Clinical trial NCT03342911
Conditions: Name Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma Stage II Oropharyngeal Squamous Cell Carcinoma Stage III Hypopharyngeal Squamous Cell Carcinoma Stage III Laryngeal Squamous Cell Carcinoma Stage III Oral Cavity Squamous Cell Carcinoma Stage III Oropharyngeal Squamous Cell Carcinoma Stage IV Hypopharyngeal Squamous Cell Carcinoma Stage IV Laryngeal Squamous Cell Carcinoma Stage IV Oral Cavity Squamous Cell Carcinoma Stage IV Oropharyngeal Squamous Cell Carcinoma Stage IVA Hypopharyngeal Squamous Cell Carcinoma Stage IVA Laryngeal Squamous Cell Carcinoma Stage IVA Oral Cavity Squamous Cell Carcinoma Stage IVA Oropharyngeal Squamous Cell Carcinoma Stage IVB Hypopharyngeal Squamous Cell Carcinoma Stage IVB Laryngeal Squamous Cell Carcinoma Stage IVB Oral Cavity Squamous Cell Carcinoma Stage IVB Oropharyngeal Squamous Cell Carcinoma Stage IVC Hypopharyngeal Squamous Cell Carcinoma Stage IVC Laryngeal Squamous Cell Carcinoma Stage IVC Oral Cavity Squamous Cell Carcinoma Stage IVC Oropharyngeal Squamous Cell Carcinoma
Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University
Start date: 2017-11-13; Completion date: 2020-10-06
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well nivolumab, carboplatin, and paclitaxel work in treating patients with stage III-IV head and neck squamous cell carcinoma that can be removed by surgery. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as carboplatin and paclitaxel, 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, carboplatin, and paclitaxel may work better in treating patients with head and neck squamous cell carcinoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate pathologic complete response (pCR) at the primary site in patients with newly diagnosed and untreated stage III-IVA squamous cell carcinoma of the head and neck (SCCHN) of the oral cavity, oropharynx, larynx, and hypopharynx with nivolumab, paclitaxel and carboplatin in addition to standard chemotherapy.

SECONDARY OBJECTIVES:

I. Safety. II. Complete pathologic response at all sites of disease. III. Major pathologic response rate at primary site. IV. Overall clinical response rate. V. Clinical complete response rate. VI. 1 year progression-free survival (PFS). VII. Overall survival.

TERTIARY OBJECTIVES:

I. To explore whether PDL1 expression is associated with treatment response. II. To explore whether there is a net change in the Th1/Th2 ratio (IFN-gamma, IL-4, IL10, etc.) or cell subset frequencies (M2 monocytes, myeloid-derived suppressor cells, etc.) within a patient's peripheral blood either at baseline or in response to treatment is associated with treatment response.

III. To explore whether exosomes or other immune related serum biomarkers change after combination therapy.

IV. To explore the predictive value of serial cell free deoxyribonucleic acid (DNA) levels and response.

Arms: arm 1: Patients receive nivolumab IV over at least 30 minutes on day 1, paclitaxel IV on days 1 and 8, and carboplatin IV on days 1 and 8. Treatment repeats every 14 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Paclitaxel intervention 2: Carboplatin intervention 3: Nivolumab
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
Version 5.0 
Protocol 17P.513 
 
05 November 2019 
 
 
 
Based on SKCC Interventional Protocol Template v.20170209 
page 1 of 124 
 
THOMAS JEFFERSON UNIVERSITY 
Sidney Kimmel Cancer Center 
 
Nivolumab plus Weekly Carboplatin and Paclitaxel as 
Induction in Resectable Locally Advanced Head and 
Neck Cancer 
 
Principal Investigator: 
Jennifer M Johnson, MD PhD 
Department of Medical Oncology 
1025 Chestnut Street, Suite 700 
Philadelphia, PA 19107 
215-955-8874 
Co-Principal 
Investigator(s): 
David Cognetti, MD 
Department of Otolaryngology 
925 Chestnut Street,6th Floor 
Philadelphia, PA 19107 
215-503-6828 
 
Athanassios Argiris, MD PhD 
Department of Medical Oncology 
1015 Walnut Street, Suite 700 
Philadelphia, PA 19107 
215-955-8874 
Abington PI: 
Melanie J. Nordlinger, MD 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
Fox Chase Cancer 
Center 
Principal Investigator: 
Jessica Bauman, MD 
333 Cottman Ave 
Philadelphia, PA 19111 
Co-Investigator(s): 
Rita Axelrod, MD 
Department of Medical Oncology 
1015 Walnut Street, Suite 700 
Philadelphia, PA 19107 
215-955-8874 
 
Avnish Bhatia, MD 
Department of Medical Oncology 
1015 Walnut Street, Suite 700 
Philadelphia, PA 19107 
215-955-8874 


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Voichita Bar Ad, MD 
Department of Radiation Oncology 
111 South 11th Street, Room G301N 
Philadelphia, PA 19107 
215-955-6702 
 
Joseph Curry, MD 
Department of Otolaryngology 
925 Chestnut Street,6th Floor 
Philadelphia, PA 19107 
215-503-6828 
 
Adam Luginbuhl, MD 
Department of Otolaryngology 
925 Chestnut Street,6th Floor 
Philadelphia, PA 19107 
215-503-6828 
 
Christopher Fundakowski, MD 
Department of Otolaryngology 
925 Chestnut Street,6th Floor 
Philadelphia, PA 19107 
215-503-6828 
 
Elizabeth Cottrill, MD 
Department of Otolaryngology 
925 Chestnut Street,6th Floor 
Philadelphia, PA 19107 
215-955-6760 
 
Andrew Yampolsky, DDS, MD 
Department of Oral and Maxillofacial Surgery 
909 Walnut St., 3rd Floor 
Philadelphia, PA 19107 
215-923-9189 
 
Pathology: 
Charalambos Solomides, MD 
Madalina Tuluc, MD 
Department of Pathology 
Main Building, Room 260 
132 South 10th Street 
Philadelphia, PA 19107 
215-503-6202 
 
Correlative Sciences: 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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Larry Harshyne, PhD 
Department of Neurosurgery 
Jefferson Alumni Hall, Suite 454 
1020 Locust St 
Philadelphia, PA 19107 
215-503-9893 
 
Bo Lu, MD PhD 
Department of Radiation Oncology 
111 South 11th Street, Room G301N 
Philadelphia, PA 19107 
215-955-6702 
 
Grace Lu Yao, PhD MPH 
Department of Medical Oncology 
Bluemle 
233 S 10th Street, Rm 812 
Philadelphia, PA 19107 
215-503-7970 
Statistician: 
Benjamin Leiby, PhD 
Department of Pharmacology and Experimental Therapeutics 
1015 Chestnut Street, Suite 520 
Philadelphia, PA 19107 
215-503-3803 
Funding Supporter and 
Nivolumab Provider 
Bristol-Myers Squibb 
IND/IDE Holder: 
Jennifer Johnson, MD, PhD 
IND/IDE Number: 
136803 
Study Product: 
Nivolumab 
Protocol IDs: 
CA209-9FT 
JeffTrial # 11182 
PRC # 2017-100 
IRB Control # 17P.513 
 
Version Number: 
Version Date: 
2.0 
2017-05-02 
2.1 
2017-11-03 
3.0 
2017-11-16 
3.1 
2018-06-29 
3.2 
2018-10-26 
3.3 
2019-03-15 


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4.0 
2019-04-09 
5.0 
2019-11-05 
 
CONFIDENTIAL 
This document is confidential and the property of THOMAS JEFFERSON UNIVERSITY. 
No part of it may be transmitted, reproduced, published, or used by other persons 
without prior written authorization from the study sponsor. 
 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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Table of Contents  
 
Signature Page .........................................................................................................................11 
Statement of Compliance ..........................................................................................................11 
List of Abbreviations ..................................................................................................................12 
Study Summary ........................................................................................................................14 
1 
Introduction .........................................................................................................................17 
1.1 
Background Information ..............................................................................................17 
1.2 
Rationale for the Proposed Study ...............................................................................25 
1.3 
Correlative Studies ......................................................................................................30 
1.4 
Potential Risks and Benefits .......................................................................................32 
1.4.1 Potential Risks.........................................................................................................32 
1.4.2 Benefits ...................................................................................................................35 
2 
Study Objectives .................................................................................................................35 
2.1 
Objectives ...................................................................................................................35 
2.1.1 Primary ....................................................................................................................35 
2.1.2 Secondary ...............................................................................................................35 
2.1.3 Exploratory ..............................................................................................................35 
2.2 
Endpoints/Outcome Measures ....................................................................................36 
2.2.1 Primary ....................................................................................................................36 
2.2.2 Secondary ...............................................................................................................36 
2.2.3 Exploratory ..............................................................................................................36 
3 
Study Design ......................................................................................................................37 
3.1 
Characteristics ............................................................................................................37 
3.2 
Number of Participants ...............................................................................................38 


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3.3 
Duration of Therapy ....................................................................................................38 
3.4 
Duration of Follow Up .................................................................................................39 
3.5 
Study Timeline ............................................................................................................39 
3.5.1 Primary Completion .................................................................................................39 
3.5.2 Study Completion ....................................................................................................39 
4 
Study Enrollment and Withdrawal .......................................................................................39 
4.1 
Eligibility Criteria .........................................................................................................39 
4.1.1 Inclusion Criteria ......................................................................................................39 
4.1.2 Exclusion Criteria ....................................................................................................40 
4.2 
Gender/Minority/Pediatric Inclusion for Research........................................................41 
4.3 
Strategies for Recruitment and Retention ...................................................................41 
4.4 
Sub-Site Enrollment Procedure ...................................................................................42 
4.5 
Participant Withdrawal ................................................................................................42 
4.5.1 Reasons for Withdrawal ..........................................................................................42 
4.5.2 Handling of Participant Withdrawals and Participant Discontinuation of Study 
Intervention .........................................................................................................................43 
4.6 
Premature Termination or Suspension of Study ..........................................................43 
5 
Study Intervention ...............................................................................................................43 
5.1 
Study Product .............................................................................................................43 
5.2 
Study Product Description ...........................................................................................43 
5.2.1 Acquisition ...............................................................................................................45 
5.2.2 Formulation, Packaging, and Labeling .....................................................................45 
5.2.3 Product Storage and Stability ..................................................................................46 
5.3 
Dosage, Preparation, and Administration ....................................................................47 
5.4 
Dose Modifications and Dosing Delays .......................................................................48 


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5.5 
Study Product Accountability ......................................................................................55 
5.6 
Assessing Participant Compliance with Study Product Administration ........................57 
5.7 
Concomitant Medications/Treatments .........................................................................57 
5.8 
Dietary Restrictions .....................................................................................................58 
6 
Study Schedule ..................................................................................................................58 
6.1 
Pretreatment Period/Screening ..................................... Error! Bookmark not defined. 
6.2 
Enrollment/Baseline ...................................................... Error! Bookmark not defined. 
6.3 
Treatment Period ........................................................................................................60 
6.4 
Post-Surgical/Follow-Up..............................................................................................63 
6.5 
End of Treatment Study Procedures ...........................................................................64 
6.6 
Post-Treatment/Follow-Up ..........................................................................................64 
6.7 
Withdrawal Visit/Discontinuation of Therapy ...............................................................64 
6.8 
Surgery .......................................................................................................................64 
6.9 
Radiation ....................................................................................................................64 
7 
Study Procedures and Evaluations .....................................................................................65 
7.1 
Study Procedures/Evaluations ....................................................................................65 
7.2 
Laboratory Procedures/Evaluations ............................................................................66 
7.2.1 Clinical Laboratory Evaluations ...............................................................................66 
7.2.2 Special Assays or Procedures .................................................................................66 
7.2.3 Specimen Preparation, Handling, and Storage ........................................................67 
7.2.4 Specimen Shipment ................................................................................................67 
8 
Evaluation of Safety ............................................................................................................67 
8.1 
Specification of Safety Parameters .............................................................................67 
8.1.1 Unanticipated Problems ..........................................................................................67 


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8.1.2 Adverse Events .......................................................................................................67 
8.1.3 Serious Adverse Events ..........................................................................................67 
8.2 
Safety Assessment and Follow-Up .............................................................................68 
8.3 
Recording Adverse Events ..........................................................................................68 
8.3.1 Relationship to Study Intervention ...........................................................................68 
8.3.2 Expectedness ..........................................................................................................69 
8.3.3 Severity of Event .....................................................................................................69 
8.3.4 Intervention .............................................................................................................69 
8.4 
Safety Reporting .........................................................................................................69 
8.4.1 Reporting to IRB ......................................................................................................69 
8.4.2 Sub-Site SAE Reporting ..........................................................................................71 
8.4.3 Reporting to SKCC DSMC ......................................................................................71 
8.4.4 Reporting to Funding Supporter ..............................................................................73 
8.4.5 Reporting to FDA .....................................................................................................73 
8.4.6 Reporting of Pregnancy ...........................................................................................75 
8.5 
Laboratory Test Result Abnormalities .........................................................................75 
8.6 
Overdose ....................................................................................................................75 
8.7 
Potential Drug Induced Liver Injury (DILI) ...................................................................76 
8.8 
Halting Rules ..............................................................................................................76 
9 
Study Oversight ..................................................................................................................76 
10 
Clinical Site Monitoring and Auditing ..............................................................................76 
11 
Statistical Considerations ...............................................................................................77 
11.1 
Study Hypotheses .......................................................................................................77 
11.2 
Analysis Plans ............................................................................................................77 


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11.3 
Interim Analyses and Stopping Rules..........................................................................78 
11.3.1 
Safety Review ......................................................................................................78 
11.3.2 
Efficacy Review ...................................................................................................78 
11.4 
Sample Size Considerations .......................................................................................79 
11.4.1 
Replacement Policy .............................................................................................79 
11.4.2 
Accrual Estimates ................................................................................................79 
11.5 
Exploratory Analysis ...................................................................................................79 
12 
Source Documents and Access to Source Data/Documents ..........................................79 
13 
Quality Control and Quality Assurance ...........................................................................79 
14 
Ethics/Protection of Human Participants .........................................................................80 
14.1 
Ethical Standard .........................................................................................................80 
14.2 
Institutional Review Board ...........................................................................................80 
14.3 
Informed Consent Process ..........................................................................................80 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) ..........................80 
14.5 
Participant Confidentiality............................................................................................80 
14.6 
Future Use of Stored Specimens and Other Identifiable Data .....................................81 
15 
Data Handling and Record Keeping ...............................................................................81 
15.1 
Data Management Responsibilities .............................................................................81 
15.2 
Data Capture Methods ................................................................................................81 
15.3 
Types of Data .............................................................................................................81 
15.4 
Study Records Retention ............................................................................................81 
15.5 
Protocol Deviations .....................................................................................................82 
16 
Study Finances ...............................................................................................................82 
16.1 
Funding Source ..........................................................................................................82 


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16.2 
Conflict of Interest .......................................................................................................82 
16.3 
Participant Stipends or Payments ...............................................................................82 
17 
Publication and Data Sharing Policy ...............................................................................82 
18 
Literature References .....................................................................................................83 
Appendices ...............................................................................................................................87 
APPENDIX A: SCHEDULE OF EVENTS ..................................................................................88 
APPENDIX B: ECOG PERFORMANCE STATUS .....................................................................92 
APPENDIX C: AJCC 8TH EDITION STAGING SYSTEM ...........................................................94 
APPENDIX D: MANAGEMENT ALGORITHMS ....................................................................... 105 
APPENDIX E: NCI PRO-CTCE ITEMS ................................................................................... 114 
APPENDIX F: UNATICIPATED PROBLEM FORM ................................................................. 121 
 


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Signature Page 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
Principal Investigator: 
Signed: 
 
Date:  
Name: 
 
Title:  
 
Statement of Compliance 
This study will be conducted in accordance with the International Conference on Harmonisation 
guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), and Thomas Jefferson University research 
policies 
 
 
 


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List of Abbreviations 
AE 
Adverse Event/Adverse Experience 
BOR 
Best Overall Response 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
Complete response 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTO 
Clinical Trials Office 
CTOC 
Clinical Trials Oversight Committee 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IRC 
Imaging Response Criteria 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OAR 
Organ At Risk 


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OHRP 
Office for Human Research Protections 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PFS 
Progression Free Survival 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PR 
Partial Response 
PRC 
Protocol Review Committee 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
SDS 
Safety Data Sheet (formerly MSDS; Material Safety Data Sheet) 
SKCC 
Sidney Kimmel Cancer Center 
SOP 
Standard Operating Procedure 
TJU 
Thomas Jefferson University 
UAP 
Unanticipated Problem 
ULN 
Upper Limit of Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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Study Summary 
Title: 
Nivolumab plus Weekly Carboplatin and Paclitaxel as Induction in Resectable 
Locally Advanced Head and Neck Cancer 
 
Précis: 
Patients with locally advanced squamous cell carcinoma of the head and 
neck who are candidates for curative intent surgery will be treated with a 
combination of induction weekly carboplatin and paclitaxel plus nivolumab, to 
assess the rate of pCR at the primary tumor over historical control with 
induction chemotherapy alone. 
 
Objectives: 
 
Primary: 
The primary objective of the study is to estimate pathologic complete 
response (pCR) at the primary site in patients with newly diagnosed and 
untreated Stage III-IVA SCCHN of the Oral Cavity, Oropharynx, Larynx, and 
Hypopharynx  treated with Nivolumab, paclitaxel, and carboplatin in addition 
to standard chemotherapy. 
 
Secondary: 
• 
Safety 
• 
Complete Pathologic Response at all sites of disease 
• 
Major pathologic response rate at primary site 
• 
Overall Clinical Response Rate  
• 
Clinical Complete Response Rate 
• 
1 year PFS. 
• 
Overall survival. 
 
Exploratory: 
• 
To explore whether PDL1 expression is associated with treatment 
response 
• 
To explore whether there is a net change in the Th1/Th2 ratio (IFN- γ , 
IL-4, IL10, etc.) or cell subset frequencies (M2 monocytes, myeloid-
derived suppressor cells, etc.) within a patient’s peripheral blood 
either at baseline or in response to treatment is associated with 
treatment response 
• 
To explore whether exosomes or other immune related serum 
biomarkers change after combination therapy. 
• 
To explore the predictive value of serial cell free DNA levels and 
response 
 
Population: 
Patients with newly diagnosed and untreated stage III-IVA SCCHN of the: 
Oral cavity, Oropharynx, Larynx, and Hypopharynx. 
 
Phase: 
II 
 
Number of 
Sites: 
• 
3: Thomas Jefferson University, USA (lead site), Fox Chase Cancer 
Center, 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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• 
 
• 
Abington Memorial Hospital 
 
Statistics: 
An optimal Simon two-stage design will be used. The null hypothesis is that 
the true pathologic complete response rate at the primary tumor site is ≤ 0.20 
and will be tested against the alternative that it is >0.20. After testing the 
regimen on 17 patients in the first stage, the trial will be terminated if 3 or 
fewer respond. If the trial goes on to the second stage, a total of 37 patients 
will be studied. If the total number responding is less than or equal to 10, the 
regimen is rejected.  This design yields a type I error rate of 9.5% and power 
of 90% when the true response rate is 0.40. It has a 55% probability of 
stopping early. The pathologic complete response rate and its associated 
score 95% confidence interval will be estimated using the methods of Tsai et 
al (2008).20   
 
Description 
of 
Intervention: 
This is a phase II trial looking at the combination of weekly carboplatin plus 
paclitaxel to which nivolumab is added as induction therapy prior to planned 
surgery for the definitive management of locally advanced squamous cell 
carcinomas of the head and neck. 
 
Treatment Plan: 
Induction Nivolumab + Carboplatin + Paclitaxel: 
• 
Nivolumab 240mg every 2 weeks x 3 doses (last dose at least 3 
weeks before surgery) 
• 
Carboplatin AUC 2 weekly x 6 doses (last dose at least 2 weeks 
before surgery) 
• 
Paclitaxel 100 mg/m2 x 6 doses (last dose at least 2 weeks before 
surgery) 
 
Study 
Duration: 
38 months 
Participant 
Participation 
Duration: 
8 months 
Estimated 
Time to 
Complete 
Enrollment: 
30 months  


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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Schematic of Study Design: 
Prior to  
Enrollment 
(Day -28 to  
Day -1) 
 
 
 
Visit 1 
Day 0 
 
 
 
 
Visit 2 
Week 1 
Day 1 
  
 
 
 
Visit 3 & 4 
Days 15 & 29 
(± 4 days) 
 
 
 
Visit 5 
Day 50 
(± 4 days) 
 
 
 
Visit 6 
Day 57 
(± 7 days) 
 
 
 
 
 
 
Obtain informed consent. Screen potential subjects by inclusion and exclusion 
criteria; obtain history and physical, document 
Perform baseline assessments. 
Confirmation of cancer histology and p16 status; IHC for PDL1 expression on 
initial biopsy; Draw blood for serologic assessment for Th1/Th2 ratio, exosomes.  
Administer initial study intervention.  
Day of surgery: 1) CT scan preop 2) Draw blood assessment for Th1/Th2 ratio, 
exosomes. 3) History & Physical exam 4) Safety assessment 
Safety assessments Day 15 & 29 
Day 29 Draw blood for serologic assessment for Th1/Th2 ratio, exosomes.  
Continuous Assessment of SAEs 
and the Recurrence
Nivolumab 240mg x q 2wk x 3 
Carboplatin AUC 2 q wk x 6 
Paclitaxel 100 mg/m2 q wk x 6 
1) Postop evaluation and exam, 2) Draw blood for Th1/Th2 ratio, exosomes.3) 
Wound assessment 
Postoperative Standard of Care (Postoperative therapy as per the HNC tumor 
board recommendations). 


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1 Introduction 
1.1 
Background Information 
Over 58,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed 
leading to more than 1300 deaths each year in the United States1. Oropharyngeal cancer remains 
one of the few cancers that is on the rise in our population with an exceptional rate of increase 
per year1. The prognosis of head and neck cancer is highly variable based on subsite location 
and stage with an overall survival of 63% and with advanced stage disease with survival rates of 
38-62%.1 Earlier stage cancers are often treated with single modality therapy of either surgery or 
radiation, with advanced stages needing multimodality therapy including platinum based 
chemoradiotherapy regardless of surgery. Moreover, for early stage tumors and for those with 
local involvement of lymph nodes, resection is the cornerstone of therapy.  Approximately 50% of 
head and neck cancer patients have primary surgery. More locally advanced cancers that are 
resected will also often require either adjuvant radiation therapy or chemoradiation to decrease 
local and regional recurrence rates. Surgical resections can cause considerable morbidity in the 
more locally advanced cases including a loss of swallowing and larynx function. Post-operative 
radiation can add further long term morbidity. In advanced local disease, after surgery and 
postoperative therapy, the current standard, 5 year survival rates are on the order of 50%.  
Patients with resectable locally advanced squamous cell carcinoma of the head and neck 
(SCCHN) remain at high risk for loco-regional and distant recurrence despite the standard 
approach of surgery followed by radiation or chemoradiation depending on the presence of 
intermediate/high risk features.2 About half of patients with advanced local oral cavity cancer will 
die of either loco-regional and/or distant metastases or a second primary cancer. 3  
For locally advanced resectable disease, the standard remains surgery followed by observation, 
radiation or chemo-radiation depending on operative findings, the patient’s condition and 
assessed level of risk of recurrence. However, given the substantial risk of recurrence and death 
after these interventions and the frequent sustained morbidity of the definitive procedures, 
presurgical induction therapy has been investigated.   
Results from two phase III trials comparing induction chemotherapy followed by radical surgery 
versus upfront radical surgery in patients diagnosed with resectable oral squamous cell carcinoma 
have been reported (figure 1). 4,5 
 
 
 
 
 
 


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Figure 1. 
 
In the conducted by Zhong et al., patients with clinical stage III-IVA OSCC were randomized to 
immediate surgery or 2 cycles of TPF followed by postoperative single modality radiation in all 
patients in both arms. 4 In the PF induction study by Licitra et al., patients with clinical stage II-IV 
(T2(>3cm)-T4, N0-N2) OSCC were randomized to induction 3 cycles of PF or immediate surgery. 
5   Postoperative radiation was given to patients in either arm only in high risk patients.    
In the study by Zhong et al., patients had clinical stage III-IVA OSCC of whom 43% had clinical 
stage N0 stage with all patients having at least T1 (figure 2). In the study by Lictra et al, resectable 
clinical stages II-IV were eligible with a requirement that primary lesions be T2 > 3cm. About 57% 
had no clinical evidence of lymph node involvement at baseline (figure 3) 
The percent of patients assigned each arm across the 2 studies who received the planned surgery 
and reasons for not getting the surgery are summarized here. A total of 256 patients were 
randomized in the TPF study of whom 124/128 in the induction arm received presurgical TPF and 
118/124 (95%) of these had surgery compared to 127/128 (99%) randomized to surgery without 
induction. Of the 6/124 in the TPF arm who did not have surgery, 3/124 (2.4%) died during 
induction not felt to be from the TPF and 3 refused surgery (2 received radiation and 1 refused 
both surgery and radiation). Toxicities were modest with 6.6% having grade 3 hematologic toxicity 
and 0.8% and 1.6% having grade 3 diarrhea or febrile neutropenia respectively. 
In the PF study, a total of 198 patients were randomized of whom 98/99 in the PF arm were 
evaluable and 96/99 completed follow-up. Of the evaluable patients on the PF arm, 92/98 (94%) 
received surgery compared to the 99 patients randomized to the control arm in which 97/99 were 
evaluable (2 lost after randomization) and 97/97 evaluable patients had surgery. Of the 6/98 (6%) 
on PF who did not have surgery, 3 died from toxicity, another 1 had an MI, one developed distant 
metastases and 1 refused. Two other patients had surgery on their primary but no planned lymph 


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node dissection but receiving radiation to the neck. Toxicities were more pronounced on this study 
compared to the TPF study with 25.5% and 11.2% of patients having at least on grade 3 or 4 
toxicity respectively though only 1% of patients had a non-hematologic toxicity of grade 4, 
mucositis (and 3 patients had grade 5 toxicity).   
Figure 2 
 
 
 
 
 
Figure 3 


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Clinical responses to induction were seen in a high percentage of patients in both studies (figure 
4). In the TPF induction study by (Zhong et al.), 122/124 (98.4%) patients received both cycles 
(2/124) just 1 cycle with a RR of 100 /124 (81%) of whom 10/124 (8%) were CRs with only 1 
patient (0.8%) with PD. In the PF study (Licitra et al.), 85/98 (87%) received at least 2 of the 3 
planned courses. The authors reported the responses on these 85 with RR of 70/85 (82%) of 
whom 28/85 (33%) were CRs at all sites of disease with PD not reported though 1 of these 
patients did have development of distant metastases and as noted above, all but 6 patients 
received the planned post induction surgery. 
Pathologic responses were evaluated as pPD, pSD, pPR, pMRT (microscopic residual tumor) 
and CR variously at the primary site and LN and the primary site alone (figure 4). pMRT was 
described as scattered foci of a few tumor cells in the paper by Licitra et al. and more specifically 
as <10% viable tumor cells in the TPF induction study (Zhong et al.). The latter more precise 
definition underlay their later analyses of overall survival (OS) in those patients who had at least 
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as patients who had either pMRT or pCR, was seen in 27% for both primary and nodal disease 
with 13% of these having a pCR. In the study by Licitra et al., patients who received induction PF 
had a 33% pFR of whom 27% had a pCR. They also reported pFR of 45% at the primary site of 
whom 27% were pCR.   
Figure 4. 
 
The induction arm did not yield increased OS in either study (figure 5, 6) though the authors of 
the TPF induction study conclude that failure to achieve a statistical improvement in OS may 
represent a type II error from a potentially underpowered study. They also observed that only 2 
cycles rather than 3 or 4 cycles of induction were offered in contrast to other studies and this could 
have limited the level of efficacy (Zhong, JCO, 2013). However, when evaluating OS among 
patients who had a pFR in the TPF induction study, there was statistical improved OS compared 
to patients whose tumors did not have a pFR and compared to the patients who had no induction 
therapy (figure 7). Interestingly, though the patients who did not have a pFR did not have a 
superior survival, they had a numerically comparable OS compared to the patients who had no 
induction TPF. In the paper by Licitra et al., the subset of patients who achieved a pCR had a 
statistically improved DFS (p=0004).   
The authors of the TPF study did not observe increased postoperative morbidity including flap 
failure (2 in each arm), postoperative hematoma (1 in each arm), and a chylous fistula after neck 
dissection in on patient in the experimental arm. Likewise, radiation toxicities were similar 
between the arms.  In the PF induction study, there were statistically fewer mandibulectomies in 
the experimental arm (31% vs. 52% with a 21% difference (95% CI 7-34%)). There were also 


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fewer patients in the experimental arm who received radiation given decrease in stage and risk 
factors with 33% vs. 46% with a 13% difference (95% CI 0-27%). This would be expected to 
reduce long term morbidity.   
Thus, in summary, the two phase III induction studies in stage II-IVA surgical OSCA were 
generally well tolerated, did not prevent surgery from toxicity or progression, did not lead to excess 
post-operative complications, and showed hints of decreased post-operative and post radiation 
morbidity compared to the control arm.  In addition, there were some intriguing survival signals 
seen in the TPF induction study by Zhong et al. In both studies, pFR or pCR predicted improved 
OS compared to the non-induction immediate surgery controls.  
Figure 5 
 
 
 
 
 
 
Figure 6 


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Figure 7 
 
Figure 8 


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Immune Therapy 
Immunotherapy with checkpoint inhibitors has demonstrated clinical efficacy in several solid 
tumors types, including melanoma, renal cell carcinoma and non-small cell lung cancer. Early 
success was achieved with the CTLA4 antagonist ipilimumab in the treatment of advanced 
melanoma.7 Further work with single agent pembrolizumab demonstrated 20-25% effectiveness 
with low rate of grade 3 or 4 toxicity in patients with recurrent/metastatic HNSCC. Since that 
time additional checkpoint inhibitors have been approved i.e. pembrolizumab for melanoma and 
nivolumab for non-small lung cancer and renal cancer.  
Recently immunotherapy has become a promising new treatment option for recurrent head and 
neck squamous cell carcinomas.8 Updated results on nivolumab  in HNSCC can be seen in the 
CheckMate-141 phase III clinical trial. This study is the first randomized trial to show improved 
overall survival for platinum-refractory recurrent or metastatic HN-SCC patients using nivolumab 
compared to single-agent chemotherapy of the investigator’s choice.8,9 Usually these patients 
with recurrent HN-SCCs, who are unresponsive to platinum-based chemotherapy, have a poor 
prognosis and average survival less than 6 months. After failing platinum-based therapy for 
recurrent HNSCC within 6 months, patients were randomized 2:1 to receive nivolumab (a PD-1 
inhibitor) or a single-agent chemotherapeutic or biological agent of the investigator’s choice, 
which included methotrexate, docetaxel, or cetuximab. At interim analysis, there was already a 
30% reduction in risk of death with nivolumab versus standard therapy. Regardless of PD-L1 
status or HPV p16 status, median overall survival was 7.5 months for the nivolumab cohort 
versus 5.1 months for the investigator’s choice of therapy. Further, HPV+ patients and patients 
with PD-L1 ≥1% had an even greater benefit and significantly longer overall survival with 
nivolumab. These patients also experienced an improvement in their quality of life across 
multiple measures. 
The impressive results of T cell-directed immunotherapies are contrasted by the fact that only a 
subset of patients enjoys long-lasting remissions after single modality immune checkpoint 
therapy. This circumstance has reinvigorated interest in understanding how systemic and local 
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control. It is now widely accepted that immunosuppressive cells and factors in the tumor 
microenvironment (TME) contribute to suboptimal responses to immune checkpoint 
therapeutics. Thus, there is interest in testing combinatorial approaches to “boost” the 
responses seen with nivolumab monotherapy. 
Nivolumab 
Nivolumab (Opdivo) is in clinical development for the treatment of subjects with melanoma, non-
small cell lung cancer (NSCLC), renal cell carcinoma (RCC), head and neck carcinoma and 
other tumors (e.g., gastric cancer, glioblastoma multiforme, hodgkins lymphoma, small cell lung 
cancer). Opdivo as monotherapy has been approved in the US in multiple indications, including, 
unresectable or metastatic melanoma and disease progression following ipilimumab and a 
BRAF inhibitor, if BRAF V600 mutation positive; previously untreated patients with BRAF wild-
type unresectable or metastatic melanoma; NSCLC with progression on or after platinum-based 
chemotherapy; and advanced renal cell carcinoma who have received prior anti-angiogenic 
therapy. The combination of nivolumab and ipilimumab has also been approved in the US for 
the treatment of previously untreated metastatic melanoma. Patients with recurrent or 
metastatic SCCHN have poor prognosis and experience limited survival benefit with standard of 
care therapies. In patients with recurrent or metastatic SCCHN who progress with platinum 
chemotherapy, nivolumab demonstrated prolonged survival benefit over standard of care in the 
Checkmate 141 study and is now the standard of care in this population. To further improve 
clinical outcomes in patients with recurrent or metastatic SCCHN in the first line treatment 
setting, nivolumab in combination with ipilimumab is being explored in the CA209651 clinical 
study.   
Mechanism of action  
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD 1) cluster 
of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory 
molecule expressed by activated T and B lymphocytes33. Binding of PD-1 to its ligands, 
programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. 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. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced 
using standard mammalian cell cultivation and chromatographic purification technologies. The 
clinical study product is a sterile solution for parenteral administration. 
1.2 
Rationale for the Proposed Study 
Patients with resectable locally advanced squamous cell carcinoma of the head and neck 
(SCCHN) remain at high risk for loco-regional and distant recurrence despite the standard 
approach of surgery followed by radiation or chemoradiation depending on the presence of 
intermediate/high risk features.2 About half of patients with advanced local oral cavity cancer will 
die of either locoregional and/or distant metastases or a second primary cancer.3 Results from 
phase III trials comparing induction chemotherapy followed by radical surgery and postoperative 
radiotherapy versus upfront radical surgery and post-operative radiotherapy in patients did not 


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show improved overall survival using TPF, and PF respectively.4 However, there were high  
response rates and patients with pathological complete response (pCR) had better PFS and 
OS.4 Induction chemotherapy may result in major tumor responses that reduce surgical 
morbidity and decrease the likelihood of positive surgical margins and potentially reduce 
postoperative radiation therapy.6 Thus, induction with TPF or PF did not reduce efficacy but 
showed evidence of reducing morbidity and afforded the chance to identify at surgery a subset 
of patients with pCR who had excellent prognosis.   
Use of weekly carboplatin/paclitaxel may be an alternative to TPF and offers an active 
backbone regimen to incorporate novel therapies.10 The addition of cetuximab to this backbone 
has been explored as induction prior to radiation therapy and may offer marginal further 
improvements in efficacy at the risk of increased toxicity.11 The advent of immune checkpoint 
inhibitors offers the potential to not only improve response, but also long term disease control 
with minimal risk of additional toxicity thus presenting a fresh opportunity to explore the potential 
of presurgical induction therapy. 
PD-1 checkpoint inhibitors are established in head and neck as second line therapy in advanced 
disease. Pembrolizumab was approved for use as second line therapy in advanced head and 
neck cancer in August 28th 2016 based on high and very sustained response rates in a single 
arm expansion cohort on a phase Ib study,  KEYNOTE-12 trial.12 Nivolumab resulted in longer 
overall survival than standard treatment in advanced platinum-refractory head and neck cancer 
with minimal increased toxicity.9  
There is preclinical evidence supporting the addition of nivolumab to standard cytotoxic agents. 
13 In a recently published randomized phase II in first-line advanced non-squamous NSCLC, 
patients randomized to carboplatin plus pemetrexed plus pembrolizumab showed improved 
response and time to progression compared to chemotherapy alone.14 Encouraging safety and 
efficacy were observed in a multi-arm study 10mg/kg nivolumab with three doublet cisplatin/ 
gemcitabine, cisplatin/pemetrexed or carboplatin/paclitaxel or nivolumab 5mg/kg combined with 
one doublet, carboplatin/paclitaxel in first line advanced NSLCC. Though the number of patients 
in each arm was small, special promise observed in the nivolumab 5mg/kg plus carboplatin 
paclitaxel arm with 2 year survivals of 62%.15 These NSCLC data support the safety of efficacy 
of standard chemotherapy combined with PD-1 inhibitors.   
Given the single agent efficacy of nivolumab in SCCHN and the promising data with platinum-
based doublets and immune checkpoint inhibitors in NSCLC we propose to study weekly 
carboplatin and paclitaxel plus nivolumab as an induction regimen in resectable SCCHN. It is 
tenable that the addition of nivolumab to carboplatin and paclitaxel will be both well tolerated 
and improve efficacy including response, pathological complete response and long term disease 
control. The induction setting is especially appealing to study nivolumab added to weekly 
carboplatin paclitaxel in resectable SCCHN given the chance to rapidly assess response, and 
the capacity to both determine the established predictive outcome of pathological complete 
response. Moreover, it affords the opportunity to obtain repeat tissue sampling for 
pharmacodynamics endpoint evaluation.    
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The addition of nivolumab to induction weekly carboplatin paclitaxel will increase the rate of 
pCR at the primary site over historical control with induction chemotherapy alone. 
Immunotherapy in SCCHN 
Immunotherapeutic approaches recently have demonstrated clinical efficacy in several cancer 
types, including melanoma, hormone-refractory renal cell carcinoma and non-small cell lung 
cancer. Tumors may modulate and evade the host immune response through a number of 
mechanisms, including down regulation of tumor-specific antigen expression and presentation, 
secretion of anti-inflammatory cytokines, and upregulation of inhibitory ligands. In SCCHN, 
down-regulation of T-cell function is thought to be mediated by multiple mechanisms: i.) 
Reduced expression of co-stimulating molecules of the B7-CD28 family71; ii.) Increased 
expression of PD-L1 in tumor cells and tumor associated fibroblasts; and, iii.) Loss of HLA-class 
I and selective down-regulation of HLA-A,B,C locus expression resulting in defective antigen 
presentation16,17,18. In a subset of HPV-infected SCCHN, data shows that antigen-processing 
machinery components are downregulated compared to the adjacent normal squamous 
epithelium with incomplete activation of tumor specific T cells or suboptimal target recognition 
enabling tumor progression19. T cell checkpoint regulators such as CTLA-4 and programmed 
death-1 (PD-1, CD279) are cell surface molecules that, when engaged by their cognate ligands, 
induce signaling cascades down-regulating T cell activation and proliferation.PD-1 engagement 
on T-cells by PD-L1-positive APC or PD-L1-positive tumor cells in the tumor microenvironment 
may limit effective immune responses. Conversely, PD-L1 expression may be a positive 
prognostic factor as it may indicate infiltration of tumor-specific T cells that secrete IFN-γ, which 
upregulates PD-L1 expression. Consistent with this hypothesis is the co-localization of lymphoid 
cell infiltrates and PD-L1 staining observed in human melanoma lesions26. PD-L1 expression in 
SCCHN has been reported, preliminary results from a phase 1 trial in patients with 27 recurrent 
or metastatic disease observed that 77.9% of patients tested (N=104) expressed PD-L1, 
defined as ≥ 1% of stained cells in the tumor microenvironment. 
The role of the PD-1 blockade in squamous cell carcinoma of the lung primary has been 
established in CA209017 study where nivolumab monotherapy in the 2nd line treatment setting 
demonstrated clinically meaningful survival benefit regardless of PD-L1 expression compared to 
standard of care docetaxel.16 In squamous cell carcinoma of the head and neck, CheckMate 
CA209141 study, is a randomized, open-label, phase 3 trial that compared nivolumab, a fully 
human anti-programmed death 1 (PD-1) monoclonal antibody, to investigator’s choice (IC) of 
systemic therapy in patients with recurrent or metastatic SCCHN who progressed from a 
platinum containing therapy.17 At a preplanned interim analysis, the median OS was 7.5 months 
(95% confidence interval [CI], 5.5 to 9.1) with nivolumab versus 5.1 months (95% CI, 4.0 to 6.0) 
with IC. There is a 30% reduction in the risk of death for patients on the nivolumab arm (hazard 
ratio 0.70; 97.73% CI, 0.51 to 0.96; P=0.0101) over standard of care. The overall response rate 
(ORR) was 12.1% with nivolumab versus 7.4% with IC. In addition, the overall safety profile of 
nivolumab was favorable compared to standard of care. Clinical benefit seen in this 
chemotherapy pre-treated SCCHN suggests the potential clinical activity of nivolumab in earlier 
treatment setting. 
Combination of Nivolumab and chemotherapy 


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The interaction of a tumor with the immune system is complex. Tumors and the tumor 
microenvironment are known to express a variety of factors that impede a robust immune 
response from eliminating the tumor. Soluble and membrane-bound factors have been shown to 
inhibit the cytolytic activity of tumor infiltrating T-cells (e.g., PD-L1 expression; TGF-beta). In 
addition, some tumor-derived factors are able to enhance immune system counter-regulatory 
systems (e.g., increased T-regulatory cells). Finally, suboptimal tumor antigen delivery and 
presentation has been postulated as another mechanism by which tumors can successfully 
evade immune system recognition. 
Cancer therapeutics such as chemotherapy may modulate tumor/immune-system interactions in 
favor of the immune system. Chemotherapy can result in tumor cell death with a resultant 
increase in tumor antigen delivery to antigen-presenting cells. Tumor cell death may also lead to 
a reduction in soluble and membrane-bound factors inhibiting tumor-infiltrating T-cells. 
Chemotherapy may also disrupt immune system regulatory networks by decreasing numbers of 
T-regulatory cells. 
Clinical insights into the toxicity and efficacy of combination nivolumab chemotherapy can be 
gleaned from a trial in NSCLC.  Nivolumab added to chemotherapy has been evaluated in 
several cohorts of chemotherapy-naive subjects with advanced NSCLC in study CA209012.18 
Nivolumab 10 mg/kg was combined with gemcitabine + cisplatin (12 patients), pemetrexed + 
cisplatin (15 patients) and Nivolumab 10 mg/kg, and 5 mg/kg, was combined with paclitaxel and 
carboplatin (15 and 14 patients respectively). 
The safety profile of nivolumab plus platinum-doublet chemotherapy reflects additive toxicities of 
the individual agents, which were manageable using established safety guidelines (Table 1.1.5-
1). The frequency of most immune-related select AEs was higher than what has been observed 
for nivolumab monotherapy. However, these treatment-related AEs, including pneumonitis, were 
effectively managed and did not lead to any deaths. 
 


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Activity was also evaluated by PD-L1 expression and was observed in subjects with both PD-L1 
expressing and non-expressing tumors (Table 1.1.4-3). Overall, 79% (44/56) of subjects had 
evaluable tumor samples. At the 1% expression level, the response rate was 48% and 43% for 
expressers and non-expressers, respectively. The 1-year overall survival was 70% and 76% for 
expressers and non-expressers, respectively. 
 


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Given the small number of patients in the study, conclusions are tentative. However, the data 
are consistent with the conclusion that the predictive value for PD-L1 expression may be 
attenuated in the nivolumab + chemotherapy setting, compared to what has been observed in 
the nivolumab monotherapy and nivolumab + ipilimumab settings in NSCLC. In NSCLC, there 
was no detectable diminution in activity for patients with PD-L1 non-expressing tumors, and 
response rates appear to be greater than in patients with PD-L1 non-expressing tumors treated 
with nivolumab, or nivolumab + ipilimumab. In patients with PD-L1 expressing tumors, 
nivolumab + chemotherapy showed a similar response rate compared to the N3 nivolumab + 
ipilimumab cohorts, but with higher toxicity. In patients with PD-L1 non-expressing tumors, 
nivolumab + chemotherapy showed a higher response rate compared to any of the nivolumab + 
ipilimumab cohorts.   
1.3 
Correlative Studies 
PDL1 expression 
Immune inhibitory receptors are expressed by tumor cells, tumor-infiltrating macrophages, and 
peripheral blood monocytes. Nivolumab has the capacity to alter expression of PDL1 in these 
cells. Therefore, we plan to monitor changes in PDL1 expression in these different cell subsets 
by immunohistochemistry and flow cytometry at various stages of treatment and look for 
association with clinical outcome.  
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We have documented extensive immune bias in peripheral blood of astrocytoma patients.  We 
have performed preliminary studies on blood samples from patients with HNSCC and observed 
similar results. In this HNSCC patient cohort, we have found that immune bias begins in tumor 
draining lymph nodes and extends to the peripheral blood. We have developed a novel in vitro 
assay where we co-culture normal human monocytes with various patient samples to 
investigate polarization capacity. Using this assay, we have shown that astrocytoma-derived 
exosomes and soluble factors can bias normal monocytes towards M2. HNSCC patient sera 
can also bias monocytes towards M2 in this assay.  
Evidence collected in other tumor models suggests that PDL1 is preferentially expressed on M2 
monocytes and tumor-infiltrating macrophages with an M2 phenotype, thereby making them 
targets in nivolumab. To date, there have been no studies looking at the capacity of nivolumab 
to alter immune bias or macrophage polarization. Therefore, we plan to analyze peripheral 
blood mononuclear cells (PBMC) subsets before treatment to establish a baseline and at every 
blood draw thereafter to monitor changes in these compartments due to nivolumab therapy.  We 
will stain PBMC with monoclonal antibodies specific for human CD3, CD4, CD8, CD11b, 
CD11c, CD14, CD33, CD163, CD204, and HLA-DR. Samples will be analyzed by flow 
cytometry. These phenotypic markers will enable us to monitor the effect of nivolumab therapy 
sizes of cell populations and activation status.  
We routinely perform multiplex cytokine analyses on serum samples in our astrocytoma clinical 
trial. We plan to utilize magnetic Milliplex assays (HCYTOMAG-60K) to track changes in serum 
cytokines over the course of treatment.  
Exosomes and nivolumab therapy 
Exosomes are small membranous vesicles released by tumor cells which modulate the local 
microenvironment and communicate with distant cells. In order to accomplish these tasks, 
exosomes contain a variety of RNA species including miRNA, protein and specialized lipids. 
These attributes make exosomes attractive therapeutic targets, excellent biomarkers, and 
indicators of therapeutic responses. We have developed novel flow cytometric analyses where 
we utilize fluorescent dyes to track and quantify exosomes directly from patient sera. We plan to 
monitor exosomes levels in patient sera and look for changes in frequency or content following 
nivolumab therapy. 
Patient Reported Outcomes (PRO): 
There has been increasing recognition that Patient-Reported Outcome (PRO) measures—
including, in particular, measures of health-related quality of life (HRQOL)—can convey 
essential supplementary information for assessing the overall burden of cancer and the 
effectiveness of interventions [21]. Hence, we will collect Functional Assessment of Cancer 
Therapy - General (FACT-G) and cancer specific FACT scales. The FACT questionnaires have 
been used by researchers previously and have shown to be optimal for use in oncology 
trials[22] .It has also been shown that depression is the most frequently found psychological 
symptom among individuals with cancer, up to 38% of cancer patients meeting criteria for a 
diagnosis of major depression [23]. Prevalence rates of depression in cancer patients differ 
extensively across studies [24, 25]. Previous studies have also shown that depression might 


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affect behavior and adherence to medical treatment [26].Hence, we will collect Patient Health 
Questionnaire (PHQ2&9). The PHQ-2 comprises the first two items of the PHQ-9.  It is a screen 
for depression; patients who screen positive are further evaluated with the PHQ-9 which is used 
for making a criteria-based diagnosis of depression (based on the Diagnostic and Statistical 
Manual of Mental Disorders (DSM)-IV criteria for depression).  The PHQ-2 has been validated in 
several studies [27].  The diagnostic validity of the PHQ was established in two large studies in 
primary care and obstetrics [28].   
 
Additional Lab tests and waist to hip ratio: 
C - reactive protein (CRP) is an acute phase reactant [29], which reflects tissue injury .It is also 
a well-established marker for inflammation[30]. However, in recent literature it has also been 
shown to be a predictive biomarker for immunotherapy[31], elevated CRP also predicted 
prognosis and treatment response[32]. The frequency of significant Immune Related adverse 
Events (irAE) in Immune Checkpoint Inhibitors (ICI) treated patients are about 10–20% and 
early recognition is critical to prevent serious morbidity and even mortality[33]. New onset 
autoimmune Diabetes Mellitus (DM) associated with immune checkpoint inhibitor treatment is 
extremely rare [33, 34]. Even though it is very rare possibility having Glycated Hemoglobin 
(HbA1c) levels will be beneficial to capture these rare events. Lipid metabolism is altered in 
proliferating cells and impact tumor progression[35, 36].  Therefore, tumor dependence towards 
lipids might hold potential for the treatment of the most intractable cancers. 
 
Waist to hip ratio (WHR) has been associated with metabolic syndrome and higher mortality[37, 
38]. Hence, WHR should be assessed in combination with BMI as part of risk assessment for 
obesity related premature mortality and risk of metabolic related conditions. 
 
1.4 
Potential Risks and Benefits 
1.4.1 
Potential Risks 
The safety profile of nivolumab is well characterized from a large safety database at different 
dose and schedules as monotherapy or in combination. Consistent with the mechanism of 
action of nivolumab, the most frequently reported drug-related adverse events observed in 
clinical trials are those associated with activation of the immune system. The most common 
types of immune-mediated adverse events include endocrinopathies, diarrhea/colitis, hepatitis, 
pneumonitis, nephritis and rash. In the combination regimen, the frequency and intensity of 
these events may vary and depend on the specific dose and schedule used. 
• 
The safety of this drug combination with chemotherapy in Non-small cell lung cancer has 
shown the following. 18 


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The safety of chemotherapy vs. chemotherapy plus pembrolizumab in NSCLC assists in making 
a judgement about the combination of nivolumab plus chemotherapy, and thus, the randomized 
chemotherapy plus/minus pembrolizumab data are instructive.19 The incidence of grade 3 or 
worse toxicities were 39% and 26% with chemotherapy plus pembrolizumab vs. chemotherapy 
alone. There was 1 and 2 treatment related deaths in the pembrolizumab containing vs. control 
arm respectively. The authors concluded the triplet pembrolizumab containing regimen was 
tolerable. 


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1.4.2 
Benefits 
Clinical activity of nivolumab monotherapy in patients with recurrent or metastatic SCCHN who 
progressed from a platinum containing therapy evaluated in CA209141 randomized phase 3 
study, demonstrated prolonged survival benefit with nivolumab as compared to investigator’s 
choice (IC) of chemotherapy. In this population, the safety profile of nivolumab was shown to be 
favorable as compared to standard of care chemotherapy. The addition of pembrolizumab to 
platinum doublets in NSCLC improved response and progression free survival compared to 
chemotherapy alone and of nivolimab plus platinum doublets compared to historical controls.  
Given the activity of both platinum doublets and nivolumab in head and neck cancer, these 
NSCLC data support the promise of improved pathologic response at the primary site of 
combination platinum doublet plus nivolumab in head and cancer.   
2 Study Objectives 
2.1 
Objectives 
2.1.1 
Primary 
The primary objective of the study is to estimate pathologic complete response (pCR) at the 
primary site in patients with newly diagnosed and untreated Stage III-IVA SCCHN of the oral 
cavity, Oropharynx, Larynx, and Hyopharynz with Nivolumab, paclitaxel and carboplatin in 
addition to standard chemotherapy. 
2.1.2 
Secondary 
• 
Safety 
• 
Complete Pathologic Response at all sites of disease 
• 
Major pathologic response rate at primary site 
• 
Overall Clinical Response Rate  
• 
Clinical Complete Response Rate 
• 
1 year PFS. 
• 
Overall survival. 
2.1.3 
Exploratory 
• 
To explore whether PDL1 expression is associated with treatment response 
• 
To explore whether there is a net change in the Th1/Th2 ratio (IFN-γ, IL-4, IL10, etc.) or 
cell subset frequencies (M2 monocytes, myeloid-derived suppressor cells, etc.) within a 
patient’s peripheral blood either at baseline or in response to treatment is associated 
with treatment response 
• 
To explore whether exosomes or other immune related serum biomarkers change after 
combination therapy. 
• 
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The aims for collecting PROs are to identify risks for poor physical and mental health outcomes; 
examine bio-behavioral factors associated with cancer treatment outcomes; and evaluate the 
physical and psychosocial needs of cancer survivors.   
 
Patient Reported Outcomes Measures-: Depression: PHQ2, PHQ9; Quality of Life: FACT-G 
and FACT-HN 
 
2.2 
Endpoints/Outcome Measures 
2.2.1 
Primary 
The primary objective of the study is to estimate the rate of pathologic complete response (pCR) 
at the primary site, defined as the absence of any residual invasive cancer on H&E evaluation of 
the resected specimen and all sampled ipsilateral lymph nodes, in patients with newly 
diagnosed and untreated Stage III-IVA SCCHN of the oral cavity, Oropharynx, Larynx, and 
Hypopharynx treated with standard neoadjuvant chemotherapy plus Nivolumab, paclitaxel, and 
carboplatin. 
2.2.2 
Secondary 
Major pathologic response. This is defined as 10% or less residual viable tumor (Hellmann M, 
Lancet Oncol. 2014).   
Safety will be continually assessed using the CTCAE version 5.0. 
Overall Survival (OS) is defined as the time between the date of study entry and the date of 
death. For subjects without documentation of death, OS will be censored on the last date the 
subject was known to be alive. 
The proportion of subjects with each category of overall clinical response will be summarized by 
presence of baseline measurable disease (i.e., CR, PR, SD, PD, UE, ND). Beta(2,5) will be 
used as priors for combination regimens in calculating the posterior distribution of the pCR for 
each respective treatment group. Among subjects with measurable disease, a 95% credible 
region will be calculated for the odds ratio for each treatment combination relative to each other. 
The association of biomarkers with pCR will be completed univariably by t-test for continuous 
measures and by chi-square test for categorical marker measures (for example positive versus 
negative expression).  Longitudinal assessments of biomarkers will be assessed for association 
with pCR via linear mixed models of biomarker measures with pCR and treatment assignment 
and the interaction of pCR and treatment assignment as potential covariates. Additional 
exploratory analysis of longitudinal biomarkers may be completed using latent class models, 
with pCR and treatment assignment as potential covariates to inform latent class membership.  
The specific hypotheses indicated will be completed via contrasts from the linear mixed models, 
as appropriate. 
2.2.3 
Exploratory 


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Blood samples: 
There will be 3 presurgical and 1 postsurgical blood draw.  The first will be within 2 weeks of the 
initiation of the induction regimen, the second will just prior to the week 5 infusion, the third will 
be presurgical on the day of surgery and the last will be > 1 < 4 weeks postsurgery. (see study 
schedule 6.0). 
• 
PDL1 expression 
We plan to monitor changes in PDL1 expression on tumor cells, tumor-infiltrating 
macrophages, and circulating monocytes by immunohistochemistry and flow cytometry. 
We will look for correlations between PDL1 expression on these cell subsets and 
treatment-induced clinical responses.  
 
• 
Immune bias 
We will monitor changes in immune bias during treatment using three assays. 
1) Changes in PBMC cell subset frequencies (M2 monocytes, myeloid-derived 
suppressor cells, etc.)  
2) Changes in patient serum cytokines (IL2, IL4, IL10, IL13, IFNg, etc.)  
3) Changes in the capacity to polarization normal human monocytes in vitro. 
 
• 
Exosomes  
We will look for changes in exosome quantity and content following nivolumab and 
carboplatin plus paclitaxel. 
 
Tumor specimen: 
PD-L1 will also be assessed using IHC on the baseline tumor tissue and the surgical specimen.  
For this, the SP263 rabbit monoclonal antibody of Ventana will be used.  Note for the baseline, 
an archived formalin fixed paraffin embedded sample can be used.  Also, we anticipate that 
some patients will have a pCR. However, peri-cancerous tissue can also be PD-L1 assessed.   
Baseline p16 status will also be obtained for all oropharyngeal cancer patients.   
3 Study Design 
3.1 
Characteristics 
This is a phase II trial looking at the combination of weekly carboplatin plus paclitaxel to which 
nivolumab is added as induction therapy prior to planned surgery for the definitive management 
of locally advanced squamous cell carcinomas of the head and neck. 
TREATMENT PLAN 
Induction Nivolumab + carboplatin + paclitaxel  


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• 
Nivolumab 240mg every 2 weeks x 3 doses (last dose at least 3 weeks before surgery) 
• 
Carboplatin AUC 2 weekly x 6 doses (last dose at least 2 weeks before surgery) 
• 
Paclitaxel 100 mg/m2 x 6 doses (last dose at least 2 weeks before surgery) 
 
Evaluation of Response to Chemotherapy 
Clinical response to chemotherapy will be measured by clinical exam by the medical and 
surgical oncologist throughout administration of chemotherapy.  PET/CT or, if patients cannot 
have a PET/CT, a CT or MRI will be obtained during the initial staging work-up for all patients. If 
the treating medical oncologist determines that there is evidence that the patient is progressing 
while on treatment (i.e., tumor size if found to be increased during treatment), imaging with MRI, 
CT, or ultrasound will be obtained for evaluation. For patients who are determined to have 
progression during treatment by their medical oncologist, study treatment will be discontinued 
and the patient will be considered for immediate surgery, as determined by the discretion of 
their treating oncologist and surgeon. Finally, pathologic response will be assessed in the final 
tumor specimen, and attainment of pathologic complete response at primary site (defined as the 
absence of any residual invasive cancer on H&E evaluation of the resected primary cancer 
specimen) will be determined by pathologic review. Pathologic complete response of the entire 
tumor will also include all sampled lymph nodes. 
Surgery 
All patients will undergo surgery after completing the induction regimen.  Surgery will be 
scheduled at least 2 weeks after the last dose of carboplatin and paclitaxel.  
3.2 
Number of Participants 
37 participants. Enrollment will be competitive across all the sites. 
3.3 
Duration of Therapy 
6 weeks 


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3.4 
Duration of Follow Up 
8 months after enrollment on trial 
3.5 
Study Timeline 
3.5.1 
Primary Completion 
We anticipate accrual of 37 patients to the study over a 30 month time period. Patients will 
remain on study for 8 months total, 2 months of induction and then 6 months of follow-up after 
surgery whether or not patients receive post-operative radiation. 
3.5.2 
Study Completion 
We anticipate completion of the study in 38 months. 
4 Study Enrollment and Withdrawal 
4.1 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent. The written informed consent must be obtained 
from the patient prior to screening procedures being performed. The following criteria apply to 
all patients enrolled onto the study unless otherwise specified. 
4.1.1 
Inclusion Criteria 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate in 
the study: 
1. Patients must be 18 years of age and older. 
2. Pathologically confirmed SCCHN, not previously treated, with a plan to undergo surgery 
3. Patients who have stage III-IV disease without distant metastases (M0) of 1) oral cavity, 
2) larynx, 3) hypopharynx 4) oropharynx (HPV neg) using AJCC 8th edition  
4. Patients who have oropharyngeal cancer that is HPV positive, Stage II-III disease 
without distant metastases (M0) using AJCC 8th edition 
5. All patients with oropharyngeal SCCHN must be tested for HPV (by p16 and/or HPV ISH 
or PCR) 
6. Patients must be evaluated by a head and neck surgeon and be deemed surgically 
resectable at baseline. 
7. Tumor sample must be available for HPV p16 and PD-L1 testing and if oropharyngeal, 
must be tested for HPV p16 
8. ECOG Performance status 0-1. 


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9. Adequate organ function:  
o While blood cells 2000/ul or more 
o Absolute neutrophil count 1500/ul or more;  
o Platelets 100,000/ul or more,  
o Hemoglobin 9 g/dl or more; (transfusion permitted) 
o Bilirubin less than or equal to 1.5 x the upper limit of normal (except subjects with 
Gilbert syndrome, who can have total bilirubin <3 mg/dl);  
o AST and ALT less than or equal to 3 x the upper limit of normal,  
o GFR greater than or equal to 40 ml/min using the Cockcroft-Gault formula or 
Serum creatinine less than or equal to 1.5 x ULN 
10. Women of reproductive potential should have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 21 days of study 
enrollment. 
11. Women of reproductive potential must use highly effective contraception methods to 
avoid pregnancy for 23 weeks after the last dose of study drugs. “Women of 
reproductive potential” is defined as any female who has experienced menarche and 
who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or 
who is not postmenopausal. Menopause is defined clinically as 12 months of 
amenorrhea in a woman over 45 in the absence of other biological or physiological 
causes. In addition, women under the age of 55 must have a documented serum follicle 
stimulating hormone (FSH) level less than 40 mIU/mL. 
12. Men of reproductive potential who are sexually active with women of reproductive 
potential must use any contraceptive method with a failure rate of less than 1% per year.  
Men who are receiving the study medications will be instructed to adhere to 
contraception for 31 weeks after the last dose of study drugs.  Men who are 
azoospermic do not require contraception. 
13. Informed Consent:  All subjects must be able to comprehend and sign a written informed 
consent document.  
4.1.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Primary nasopharyngeal carcinoma. 
2. Patients who have participated in a study with an investigational agent or device within 2 
weeks of initiation of treatment. 
3. Any prior radiotherapy to the neck. 
4. Any prior treatment for SCCHN. 
5. Any prior therapy with anti-PD-1, anti-PD-L2, anti-CTLA-4 antibody, or any other 
antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint 
pathways 
6. Any history of a sever hypersensitivity reaction to any monoclonal antibody. 
7. Any history of allergy to the study drug components. 
8. Any concurrent malignancies- exceptions include- basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer 
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malignancy must have been treated with curative intent and must have remained 
disease-free for 3years post-diagnosis. 
9. Any diagnosis of immunodeficiency or current immunosuppressive therapy including 
>10mg/day of prednisone within 14 days of enrollment is not permitted (excludes 
emergency transient steroid use at discretion of the treating physician).     
10. Patients that have an active autoimmune disease requiring systemic treatment within the 
past 3 months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids (> 10 mg daily prednisone equivalents)  or 
immunosuppressive agents. Subjects with vitiligo, type I diabetes mellitus, or resolved 
childhood asthma/atopy would be an exception to this rule. Inhaled or topical steroids, 
and adrenal replacement steroid doses ≤10 mg daily prednisone equivalent, are 
permitted in the absence of active autoimmune disease. Subjects with hypothyroidism 
stable on hormone replacement or Sjorgen’s syndrome will not be excluded from the 
study.  
11. Patients with a known Human Immunodeficiency Virus infection (HIV 1/2 antibodies) or 
Acquired Immunodeficiency Syndrome (HIV/AIDS), active Hepatitis B (e.g., HBsAg 
reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). 
12. Patients with evidence of non-infectious pneumonitis or history of interstitial lung 
disease. 
13. Patients who have received a live vaccine within 30 days prior initiation of the systemic 
regimen. 
14. Patients must not be receiving any other investigational agents. 
15. Patients with uncontrolled intercurrent illnesses including, but not limited to an active 
infection requiring systemic therapy or a known psychiatric or substance abuse 
disorder(s) that would interfere with cooperation with the requirements of the trial. 
16. Women must not be pregnant (as above) or breastfeeding. 
4.2 
Gender/Minority/Pediatric Inclusion for Research  
We will not exclude potential subjects from participating in this study based on ethnic origin or 
socioeconomic status. Every attempt will be made to enter all eligible patients in this protocol 
and therefore address the study objectives in a patient population representative of the entire 
head and neck squamous cell cancer population treated at Thomas Jefferson University 
Hospital. There is nearly a 3:1 predominance of males to females in this diagnosis. We will 
review accruals to this trial quarterly in the Head and Neck MDG and review the number of 
males and females accrued. If this deviates from the expected ratio we will review our actual 
patient ratio for that time and determine a remediation plan within the MDG to ensure accrual of 
women. 
4.3 
Strategies for Recruitment and Retention 
37 subjects will be recruited. Potential research subjects will be identified by a member of the 
patient’s treatment team, the protocol investigator, or research team at participating centers 
from Medical Oncology, Radiation Oncology and Surgical offices.  Investigators will screen the 
patient’s medical records for suitable research study subjects and discuss the study and their 
potential for enrolling in the research study. Patients will be screened based on pathology, 


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image studies etc. 37 patients will be enrolled (see Statistical Analysis Plan) with replacement of 
patients who do not begin therapy. 
4.4 
Sub-Site Enrollment Procedure 
When a potential patient is identified at the sub-site, the Thomas Jefferson University (TJU) 
study site contacted must be contacted within 1 business day via email or phone. Please see 
the Site Contact List for email and phone number for the TJU Study Site Contact. The sub-site 
will send the following to the TJU Study Site Contact: 
1. Notify them of the pending patient registration 
2. Email registration documents  
3. Communicate the desired timeline of the registration. 
The sub-site must include the eligibility checklist, signed informed consent, and any applicable 
documentation supporting eligibility.  
Once eligibility has been confirmed locally, TJU study site contact or delegated personnel will 
email the Research Coordinator at the sub-site site to confirm eligibility. The participant will then 
be assigned a registration number. This number is unique to the participant on this trial and 
must be used moving forward. The TJU Research Nurse/Coordinator will enter patients enrolled 
at the sub-site into the protocol management system, JeffTrial. 
A master study enrollment log will be maintained by the study team at Thomas Jefferson 
University. The sub-site site will also be asked to maintain an enrollment/screening log on-site, 
and email this information to the TJU Study Site Contact at least once a month.  
Patients cannot be registered to this study on the weekends. If a patient is to be registered on a 
Friday, the sub-site will need to contact the TJU Study Site Contact by Friday at noon at the 
latest.   
If a patient is enrolled at the sub-site without approval from the lead site, TJU will: 
1)  Temporarily suspend the sub-site  
2)  Complete mandatory re-training of staff at the sub-site on the enrollment process.  
This training will be fully documented. 
If enrollment without approval occurs a second time, the sub- site will not be able to continue to 
participate in this study. 
4.5 
Participant Withdrawal 
4.5.1 
Reasons for Withdrawal 


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Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may terminate a study participant’s participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant. 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. 
4.5.2 
Handling of Participant Withdrawals and Participant Discontinuation of 
Study Intervention 
Patients who are discontinued from the study prior to initiation of study drug will not be 
considered as evaluable for this study and will be replaced. 
4.6 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to investigator, funding agency, the Food and 
Drug Administration (FDA) and regulatory authorities. If the study is prematurely terminated or 
suspended, the principal investigator will promptly inform the IRB and will provide the reason(s) 
for the termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants. 
• 
Insufficient adherence to protocol requirements. 
• 
Data that is not sufficiently complete and/or evaluable.  
• 
Determination of futility. 
5 Study Intervention 
5.1 
Study Product  
• 
Nivolumab 
• 
Paciltaxel 
• 
Carboplatin 
5.2 
Study Product Description 


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Nivolumab: 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) cluster 
of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory 
molecule expressed by activated T and B lymphocytes.1 Binding of PD-1 to its ligands, 
programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. 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. Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced 
using standard mammalian cell cultivation and chromatographic purification technologies. The 
clinical study product is a sterile solution for parenteral administration. OPDIVO  (nivolumab) is 
approved for use in multiple countries including the United States (US, Dec-2014), the 
European Union (EU, Jun-2015), and Japan (Jul-2014). 
Carboplatin 
Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA-
protein cross-links. This effect is apparently cell-cycle nonspecific. The aquation of carboplatin, 
which is thought to produce the active species, occurs at a slower rate than in the case of 
cisplatin. Despite this difference, it appears that both carboplatin and cisplatin induce equal 
numbers of drug-DNA cross-links, causing equivalent lesions and biological effects. The 
differences in potencies for carboplatin and cisplatin appear to be directly related to the 
difference in aquation rates.  
In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of intact 
carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 300 to 500 
mg/m2 of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n=6), 
and the postdistribution plasma half-life (beta) was found to be 2.6 to 5.9 hours (n=6). The total 
body clearance, apparent volume of distribution and mean residence time for carboplatin are 4.4 
L/hour, 16 L and 3.5 hours, respectively. The Cmax values and areas under the plasma 
concentration vs time curves from 0 to infinity (AUC inf) increase linearly with dose, although the 
increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear 
pharmacokinetics over the dosing range studied (300 - 500 mg/m2).  
Carboplatin is not bound to plasma proteins. No significant quantities of proteinfree, 
ultrafilterable platinum-containing species other than carboplatin are present in plasma. 
However, platinum from carboplatin becomes irreversibly bound to plasma proteins and is 
slowly eliminated with a minimum half-life of 5 days.  
The major route of elimination of carboplatin is renal excretion. Patients with creatinine 
clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine within 12 
hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour urine is present as 
carboplatin. Only 3 to 5% of the administered platinum is excreted in the urine between 24 and 
96 hours. There are insufficient data to determine whether biliary excretion occurs. 


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In patients with creatinine clearances below 60 mL/min the total body and renal clearances of 
carboplatin decrease as the creatinine clearance decreases. PARAPLATIN Bristol-Myers 
Squibb Company Approved 1.0 Item 2 proposed.pdf Page 002 3 of 24 dosages should therefore 
be reduced in these patients 
Paclitaxel 
Paclitaxel is a natural product with antitumor activity. TAXOL (paclitaxel) is obtained via a semi-
synthetic process from Taxus baccata. The chemical name for paclitaxel is 5β,20-Epoxy-
1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with 
(2R,3S)-N-benzoyl-3-phenylisoserine. Paclitaxel has the following structural formula: Paclitaxel 
is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a 
molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216–
217° C. CLINICAL PHARMACOLOGY Paclitaxel is a novel antimicrotubule agent that promotes 
the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization. This stability results in the inhibition of the normal dynamic reorganization of 
the microtubule network that is essential for vital interphase and mitotic cellular functions. In 
addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell 
cycle and multiple asters of microtubules during mitosis. 
5.2.1 
Acquisition 
Nivolumab will be supplied by, Bristol-Myers Squibb.  Nivolumab will be supplied directly to each 
participating site from Bristol-Myers Squibb. 
Carboplatin is a standard of care medicine which will be supplied through the standard 
pharmacy.  Each site will acquire this agent through their pharmacies. 
Paclitaxel is a standard of care medicine which will be supplied through the standard pharmacy.  
Each site will acquire this agent through their pharmacies. 
 
5.2.2 
Formulation, Packaging, and Labeling 
Nivolumab: 
 
Nivolumab, also referred to as BMS-936558-01 or BMS-936558, is a soluble protein consisting 
of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical light chains. The 
physical and chemical properties of nivolumab are: 
 
BMS Number 
BMS-936558-01 
Other Names 
Nivolumab, BMS-936558, MDX1106, ONO-4538, anti-PD-1 
Molecular Weight 
146,221 daltons (143,619.17 daltons, protein portion) 
Appearance 
Clear to opalescent, colorless to pale yellow liquid, light (few) 
particulates may be present 


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Solution pH 
5.5 to 6.5 
 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is a clear to opalescent, colorless to pale yellow 
liquid, which may contain light (few) particulates. The drug product is a sterile, non-pyrogenic, 
single-use, isotonic aqueous solution formulated at 10 mg/mL in sodium citrate, sodium 
chloride, mannitol, diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 
(Tween
 80), pH 6.0 and includes an overfill to account for vial, needle, and syringe holdup. It 
is supplied in 10-cc Type I flint glass vials, stoppered with butyl rubber stoppers and sealed with 
aluminum seals. The only difference between the two drug product presentations is the vial fill 
volume. 
Carboplatin 
PARAPLATINÆ (carboplatin aqueous solution) INJECTION is supplied as a sterile, pyrogen-
free, 10 mg/mL aqueous solution of carboplatin. Carboplatin is a platinum coordination 
compound. The chemical name for carboplatin is platinum, diammine [1,1- cyclobutane-
dicarboxylato(2-)-0,0í]-,(SP-4-2).  Carboplatin is a crystalline powder with the molecular formula 
of C6H12N2O4Pt and a molecular weight of 371.25. It is soluble in water at a rate of 
approximately 14 Bristol-Myers Squibb Company Approved 1.0 Item 2 proposed.pdf Page 001 2 
of 24 mg/mL, and the pH of a 1% solution is 5-7. It is virtually insoluble in ethanol, acetone, and 
dimethylacetamide. 
Paclitaxel 
TAXOL (paclitaxel) Injection is a clear, colorless to slightly yellow viscous solution. It is 
supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid 
prior to intravenous infusion. TAXOL is available in 30 mg (5 mL), 100 mg (16.7 mL), 
and 300 mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 
6 mg paclitaxel, 527 mg of purified Cremophor® EL* (polyoxyethylated castor oil) and 
49.7% (v/v) dehydrated alcohol, USP. 
 
5.2.3 
Product Storage and Stability 
Nivolumab: 
Vials of nivolumab injection must be stored at 2°C to 8°C (36°F to 46°F) and protected from light 
and freezing. 
The administration of nivolumab infusion must be completed within 24 hours of preparation. If 
not used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20°C to 25°C, 68°F to 77°F) and room light. The maximum 8-hour period 
under room temperature and room light conditions includes the product administration period. 


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Carboplatin 
Unopened vials of PARAPLATIN (carboplatin aqueous solution) INJECTION are stable to the 
date indicated on the package when stored at 25° C (77° F); excursions permitted from 15°-30° 
C (59°-86° F) [see USP Controlled Room Temperature]. Protect from light. PARAPLATIN 
(carboplatin aqueous solution) INJECTION multidose vials maintain microbial, chemical, and 
physical stability for up to 14 days at 25° C following multiple needle entries. Parenteral drug 
products should be inspected visually for particulate matter and discoloration prior to 
administration. Solutions for infusion should be discarded 8 hours after preparation. 
Paclitaxel 
Stability  
Unopened single-dose vials of TAXOL (paclitaxel) Injection for Dilution are stable until the date 
indicated on the package when stored in the original package below 25 degrees C. (Freezing 
does not adversely affect the product). 
5.3 
Dosage, Preparation, and Administration  
Nivolumab: 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding (polyethersulfone membrane) in-line filter at the protocol specified 
doses and infusion times. It is not to be administered as an IV push or bolus injection. 
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL. 
During drug product preparation and handling, vigorous mixing or shaking is to be avoided. 
Instructions for dilution and infusion of nivolumab injection may be provided in the clinical 
protocol, pharmacy binder, pharmacy manual, or pharmacy reference sheet. Care must be 
taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. Nivolumab infusions are compatible with 
polyvinyl chloride (PVC) or polyolefin containers and infusion sets, and glass bottles. 
Carboplatin 
Per standard of care 
Paclitaxel 
Per standard of care 
Dosage & Administration Time of Nivolumab 
The dose of nivolumab is a flat dose 240mg administered intravenously over at least 30 
minutes.  Do not co-administer other drugs through the same intravenous line. Flush the 
intravenous line at end of infusion.  


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Frequency of Treatment: 
For the duration of the study, nivolumab is to be administered on a Q2 weeks and carboplatin 
and paclitaxel Q weekly.  On the weeks of nivolumab administration, it will precede 
chemotherapy administration. 
5.4 
Dose Modifications and Dosing Delays 
Nivolumab: 
There will not be dose modifications 
• 
Renal Impairment:  The effect of renal impairment on the CL of nivolumab was evaluated 
in subjects with mild (GFR < 90 and ≥ 60 mL/min/1.73 m2; n=379), moderate (GFR < 60 
and ≥ 30 mL/min/1.73 m 2; n=179), or severe (GFR <30 and ≥ 15 mL/min/1.73 m2; n=2) 
renal impairment compared to subjects with normal renal function (GFR ≥ 90 
mL/min/1.73 m2; n=342) in the PPK analysis. No clinically important differences in the 
CL of nivolumab were found between subjects with mild or moderate renal impairment 
and subjects with normal renal function. Data from subjects with severe renal impairment 
are too limited to draw conclusions on this population.  Thus, patients with severe renal 
impairment are excluded from the student presented here. 
 
• 
Hepatic Impairment: The effect of hepatic impairment on the CL of nivolumab was 
evaluated in subjects with mild hepatic impairment (total bilirubin 1.0 to 1.5 times ULN or 
AST > ULN as defined using the National Cancer Institute criteria of hepatic dysfunction; 
n=92) compared to subjects with normal hepatic function (total bilirubin and AST ≤ ULN; 
n=804) in the population PK analyses. No clinically important differences in the CL of 
nivolumab were found between subjects with mild hepatic impairment and normal 
hepatic function. Nivolumab has not been studied in subjects with moderate (total 
bilirubin > 1.5 to 3 times ULN and any AST) or severe hepatic impairment (total bilirubin 
> 3 times ULN and any AST). 
 
 
 
 
 
 
Dose Delays: 
Dose delay criteria apply for all drug-related AEs.  
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed. 
Nivolumab administration should be delayed for the following: 
• 
Any Grade ≥ 2 non-skin, drug-related adverse event, except for fatigue and laboratory 
abnormalities 
• 
Any Grade ≥ 3 skin drug-related AE  


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• 
Any Grade ≥ 3 drug-related laboratory abnormality with the following exceptions for 
lymphopenia, AST, ALT, or total bilirubin or asymptomatic amylase or lipase 
o Grade 3 lymphopenia does not require a dose delay 
o If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, 
delay dosing for drug-related Grade 2 toxicity (Increase frequency of monitoring 
to every 3 days). 
o Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated 
with symptoms or clinical manifestations of pancreatitis does not require dose 
delay. The TJU PI should be consulted for such Grade ≥ 3 amylase or lipase 
abnormalities. 
• 
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
Rescheduling: 
• 
Nivolumab may be delayed until the next planned carboplatin plus paclitaxel dose if the 
next carboplatin plus paclitaxel doses are scheduled within the next 12 days. This will 
permit periodic carboplatin plus paclitaxel dosing to be synchronized with nivolumab 
dosing.  
• 
It should be noted delay of nivolumab of a week could result in a dose of nivolumab on 
the last scheduled infusion of carboplatin plus paclitaxel just 2 weeks before scheduled 
surgery which is permitted. 
Criteria to Resume Nivolumab Dosing: 
• 
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) 
to Grade ≤ 1 or baseline, with the following exceptions: 
o Subjects may resume treatment in the presence of Grade 2 fatigue. 
o Subjects who have not experienced a Grade 3 drug-related (non-radiation 
dermatitis) skin AE may resume treatment in the presence of Grade 2 skin 
toxicity. 
o Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued. 
o Drug-related pulmonary toxicity, neurologic toxicity, and hepatic toxicity must 
have resolved to baseline before treatment is resumed. Subjects with persistent 
Grade 1 pneumonitis after completion of a steroid taper over at least 1 month 
may be eligible for retreatment if discussed with and approved by the TJU PI. 


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o Subjects who received systemic corticosteroids for management of any drug-
related toxicity must be off corticosteroids or have tapered down to an equivalent 
dose of prednisone ≤10 mg/day. 
o Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment. 
o Subjects who delay study treatment due to any Grade ≥ 3 amylase or lipase 
abnormality that is not associated with symptoms or clinical manifestations of 
pancreatitis, and that is assessed by the investigator to be related to nivolumab, 
may resume nivolumab when the amylase or lipase abnormality has resolved to 
Grade < 3. The TJU PI should be consulted prior to resuming nivolumab in such 
subjects. 
Criteria to Discontinue Nivolumab 
Treatment with nivolumab should be permanently discontinued for any of the following: 
• 
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 
• 
Any Grade ≥ 2 drug-related pneumonitis or interstitial lung disease that does not resolve 
to dose delay and systemic steroids  
• 
Any Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction, 
regardless of duration 
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
hypersensitivity reactions, infusion reactions, endocrinopathies, and laboratory 
abnormalities: 
o Any Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic toxicity, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation. 
o Any Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
o Any Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
 
Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation. 


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o Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation (also see Hepatic Adverse Event Management 
Algorithm): 
 
AST or ALT > 8x ULN 
 
Total bilirubin > 5 x ULN 
 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events, which do not require discontinuation: 
o Grade 4 neutropenia ≤ 7 days 
o Grade 4 lymphopenia or leukopenia 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset. The TJU PI should be consulted for Grade 4 amylase or 
lipase abnormalities 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
o Grade 4 drug-related endocrinopathy adverse events such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, 
which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose controlling agents, 
respectively, may not require discontinuation after discussion with and approval 
from the TJU PI. 
• 
Dose delay of nivolumab which results in treatment interruption of > 2 weeks requires 
treatment discontinuation. 
• 
Dosing delays lasting > 2 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the TJU PI.  
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment 
of the Investigator, presents a substantial clinical risk to the subject with continued 
nivolumab dosing.  
Please see Appendix D for Strategies to Treat Adverse Events. 
For subjects expected who require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an adverse event, consider the following recommendations  


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• 
Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic 
infections such as Pneumocystis jiroveci and fungal infections. 
• 
Early consultation with an infectious disease specialist should be considered. Depending 
on the presentation, consultation with a pulmonologist for bronchoscopy or a 
gastroenterologist for endoscopy may also be appropriate. 
• 
In patients who develop recurrent adverse events in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the 
differential diagnosis. 
Treatment of Nivolumab Related Infusion Reactions 
Since nivolumab contain 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, pruritus, arthralgias, hypo- 
or hypertension, bronchospasm, or other symptoms.  
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE 5.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
additional nivolumab administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours). 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the infusion 
is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% 
of the original infusion rate. Monitor subject closely. If symptoms recur then no further nivolumab 
will be administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside 
and monitor the subject until resolution of symptoms. The amount of study drug infused must be 
recorded on the electronic case report form (eCRF). The following prophylactic premedications 


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are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 30 minutes 
before additional nivolumab administrations. If necessary, corticosteroids (recommended dose: 
up to 25 mg of IV hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: 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).  
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and treat 
the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly 
for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed. Subject should be monitored until the investigator is comfortable that 
the symptoms will not recur. Nivolumab will be permanently discontinued. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery from symptoms. In the case of late-occurring hypersensitivity 
symptoms (e.g., appearance of a localized or generalized pruritus within 1 week after 
treatment), symptomatic treatment may be given (e.g., oral antihistamine, or corticosteroids). 
Chemotherapy Dose Modifications: 
Doses of carboplatin and paclitaxel may require reduction for hematologic or non-hematologic 
toxicities (see sections below). Dose adjustments should be made according to the organ 
system showing the greatest toxicity as graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE). Treatment may be delayed for up to two weeks. If a 
patient does not fulfill re-treatment criteria by that time, the responsible chemotherapy agent(s) 
should be discontinued. Table 5.A.5 summarizes the guidelines for paclitaxel and carboplatin 
doses to be used when modifications are required. If chemotherapy is discontinued, nivolumab 
therapy should also conclude and the patient will advance to surgery. The total induction 
treatment period should not exceed 8 weeks.  If there are further toxicities warranting 
adjustments after the first dose reduction, the chemotherapy will be discontinued, nivolumab 
therapy should also conclude and the patient will advance to surgery. 
Dose level reductions for paclitaxel and carboplatin 
Dose Level 
Paclitaxel 
(mg/m2) 
Carboplatin 
(target AUC) 
Starting Dose 
100 
2.0 
First Reduction 
75 
1.5 
 


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Hematologic Toxicity 
In general, courses of paclitaxel and carboplatin should not be repeated until the neutrophil 
count is at least 1500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. The 
severity of neutropenia increases with dose. Table 5.A.5.a summarizes the guidelines for dose 
modifications based on hematologic toxicities. Mid-week use of filgrastim (suggest 5μg/kg SC 
days 3 and 4) will be included.   
Table 5.A.5.a.  Dose adjustments for paclitaxel and carboplatin for 
hematologic toxicity are based on weekly CBC results: 
ANC 
 
PLT 
Dose Modification 
500-1500/mm3 
or 
75-100 000/mm3 
1 week delay 
 
<500/mm3 
or 
<75 000/ mm3 
1 week delay then reduce dose 
(see table 5.A.5) 
Note: 
• 
If blood counts have not recovered to ANC>1500/mm3 and 
PLT>100,000/mm3after a two week delay, then proceed to surgery. 
• 
If febrile neutropenia occurs, discontinue chemotherapy and proceed to 
surgery, after recovery. 
• 
Filgrastim 5mg/kg SC, at physician’s discretion, may be administered on 
any 2 days inclusive days 2 -6 (preferred days 3 & 4) of each treatment 
week to reduce marrow suppression. 
Peripheral Neuropathy 
If grade 2 peripheral neuropathy occurs, the paclitaxel dose should be decreased by one dose 
level (see Table 5.A.5).  If grade 3 or higher toxicity occurs, the chemotherapy should be 
discontinued. 
Hypersensitivity Reactions to Paclitaxel 
Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not 
require interruption of therapy. However, severe reactions attributed to paclitaxel such as 
hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or 
generalized urticaria require immediate discontinuation of paclitaxel and aggressive 
symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not 


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be rechallenged with paclitaxel. The attending physician will make the ultimate determination of 
the advisability of continuing paclitaxel or not.   
Hepatic Toxicity 
Paclitaxel is not known to cause hepatic toxicity; however, its elimination may be delayed in 
patients with severe hepatic dysfunction. Therefore, the dose of paclitaxel in patients with 
hepatic dysfunction should be modified according to Table 5.A.5.d. 
 
Table 5.A.5.d.  Paclitaxel dose reductions for hepatic toxicity 
NCI Liver function abnormalities 
Paclitaxel dose modification 
Grade 0-1 
No change 
Grade 2 
Dose reduction (see table 5.A.5) 
 
5.5 
Study Product Accountability 
Table 1 
Product Description 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packagi
ng 
(Volume)
/ Label 
Type 
Appearance 
Storage 
Conditions 
(per label) 
Nivolumab BMS-
936558-01 
Solution for 
Injectiona 
100 mg 
(10 
mg/mL) 
10 mL 
vial 
Clear to 
opalescent 
colorless to pale 
yellow liquid. May 
contain particles 
2 to 8°C. Protect 
form light and 
freezing 
Drug Destruction: 
Sponsor/Investigator drug destruction is allowed provided the following minimal standards are 
met: 
On-site disposal practices must not expose humans to risks from the drug. 
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 


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Written procedures for on-site disposal are available and followed. The procedures must be filed 
with the Sponsor SOPs and a copy provided to BMS upon request. 
Records are maintained that allow for traceability of each container, including the date disposed 
of, quantity disposed, and identification of the person disposing the containers. The method of 
disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal vendor must be 
documented. 
Accountability and disposal records are complete, up-to-date, and available for BMS to review 
throughout the clinical trial period as per the study agreement. A copy of the drug destruction 
certificate should be maintained for provision to BMS at the end of the study. 
It is the Sponsor Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to applicable 
federal, state, local, and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
Paclitaxel 
Paclitaxel must be obtained from commercial sources and will be provided and stored according 
to institutional guidelines. Paclitaxel 100 mg/m2 will be administered intravenously weekly on a 
14-day cycle. Paclitaxel will be administered prior to carboplatin on the same schedule.  
The following adverse events are expected with the administration of Paclitaxel. For complete 
information, see Package Insert. 
Carboplatin 
Carboplatin must be obtained from commercial sources and will be provided and stored 
according to institutional guidelines. Carboplatin AUC=2 will be administered weekly of a 14-day 
cycle. Carboplatin will be administered after paclitaxel.  
The dose of carboplatin will be adjusted for renal dysfunction to achieve a calculated AUC as 
defined by the following Calvert Formula. The calculated GFR for the carboplatin dose will be 
based on the calculated creatinine clearance using the Cockroff-Gault formula.  
Calvert Formula for carboplatin dose: 
AUC Dose = 2.0 X (GFR + 25) 
WHERE GFR (Cockroff-Gault): 
GFR = (140 – Pt. Age in Yrs) (Weight in Kg) X 0.85 (females) or 1.0 (males) 
Serum Creatinine X 72 
The GFR dosing should not exceed 125 mL/min under any circumstance. If the calculated 
creatinine clearance is larger than 125 mL/min, a clearance of 125 mL/min should be used. 


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5.6 
Assessing Participant Compliance with Study Product Administration 
Patient records will be reviewed for compliance with chemotherapy and nivolumab treatments 
with all deviations and delays noted. 
5.7 
Concomitant Medications/Treatments 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this with 
the Dr. Jennifer Johnson The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician. However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator, and the subject 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication and therapies will be recorded on the case report form 
(CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids. If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date should also be included on the CRF.  
All concomitant medications received within 28 days before informed consent is signed and 30 
days after the last dose of trial treatment should be recorded. Concomitant medications 
administered to treat SAEs and ECIs should be recorded as defined. 
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event): 
• 
Immunosuppressive agents. 
• 
Immunosuppressive doses of systemic corticosteroids, with the following exceptions: 
o Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption).  
o Adrenal replacement steroid doses > 10 mg daily prednisone are permitted.  
o A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g., 
contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
• 
Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, extensive, non-palliative radiation therapy, or standard or investigational 
agents for treatment of cancer. 


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• 
The use of amifostine is not permitted. 
• 
The use of hematopoietic growth factors can be considered at the discretion of the 
treating physician  
• 
All other medications are permitted except those that are contraindicated in the 
exclusion criteria (section 4.1.2). 
Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of 
corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune 
conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted. 
Although monoclonal antibodies are not direct inhibitors/inducers of metabolizing enzymes, 
recent literature reports suggest that therapeutic proteins that are modulators of cytokines may 
indirectly affect expression of cytochrome (CYP) enzymes. The indirect drug-drug interaction 
potential of nivolumab was assessed using systemic cytokine modulation data for cytokines 
known to modulate CYP enzymes, at single and multiple doses of 0.3 to 10 mg/kg Q3W from 
CA209009. There were no meaningful changes in cytokines known to have indirect effects on 
CYP enzymes across all dose levels of nivolumab (0.3, 2 and 10 mg/kg) during the course of 
treatment. 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. 
Nivolumab is an IgG4 monoclonal antibody, which is eliminated by mechanisms similar to that of 
other antibodies, namely by non-specific catabolism (mainly by enzymes in the 
reticuloendothelial system). These enzymes are not known to be inhibited or induced by drugs, 
and therefore it is unlikely that other drugs will have an impact on the PK of nivolumab. 
All supportive measures consistent with optimal patient care will be given throughout the study.  
This includes the use of antiemetic therapy at the discretion of the treating physician, as well as 
pilocarpine and cevimeline. Use of these agents will be recorded on the data forms. 
Aggressive oral and skin can is recommended, as are analgesics. 
The prophylactic placement of a gastrostomy tube before treatment begins is at the discretion of 
the treating physician but it not encouraged. It is strongly recommended for patients with 
significant dysphagia and weight loss. 
Salvage surgery may be performed after chemoradiotherapy is there is local and / or regional 
progression of disease.   
5.8 
Dietary Restrictions 
There are no dietary restrictions 
6 Study Schedule  


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6.1 
Enrollment/Baseline (Visit 1, Day 0) 
• 
Obtain and document consent from potential participant on protocol consent form. 
• 
Review medical/dental history to determine eligibility based on inclusion/exclusion 
criteria. 
• 
Review medications history to determine eligibility based on inclusion/exclusion criteria. 
• 
Verify baseline tumor tissue specimen available. FFPE core/excisional specimen 
archived is highly encouraged preferably with at least 5 cores. Tissue for frozen and 
FFPE core or excisional biopsy will be obtained as feasible. 
o Tumor sample prior to therapy is mandatory to confirm the presence of 
squamous cell carcinoma, for HPV p16 testing in oropharyngeal carcinomas, and 
for PD-L1 testing for all patients. If a recent (obtained within 3 months of 
enrollment without interim therapy as dictated in the eligibility criteria) tumor 
sample is not available at screening, a fresh biopsy will be taken prior to 
enrollment. 
• 
Perform medical examinations needed to determine eligibility, including complete head 
and neck examination including laryngoscopy. Standard of care oral and maxillofacial 
examinations. Dental examination will be done before surgery; ok to be done after 
initiating systemic therapy on study.  
• 
Verify inclusion/exclusion criteria. 
• 
Obtain demographic information, medical/dental history, medication history, alcohol, and 
tobacco use history. 
• 
Record results of physical including ECOG Performance Status, Vital Signs, Complete 
Physical Exam (including BMI and waist to hip ratio [WHR]). 
• 
Schedule study visits for individuals who are eligible and available for the initial 
treatments of the trial- carboplatin, paclitaxel, nivolumab. 
 
The following procedures must be completed within 28 days of study enrollment unless 
otherwise indicated: 
• 
PET/CT or, if a patient cannot have PET/CT, then a CT or MRI of the Head and/or Neck,  
and Chest, abdomen and pelvis with and without contrast must be completed within 28 
days of initiation of therapy. If contraindicated in patient, scans will be done without 
contrast only.  
• 
EKG  


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• 
Collect blood for baseline correlative studies (Luminex panel and exosomes), pre-
treatment serum chemistries (Albumin, LDH, AST, ALT, ALK Phos, T.Bili, BUN, 
creatinine, Calcium, Mag, Phos, Na, Cl, Phos, Glucose, Amylase, Lipase, TSH, Free T4, 
Free T3, cortisol), PT/PTT, CBC with differential, viral studies (HepB surface antigen and 
hepatitis C antibody or hepatitis C RNA) within 14 days of initiation of study treatment.  
• 
Serum or urine pregnancy test for women of childbearing potential must be done within 
21 days of study enrollment. 
The following procedures will only be performed for patients enrolled at Thomas Jefferson 
University: 
• 
Complete PROs: 
o FACT-G 
o FACT-HN 
o PHQ2 
o PHQ9 
• 
C-reactive protein (CRP), glycated hemoglobin (HbA1c), and lipid panel 
• 
Body Mass Index (BMI) and Waist Hip Ratio (WHR) 
 
6.2 
Treatment Period 
Visit 2, Week 1, Day 1- RUN-IN TREATMENT PHASE 
• 
Targeted and complete physical examination 
• 
Review entry labs, performed within 3 days of first administration of nivolumab and 
paclitaxel plus carboplatin. For WOCBP serum or urine pregnancy should be within 24 
hours of the first study drug administration. 
• 
Review concomitant medications. 
• 
Administer the nivolumab (dose #1) and paclitaxel plus carboplatin (dose #1). 
• 
Ensure that surgery dates and treatment planning are scheduled 
• 
Record adverse events as reported by participant (PRO-CTCAE) or observed by 
investigator. 


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For patients who have agreed to collection and if determined feasible by the physician, an 
optional biopsy may be performed from and including days 14 and 23 of each cycle during the 
visit for weekly chemotherapy. Patients who have agreed to the collection and if determined 
feasible by the physician. The tissue collected will be sent for formalin fixed/paraffin embedded 
and a portion may also be frozen.  
Visit 3 , Week 3, ± 4 days- (there will be no visit week 2.  Visits are every other week 
during systemic therapy induction) 
• 
Record adverse events as reported by participant (PRO-CTCAE) or observed by 
investigator. 
• 
Targeted and complete physical examination. 
• 
CBC with differential, CMP, Mag, Phos, Amylase, Lipase, LDH, TSH, cortisol, Free T4, 
and Free T3 prior to administration of the study drug; to be drawn within 3 days of 
administration. Serum or urine pregnancy test for women of childbearing potential within 
24 hours of study drug administration  
• 
Review concomitant medications. 
• 
ECOG Performance Status 
• 
Record adverse events reported by participant or observed by investigator 
Administer the nivolumab (dose #2) and paclitaxel plus carboplatin (dose #3).Visit 4, Week 5 ±4 
days (there will be no visit week 4.  Visits are every other week during systemic therapy 
induction) 
• 
Record adverse events as reported by participant (PRO-CTCAE) or observed by 
investigator. 
• 
Targeted and complete physical examination. 
• 
CBC with differential, CMP, Mag, Phos, Amylase, Lipase, LDH prior to administration of 
the study drug; to be drawn within 3 days of administration. TSH, Free T3, Free T4 
cortisol. Serum or urine pregnancy test for women of childbearing potential within 24 
hours of study drug administration 
• 
Review concomitant medications. 
• 
ECOG Performance Status 
• 
Draw correlative laboratory studies  


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Administer the nivolumab (dose #3) and paclitaxel plus carboplatin (dose #5).Visit 5, Week 8 ± 
4 days (Surgery scheduled) 
• 
CT scan Preop (morning of surgery or day prior) 
• 
Record adverse events as reported by participant (PRO-CTCAE) or observed by 
investigator. 
• 
Targeted and complete physical examination. 
• 
Correlative labs 
• 
ECOG Performance Status 
• 
CBC with differential, platelet count, CMP, Mag, Phos, amylase, lipase, LDH,  PT/PTT, 
TSH, T4, T3, cortisol prior to surgery 
• 
EKG  
• 
Intraoperative specimens sent fresh on ice for correlative studies.  
The following procedures will only be performed for patients enrolled at Thomas Jefferson 
University: 
• 
Complete PROs: 
o FACT-G 
o FACT-HN 
o PHQ2 
o PHQ9 
o C-reactive protein (CRP), glycated hemoglobin (HbA1c), and lipid panel 
 
Study Procedures-Administration of Paclitaxel and Carboplatin and Nivolumab and 
Surgery 
Cycle 1-3 (Medical Oncologist): Each cycle is 2 weeks long.  Full medical history, general 
physical exam, clinical tumor assessment and measurement by clinical exam, comprehensive 
metabolic panel (CMP), CBC, magnesium, phosphate, height, weight. Intravenous 
administration of paclitaxel 100 mg/m2 and carboplatin AUC=2. ON Days 1 and 8 of each cycle, 
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Surgery will be performed approximately 2 weeks (Week 8) after the last dose of study 
treatment. Surgery is to be performed no later than 28 days after last chemotherapy dose (to 
allow patients to recover after chemotherapy) 
 
6.3 
Post-Surgical/Follow-Up 
Visit 6, Week 9 ± 5 days    Postop visit 
• 
Postop evaluation and exam 
• 
Whole blood Collection – Correlative labs 
• 
Wound assessment 
• 
Safety Assessment 
The following procedures will only be performed for patients enrolled at Thomas Jefferson 
University: 
• 
Complete PROs: 
o FACT-G 
o FACT-HN 
o PHQ2 
o PHQ9 
• 
C-reactive protein (CRP), glycated hemoglobin (HbA1c), and lipid panel 
• 
Body Mass Index (BMI) and Waist Hip Ratio (WHR) 
Visit 7, 3 months ±2 weeks post-surgical completion* 
• 
Focused physical assessment 
• 
History 
• 
Wound assessment 
• 
Whole Blood collection for correlative labs   
• 
PET scan at 3 months post treatment ± 2 weeks.  
• 
Record adverse events as reported by participant (PRO-CTCAE) or observed by 
investigator 


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*If post-op xrt, then repeat PET scan will be delayed to 3 months ± 2 weeks after completion of 
radiation. If surgery is not done, the post-treatment date establishing mandatory follow-up visits 
will be 1-3 weeks after last chemo dose. 
6.4 
End of Treatment Study Procedures 
Final Study Visit (Visit 8, 6 months ± 3 weeks post-surgical completion) 
Record adverse events as reported by participant (PRO-CTCAE) or observed by investigator. 
• 
Complete Physical Exam  
• 
Review concomitant medications. 
• 
Draw correlative laboratory studies (end of treatment time point). 
6.5 
Post-Treatment/Follow-Up 
Patient’s medical records will be reviewed every 3 months for the next 6 months to obtain 
information on survival and disease recurrence. 
Follow Up Imaging is to be completed per the institutional standards. 
6.6 
Withdrawal Visit/Discontinuation of Therapy 
At the time of withdrawal from the study, patients will be offered the opportunity to provide 
serum samples for correlative studies. 
Adverse events will be collected and recorded as will the reason for discontinuation. 
6.7 
Surgery 
The resection volume will be planned considering the tumor extension at the initial clinical 
evaluation, but the final surgical choice will be left to the judgment of the responsible surgeon, 
also on the basis of the actual extent at the time of surgery. A macroscopic safe margin of at 
least 1.5 cm is mandatory. Surgical procedures can include transoral or transcervical 
approaches with mandibulotomy or, marginal, or segmental mandibulectomy as necessary. In 
all cases, an ipsilateral neck dissection will be performed. Bilateral neck dissection will be 
performed when contralateral lymph nodes are present, when the tumor extends to within 1 cm 
of midline, or at the surgeon’s discretion. Reconstruction will be performed as needed by means 
of local, regional, or free tissue flaps. 
6.8 
Radiation 
After surgical resection, the decision for postoperative radiotherapy ± concurrent chemotherapy 
will be determined by the HNC tumor board. Radiation therapy will start 4 to 6 weeks after 
surgery, if not postoperative complications occur.  


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Treatment planning 
The immobilization device should include head, neck and shoulder immobilization. The 
treatment planning CT scan should have a thickness of 0.3 cm or smaller slices through the 
region that contains the primary target volumes.   
Volumes     
The prescribed radiotherapy dose will be 60-66 Gy in 2 Gy once-daily fraction size (total of 30-
33 fractions), based on the status of the surgical margins and the presence of nodal extra 
capsular extension. Radiotherapy should begin on a Monday, Tuesday or Wednesday. 
Megavoltage energy photon beam irradiation is required. 
All plans must be normalized such of 95% of the volume of the PTVs are covered with the 
prescription dose. At 1 cc PTV volume, the dose should not be > 110% of the prescribed dose.  
Definition of Target Volumes CTV60: This volume will receive 2 Gy per day. CTV60 will include 
the primary tumor bed (based on preoperative imaging, preoperative physical exam/endoscopy, 
operative findings, pathologic findings) plus region(s) of grossly involved lymphadenopathy. 
CTV56: This will include all other regions felt to be at risk for harboring microscopic cancer that 
do not meet the criteria for CTV60. For example, this would apply to the contralateral hemineck 
being irradiated electively for base of tongue cancer. This volume will receive approximately 
1.85 Gy per day. CTV66: This would include a region or regions felt to be at especially high risk 
for recurrence (e.g., an area of positive margin of resection, or nodal extracapsular extension). 
This area will be receiving a daily fraction size of 2.0 Gy and will be delivered sequentially after 
the 60 Gy treatment will be finished. 
Image Guidance for Image Guided Radiation Therapy (IGRT) 
Daily image guidance of IMRT/VMAT will be achieved using linear-accelerator mounted kV or 
MV helical conebeam CT images. For those institutions that are using daily IGRT the minimum 
CTV-to-PTV expansion is 3.0 mm. 
7 Study Procedures and Evaluations 
7.1 
Study Procedures/Evaluations 
• 
Medical History including intercurrent illnesses and specific attention to autoimmune 
disorders, may be obtained from the medical record 
• 
Concomitant meds: prescription medications taken for the 28 days prior to enrollment 
• 
Physical exam: height, weight, obtained from the medical record 
• 
ECOG performance status from the medical record 


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• 
Obtain histologic confirmation of disease, including p16 status for oropharyngeal 
primaries from the medical record 
• 
Standard oral evaluation pre-radiation therapy by OMFS 
• 
Vital Signs 
The following procedures are only for patients enrolled at Thomas Jefferson University: 
• PROs are self-administered 
 
• Waist Hip Ratio: measurement to be taken per the NHLBI, NIH guideline to 
measure waist circumference. 
https://www.nhlbi.nih.gov/files/docs/guidelines/prctgd_c.pdf  
o To measure waist circumference, locate the upper hip bone and the top of 
the right iliac crest. Place a measuring tape in a horizontal plane around 
the abdomen at the level of the iliac crest. Before reading the tape 
measure, ensure that the tape is snug, but does not compress the skin, 
and is parallel to the floor. The measurement is made at the end of a 
normal expiration. 
o Hip circumference should be measured around the widest portion of the 
buttocks, with the tape parallel to the floor.  
• Body Mass Index (BMI) to calculated as kg/m2 
 
7.2 
Laboratory Procedures/Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
• 
Pregnancy Test: WOCBP prior to dosing nivolumab.  
• 
A serum or urine pregnancy testing is required within 24 hrs of starting study treatment  
• 
Laboratory testing prior to each dose of nivolumab: Within 72 hours prior to re-dosing- 
CBC w/ differential, LFTs, BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, 
Glucose, amylase, lipase.  Within 72 hours prior to re-dosing- TSH (with reflexive Free 
T4 and Free T3) 
7.2.2 
Special Assays or Procedures 
Please see accompanying laboratory manual 


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7.2.3 
Specimen Preparation, Handling, and Storage 
Two 10 ml purple top tubes will be collected for correlative studies. Samples can be held at 
room temperature and will be brought directly to the Harshyne Laboratory: 233 South 10th Street 
Rm 606, Philadelphia, PA 19107, USA. 
Samples collected at the sub-site will be sent to the Harshyne Laboratory. Please see the 
accompanying laboratory manual additional information.  
7.2.4 
Specimen Shipment 
Please see accompanying laboratory manual 
8 Evaluation of Safety 
8.1 
Specification of Safety Parameters 
8.1.1 
Unanticipated Problems 
Unanticipated problems (UAPs) include, in general, any incident, experience, or outcome that 
meets the following criteria: 
• 
unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
UAPs are considered to pose risk to participants or others when they suggest that the research 
places participants or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
8.1.2 
Adverse Events 
An adverse event is any untoward or unfavorable medical occurrence in a human participant, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the participant’s participation in the research, 
whether or not considered related to the participant’s participation in the research. 
8.1.3 
Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• 
Results in death 
• 
Is life-threatening (places the participant at immediate risk of death from the event as it 
occurred) 


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• 
Is disabling or incapacitating 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in a persistent or significant disability or incapacity 
• 
Results in a congenital anomaly or birth defect  
• 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the participant or may require intervention to 
prevent one of the outcomes listed in this definition. 
• 
Suspected transmission of an infectious agent (e.g. pathogenic or nonpathogenic) via 
the study drug is an SAE 
• 
Although pregnancy, overdose, cancer and potential DILI are not always serious by 
regulatory definition, these events must be handled as SAEs 
Following the subject’s start of treatment, all SAEs, whether related or not related to study 
drug, must be collected, including those thought to be associated with protocol-specified 
procedures. All SAEs must be collected, that occur within 100 days of discontinuation of 
dosing. 
• 
A nonserious adverse event is an AE not classified as serious.  
Non-serious Adverse Event Collection and Reporting: 
• 
The collection of nonserious AE information should begin at initiation of study drug. All 
treated related nonserious adverse events should be collected continuously during the 
treatment period and for a minimum of 100 days following the last dose of study 
treatment. During this time, the clinical research staff will call the patient monthly. 
8.2 
Safety Assessment and Follow-Up 
Adverse event reporting will begin after study treatment, unless AE/SAE is caused by a study 
specific screening procedure, and continue until 100 days (for non-serious AEs) or 100 days (for 
SAEs) after the last day of study participation. At each study visit, the investigator (or designee) 
will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization. 
8.3 
Recording Adverse Events 
The following subsections detail what information must be documented for each adverse event 
occurring during the time period specified in Section 8.2 Safety Assessment and Follow-Up.  
8.3.1 
Relationship to Study Intervention 


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The relationship to study intervention or study participation must be assessed and documented 
for all adverse events. Evaluation of relatedness must consider etiologies such as natural 
history of the underlying disease, concurrent illness, concomitant therapy, study-related 
procedures, accidents, and other external factors.  
The following guidelines are used to assess relationship of an event to study intervention: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event onset. 
b. An alternate etiology has been established. 
8.3.2 
Expectedness 
The PI is responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the intervention. Risk information to assess 
expectedness can be obtained from preclinical studies, the investigator’s brochure, published 
medical literature, the protocol, or the informed consent document. 
8.3.3 
Severity of Event 
Adverse events will be graded for severity according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0.  
8.3.4 
Intervention 
Any intervention implemented to treat the adverse event must be documented for all adverse 
events. 
8.4 
Safety Reporting  
8.4.1 
Reporting to IRB 
8.4.1.1 Unanticipated Problems 


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Thomas Jefferson University: All incidents or events that meet criteria for unanticipated 
problems (UAPs) as defined in Section 8.1.1 Unanticipated Problems require the creation and 
completion of an unanticipated problem report form (OHR-20).  
UAPs that pose risk to participants or others, and that are not AEs, will be submitted to the IRB 
on an OHR-20 form via the eazUP system within 5 working days of the investigator becoming 
aware of the event.  
UAPs that do not pose risk to participants or others will be submitted to the IRB at the next 
continuing review.  
Sub-Site: All incidents or events that meet criteria for unanticipated problems (UAPs) as defined 
in Section 8.1.1 Unanticipated Problems are to be reports to the sub-site IRB per institutional 
guidelines.  
UAPs occurring at the sub-site must also be reported to Thomas Jefferson University using the 
Unaticipated Problems Form (see Appendix F). The TJU study site contact will submit the UAPs 
occurring at the sub-site to the TJU IRB. 
8.4.1.2 Adverse Events  
Grade 1 AEs will be reported to the IRB at continuing review.  
Grade 2 AEs will be reported to the IRB at the time of continuing review.  
8.4.1.3 Serious Adverse Events  
Thomas Jefferson University: 
SAEs will be reported to the IRB on OHR-10 forms via the electronic reporting system (eSAEy) 
according to the required time frames described below. 
Grade 3-4 AEs that are unexpected and deemed to be at least possibly related to the study will 
be reported to the IRB within 2 working days of knowledge of the event. 
Grade 3-4 AEs that are deemed unrelated to the study will be reported to the IRB within 5 
working days.  
Grade 5 AEs will be reported to the IRB within one working day of knowledge of the event. 
All SAEs will be submitted to the IRB at continuing review, including those that were reported 
previously. 
Sub-Sites: 
SAEs occurring at the sub-site are to be reported to the sub-site IRB per institutional guidelines. 
Section 8.4.2 provides information on reporting SAEs to TJU.   


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8.4.2 
Sub-Site SAE Reporting 
All SAEs occurring at the sub-site must be reported to the TJU Study Site Contact within 24 
hours of notification. This initial notification can take place via email or phone, followed by the 
submission of a formal report.   
SAEs should be reported to TJU using the Sub-Site Serious Adverse Event form (Appendix G) 
or the FDA Medwatch 3500A, and should comprise a full written summary, detailing relevant 
aspects of the adverse events in questions, including grading and attribution to study drug.  
Where applicable, information from relevant hospital case records and autopsy reports should 
be included.   
SAE Reports should be signed by the sub-site PI, and then emailed to the Thomas Jefferson 
University Study Site Contact within 24 hours.  
The TJU coordinator will notify the TJU PI and obtain the TJU PI signature, and report these 
events to the TJU Medical Monitor/IRB appropriately (within 5 working days if it deems an 
amendment, or in a spreadsheet at the time of annual review if no amendment is necessary). 
Additional follow-up SAE reports should be submitted when available. 
All reportable Adverse Events (AEs) should be reported to the TJU Research Coordinator within 
48 hours using the FDA MedWatch 3500 form.  
A reportable AE is any adverse event NOT identified in the IB or consent form as a risk.  
Any non-reportable AE must be kept by the sub-site on an ongoing tracking log to be reviewed 
by TJU quarterly. 
Unanticipated problems (UAPs) that pose risk to subjects or others, and that are not AEs/SAEs 
should be reported to TJU within 5 working days using form Unanticipated Problems Form (see 
Appendix F) and should be email to the Thomas Jefferson University study site contact within 5 
days. 
8.4.3 
Reporting to SKCC DSMC 
All AEs and SAEs, safety and toxicity data, and any corrective actions will be submitted to the 
DSMC per the frequency described in the SKCC DSMP. The report to the SKCC DSMC will 
also include any unanticipated problems that in the opinion of the PI should be reported to the 
DSMC. 
The sub-site is required to provide copies of any Unanticipated Problems, protocol deviations, 
and AE logs to the TJU study site contact for submission to the SKCC DSMC. 
For expedited reporting requirements, see table below:                                             
DSMC AE/SAE Reporting Requirements 


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8.4.4 
Reporting to Funding Supporter 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies must be 
reported on a Pregnancy Surveillance Form. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS (or designee) 
using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
Site specific forms will be requested for review. 
The sponsor/investigator will be required to reconcile SAEs reported in  the clinical database 
with SAE cases transmitted to BMS Global Pharmacovigilance (GPV&E); 
worldwide.safety@bms. BMS requests this to be done quarterly and prior to the database lock 
or final data summary.  
A summary of the process for the sponsor/investigator:  
• 
Sponsor/Investigator sends a request to BMS GPV&E for a “GPV&E reconciliation 
report”. Requests for reconciliation should be sent to 
aepbusinessprocess@bms.com. The request should provide the BMS protocol ID, 
study title and PI, and sponsor/investigator protocol ID.  
• 
BMS will send a report back to the sponsor/investigator. The data elements listed on 
the GPV&E reconciliation report will contain information the investigator can use for 
individual case identification. Cases on the list from BMS GPV&E should be 
compared to the SAE cases in the clinical database.  
• 
If the sponsor/investigator determines a SAE case was not transmitted to BMS 
GPV&E, the case should be sent immediately to BMS 
The sub-site will complete the Medwatch 3500 Form and provide this to the TJU study site 
contact via email. 
8.4.5 
Reporting to FDA 
For studies conducted under an Investigator IND in the US, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as possible 


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and no later than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. BMS will be provided with 
a simultaneous copy of all adverse events filed with the FDA.  
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
• 
An SAE report should be completed for any event where doubt exists regarding its 
seriousness.  
• 
For studies with long-term follow-up periods in which safety data are being reported, 
include the timing of SAE collection in the protocol. 
• 
If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the narrative 
section of the SAE Report Form. 
• 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) 
• 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to 
BMS using the same procedure used for transmitting the initial SAE report. All SAEs 
should be followed to resolution or stabilization. All SAEs should be followed to 
resolution or stabilization. 
For any fatal or life-threatening adverse event that is unexpected and assessed by the 
investigator as possibly related to the use of nivolumab, the sub-site must submit a completed 
FDA Medwatch 3500A Form and email form to the TJU study site contact for submission to the 
FDA and BMS. The initial communication may take place via telephone but should be followed 
up with the completed form within 24 hours of first learning of the event. 


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8.4.6 
Reporting of Pregnancy 
• 
Women of childbearing potential” is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 
months of amenorrhea in a woman over 45 in the absence of other biological or 
physiological causes. In addition, women under the age of 55 must have a documented 
serum follicle stimulating hormone (FSH) level more than 40 mIU/ml. 
• 
Women of childbearing potential (WOCBP) must use appropriate method(s) of 
contraception. WOCBP should use an adequate method to avoid pregnancy for 23 
weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the 
last dose of investigational drug  
• 
Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 21 days prior to the start 
of nivolumab 
• 
Women must not be breastfeeding 
• 
Men who are sexually active with WOCBP must use any contraceptive method with a 
failure rate of less than 1% per year Men receiving nivolumab and who are sexually 
active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks 
after the last dose of investigational product Women who are not of childbearing 
potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men 
do not require contraception 
• 
Should a woman be found to be pregnant during the study further treatment will be 
immediately discontinued. Permission from the patient will be sought to continue to 
assess her for adverse events and for fetal outcomes. 
8.5 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities must be captured as appropriate  
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted 
• 
any laboratory test result that required the subject to receive specific corrective therapy 
• 
It is expected that wherever possible the clinical rather than laboratory term would be 
used by the reporting investigator 
8.6 
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An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
Any such events will be recorded on an SAE form and reported to BMS within 24 hours/1 
business day. 
Sub-site: If an overdose occurs, the sub-site must submit a completed FDA Medwatch 3500A 
Form and email form to the TJU study site contact for submission to BMS. 
8.7 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs. 
Potential drug induced liver injury is defined as: 
• 
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) AND 
• 
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase), AND 
• 
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
8.8 
Halting Rules 
Please see Section 11.3 for stopping rules. 
9 Study Oversight 
In addition to the PI’s responsibility for oversight, study oversight will be under the direction of 
the SKCC’s Data and Safety Monitoring Committee (DSMC). The SKCC DSMC operates in 
compliance with a Data and Safety Monitoring Plan (DSMP) that is approved by the NCI. 
10 Clinical Site Monitoring and Auditing 
Clinical site monitoring and auditing is conducted to ensure that the rights of human participants 
are protected, that the study is implemented in accordance with the protocol and/or other 
operating procedures, and that the quality and integrity of study data and data collection 
methods are maintained. Monitoring and auditing for this study will be performed in accordance 
with the SKCC’s Data and Safety Monitoring Plan (DSMP) developed by the SKCC Data and 
Safety Monitoring Committee (DSMC). The DSMP specifies the frequency of monitoring, 
monitoring procedures, the level of clinical site monitoring activities (e.g., the percentage of 


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participant data to be reviewed), and the distribution of monitoring reports. Some monitoring 
activities may be performed remotely, while others will take place at the study site(s). 
Appropriate staff will conduct monitoring activities and provide reports of the findings and 
associated action items in accordance with the details described in the SKCC DSMP. 
11 Statistical Considerations  
11.1 Study Hypotheses 
Our hypothesis is that in patients with newly diagnosed, previously untreated squamous cell 
carcinoma of the head and neck, the administration of nivolumab in combination with weekly 
carboplatin and paclitaxel will increase the pathological complete response rate at the primary 
cancer compared to the historical control of carboplatin and paclitaxel alone. 
11.2 Analysis Plans 
Primary Endpoint Evaluation:  
An optimal Simon two-stage design will be used. The null hypothesis is that the true pathologic 
complete response rate is ≤ 0.20 and will be tested against the alternative that it is >0.20. After 
testing the regimen on 17 patients in the first stage, the trial will be terminated if 3 or fewer have 
a pCR of the primary tumor. If the trial goes on to the second stage, a total of 37 patients will be 
studied. If the total number having a pCR of the primary tumor is less than or equal to 10, the 
regimen is rejected. This design yields a type I error rate of 9.5% and power of 90% when the 
true response rate is 0.40.  It has a 55% probability of stopping early. The pathologic complete 
response rate and its associated score 95% confidence interval will be estimated using the 
methods of Tsai et al (2008). 20  
Secondary Endpoint Analyses:  
Descriptive statistics, including means, standard deviations, medians, quartiles, frequency 
counts, and percentages will be computed for all study variables.   
All secondary response rates (complete pathologic response at all sites of disease, major 
pathologic response at primary site, overall clinical response, clinical complete response) will be 
estimated.   
Kaplan-Meier methods will be used to describe and display the survival experiences of the study 
patients and estimate their 1 year PFS and assess their overall survival at 1 year.  
Exploratory Endpoint Analyses (CORRELATIVE STUDIES):  
T cell subsets will be analyzed by flow cytometry before, at the 5th week, and on the day of 
surgery after carboplatin/paclitaxel/nivolumab to explore their potential as predictive and/or 
prognostic markers that are related to response or clinical benefit of this induction regimen.   
The T cell subtypes will be analyzed from peripheral mononuclear cells (PBMC) via flow 
cytometry. These data and other biomarkers, including cytokine and exosome variables, will be 


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explored by first categorizing the before and after carboplatin/paclitaxel/nivolumab T cell data as 
well as the change observed and then using these categories as strata for cross-tabulation with 
complete pathologic response and for Kaplan-Meier subgroup analyses of the survival 
endpoints.  
Association of PDL1 expression and other baseline marker levels with response will be 
evaluated using logistic regression.  Association of change in markers with response will be 
evaluated using two-sample tests (e.g., t-tests or Wilcoxon rank sum tests).  When longitudinal 
marker measurements are available, responders will be compared to non-responders using 
mixed effects linear regression.  In addition, potential correlations of these pharmacodynamics 
markers with the duration of treatment, safety, survival, and anti-tumor activity of the regimen 
will be explored by summary statistics, data plots, and regression modeling tools.   
We plan to conduct descriptive statistics on all study variable, including PROs, lab data, 
demographics, and anthropometrics using standard statistics such as frequency tables, 
means, and standard deviations.   
 
For the correlative studies on PROs and metabolic measures (e.g., CRP, HbA1c, and 
lipid panel), we plan to estimate Spearman’s ranks-based correlations and explore 
multivariable relationships with ordinary least squares regression modeling. These 
variables will also be considered for their potential role in the planned Cox survival and 
logistic regression response modeling. 
11.3 Interim Analyses and Stopping Rules 
Stopping Rules:  
The study will stop for futility if pathologic complete response at the primary tumor is not 
observed in more than 3 of the first 17 patients.   
There are no formal stopping rules for safety, however, rates of grade 3-5 toxicities will be 
monitored continually. The selected doses of nivolumab were safe in previous studies. There is 
no dose escalation or de-escalation planned in this study. Individual patients can have dose 
modification during the study.   
The study will stop if 3 of the first 17 patients experience excessive toxicity due to study 
treatment, leading to delays in definitive surgery greater than 56 days from enrollment.  
11.3.1 Safety Review 
See above.in stopping rules.  We meet weekly as a group to review adverse events on all trial 
patients.  A running tab is kept of the number of patients with serious adverse events and their 
grade, nature and attribution.   
11.3.2 Efficacy Review 


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The principle endpoint of this study is pathologic complete response.  The early stopping rule 
requires cessation of further accrual if there are 2 or fewer pathologic complete response 
among the first 17 patients. If there are 3 or more pCRs obvserved prior to the accrual of 17 
patients, this minimal condition for continuing accrual will be met and there will be no need to 
halt the study on the basis of therapeutic futility.  However, if it has not been met prior to the 
accrual of 17 patients, then, with the further accrual will be halted at the time the 17th potentially 
evaluable patient signs consent until all 17 evaluable patients have had their surgical specimens 
evaluable for pathologic response.  Accrual can then restart only if there are 3 or more pCRs as 
per the stopping rules.   
11.4 Sample Size Considerations 
An optimal Simon two-stage design will be used. The null hypothesis is that the true pathologic 
complete response rate at the primary site is ≤ 0.20 and will be tested against the alternative 
that it is >0.20. After testing the regimen on 17 patients in the first stage, the trial will be 
terminated if 3 or fewer respond. If the trial goes on to the second stage, a total of 37 patients 
will be studied. If the total number responding is less than or equal to 10, the regimen is 
rejected. This design yields a type I error rate of 9.5% and power of 90% when the true 
response rate is 0.40. It has a 55% probability of stopping early.   
11.4.1 Replacement Policy 
Patients who do not have surgery will be replaced on the study. 
11.4.2 Accrual Estimates 
We hope to enroll 37 participants onto this trial and accrual is competitive across all sites.  
11.5 Exploratory Analysis 
Please see the attached laboratory manual 
12 Source Documents and Access to Source Data/Documents 
Study staff will maintain appropriate medical and research records for this study, in compliance 
with ICH E6, and regulatory and institutional requirements for the protection of confidentiality of 
participant information. Study staff will permit authorized representatives of SKCC and 
regulatory agencies to examine (and when required by applicable law, to copy) research 
records for the purposes of quality assurance reviews, audits, and evaluation of the study 
safety, progress and data validity.  
13 Quality Control and Quality Assurance 
The investigator will allocate adequate time for monitoring activities. The Investigator will also 
ensure that the medical monitor or other compliance or quality assurance reviewer is given 


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access to all of the  above  noted  study-related  documents  and  study  related  facilities  (e.g. 
pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
14 Ethics/Protection of Human Participants  
14.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, as drafted by the US National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 
46 and/or the ICH E6.  
14.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented in the study.  
14.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout study participation. Extensive discussion of risks and possible 
benefits of study participation will be provided to participants and their families, if applicable. A 
consent form describing in detail the study procedures and risks will be given to the participant. 
Consent forms will be IRB-approved, and the participant is required to read and review the 
document or have the document read to him or her. The investigator or designee will explain the 
research study to the participant and answer any questions that may arise. The participant will 
sign the informed consent document prior to any study-related assessments or procedures. 
Participants will be given the opportunity to discuss the study with their surrogates or think about 
it prior to agreeing to participate. They may withdraw consent at any time throughout the course 
of the study. A copy of the signed informed consent document will be given to participants for 
their records. The rights and welfare of the participants will be protected by emphasizing to them 
that the quality of their clinical care will not be adversely affected if they decline to participate in 
this study. The consent process will be documented in the clinical or research record.  
14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
Pregnant and breastfeeding women are excluded from this trial due to the nature of the agents 
being used.  Otherwise, we will attempt to accrue women and men equally on this study, 
representative of the epidemiologic distribution of the disease. 
14.5 Participant Confidentiality 


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Participant confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to any study information relating to participants. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all study 
documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) for the study participants. The clinical study site 
will permit access to such records. 
14.6 Future Use of Stored Specimens and Other Identifiable Data  
No identifiable data will be retained. 
15 Data Handling and Record Keeping 
The investigators are responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data. The investigators will maintain adequate case 
histories of study participants, including accurate case report forms (CRFs), and source 
documentation. 
15.1 Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the investigator. All source documents and laboratory reports must be reviewed 
by the study team and data entry staff, who will ensure that they are accurate and complete.  
Unanticipated problems and adverse events must be reviewed by the investigator or designee. 
15.2 Data Capture Methods 
Data will be captured on paper case report forms and transferred to an electronic database 
which will be kept behind a password protected firewall- RedCap. Each site will enter data as 
described into the electronic database. The lead site (Thomas Jefferson University) will query 
the database at regular intervals. 
15.3 Types of Data 
Data that will be collected include patient history and physical examination data, safety, 
laboratory studies, patient reported outcomes, pathology staging studies, and 
immunohistochemistry as determined in the laboratory. 
15.4 Study Records Retention 


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Study records will be maintained for at least three years from the date that the grant federal 
financial report (FFR) is submitted to the NIH. 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents should 
be retained for a longer period, however, if required by local regulations.  No records will be 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained. 
15.5 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or Manual of Procedures requirements. The noncompliance may be on the part of the 
participant, the investigator, or study staff. As a result of deviations, corrective actions are to be 
developed by the study staff and implemented promptly. 
All deviations from the protocol must be addressed in study participant source documents and 
promptly reported to the IRB and other regulatory bodies according to their requirements.  
16 Study Finances 
16.1 Funding Source 
Bristol-Myers Squibb is providing the investigational products, Nivolumab, for this study. 
16.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study. All Jefferson University Investigators will follow the TJU Conflicts of 
Interest Policy for Employees (107.03). 
16.3 Participant Stipends or Payments 
Subjects will receive a payment of $50 at each study visit for participation in the study. Subjects 
will be paid via Clincard. 
17 Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 


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peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial 
as any research project that prospectively assigns human participants to intervention or 
concurrent comparison or control groups to study the cause-and-effect relationship between a 
medical intervention and a health outcome. Medical interventions include drugs, surgical 
procedures, devices, behavioral treatments, process-of-care changes, and the like. Health 
outcomes include any biomedical or health-related measures obtained in patients or 
participants, including pharmacokinetic measures and adverse events. The ICMJE policy 
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, 
which is sponsored by the National Library of Medicine. Other biomedical journals are 
considering adopting similar policies. The ICMJE does not review specific studies to determine 
whether registration is necessary; instead, the committee recommends that researchers who 
have questions about the need to register err on the side of registration or consult the editorial 
office of the journal in which they wish to publish. 
U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 or FDAAA), 
Title VIII, Section 801 mandates that a "responsible party" (i.e., the sponsor or designated 
principal investigator) register and report results of certain "applicable clinical trials:"  
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I 
investigations, of a product subject to FDA regulation;  
Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation 
(other than small feasibility studies) and pediatric postmarket surveillance studies. 
NIH grantees must take specific steps to ensure compliance with NIH implementation of 
FDAAA. 
18 Literature References 
1. Cancer Facts & Figures 2016. (n.d.). Retrieved February 09, 2017, from 
https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-
facts-figures-2016.html 
2. Pfister DG, Spencer S, Brazil DM, et al. Head and neck cancers, Version 2.2014.  
Clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer 
Network: JNCCN. 2014; 12:1454-87.  
3. Pulte D, Brenner H. Changes in survival in head and neck cancer in the late 20th and 
early 21st century: a period analysis. Oncologist, 2010;15:994-1001 
4. Zhong LP, Zhang CP, Guo-Xin R, et al. Long-term results of a randomized phase III trial 
of TPF induction chemotherapy followed by surgery and radiation in locally advanced 
oral squamous cell carcinoma. Oncotarget, 2013;6:18707-714. 


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5. Licitra, L., Grandi, C., Guzzo, M., Mariani, L., Vullo, S. L., Valvo, F., ... & Cantù, G. 
(2003). Primary chemotherapy in resectable oral cavity squamous cell cancer: a 
randomized controlled trial. Journal of Clinical Oncology, 21(2), 327-333. 
6.  Bossi P, Lo Villa S, Gusto M, et al. Preoperative chemotherapy in advanced resectable 
OCSCC: long-term results of a randomized phase III trial. Annals of Onc. 2014;25:426-
466. 
7. Pignon, J.P., et al., Meta-analysis of chemotherapy in head and neck cancer (MACH-
NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol, 2009. 
92(1): p. 4-14. 
8. Gillison M, et al.; oral presentation at AACR Annual Meeting 2016; New Orleans, LA 3,4. 
At the 2016 AACR Annual Meeting 
9. Ferris, R. L., Blumenschein Jr, G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., ... & 
Worden, F. (2016). Nivolumab for recurrent squamous-cell carcinoma of the head and 
neck. N Engl J Med, 2016(375), 1856-1867.  
10. Herman LC, Chen L, Garnett A, et al. Comparison of carboplatin-paclitaxel to docetaxel-
cisplatin-5-flurouracil induction chemotherapy followed by concurrent chemoradiation for 
locally advanced head and neck cancer. Oral Onc. 2014;50:52-58. 
11.  Kies M, Holisnger C, Lee JJ, et al. Induction chemotherapy and cetuximab for locally 
advanced squamous cell carcinoma of the head and neck: results from a phase II 
prospective trial.  J Clin Oncol, 2010;28:8-14. 
12. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for 
treatment of recurrent or metastatic squamous cell carcinoma of the head and neck 
(KENOTE-012): an open label, multicenter, phase 1b trial. Lancet Oncol, 2016;7:958-65, 
13. Hato SV, Khong A, de Vries IJ et al. Molecular pathway: the immunogenic effects of 
platinum-based chemotherapeutics. Clin Cancer Res, 2014;20:2831-7. 
14. Lancer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomized, 
phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol, 2016;Oct 10 
(Epub ahead of print). 
15. Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in combination with platinum-
based doublet chemotherapy for first-line treatment of advanced non-small-cell lung 
cancer. J Clin Oncol;34:2969-79. 
16. Kazandjian, D., Khozin, S., Blumenthal, G., Zhang, L., Tang, S., Libeg, M., ... & Pazdur, 
R. (2016). Benefit-risk summary of nivolumab for patients with metastatic squamous cell 
lung cancer after platinum-based chemotherapy: a report from the US Food and Drug 
Administration. JAMA oncology, 2(1), 118-122.  
17. Trial of Nivolumab vs Therapy of Investigator's Choice in Recurrent or Metastatic Head 
and Neck Carcinoma (CheckMate 141). (n.d.). Retrieved February 09, 2017, from 
https://clinicaltrials.gov/ct2/show/NCT02105636 


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18. Rizvi, N.A., 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. 
19. Gadgeel, S. M., Stevenson, J., Langer, C. J., Gandhi, L., Borghaei, H., & Patnaik, A. 
(2016). Pembrolizumab (pembro) plus chemotherapy as front-line therapy for advanced 
NSCLC: KEYNOTE-021 cohorts AC. In Proc Am Soc Clin Oncol (Vol. 34). 
20. Tsai WY, Chi Y, Chen CM. Interval estimation of binomial proportion in clinical trials with 
a two-stage design.   Stat Med. 2008 Jan 15;27(1):15-35.   
21. Lipscomb, J., C.C. Gotay, and C.F. Snyder, Patient-reported outcomes in cancer: 
a review of recent research and policy initiatives. CA Cancer J Clin, 2007. 57(5): 
p. 278-300. 
22. Cella, D.F., et al., The Functional Assessment of Cancer Therapy scale: 
development and validation of the general measure. J Clin Oncol, 1993. 11(3): p. 
570-9. 
23. Massie, M.J., Prevalence of depression in patients with cancer. J Natl Cancer 
Inst Monogr, 2004(32): p. 57-71. 
24. Currier, M.B. and C.B. Nemeroff, Depression as a risk factor for cancer: from 
pathophysiological advances to treatment implications. Annu Rev Med, 2014. 65: 
p. 203-21. 
25. Mitchell, A.J., et al., Prevalence of depression, anxiety, and adjustment disorder 
in oncological, haematological, and palliative-care settings: a meta-analysis of 94 
interview-based studies. The Lancet Oncology. 12(2): p. 160-174. 
26. Spiegel, D. and J. Giese-Davis, Depression and cancer: mechanisms and 
disease progression. Biol Psychiatry, 2003. 54(3): p. 269-82. 
27. Gilbody, S., et al., Screening for depression in medical settings with the Patient 
Health Questionnaire (PHQ): a diagnostic meta-analysis. J Gen Intern Med, 
2007. 22(11): p. 1596-602. 
28. Kroenke, K., R.L. Spitzer, and J.B. Williams, The PHQ-9: validity of a brief 
depression severity measure. J Gen Intern Med, 2001. 16(9): p. 606-13. 
29. Morley, J.J. and I. Kushner, Serum C‐reactive protein levels in disease.  Annals 
of the New York Academy of Sciences, 1982. 389(1): p. 406-418. 
30. Pepys, M.B. and G.M. Hirschfield, C-reactive protein: a critical update. Journal of 
Clinical Investigation, 2003. 111(12): p. 1805. 
31. Brustugun, O.T., M. Sprauten, and A. Helland, C-reactive protein (CRP) as a 
predictive marker for immunotherapy in lung cancer. 2016, American Society of 
Clinical Oncology. 
32. Shrotriya, S., et al., C-reactive protein is an important biomarker for prognosis 
tumor recurrence and treatment response in adult solid tumors: a systematic 
review. PloS one, 2015. 10(12): p. e0143080. 
33. Godwin, J.L., et al., Nivolumab-induced autoimmune diabetes mellitus presenting 
as diabetic ketoacidosis in a patient with metastatic lung cancer. Journal for 
immunotherapy of cancer, 2017. 5(1): p. 40. 
34. Okamoto, M., et al., Fulminant type 1 diabetes mellitus with anti‐programmed 
cell death‐1 therapy.  Journal of diabetes investigation, 2016. 7(6): p. 915-918. 


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35. Merino, S.M., et al., Lipid metabolism and lung cancer. Critical reviews in 
oncology/hematology, 2017. 112: p. 31. 
36. Beloribi-Djefaflia, S., S. Vasseur, and F. Guillaumond, Lipid metabolic 
reprogramming in cancer cells. Oncogenesis, 2016. 5(1): p. e189. 
37. Sokol, A., et al., Association between the dietary inflammatory index, waist-to-hip 
ratio and metabolic syndrome. Nutrition research, 2016. 36(11): p. 1298-1303. 
38. Cerhan, J.R., et al. A pooled analysis of waist circumference and mortality in 
650,000 adults. in Mayo Clinic proceedings. 2014. Elsevier. 
 
 
 


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Appendices 
Appendix A: Schedule of Events 
Appendix B: ECOG Performance Status 
Appendix C: AJCC 8th Edition Staging System 
Appendix D: Management of Algorithms  
Appendix E: NCI-PRO-CTCAE Items 
Appendix F: Sub-Site Unanticipated Problems Form 
Appendix G: Sub-Site Serious Adverse Event Form 
 
 
 


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APPENDIX A: SCHEDULE OF EVENTS 
Study Period 
Visit 1, 
Day 0 
(Baseline) 
Treatment 
Observation 
(d) 
Week 
 
1 
2 
3 
4 
5 
6 
8 
9 
 
Treatment 
 
Paclitaxel+Carboplatin 
+ Nivolumab  
Surgery  
Standard of 
care (d)  
Nivolumab 
 
X 
 
X 
 
X 
 
 
 
 
Paclitaxel 
 
X 
X 
X 
X 
X 
X 
 
 
 
Carboplatin 
 
X 
X 
X 
X 
X 
X 
 
 
 
Filgrastim (i) 
 
X 
X 
X 
X 
X 
X 
 
 
 
Consent form 
signed by 
patient 
X 
 
 
 
 
 
 
 
 
 
Biopsy/Marking 
of primary site 
X 
 
 
 
 
 
 
X (f,g) 
 
 
History and 
physical exam 
(including vital 
signs, weight, 
BMI, height) 
(p) 
X(s) 
X 
 
X 
 
X 
 
X(s) 
X(s) 
X 
ECOG 
Performance 
Status (p) 
X 
X 
 
X 
 
X 
 
X 
 
X 
Assessment of 
concurrent 
therapies (p) 
X 
X 
 
X 
 
X 
 
   X 
 
 
Tumor 
assessment by 
X 
X 
 
X 
 
X 
 
X 
 
X 


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physical exam 
with intent to 
be alert to 
signs of early 
failure of 
efficacy as per 
the judgement 
of treating 
physicians (p).  
PET/CT  
X(r) 
 
 
 
 
 
 
 
 
X (e) 
CT or MRI 
X(r) 
 
 
 
 
 
 
X 
 
 
CBC, 
differential, 
platelet count 
(j) 
X 
X 
X X 
X X 
X X 
 
X 
CMP, (j)  
X 
X 
X X 
X X 
X X 
 
X 
magnesium, 
phosphate, 
Amylase, 
Lipase, LDH 
(k) 
X 
X 
 
X 
 
X 
 
X 
 
 
PT/PTT (l) 
X 
X 
 
 
 
 
 
X 
 
 
C-reactive 
protein (CRP), 
HbA1c, and 
lipid panel* 
X 
 
 
 
 
 
 
X 
X 
 
Endocrine 
(TSH, Free T4, 
Free T3, 
cortisol) (m) 
X 
X 
 
X 
 
X 
 
X 
 
X 
Pregnancy test 
(women of 
childbearing 
potential)(o) 
X 
X  
 
X  
 
X  
 
 
 
 


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EKG (n) 
X 
 
 
 
 
 
 
X (h) 
 
 
Blood Draw for 
CTCs(q) 
X 
 
 
 
 
X 
 
X (b) 
X(c) 
X(c) 
Adverse Event 
Assessment + 
PRO-CTCAE 
 
X 
X X 
X X 
X X 
 
X 
PROs* 
 
X 
 
 
 
 
 
X 
X 
 
Tumor Biopsy 
(a)  
X 
 
X  
X  
 
X 
 
 
*These procedures are only to be performed for patients enrolled at Thomas Jefferson University 
(a) Five cores or excisional specimen. Archival tissue within 3 months of study enrollment can be 
used. If recent tumor is unavailable, a fresh biopsy will be taken prior to enrollment (see section 
6.1). Optional biopsies from and including days 14 to 23 will be done if patients agree to the 
collection and if feasible at the discretion of the physician.  
(b) Prior to surgery 
(c) At least a week after surgery and less than 4 weeks after surgery.  If post-operative radiation 
therapy to be done, draw prior to this therapy.  A fifth blood draw 2 months later.  If radiation is 
given after surgery, then this last blood draw 2 months after 
(d) Observation or further therapy (for example post-operative radiation) as per standard of care.  
Follow for adverse events at least until 8 months s/p day 1 of induction therapy. 
(e) Timing of first post-operative repeat as per standard of care.  For patients who will not have post-
op xrt, the PET/CT will be 3 months ± 2 weeks post-op.  For patients who do receive post-op xrt, 
the PET/CT will be 3 months ± 2 weeks after the completion of xrt.  Further imaging (standard of 
care imaging will not be repeat PET/CT at this timepoint) will be another 3 months ±2 weeks after 
the follow-up PET/CT.   
(f) Intraoperative specimens sent fresh on ice for correlative studies. 
(g) Formal assessment and documentation of degree of pathologic response (as in appendix) 
(h) EKG alone  
(i) Filgrastim, at physician’s discretion, any 2 consecutive days between days 2-6 (preferred days 
3,4) of each treatment week 
(j) CBC with differential, CMP, need to be done baseline (within 14 days of initiation of study 
treatment ), within 3 days of first dose of chemotherapy, and no more than 1 days before each 
weekly chemotherapy administration.  No more than 7 days before surgery.   
(k) Magnesium, phosphate, amylase, lipase, and LDH baseline (within 4 weeks of screening), weeks 
3 and 5. No more than 7 days before surgery. 
(l) PT/PTT baseline (within 4 weeks of screening) No more than 7 days before surgery. 
(m) Endocrine (TSH, Free T4, Free T3, cortisol, baseline (within 4 weeks of screening).  Again at 
weeks 3 and 5.  No more than 7 days before surgery. After surgery as per standard of care. 
(n) EKG:  baseline (within 4 weeks of study enrollment) and after last dose of chemo and before 
surgery. 


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(o) Pregnancy test at baseline must be within 21 days of study enrollment. Pregnancy test must be 
re-tested within 24 hours of start of study drug. 
(p) Must be done within 4 weeks of study enrollment and then during visits 2, 3, 4, end of study visit 
(q) Must be done within 2 weeks of study enrollment 
(r) If patient cannot have PET/CT, then a CT or MRI of the Head and/or Neck, Chest, Abdomen, and 
Pelvis and a bone scan must be performed.  
(s) For patients enrolled at Thomas Jefferson University only: Physical examination at baseline and 
end of treatment must include BMI and waist to hip ratio (WHR) 
 
 
 
 
 
 
 
 


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APPENDIX B: ECOG PERFORMANCE STATUS 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined 
to bed or chair 
5 
Dead 
 
 
 
 
 
 
 
 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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APPENDIX C: AJCC 8TH EDITION STAGING SYSTEM 
1. LIP AND ORAL CAVITY 
DEFINITIONS 
Primary Tumor (T) 
TX 
Primary tumor cannot be assessed 
Tis Carcinoma in situ 
Tis Carcinoma in situ 
T1 
Tumor <2 cm <5 mm depth of invasion (DOI) (DOI is depth of invasion and not tumor 
thickness) 
T2 
Tumor <2 cm DOI >5 mm and <10 mm or tumor > 2cm but <4 cnm abd <10 mm DOI 
T3 
Tumor >4 cm or any tumor > 10 mm DOI 
T4 
Moderately advanced or very advanced local disease 
T4a Moderately advanced local disease: (lip) tumor invades through corical bone orinvolves 
the inferior alveolar nearve, floor of mouth, or skin of face (ie, chin or nose); (oral cavidty) 
tumor invades adjacent structures only (eg, through corical bone of the mandible or 
maxilla, or involves the maxillary sinus or skin or the face); note that superficial erosion of 
bone/tooth socket (alone) by a gingival primary is not sufficient to classify a tumor as T4. 
T4b Very advanced local disease: tumor invades masticator space, pterygoid plates, or skull 
base and/or encases the internal carotid artery 
 
Regional Lymph Nodes (N) 
Lip and Oral Cavity Clinical 
NX Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE 
negative 
N2 
Metastasis in a single ipsilateral lymph node, larger than 3 cm but not larger than 6 cm in 
greatest dimension and ENE negative3; or metastases in multiple ipsilateral lymph nodes, 
none larger than 6 cm in greatest dimension and ENE negative, or metastases in bilateral or 
contralateral lymph nodes, none more than 6 cm in greatest dimension and ENE negative 
N2a Metastasis in a single ipsilateral lymph node larger than 3 cm but not larger than 6 cm in 
greatest dimension and ENE negative 
N2b Metastasis in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension 
and ENE negative 
N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE negative 
N3 
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE-negative; or 
metastasis  in any lymph node(s) and clinically overt ENE-positive 
N3a Metastatis in a lymph node larger than 6 cem in greatest dimension and ENE-negative 
N3b Metastasis in any node(s) and clinically overt ENE-positive 
 
 
Lip and Oral Cavity Pathologic 
NX Regional lymph nodes cannot be assessed 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE 
negative 
N2 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension and ENE-
positive; or more than 3 cm but not more than 6 cm in greatest dimension and ENE-
negative; or metastases in multiple ipsilateral lymph nodes, none more than 6 cm in 
greater dimension and ENE-negative; or metastasis in bilateral or contralateral lymph 
nodes, none more than 6 cm in greatest dimension, ENE-negative 
N2a Metastasis in a single ipsilateral or contralateral  lymph node 3 cm or less in greatest 
dimension and ENE-positive; or metastasis in a single ipsilateral lymph node more than 3 
cm but not more than 6 cm in greatest dimension an ENE-negative 
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension 
and ENE-negative 
N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE negative 
N3 
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE-negative; or 
metastasis  in a single ipsilateral lymph node more than 3 cm in greatest dimension and 
ENE-positive; or metastasis in multiple ipsilateral, contralateral, or bilateral lymph nodes, 
with any ENE-positive 
N3a Metastasis in a single ipsilateral node more than 6 cm in greatest dimension and ENE-
negative 
N3b Metastasis in a single ipsilateral node more than 3 cm in greatest dimension and ENE-
positive; or metastasis in multiple ipsilateral, contralateral, or bilateral lymph nodes, with 
any ENE-positive 
 
 
Distant Metastasis (M) 
MX Distant metastasis cannot be assessed 
M0 No distant metastasis 
M1 Distant metastasis 
 
Biopsy of metastatic site performed 
 
Source of pathologic metastatic specimen 
 
 
 
Stage Grouping 
0 
Tis 
N0 
M0 
I 
T1 
N0 
M0 
II 
T2 
N0 
M0 
III 
T3 
N0 
M0 
 
T1 
N1 
M0 
 T2 
N1 
M0 
 T3 
N1 
M0 
IVA T4a 
N0 
M0 
 
T4a 
N1 
M0 
 
T1 
N2 
M0 
 
T2 
N2 
M0 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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T3 
N2 
M0 
 
T4a 
N2  
M0 
IVB Any T 
N3 
M0 
 
T4b 
Any N 
M0 
IVC Any T Any N M1 
 
Histologic Grade (G) 
GX 
Grade cannot be assessed 
G1 
Well differentiated 
G2 
Moderately differentiated 
G3 
Poorly differentiated 
 
Residual Tumor (R) 
RX: Presence of residual tumor cannot be assessed 
R0: No residual tumor 
R1: Microscopic residual tumor 
R2: Macroscopic residual tumor 
 
Additional Descriptors 
For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y," "r," and 
"a" prefixes are used. Although they do not affect the stage grouping, they indicate cases 
needing separate analysis. 
m suffix indicates the presence of multiple primary tumors in a single site and is recorded in 
parentheses: pT(m)NM. 
y prefix indicates those cases in which classification is performed during or following initial 
multimodality therapy. The cTNM or pTNM category is identified by a "y" prefix. The ycTNM or 
ypTNM categorizes the extent of tumor actually present at the time of that examination. The "y" 
categorization is not an estimate of tumor prior to multimodality therapy. 
r prefix indicates a recurrent tumor when staged after a disease-free interval, and is identified 
by the "r" prefix: rTNM. 
a prefix designates the stage determined at autopsy: aTNM. 
 
 
 
2. PHARYNX (INCLUDING BASE OF TONGUE, SOFT PALATE, AND UVULA) 
DEFINITIONS 
 
 
Oropharynx (HPV neg) Clinical and Pathologic 
Tx 
Primary tumor cannot be assessed 
Tis Carcinoma in situ 
Tl 
Tumor 2 cm or smaller in greatest dimension 
T2 
Tumor more than 2 cm but not larger than 4 cm in greatest dimension 
T3 
Tumor larger than 4 cm in greatest dimension or extension to lingual surface of epiglottis 
T4 
Moderatley advanced or very advanced local disease 
T4a Moderaly advanced local diseae; tumor invades the larynx, extrinsic muscle of tongue, medial 
pterygoid, hard palate, or mandible (Mucosal extension to lingual surface of epiglottis from 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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primary tumors of the base of the tongue and vallecular does not constitute invasion of the 
larynx). 
T4b Very advanced local disease; tumor invades lateral pterygoid muscle, pterygoid plates, lateral 
nasopharynx, or skull base or encases carotid artery 
 
Oropharynx (HPV pos) Clinical and Pathologic  
T0 
No primary identified 
Tl 
Tumor 2 cm or smaller in greatest dimension 
T2 
Tumor larger than 2 cm but not larger than 4 cm in greatest dimension 
T3 
Tumor larger than 4 cm in greatest dimension or extension to lingual surface of epiglottis 
T4 
Moderately advanced local disease: tumor invades the larynx, extrinsic muscle of tongue, 
medial pterygoid, hard palate, or mandible or beyond* 
 
*  Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does 
not constitute invasion of the larynx. 
 
 
Regional Lymph Nodes (N) 
 
Oropharynx (HPV neg) Clinical 
NX Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE 
negative 
N2 
Metastasis in a single ipsilateral lymph node, larger than 3 cm but not larger than 6 cm in 
greatest dimension and ENE negative3; or metastases in multiple ipsilateral lymph nodes, 
none larger than 6 cm in greatest dimension and ENE negative, or metastases in bilateral or 
contralateral lymph nodes, none more than 6 cm in greatest dimension and ENE negative 
N2a Metastasis in a single ipsilateral lymph node larger than 3 cm but not larger than 6 cm in 
greatest dimension and ENE negative 
N2b Metastasis in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension 
and ENE negative 
N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE negative 
N3 
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE-negative; or 
metastasis  in any lymph node(s) and clinically overt ENE-positive 
N3a Metastatis in a lymph node larger than 6 cem in greatest dimension and ENE-negative 
N3b Metastasis in any node(s) and clinically overt ENE-positive 
 
 
Oropharynx (HPV neg) Pathologic 
NX Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE 
negative 
N2 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension and ENE-
positive; or more than 3 cm but not more than 6 cm in greatest dimension and ENE-


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negative; or metastases in multiple ipsilateral lymph nodes, none more than 6 cm in 
greater dimension and ENE-negative; or metastasis in bilateral or contralateral lymph 
nodes, none more than 6 cm in greatest dimension, ENE-negative 
N2a Metastasis in a single ipsilateral or contralateral  lymph node 3 cm or less in greatest 
dimension and ENE-positive; or metastasis in a single ipsilateral lymph node more than 3 
cm but not more than 6 cm in greatest dimension an ENE-negative 
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension 
and ENE-negative 
N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE negative 
N3 
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE-negative; or 
metastasis  in a single ipsilateral lymph node more than 3 cm in greatest dimension and 
ENE-positive; or metastasis in multiple ipsilateral, contralateral, or bilateral lymph nodes, 
with any ENE-positive 
N3a Metastasis in a single ipsilateral node more than 6 cm in greatest dimension and ENE-
negative 
N3b Metastasis in a single ipsilateral node more than 3 cm in greatest dimension and ENE-
positive; or metastasis in multiple ipsilateral, contralateral, or bilateral lymph nodes, with 
any ENE-positive 
 
 
Oropharynx(HPV pos) Clinical  
NX Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
One or more ipsilateral lymph nodes, none larger than 6cm 
N2 
Contralateral or bilateral lymph nodes, none larger than 6cm 
N3 
Metastasis in a lymph node more than 6 cm in greatest dimension 
 
Distant Metastasis (M) 
MX Distant metastasis cannot be assessed 
M0 No distant metastasis 
M1 Distant metastasis 
 
Biopsy of metastatic site performed 
 
Source of pathologic metastatic specimen 
 
 
Stage Grouping: Oropharynx (HPV neg)  
0 
Tis 
N0 
M0 
I 
T1 
N0 
M0 
II 
T2 
N0 
M0 
III 
T3 
N0 
M0 
 
T1 
N1 
M0 
 
T2 
N1 
M0 
 
T3 
N1 
M0 
IVA T4a 
N0 
M0 
 
T4a 
N1 
M0 
 
T1 
N2 
M0 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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T2 
N2 
M0 
 
T3 
N2 
M0 
 
T4a 
N2 
M0 
IVB T4b 
Any N 
M0 
 
Any T 
N3 
M0 
IVC Any T 
Any N 
M1 
 
 
Stage Grouping: Oropharynx (HPV pos) Clinical Stage 8th Edition Staging Manual 
 
N0 
N1 
N2  
N3 
T0 
NA 
I 
II 
 
III 
T1 
I 
I 
II 
 
III 
T2 
I 
I 
II 
 
III 
T3 
II 
II 
II 
 
III 
T4 
III 
III 
III 
 
III 
 
Any M1 is stage IV 
 
 
Histologic Grade (G) (Oropharynx) 
GX Grade cannot be assessed 
G1 Well differentiated 
G2 Moderately differentiated 
G3 Poorly differentiated 
 
Residual Tumor (R) 
RX Presence of residual tumor cannot be assessed 
R0 
No residual tumor 
R1 
Microscopic residual tumor 
R2 
Macroscopic residual tumor 
 
Additional Descriptors 
For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y," "r," and 
"a" prefixes are used. Although they do not affect the stage grouping, they indicate cases 
needing separate analysis. 
m suffix indicates the presence of multiple primary tumors in a single site and is recorded in 
parentheses: pT(m)NM. 
y prefix indicates those cases in which classification is performed during or following initial 
multimodality therapy. 
The cTNM or pTNM category is identified by a "y" prefix. The ycTNM or ypTNM categorizes the 
extent of tumor actually present at the time of that examination. The "y" categorization is not an 
estimate of tumor prior to multimodality therapy. 
r prefix indicates a recurrent tumor when staged after a disease-free interval, and is identified 
by the "r" prefix: rTNM. 
a prefix designates the stage determined at autopsy: aTNM. 
 
 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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3. HYPOPHARYNX 
 
Hypopharynx 
T 1 Tumor limited to one subsite of hypopharynx and 2 cm or less in greatest dimension 
T2 
Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures 
more than 2 cm but not more than 4 cm in greatest diameter without fixation of hemilarynx 
T3 
Tumor measures more than 4 cm in greatest dimension or with fixation of hemilarynx 
T4a Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus or central 
compartment soft tissue(2) 
T4b Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal 
structures 
 
Hypopharynx Clinical 
NX Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE 
negative 
N2 
Metastasis in a single ipsilateral lymph node, larger than 3 cm but not larger than 6 cm in 
greatest dimension and ENE negative3; or metastases in multiple ipsilateral lymph nodes, 
none larger than 6 cm in greatest dimension and ENE negative, or metastases in bilateral or 
contralateral lymph nodes, none more than 6 cm in greatest dimension and ENE negative 
N2a Metastasis in a single ipsilateral lymph node larger than 3 cm but not larger than 6 cm in 
greatest dimension and ENE negative 
N2b Metastasis in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension 
and ENE negative 
N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE negative 
N3 
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE-negative; or 
metastasis  in any lymph node(s) and clinically overt ENE-positive 
N3a Metastatis in a lymph node larger than 6 cem in greatest dimension and ENE-negative 
N3b Metastasis in any node(s) and clinically overt ENE-positive 
 
 
Hyphopharynx Pathologic 
NX Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE 
negative 
N2 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension and ENE-
positive; or more than 3 cm but not more than 6 cm in greatest dimension and ENE-
negative; or metastases in multiple ipsilateral lymph nodes, none more than 6 cm in 
greater dimension and ENE-negative; or metastasis in bilateral or contralateral lymph 
nodes, none more than 6 cm in greatest dimension, ENE-negative 
N2a Metastasis in a single ipsilateral or contralateral  lymph node 3 cm or less in greatest 
dimension and ENE-positive; or metastasis in a single ipsilateral lymph node more than 3 
cm but not more than 6 cm in greatest dimension an ENE-negative 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension 
and ENE-negative 
N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE negative 
N3 
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE-negative; or 
metastasis  in a single ipsilateral lymph node more than 3 cm in greatest dimension and 
ENE-positive; or metastasis in multiple ipsilateral, contralateral, or bilateral lymph nodes, 
with any ENE-positive 
N3a Metastasis in a single ipsilateral node more than 6 cm in greatest dimension and ENE-
negative 
N3b Metastasis in a single ipsilateral node more than 3 cm in greatest dimension and ENE-
positive; or metastasis in multiple ipsilateral, contralateral, or bilateral lymph nodes, with 
any ENE-positive 
 
 
Distant Metastasis (M) 
MX Distant metastasis cannot be assessed 
M0 No distant metastasis 
M1 Distant metastasis 
 
Biopsy of metastatic site performed 
 
Source of pathologic metastatic specimen 
 
Stage Grouping: Hypopharynx 
0 
Tis 
N0 
M0 
I 
T1 
N0 
M0 
II 
T2 
N0 
M0 
III 
T3 
N0 
M0 
 
T1 
N1 
M0 
 
T2 
N1 
M0 
 
T3 
N1 
M0 
IVA T4a 
N0 
M0 
 
T4a 
N1 
M0 
 
T1 
N2 
M0 
 
T2 
N2 
M0 
 
T3 
N2 
M0 
 
T4a 
N2 
M0 
IVB T4b 
Any N 
M0 
 
Any T 
N3 
M0 
IVC Any T 
Any N 
M1 
 
Histologic Grade (G) (Hypopharynx) 
GX Grade cannot be assessed 
G1 Well differentiated 
G2 Moderately differentiated 
G3 Poorly differentiated 
 
Residual Tumor (R) 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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RX Presence of residual tumor cannot be assessed 
R0 
No residual tumor 
R1 
Microscopic residual tumor 
R2 
Macroscopic residual tumor 
 
Additional Descriptors 
For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y," "r," and 
"a" prefixes are used. Although they do not affect the stage grouping, they indicate cases 
needing separate analysis. 
m suffix indicates the presence of multiple primary tumors in a single site and is recorded in 
parentheses: pT(m)NM. 
y prefix indicates those cases in which classification is performed during or following initial 
multimodality therapy. 
The cTNM or pTNM category is identified by a "y" prefix. The ycTNM or ypTNM categorizes the 
extent of tumor actually present at the time of that examination. The "y" categorization is not an 
estimate of tumor prior to multimodality therapy. 
r prefix indicates a recurrent tumor when staged after a disease-free interval, and is identified 
by the "r" prefix: rTNM. 
a prefix designates the stage determined at autopsy: aTNM. 
 
 
 
4. LARYNX 
DEFINITIONS 
Primary Tumor (T) 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis Carcinoma in situ 
 
Supraglottis 
T1 
Tumor limited to one subsite of supraglottis with normal vocal cord mobility 
T2 
Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or 
region outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of 
pyriform sinus) without fixation of the larynx 
T3 
Tumor limited to larynx with vocal cord fixation and/or invades any of the following: 
postcricoid area, pre-epiglottic tissues, paraglottic space, and/or minor thyroid cartilage 
erosion (e.g., inner cortex) 
T4a Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx 
(e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap 
muscles, thyroid, or esophagus) 
T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal 
structures 
 
Glottis 
T1 
Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with 
normal mobility 


Nivolumab with Carboplatin & Paclitaxel in SCCHN 
 
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T1a Tumor limited to one vocal cord 
T1b Tumor involves both vocal cords 
T2 
Tumor extends to supraglottis and/or subglottis, or with impaired vocal cord mobility 
T3 
Tumor limited to the larynx with vocal cord fixation, and/or invades paraglottic space, 
and/or minor thyroid cartilage erosion (e.g., inner cortex) 
T4a Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx 
(e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap 
muscles, thyroid, or esophagus) 
T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal 
structures 
 
Subglottis 
T1 
Tumor limited to the subglottis 
T2 
Tumor extends to vocal cord(s) with normal or impaired mobility 
T3 
Tumor limited to larynx with vocal cord fixation 
T4a Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., 
trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, 
thyroid, or esophagus) 
T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal 
structures 
 
 
Regional Lymph Nodes (N) 
Larynx Clinical 
NX Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE 
negative 
N2 
Metastasis in a single ipsilateral lymph node, larger than 3 cm but not larger than 6 cm in 
greatest dimension and ENE negative3; or metastases in multiple ipsilateral lymph nodes, 
none larger than 6 cm in greatest dimension and ENE negative, or metastases in bilateral or 
contralateral lymph nodes, none more than 6 cm in greatest dimension and ENE negative 
N2a Metastasis in a single ipsilateral lymph node larger than 3 cm but not larger than 6 cm in 
greatest dimension and ENE negative 
N2b Metastasis in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension 
and ENE negative 
N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE negative 
N3 
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE-negative; or 
metastasis  in any lymph node(s) and clinically overt ENE-positive 
N3a Metastatis in a lymph node larger than 6 cem in greatest dimension and ENE-negative 
N3b Metastasis in any node(s) and clinically overt ENE-positive 
 
 
Larnynx Pathologic 
NX Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 


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N1 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE 
negative 
N2 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension and ENE-
positive; or more than 3 cm but not more than 6 cm in greatest dimension and ENE-
negative; or metastases in multiple ipsilateral lymph nodes, none more than 6 cm in 
greater dimension and ENE-negative; or metastasis in bilateral or contralateral lymph 
nodes, none more than 6 cm in greatest dimension, ENE-negative 
N2a Metastasis in a single ipsilateral or contralateral  lymph node 3 cm or less in greatest 
dimension and ENE-positive; or metastasis in a single ipsilateral lymph node more than 3 
cm but not more than 6 cm in greatest dimension an ENE-negative 
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension 
and ENE-negative 
N2c Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE negative 
N3 
Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE-negative; or 
metastasis  in a single ipsilateral lymph node more than 3 cm in greatest dimension and 
ENE-positive; or metastasis in multiple ipsilateral, contralateral, or bilateral lymph nodes, 
with any ENE-positive 
N3a Metastasis in a single ipsilateral node more than 6 cm in greatest dimension and ENE-
negative 
N3b Metastasis in a single ipsilateral node more than 3 cm in greatest dimension and ENE-
positive; or metastasis in multiple ipsilateral, contralateral, or bilateral lymph nodes, with 
any ENE-positive 
 
 
Distant Metastasis (M) 
MX Distant metastasis cannot be assessed 
M0 No distant metastasis 
M1 Distant metastasis 
 
Biopsy of metastatic site performed 
 
Source of pathologic metastatic specimen 
 
Stage Grouping 
0 
Tis 
N0 
M0 
I 
T1 
N0 
M0 
II 
T2 
N0 
M0 
III 
T3 
N0 
M0 
 
T1 
N1 
M0 
 
T2 
N1 
M0 
 
T3 
N1 
M0 
IVA T4a 
N0 
M0 
 
T4a 
N1 
M0 
 
T1 
N2 
M0 
 
T2 
N2 
M0 
 
T3 
N2 
M0 
 
T4a 
N2  
M0 
IVB T4b 
Any N 
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Any T 
N3 
M0 
IVC Any T 
Any N 
M1 
 
Histologic Grade (G) 
GX Grade cannot be assessed 
G1 Well differentiated 
G2 Moderately differentiated 
G3 Poorly differentiated 
 
 
Residual Tumor (R) 
RX Presence of residual tumor cannot be assessed 
R0 
No residual tumor 
R1 
Microscopic residual tumor 
R2 
Macroscopic residual tumor 
 
Additional Descriptors 
For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y," "r," and 
"a" prefixes are used. Although they do not affect the stage grouping, they indicate cases 
needing separate analysis. 
m suffix indicates the presence of multiple primary tumors in a single site and is recorded in 
parentheses: pT(m)NM. 
y prefix indicates those cases in which classification is performed during or following initial 
multimodality therapy. 
The cTNM or pTNM category is identified by a "y" prefix. The ycTNM or ypTNM categorizes the 
extent of tumor actually present at the time of that examination. The "y" categorization is not an 
estimate of tumor prior to multimodality therapy. 
r prefix indicates a recurrent tumor when staged after a disease-free interval, and is identified 
by the "r" prefix: rTNM. 
a prefix designates the stage determined at autopsy: Atnm 
 
 
 
 
 
APPENDIX D: MANAGEMENT ALGORITHMS 
These general guidelines constitute guidance to the Investigator and may be 
supplemented by discussions with the Medical Monitor representing the Sponsor. The 
guidance applies to all immuno-oncology agents and regimens. 


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A general principle is that differential diagnoses should be diligently evaluated according 
to standard medical practice. Non-inflammatory etiologies should be considered and 
appropriately treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse 
events. The oral equivalent of the recommended IV doses may be considered for 
ambulatory patients with low-grade toxicity. The lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of 
oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive 
diagnostic or therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms 
will depend on the immuno-oncology agent or regimen being used. 
 
 
 
 
 
 
 
 
 
 
 
 


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GI Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. Opiates/narcotics may mask 
symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis. 


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Renal Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy 


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Pulmonary Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging and pulmonary 
consultation. 


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Hepatic Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for obstruction. 
 


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Endocrinopathy Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider visual field testing, endocrinology 
consultation, and imaging. 
 
 


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Skin Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 


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Neurological Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 
 


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APPENDIX E: NCI PRO-CTCAE ITEMS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F: SUB-SITE UNATICIPATED PROBLEM FORM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix G: SUB-SITE SERIOUS ADVERSE EVENT FORM 


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