1). 
• Toxicity based on CTCAE v5.0  
Hypothesis: The platinum-gemcitabine-nivolumab combination would have a similar 
toxicity profile as the platinum-gemcitabine arm. 
 
14.7.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Except for within PRO endpoints, no multiplicity adjustments will be done for other secondary 
endpoints. 
 
Time-to-Event Endpoints 
The distribution of the progression-free survival (PFS), defined as the time from randomization 
to disease progression or death due to any cause will be estimated using the Kaplan-Meier 
method and between-arm differences compared using the log-rank test (Kaplan 1958).   
 
All other secondary time to event endpoints have precluding events that act as competing risks. 
Failure events and competing risks for local-regional and distant metastasis failure endpoints is 
outlined in the table below. 
 
First event 
Local-regional 
failure 
Distant metastasis 
None 
Censored 
Censored 
Local-regional progression or recurrence 
Failure 
Competing risk 
Distant metastasis 
Competing risk 
Failure 
Death due to study cancer or unknown causes 
Failure 
Competing risk 
Death due to any other reason 
Competing risk 
Competing risk 
 
 Time to locoregional failure will be measured from the time of randomization to the date of 
failure, date of precluding event, or last known follow-up date. Time to distant metastasis will 
similarly be measured from the time of randomization to the date of distant metastasis, date of 
precluding event, or last known follow-up date. The cumulative incidence estimator will be 
used to estimate time to event distributions for locoregional failure and distant metastasis with 
between arm differences tested using cause-specific log-rank test.  
 
 For all efficacy endpoints, Cox proportional hazards models will be used to determine hazard 
ratios (cause-specific hazard ratios in the case of endpoints with competing risks)  and to assess 
the effects of covariates of interest mentioned in Section 14.3.2 (Cox 1972). The Fine-Gray 


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subdistribution hazards model may be applied to further explore outcomes by treatment arm and 
other covariates for endpoints with competing risks (Fine and Gray 1999). 
 
 All efficacy endpoints will be reported at the time of the primary endpoint analysis. A two-sided 
significance level of 0.05 will be used to determine significance for these secondary endpoints. 
All the analysis for secondary time-to-event endpoints will be done in the intent-to-treat (ITT) 
population.  
 
Tumor Response 
Tumor response in patients with measurable disease will be assessed according to RECIST 1.1. 
The Objective Response Rate (ORR), defined as the proportion of confirmed complete and 
partial response will be calculated with their respective 95% confidence intervals (CI). An 
estimate of the difference in ORR between the experimental and control arms along with the 
95% CI will be also provided. Between-arm difference in ORR will be assessed using a chi-
square test for proportions based on normal approximation. The confidence intervals will be also 
based on a normal approximation. A two group chi-square test with a 5% one-sided significance 
level will have 89% power to detect the difference between arms of 60% (control arm; Zhang et 
al 2016) and 75% (experimental arm) with 316 randomized patients. 
 
Toxicity 
Adverse events (AEs) will be graded using CTCAE v5.0. Counts of all AEs by grade will be 
provided by treatment arm. Counts and frequencies will be provided for the worst grade AE 
experienced by the patient by treatment arm. The number of patients with at least 1 grade 3 or 
higher AE will be compared between the treatment arms. All comparisons will be tested using a 
chi-Square test, or Fisher’s exact test if cell frequencies are < 5, with a significance level of 0.05. 
Toxicity analyses will be based on an as-treated population, which includes all patients who 
received at least one dose of the assigned trial treatment. 
 
The mean number of grade 3-4 adverse events after adjusting by follow-up time between arms will 
be compared using a negative binomial regression (Tang 2015). The mean toxicity ratio between 
arms and its 95% confidence interval (CI) will be reported. As recommended by Trotti and 
colleagues (Trotti 2007), further toxicity analyses separated by cycles (concurrent and 
maintenance) will be explored. 
 
All toxicity analyses will be conducted at the time of the primary endpoint analysis.  
 
PRO-CTCAE 
Adverse events will also be assessed using PRO-CTCAE items. The specific symptoms to be 
evaluated for this study are listed in the table in Section 7.4.1. Assessments will be collected at 
the same time points as the PROs. For each symptom, counts and frequencies will be provided 
for the worst score experienced by the patient by treatment arm. The proportion of patients with 
scores ≥ 1 and ≥ 3 will be compared between groups using a Chi-square test, or Fisher’s exact 
test if cell frequencies are < 5, using a significance level of 0.05. Analysis of changes in patient 
reported outcomes over time will analyzed by fitting GEE models using a logit link 
(dichotomizing the symptom scores as 0 vs. > 1 and 0-2 vs. 3-4) with time of assessment, 
treatment arm, and treatment-by-time interaction terms in the model. 


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Patient-Reported Outcomes (PROs) 
The EORTC QLQ-C30 and Multidimensional Fatigue Inventory (MFI)-20 are the two PRO tools 
in this trial, collected at time points specified in Section 4.0 - Study Assessment Calendars. A 
description of these tools and background information can be found in Section 11.1. The primary 
PRO endpoint is the global health status (GHS/QOL) from the EORTC QLQ-C30 at the end of 
cycle 6 (end of the chemo doublet or 18 weeks from start of treatment). This subscale comprises 
two items with a score ranging from 0 to 100 with a higher scale score representing better 
functioning. The selection of the GHS from EORTC QLQ-C30 as the primary PRO objective 
will allow an easy comparison with other published immunotherapy trials, because the majority 
have used the global health status from EORTC QLQ-C30 as the primary endpoint (Hall 2019). 
The secondary PRO endpoint is the MFI overall score at the end of cycle 6. The MFI overall 
score is the sum of the 20 items or the sum of the five dimensions, ranging from 20 to 100 with a 
higher score representing more fatigue. Fatigue is a multidimensional symptom including 
physical, emotional, and/or cognitive tiredness. The overall score of MFI is a good measure for 
burden from fatigue in cancer patients and a valid summary score for people with fatiguing 
illnesses (Lin 2009, Hinz 2020).  
 
The following are the PRO objectives and hypotheses in this trial: 
• Primary PRO Objective: To assess quality of life (QOL), as measured by EORTC QLQ-C30, 
between the two arms. 
Primary PRO Hypothesis: The EORTC QLQ-C30 GHS/QOL mean score change from 
baseline to cycle 6 will be non-inferior in the platinum-gemcitabine-nivolumab combination 
arm compared to the control arm. 
• Secondary PRO Objectives: To assess fatigue, as measured by Multidimensional Fatigue 
Inventory (MFI-20), between the two arms. 
Secondary PRO Hypothesis: The MFI overall mean score change from baseline to cycle 6 
will be non-inferior in the platinum-gemcitabine-nivolumab combination arm compared to 
the control arm. 
• Exploratory PRO Objective: To determine changes in patient QOL and fatigue as measured 
by the EORTC QLQ-C30 and the MFI-20, respectively, between and within arms over time 
until the end of the nivolumab maintenance. 
 
Cycle 6 was selected for the primary and secondary PRO objectives based on the following 
reasons: 1) cycle 6 is the end the chemo doublet and beginning of nivolumab maintenance phase, 
which will allow us to capture patients’ acute responses to treatment, platinum-gemcitabine-
nivolumab combination vs. chemo doublet; 2) current literature has suggested that most PRO 
studies in immunotherapy trials have used acute changes in PROs as the endpoints (ranging from 
12-24 weeks from baseline; Hall 2019) and shown similar to favorable findings in PROs for 
immunotherapy arms; and 3) given the potential attrition rate in PRO measures for longitudinal 
follow-ups, using PRO at the end of chemo doublet would reduce potential attrition and improve 
the study power.   
 
An exploratory aim has been added into the study to examine the long-term changes in PROs 
between and within the arms. Since the nivolumab maintenance will continue up to 2 years, it is 
important to study the long-term effect on PROs up to 2 years as well. The assessment at 1 year 


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will allow us to study the effect of nivolumab in the middle of the maintenance phase. 
 
Analysis Plan for PROs 
The EORTC QLQ-C30 subscales (global health status, five functional subscales, and three multi-
item symptom subscales – Fatigue; Nausea and Vomiting; and Pain) and the change score from 
baseline to each time point will be summarized using descriptive statistics (e.g. mean, standard 
deviation, etc.). Similarly, descriptive statistics will be reported for the five subscales (general 
fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity) and overall 
score in the MFI. 
 
To test the primary and secondary PRO hypotheses, an ANCOVA model using the scores at the 
end of cycle 6, baseline scores, the stratification factors, and important prognostic factors in NPC 
(keratinizing squamous carcinoma and prior definitive RT) will be used. No variable selection 
will be performed for the main analyses. The proposed adjusted ANCOVA estimator has shown 
desirable statistical properties even under the presence of missing data (Tsiatis 2008, Wang 
2019). For the primary non-inferiority hypothesis, a 97.5% confidence interval (CI) for the 
treatment effect at the end of cycle 6 will be calculated using the proposed model (one-sided 
alpha of 0.0125). If the lower bound of this CI > -10, the MID for the GHS score, then the 
experimental arm will be declared non-inferior to the control arm in terms of the global health-
related QOL. The non-inferiority margin was based on the MID, which in turn is based on a 
moderate change in a subjective significance questionnaire associated with mean change in 
scores about 10 to 20 points in the  EORTC QLQ-C30 domains (Osoba 1998, Mazieres 2019).  
 
For the secondary PRO hypothesis based on the MFI overall score, a 97.5% CI will be used to 
determine if the MFI overall mean scores at the end of cycle 6 for the experimental arm is non-
inferior to the control arm after adjusting for the baseline scores and additional covariates 
mentioned previously (one-sided alpha of 0.0125). If the upper bound of this CI < 9, the MID for 
the MFI overall score, then the experimental will be declared non-inferior to the control arm in 
terms of fatigue. The MID for the MFI overall score in cancer populations is currently not 
available. According to data from non-cancer patients, the MID for the MFI overall score ranges 
from 7-13 points (Nordin 2016). A range of 5%-10% differences in instrument range has been 
recommended for clinical meaningful changes (Ringash 2007), if no specific MID is proposed 
for patient-reported outcomes. So conservatively speaking, a MID of 9 points is used in this 
study.  
 
The proposed hypothesis testing and alpha levels for the primary and secondary PRO endpoints 
will keep control of the type-1 error at 0.025 (one-sided alpha). 
 
In addition to the primary and secondary PRO analyses, exploratory analyses with each of the 
subscales of the EORTC QLQ-C30 and MFI will be performed. A longitudinal ANCOVA model 
involving all the time points (discrete), the treatment factor and its interaction, and the same 
covariates as before, will be adjusted for each of the subscales in the EORTC QLQ-C30 and MFI 
tools (Liu et al 2009). A reduced model without the treatment by time interaction terms will be 
also adjusted. Using the previous two models, a likelihood ratio test will be done to determine if 
treatment arms differ for a given subscale in at least one time point (alpha level of 0.05). If the 
null hypothesis of no difference at all time points is rejected then 95% CIs for the between arms 


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difference will be reported at every time point. No multiplicity adjustment due to subscales or 
time points or missing data imputation will be performed with these exploratory analyses. These 
analyses aim at describing changes in quality of life or symptoms between and within arms over 
time. The same 10 points will be used as the MID for the EORTC QLQ-C30 domains for 
purposes of these exploratory analyses. For purposes of interpretations of the MFI results in 
these exploratory analyses, the following MIDs will be used: 2.1 for the general fatigue, 2.1 for 
physical fatigue, 2.4 for reduced activity, 1.6 for reduced motivation, and 1.6 for mental fatigue 
(Purcell 2010).  
 
Handling Missing PRO Data 
Prior to performing analyses, an evaluation of the amount, reasons and patterns of missing data 
will be performed, using the well-known categories of missing completely at random (MCAR), 
missing at random (MAR) and missing not at random (MNAR) (Fairclough 1998, 2010; Verbeke 
2000). If > 20% of the data is missing at any time point for the PROs, patient and tumor 
characteristics will be compared between patients with completed assessments and those with 
missing assessments using, for instance, a logistic model and a variable selection model. If any 
are found to differ significantly, they will be included in the analytic models, which assumes that 
the data is MAR. Multiple imputation under the MAR assumption could also be considered 
(Rubin 1987). Given that non-ignorable missing data is a concern in health-related QOL studies, 
other methods to handle MNAR data will be applied. Specifically, a joint model that allows a 
shared parameter between the repeated measurements and time to death or drop out can be used 
if considered MNAR due to the high number of patient deaths or dropouts (Rizopoulos 2012). 
Other options for MNAR data are pattern mixture, selection models and single-step full-
likelihood methods for the outcome and missing data models (Little 1995, Fairclough 2010, 
Gomes 2019). More recent approaches to assess the nonignorability assumption in the MAR 
approaches could be also explored (Yuan 2014, Xie 2018). Sensitivity analyses will be 
performed to compare the results of different missing data handling strategies. 
 
Sample size justification and Power for PROs 
The following assumptions were used to calculate the power for the primary PRO endpoint 
analysis: 
• The compliance rate at the end of cycle 6 for the EORTC QLQ-C30 tool is estimated to be 
around 70% based on PRO compliance data from the randomized phase II/III NRG-
HN001 trial, an international study with non-recurrent/non-metastatic nasopharyngeal 
cancer. 
• The non-inferiority margin for the between arms difference at the end of cycle 6 is based 
on the MID of 10 points for the GHS score (Mazieres 2019). That is, the experimental arm 
is allowed to be, on average, worse than the control arm but the detriment in health-related 
QOL has to be within the MID or non-inferiority margin (i.e. a non-clinically meaningful 
detriment). 
• The common standard deviation (SD) of the GHS scores at the end of cycle 6 is around 
18-22 points. These figures are based on the data from Keynote 141, a randomized phase 
III trial for recurrent and metastatic SCC of the head and neck (Harrington et al 2017).  
• The power calculations are based on a t-test for two independent groups. The proposed 
ANCOVA model is expected to have a higher power since the adjusted estimator is more 
efficient than the one based on the t-test (Wang 2019). 


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• A one-sided alpha level of 0.0125 is used for the non-inferiority test, or equivalently, a 
97.5% CI. 
• Under the null inferiority hypothesis, no difference between arms in terms of the GHS 
scores at the end of cycle 6 is assumed. 
 
Power of the test for the non-inferiority (primary) PRO hypothesis based on 220 evaluable 
patients (70% compliance rate; target accrual is 316 randomized patients) 
SD of GHS scores at the end of 
cycle 6 (EORTC QLQ-C30) 
Cohen’s Effect Size 
Power 
18 
0.56 
97% 
19 
0.53 
95% 
20 
0.50 
93% 
22 
0.45 
87% 
 
 
Based on the power figures in the previous table, the proposed statistical method to test the non-
inferiority hypothesis will have good power to reject the inferiority hypothesis on the global 
health score at the end of cycle 6 on the experimental arm compared to the control arm. This 
power analysis is based on small to moderate Cohen’s effect sizes. 
 
The following assumptions were used to calculate the power for the secondary PRO endpoint 
analysis related to the MFI overall score: 
• The non-inferiority margin is based on the MID for the MFI overall score which is taken 
to be 9 points.  
• The common standard deviation (SD) of the MFI overall scores at the end of cycle 6 is 
assumed to be around 18-21 points (Lin et al. 2009, Hinz 2020).   
• A one-sided alpha level of 0.0125 is used for the non-inferiority test, or equivalently, a 
97.5% CI. 
• Under the null inferiority hypothesis, no difference between arms in terms of the MFI 
overall mean scores at the end of cycle 6 is assumed. 
 
Power of the test for the secondary PRO hypothesis based on 220 evaluable patients  
(70% compliance rate; target accrual is 316 randomized patients) 
SD of MFI overall scores at the 
end of cycle 6 
Cohen’s Effect Size 
Power 
18 
0.50 
93% 
19 
0.47 
89% 
20 
0.45 
86% 
21 
0.43 
82% 
 
Based on the power figures in the previous table, the proposed statistical method to test the 
secondary PRO hypothesis will have good power to reject the inferiority hypothesis on the MFI 
overall mean score at the end of cycle 6 for the experimental arm compared to the control arm. 
This power analysis is based on small to moderate Cohen’s effect sizes. 
 
PFS analysis based on PD-L1 CPS cut-off 


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Hypothesis: A subset of patients based on a cutoff for PD-L1 CPS is more likely to benefit in 
terms of PFS from the platinum-gemcitabine-nivolumab combination. 
 
The finding of an optimal cutoff value for PD-L1 CPS on PFS will be performed according to 
the two-step testing procedure (Procedure A) suggested by Jian et al (2007). This analytical 
proposal assumes that the underlying true Cox model between PFS and PD-L1 CPS is a cut-point 
model, that is, only a subset of patients will benefit from the experimental therapy. The steps 
involved in this algorithm are given next. 
• A biomarker-subset effect will determined using the maximum of the log likelihood ratio 
test for the treatment effect limited to patients with PD-L1 CPS ≥ c, where c is restricted 
to a subinterval on the CPS scale. Existing data suggest that 85% of patients with 
HNSCC have CPS ≥ 1 and about 40% have CPS ≥ 20 in the KEYNOTE-048 trial 
(Burtness 2018).  
• The p-value associated with the previous test statistic will be calculated using a 
permutation test based on permutations of the treatment labels. A two-sided alpha level of 
0.020 will be used for the testing of the treatment effect in the overall population (Step 1) 
and 0.030 for the biomarker-defined subset effect (Step 2). The overall two-sided alpha 
level for this analysis is 0.05.  
• If a treatment effect in a subset of patients is determined by the previous steps then an 
estimate of the optimal cutoff value for PD-L1 CPS will be obtained by maximizing the 
partial log likelihood. 
 
The table below shows the statistical power for the proposed method to find the optimal cutoff 
value based on PFS (i.e. find a biomarker-defined subset effect). Power calculations in the table 
below are based on a simulation study under the following assumptions: survival times were 
generated from a Cox-exponential model using the method proposed by Bender et al. (2005), 
biomarker values are assumed to follow a (0, 1) uniform distribution, PFS at 1 year is 20% 
(Zhang et al. 2016), 300 patients enrolled, and 500 simulations for each scenario with 300 
samples to calculate the permutation distribution of the maximum test statistic. The PFS-based 
analysis is projected to occur when 295 PFS events have been observed. The listed HRs for the 
biomarker subgroup were chosen to illustrate scenarios in which the power to detect an overall 
treatment effect is relatively low at the final analysis. For instance, if the HR=0.53 for 40% of 
patients with high CPS (≥ 0.60 in the [0,1] scale) then the proposed method will have a 
reasonable power (77%) to detect a treatment effect in this biomarker subgroup while the overall 
test will have a lower power (69%). With a two-sided alpha of 0.020, the test for the overall 
treatment effect on PFS will have an 81% power to detect a HR of 0.69 with the number of PFS 
events expected at the final analysis based on the current design.   
 
 
 
Model 
Biomarker 
subgroup HR 
(exp./control) 
Empirical Power 
Procedure A (%)  
Only patients with c ≥ 0.50 benefit from 
experimental therapy (i.e., 50% of patients) 
0.50 
94% 
0.55 
77% 
 
0.60 
74% 
Only patients with c ≥ 0.60 benefit from 
experimental therapy (i.e., 40% of patients) 
0.45 
94% 
0.50 
88% 


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0.53 
77% 
Only patients with c ≥ 0.75 benefit from 
experimental therapy (i.e., 25% of patients) 
0.40 
84% 
*Quantile of PD-L1 CPS. Cutoff values on interval [0.2, 0.9]. 
 
A similar approach will be used to examine the role of PD-L1 TPS on PFS.  
 
14.7.3 Exploratory Hypotheses and Endpoints 
 
OS analysis based on PD-L1 CPS cut-off 
The recent KEYNOTE-048 study on the first-line therapy for recurrent or metastatic head and 
neck squamous cell carcinoma (HNSCC) concluded that pembrolizumab/chemotherapy had 
superior overall survival in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total populations, with 
comparable safety, compared to cetuximab/chemotherapy (Burtness 2018). Although this is 
already being established in HNSCC, the role of PD-L1 in recurrent and metastatic NPC is not 
well understood. Therefore, an exploratory objective in this trial is to determine whether a subset 
of patients will more likely to benefit in terms of OS from the experimental arm.    
 
Hypothesis: A subset of patients based on a cutoff for PD-L1 CPS is more likely to benefit in 
terms of OS from the platinum-gemcitabine-nivolumab combination. 
 
If the statistical test for the overall population based on OS, discussed in Section 14.3.2, is not 
significant then an algorithm to find an optimal cutoff value for PD-L1 will be executed based on 
the second step of the biomarker-adaptive threshold design (see details in Section 14.7 and 
Procedure A in Jiang et al 2007). A two-sided alpha level of 0.05 will be used for this 
exploratory analysis. A similar approach will be used to examine the role of PD-L1 TPS on OS.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.8 
Gender/Ethnicity/Race Distribution 
The expected racial/ethnicity/gender distribution for this trial is based on data from a phase II 
trial of nivolumab for treating patients with recurrent and/or metastatic NPC cancer 
(NCT02339558) and the data from the ongoing NRG-HN001 study, a phase II/III trial of 
individualized treatment based on EBV DNA for non-recurrent/metastatic NPC patients 
(NCT02135042). It is assumed a 50%-50% distribution for domestic and international 
enrollment, respectively.   
 
 
 
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 
26 
64 
0 
0 
90 
Native Hawaiian or Other 
Pacific Islander 
3 
3 
1 
0 
7 
Black or African American 
5 
7 
0 
0 
12 
White  
7 
34 
1 
6 
48 
More Than One Race 
0 
1 
0 
0 
1 
Total 
41 
109 
2 
6 
158 
 
 
 
 
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 
2 
0 
0 
2 


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Asian 
31 
110 
0 
2 
143 
Native Hawaiian or Other 
Pacific Islander 
0 
2 
0 
0 
2 
Black or African American 
0 
0 
0 
0 
0 
White  
3 
7 
0 
0 
10 
More Than One Race 
0 
1 
0 
0 
1 
Total 
34 
122 
0 
2 
158 
 
 
 
 
 
 
REFERENCES 
 
Abdel-Rahman O, Helbling D, Schmidt J, et al. Treatment-associated Fatigue in Cancer Patients 
Treated with Immune Checkpoint Inhibitors; a Systematic Review and Meta-analysis. Clinical 
oncology (Royal College of Radiologists (Great Britain)). 2016;28(10):e127-138. 
 
Andic F, Miller AH, Brown G, et al. Instruments for determining clinically relevant fatigue in 
breast cancer patients during radiotherapy. Breast Cancer. 2019 Sep 6. DOI: 10.1007/s12282-
019-01008-8. [Epub ahead of print]. 
  
Bender R, Augustin T, Blettner M. Generating survival times to simulate Cox proportional 
hazards models. Stat Med. 2005;24(11):1713-1723.  
 
Borghaei H, Hellman MH, Paz-Ares LG, et al. Nivolumab (Nivo) + platinum-doublet 
chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell 
lung cancer (NSCLC) with <1% tumor PD-L1 expression: Results from CheckMate 227. J Clin 
Oncol. 2018;36(15):90001-9001. DOI: 10.1200/JCO.2018.36.15_suppl.9001. 
 
Brahmer JR, Rodriguez-Abreu D, Robinson AG, et al. Health-related quality-of-life results for 
pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a 
multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 
2017;18(12):1600-1609. 
 
Burtness B, Harrington K, Greil R et al. Pembrolizumab alone or with chemotherapy versus 
cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head 
and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019; 394 
(10212):1915-1928. 
 
Cella D, Grunwald V, Escudier B, et al. Patient-reported outcomes of patients with advanced 
renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): 
a randomised, phase 3 trial. Lancet Oncol. 2019;20(2):297-310. 
 
Chan AWH, Tong JHM, Kwan JSH. Assessment of programmed cell death ligand-1 expression 
by 4 diagnostic assays and its clinicopathological correlation in a large cohort of surgical 


NRG-HN007 
93  
Version Date: February 16, 2021 
 
resected non-small cell lung carcinoma.  Mod Pathol. 2018 Sep;31(9):1381-1390. DOI: 
10.1038/s41379-018-0053-3. 
 
Chan KC, Jiang P, Zheng YW, et al. Cancer genome scanning in plasma: detection of tumor-
associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by 
massively parallel sequencing. Clin Chem. 2013;59(1):211-24. DOI: 
10.1373/clinchem.2012.196014. 
 
Chan OS, Kowanetz M, Ng WT, et al. Characterization of PD-L1 expression and immune cell 
infiltration in nasopharyngeal cancer. Oral Oncol. 2017;67:52-60. DOI: 
10.1016/j.oraloncology.2017.02.002. 
 
Chua MLK, Wee JTS, Hui EP, Chan ATC. Nasopharyngeal carcinoma. Lancet. 
2016;387(10022):1012-1024. DOI: 10.1016/S0140-6736(15)00055-0. 
 
Chuang LL, Chuang YF, Hsu MJ, Huang YZ, Wong AMK, Chang YJ. Validity and reliability of 
the Traditional Chinese version of the Multidimensional Fatigue Inventory in general population. 
PLoS One. 2018;13(5):e0189850. 
 
Chung KF, Yu BY, Yung KP, Yeung WF, Ng TH, Ho FY. Assessment of fatigue using the 
Multidimensional Fatigue Inventory in patients with major depressive disorder. Compr 
Psychiatry. 2014;55(7):1671-1678. 
 
Cohen EEW, Soulieres D, Le Tourneau C, et al. Pembrolizumab versus methotrexate, docetaxel, 
or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-
040): a randomised, open-label, phase 3 study. Lancet. 2019;393(10167):156-167. 
 
Dmitrienko A, Tamhane AC, Bretz F. Multiple Testing in Pharmaceutical Statistics. Chapman & 
Hall/CRC, Boca Raton, FL; 2010.  
Eisenhauer EA, Therasse P. Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revied RECIST guideline (version 1.1.). Eur J Cancer. 2009 Jan;45(2):228-47. 
Fairclough DL, Peterson HF, Cella D, Bonomi P. Comparison of several model-based methods 
for analysing incomplete quality of life data in cancer clinical trials. Stat Med. Mar 15-Apr 15 
1998;17(5-7):781-796. 
 
Fairclough D. Design and analysis of quality of life studies in clinical trials (2nd ed.). Boca 
Raton, FL: Chapman & Hall/CRC; 2010. 
 
Fang W, Zhang J, Hong S, et al. EBV-driven LMP1 and IFN-gamma up-regulate PD-L1 in 
nasopharyngeal carcinoma: Implications for oncotargeted therapy. Oncotarget. 
2014;5(23):12189-12202. DOI: 10.18632/oncotarget.2608. 
 
Fang W, Yang Y, Ma Y, et al. Camrelizumab (SHR-1210) alone or in combination with 
gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 
trials. Lancet Oncol. 2018;19(10):1338-1350. DOI: 10.1016/S1470-2045(18)30495-9. 
 
Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper 
S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota 
N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for 
Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016 Nov 
10;375(19):1856-1867. 
 


NRG-HN007 
94  
Version Date: February 16, 2021 
 
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J 
Am Stat Assoc. 1999;94:496–509. 
 
Freidlin B, Korn EL, Gray R. A general inefficacy interim monitoring rule for randomized 
clinical trials. Clin Trials. 2010;7(3):197-208. 
 
Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in 
Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378(22):2078-2092. DOI: 
10.1056/NEJMoa1801005. 
 
Gomes M, Kenward MG, Grieve R, Carpenter J. Estimating treatment effects under untestable 
assumptions with nonignorable missing data. Stat Med. 2020;1-17. 
https://doi.org/10.1002/sim.8504 
 
Gupta S, Weight CJ, Agarwal N, et al. Abstract A008: Neoadjuvant nivolumab, gemcitabine and 
cisplatin in muscle-invasive bladder cancer: Study update. Cancer Immunol Res. 2019;7(2) 
Supplement) A008. DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A008. Hepatitis B Virus 
Screening for Patients With Cancer Before Therapy: American Society of Clinical Oncology 
Provisional Clinical Opinion Update. J Clin Oncol. 2015;33(19):2212-20. DOI: 
10.1200/JCO.2015.61.3745. 
 
Hall ET, Singhal S, Dickerson J, et al. Patient-Reported Outcomes for Cancer Patients Receiving 
Checkpoint Inhibitors: Opportunities for Palliative Care-A Systematic Review. J Pain Symptom 
Manage. 2019;58(1):137-156 e131. PMID: 30905677.  
 
Harrington KJ, Ferris RL, Blumenschein G, et al. Nivolumab versus standard, single-agent 
therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head 
and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 
trial. The Lancet Oncology. 2017;18(8):1104-1115. 
 
Haybittle, JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 
1971;44(526):793-797. DOI: 10.1259/0007-1285-44-526-793. 
 
Hinz A, Weis J, Brähler E, Härter M, Geue K, Ernst J. Fatigue in cancer patients: comparison 
with the general population and prognostic factors. Support Care Cancer. 2020. doi: 
10.1007/s00520-019-05260-8. [Epub ahead of print].  
 
Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry Assays for Lung 
Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac 
Oncol. 2017 Feb;12(2):208-222. DOI: 10.1016/j.jtho.2016.11.222  
Hsu C, Lee SH, Ejadi S, et al. Safety and Antitumor Activity of Pembrolizumab in Patients With 
Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-
028 Study. J Clin Oncol. 2017;35(36):4050-4056. DOI: 10.1200/JCO.2017.73.3675. 
 
Hwang JP, Somerfield MR, Alston-Johnson DE, et al. Hepatitis B Virus Screening for Patients 
With Cancer Before Therapy: American Society of Clinical Oncology Provisional Clinical 
Opinion Update. J Clin Oncol. 2015 Jul 1;33(19):2212-20. DOI: 10.1200/JCO.2015.61.3745. 
 
Jiang W, Freidlin B, Simon R. Biomarker-adaptive threshold design: a procedure for evaluating 
treatment with possible biomarker-defined subset effect. J Natl Cancer Inst. 2007;99(13):1036-
43. DOI:10.1093/jnci/djm022.  
 
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat Assoc. 
1958;53:457-481. 
 


NRG-HN007 
95  
Version Date: February 16, 2021 
 
Lam WKJ, Jiang P, Chan KCA, et al. Sequencing-based counting and size profiling of plasma 
Epstein-Barr virus DNA enhance population screening of nasopharyngeal carcinoma. Proc Natl 
Acad Sci U S A. 2018;115(22):E5115-E5124. DOI: 10.1073/pnas.1804184115. 
 
Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 
cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508. DOI: 
10.1016/S1470-2045(16)30498-3. 
 
Lee AW, Ma BB, Ng WT, Chan ATC. Management of Nasopharyngeal Carcinoma: Current 
Practice and Future Perspective. J Clin Oncol. 2015;33(29):3356-3364. DOI: 
10.1200/JCO.2015.60.9347. 
 
Li YY, Chung GT, Lui VW, et al. Exome and genome sequencing of nasopharynx cancer 
identifies NF-kappaB pathway activating mutations. Nat Commun. 2017;8:14121. DOI: 
10.1038/ncomms14121. 
 
Lin DC, Meng X, Hazawa M, et al. The genomic landscape of nasopharyngeal carcinoma. Nat 
Genet. 2014;46(8):866-871. DOI: 10.1038/ng.3006. 
 
Lin JM, Brimmer DJ, Maloney EM, Nyarko E, BeLue R, Reeves WC. Further validation of the 
Multidimensional Fatigue Inventory in a US adult population sample. Popul Health Metr. 2009; 
7:18. PMID: 20003524. 
 
Little RA. Modeling the drop-out mechanism in repeated-measures studies. J Am Stat Assoc. 
1995;90(431):1112-1121. 
 
Liu GF, Lu K, Mogg R, Mallick M and Mehrotra DV. Should baseline be a covariate or 
dependent variable in the analyses of change from baseline clinical trials? Statistics in Medicine, 
2009; 28:2509-2530. 
 
Ma BB, Tannock IF, Pond GR, Edmonds MR, Siu LL. Chemotherapy with gemcitabine-
containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma. Cancer. 2002; 
15;95(12):2516-23. PMID: 12467065. 
  
Ma BBY, Lim WT, Goh BC, et al. Antitumor Activity of Nivolumab in Recurrent and Metastatic 
Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 
Consortium (NCI-9742). J Clin Oncol. 2018;36(14):1412-1418. DOI: 
10.1200/JCO.2017.77.0388. 
 
Ma Y, Fang W, Zhang Y, et al. A Phase I/II Open-Label Study of Nivolumab in Previously 
Treated Advanced or Recurrent Nasopharyngeal Carcinoma and Other Solid Tumors. 
Oncologist. 2019;24(7):891-e431. PMID: 31048330. 
 
Mantel N. Evaluation of survival data and two new rank order statistics arising in its 
consideration. Cancer Chemother. Rep. 1966;50:163-170. 
 
 
Mazieres, J, Kowalski, D, Luft A, et al. Health-Related Quality of Life With Carboplatin-
Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic 
Squamous Non–Small-Cell Lung Cancer. Nov 2019 doi:10.1200/JCO.19.01348 
 
NCT02605967. A Phase II, Open-label, Randomized Controlled Study of PDR001 in Patients 
With Moderately Differentiated/Undifferentiated Locally Advanced Recurrent or Metastatic 
Nasopharyngeal Carcinoma Who Progressed on Standard Treatment.  
 


NRG-HN007 
96  
Version Date: February 16, 2021 
 
Ngan RK, Yiu HH, Lau WH, et al. Combination gemcitabine and cisplatin chemotherapy for 
metastatic or recurrent nasopharyngeal carcinoma: report of a phase II study. Ann Oncol. 
2002;13(8):1252-1258. PMID: 12181249. 
 
Nordin Å, Taft C, Lundgren-Nilsson Å, Dencker A. Minimal important differences for fatigue 
patient reported outcome measures-a systematic review. BMC Med Res Methodol. 2016;16:62-
62. PMID: 27387456.  
 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol. 1998;16(1):139-144. 
 
Purcell A, Fleming J, Bennett S, Burmeister B, Haines T. Determining the minimal clinically 
important difference criteria for the Multidimensional Fatigue Inventory in a radiotherapy 
population. Support Care Cancer. 2010;18(3):307-315. PMID: 19468758. 
 
Ringash J, O'Sullivan B, Bezjak A, Redelmeier DA. Interpreting clinically significant changes in 
patient-reported outcomes. Cancer. 2007;110(1):196-202. PMID: 17546575.  
 
Rischin D, Harrington KJ, Greil R, et al. Protocol-specified final analysis of the phase 3 
KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic 
head and neck squamous cell carcinoma (R/M HNSCC). ASCO Meeting 2019. 
  
Rizopoulos D. Joint models for longitudinal and time-to-event data with applications in R. Boca 
Raton, FL: Chapman & Hall/CRC; 2012. 
 
Rizvi N, Hellmann MD, Brahmer J, et al. Nivolumab in Combination With Platinum-Based 
Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J 
Clin Oncol. 2016;34(25):2969-2979. DOI: 10.1200/JCO.2016.66.9861. 
 
Rubin DB. Multiple Imputation for Nonresponse in Surveys, New York: John Wiley & Sons, 
Inc; 1987. 
 
Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) 
psychometric qualities of an instrument to assess fatigue. J Psychosom Res. 1995;39(3):315-325. 
 
Sun K, Jiang P, Cheng SH. Orientation-aware plasma cell-free DNA fragmentation analysis in 
open chromatin regions informs tissue of origin. Genome Res. 2019 Mar;29(3):418-427. DOI : 
10.1101/gr.242719.118. 
 
Tang Y. Sample size estimation for negative binomial regression comparing rates of recurrent 
events with unequal follow-up time. Journal of Biopharmaceutical Statistics, 25: 1100-1113, 
2015. 
 
Trotti A, Pajak TF, Gwede CK, et al. TAME: development of a new method for summarizing 
adverse events of cancer treatment by Radiation Oncology Group. Lancet Oncology 2007; 
8:613-24. 
 
Tsiatis AA, Davidian M, Zhang M, Lu X. Covariate adjustment for two-sample treatment 
comparisons in randomized clinical trials: a principled yet flexible approach. Stat Med. 
2008;27(23); 4658–4677. https://doi.org/10.1002/sim.3113 
 
Ueno M, Ikeda M, Morizane C. Nivolumab alone or in combination with cisplatin plus 
gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-
randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol Hepatol. 2019 
Aug;4(8):611-621. PMID: 31109808.  
 
Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data. New York, NY: 
Springer-Verlag; 2000. 


NRG-HN007 
97  
Version Date: February 16, 2021 
 
 
Wang B, Ogburn EL, Rosenblum M. Analysis of covariance inrandomizedtrials: Moreprecision 
and valid confidence intervals, without model assumptions. Biometrics. 2019;75: 1391-1400. 
https://doi.org/10.1111/biom.13062. 
 
Wang WY, Twu CW, Chen HH, et al. Plasma EBV DNA clearance rate as a novel prognostic 
marker for metastatic/recurrent nasopharyngeal carcinoma. Clin Cancer Res. 2010;16(3):1016-
24. PMID: 20103659. 
 
Weiss GJ, Waypa J, Blaydorn L, et al. A phase Ib study of pembrolizumab plus chemotherapy in 
patients with advanced cancer (PembroPlus). Br J Cancer. 2017;117(1):33-40. DOI: 
10.1038/bjc.2017.145. 
 
Xie H, Gao W, Xing B, Heitjan DF, Hedeker D, Yuan, C. (2018). Measuring the Impact of 
Nonignorable Missingness Using the R Package isni. Comput Methods Programs Biomed. 
2018;164:207-220. PMID: 30195428. 
 
Yang Y. Sensitivity Analysis in Multiple Imputation for Missing Data, Paper SAS270-2014. 
SAS Institute Inc. https://support.sas.com/resources/papers/proceedings14/SAS270-2014.pdf 
 
Yoon J, Sim SH, Kang D, et al. Reliability and Validity of the Korean Language Version of the 
U.S. National Cancer Institute's Patient-Reported Outcomes Common Terminology Criteria for 
Adverse Events. J Pain Symptom Manage. 2020. doi: 10.1016/j.jpainsymman.2020.01.015. 
[Epub ahead of print].  
 
Zhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in 
recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 
3 trial. Lancet. 2016;388(10054):1883-1892. DOI: 10.1016/S0140-6736(16)31388-5 
 
Zhang Y, Chen L, Hu GQ, et al. Gemcitabine and Cisplatin Induction Chemotherapy in 
Nasopharyngeal Carcinoma. N Engl J Med. 2019 May 31. DOI: 10.1056/NEJMoa1905287. 
[Epub ahead of print]. PMID: 31150573. 
 


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APPENDIX II: MEDIDATA PATIENT CLOUD EPRO OPERATIONAL 
INSTRUCTIONS 
1.1 Introduction 
Electronic collection of patient-reported outcomes (ePRO) through Medidata Patient Cloud 
ePRO is preferred but not mandatory.  Traditional paper submission is the other option. Patients 
who will be submitting PRO data via Patient Cloud ePRO must be registered to Patient Cloud 
ePRO by an authorized site user after the patient has been registered to the study. Patients may 
use their own device or one provisioned by the site.  
 
Sites can use a site-specific tablet for multiple study patients.  If a site-specific tablet is used, 
CRAs need to setup the tablet for multiple users.  Multi-user mode lets multiple study patients 
log in to Patient Cloud ePRO 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 
 
 
 
Patient Cloud 
 
 
 
 
1.2 CRA Site Users 
Site users of Patient Cloud ePRO require the same access as Rave. Access to the trial in the 
Patient Cloud ePRO is granted through the iMedidata. Site users will receive an invitation to 
Patient Cloud ePRO 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 ePRO 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.   
 
1.3 CRA Instructions for Setting the Patient Cloud ePRO App to Multi-User Mode 
Sites conducting studies entirely on-premise, where patients travel to the sites to fill out 
questionnaires, can use multi-user mode. Multi-user mode lets multiple study patients 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 


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device if the device is locked. 
 
The study provider will download the Patient Cloud ePRO 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. 
 
1.4 Patient Users 
To use the Patient Cloud ePRO, 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 patients 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 patients log into Patient Cloud ePRO with their passwords or their PIN codes on 
the same device. Refer to Appendix E on Setting the Patient Cloud ePRO App to Multi-User 
Mode.   
 
1.5 Patient Instructions for Accessing the Patient Cloud Using Your Personal Device 
Downloading the Patient Cloud ePRO App 
If you are using your personal device, and you do not have the Patient Cloud ePRO 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 ePRO 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-
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. 
 
 
 


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For iOS:  
 
1. An Apple ID is required for downloading the Patient Cloud ePRO app. 
2. Tap the App Store icon. 
3. Search for Medidata Patient Cloud and follow the installation instructions. 
Note: Patient Cloud ePRO 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 ePRO 
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 ePRO app. 
 
Note: You must have an activation code to begin this process. If you do not have an activation 
code, please contact your provider.  
There are two possible ways to register. Your provider may have sent you a link to a web address 
where you may register from any web browser, including the one on your device. The other way 
to register is on the Patient Cloud ePRO 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 ePRO app, it automatically logs you out. If you registered 
on the web, you are presented with the option to download the Patient Cloud ePRO app. You can 
then proceed to log in with the credentials you created. 
 
 
 


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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 ePRO 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 ePRO 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 
completed the form. If you start a form, but do not complete it, you will see an 
'Incomplete" status beneath the form name, along with a half-moon icon.  


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NRG-HN007 
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Version Date: February 16, 2021 
 
APPENDIX III: CARBOPLATIN DOSE CALCULATION INSTRUCTIONS  
 
1) The Cockcroft-Gault formula will be used in NRG Oncology trials. 
 
Dosing of Carboplatin: 
1) The carboplatin dose will be calculated to reach a target area under the curve (AUC) 
according to the Calvert formula using creatinine clearance (mL/min) from the Cockcroft-
Gault formula. 
 
2) In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dL.   
 
3) The initial dose of carboplatin must be calculated using GFR. In the absence of renal toxicity 
greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or toxicity requiring 
dose modification, the dose of carboplatin will not need to be recalculated for subsequent 
cycles, but will be subject to dose modification for toxicity as noted in the protocol. 
 
4) Carboplatin doses are required to be recalculated if the patient has a weight change of greater 
than or equal to 10%. Patients are permitted to have chemotherapy doses recalculated for < 
10% weight changes. 
 
5) At the time of dose modification, if the patient’s age had changed (the patient has had a 
birthday), the site can use the current age. 
 
CALVERT FORMULA: 
Carboplatin dose (mg) = target AUC x (GFR [or estimated CrCl] + 25) 
 
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min. 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
 
The maximum allowed doses of carboplatin are: 
AUC 6 = 900 mg 
AUC 5 = 750 mg 
AUC 4 = 600 mg 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance. The estimated creatinine clearance (mL/min) is calculated by the method of 
Cockcroft-Gault using the following formula: 
 
Creatinine Clearance (mL/min) =    [140-Age (years)] x actual body Weight* (kg)   {x 0.85 if female}  
                                                                
72 x serum creatinine (mg/dl)  
 
Notes: 
1) Weight in kilograms (kg): 
a. Body Mass Index (BMI) should be calculated for each patient.  
 
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 25. 


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Version Date: February 16, 2021 
 
 
c. Adjusted weight should be used for estimation of GFR for patients with BMI of greater 
than or equal to 25  
 
d. Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) (+ 45.5 females) or (+ 50 for men)  
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
At the time of a dose modification for toxicity: 
If the creatinine at the time of a dose modification is lower than the creatinine used to 
calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the time 
of a dose modification is higher than the creatinine used to calculate the previous dose, use 
the current (higher) creatinine. This will ensure that the patient is actually receiving a dose 
reduction. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version Date: February 16, 2021 
 
APPENDIX IV: COLLABORATIVE AGREEMENTS 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2.   For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as “Multi-Party Data”): 
 
a.   NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b.   Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c.   Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 


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


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APPENDIX V: PATIENT CLINICAL TRIAL WALLET CARD 
 
                                          
 
 
 
CLINCIAL TRIAL WALLET 
CARD 
Show this card to all of 
your healthcare 
providers and keep it 
with you in case you go 
to the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:        
Study Drug(S):        
 
 
 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov