Nivolumab, Cisplatin, and Pemetrexed Disodium or Gemcitabine Hydrochloride in Treating Patients With Stage I-IIIA Non-small Cell Lung Cancer That Can Be Removed by Surgery
Phase: PHASE2
Conditions: Non-Squamous Non-Small Cell Lung Carcinoma, Stage I Non-Small Cell Lung Cancer, Stage IA Non-Small Cell Lung Carcinoma, Stage IB Non-Small Cell Lung Carcinoma, Stage II Non-Small Cell Lung Cancer, Stage IIA Non-Small Cell Lung Carcinoma, Stage IIB Non-Small Cell Lung Carcinoma, Stage IIIA Non-Small Cell Lung Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 1 of 127 
 
 
THOMAS JEFFERSON UNIVERSITY 
Sidney Kimmel Cancer Center 
Nivolumab plus Cisplatin/Pemetrexed or 
Cisplatin/Gemcitabine as Induction in Resectable 
Non-Small Cell Lung Cancer 
 
 
Principal Investigators: 
Rita Axelrod, MD 
Department of Medical Oncology 
1025 Chestnut Street, Suite 700 
Philadelphia, PA 19107 
215-955-8875 
Co-Principal 
Investigators 
Nathaniel Evans, MD 
Cardiothoracic Surgery 
1025 Chestnut Street, Suite 600 
Philadelphia, PA 19107 
215-955-6010 
 
Athanassios Argiris, MD PhD 
Department of Medical Oncology 
1015 Walnut Street, Suite 700 
Philadelphia, PA 19107 
215-955-8875 
 
Abington PI: 
Mark L. Sundermeyer,MD 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
Main Line Health PI: 
Paul Gilman, MD 
Lankenau Institute for Medical Research 
Suite L-41 
100 Lancaster Avenue 
Wynwood, PA 19096 
Phone: 484-476-4837 
Co-Investigator(s): 
Thomas Jefferson University: 
 
Jennifer M Johnson, MD PhD 
Department of Medical Oncology 
1015 Walnut Street, Suite 700 
Philadelphia, PA 19107 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 2 of 127 
 
 
215-955-8874 
 
Avnish Bhatia, MD 
Department of Medical Oncology 
1015 Walnut Street, Suite 700 
Philadelphia, PA 19107 
215-955-8875 
 
Scott Cowen, MD 
Cardiothoracic Surgery 
1025 Chestnut Street, Suite 600 
Philadelphia, PA 19107 
215-955-6010 
 
Bo Lu, MD PhD 
Department of Radiation Oncology 
111 South 11th Street, Room G301N 
Philadelphia, PA 19107 
215-955-6702 
 
William Tester, MD 
Department of Medical Oncology 
1015 Walnut Street, Suite 700 
Philadelphia, PA 19107 
215-955-8874 
 
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: 
Larry Harshyne, PhD 
Department of Neurosurgery 
Jefferson Alumni Hall, Suite 454 
1020 Locust St 
Philadelphia, PA 19107 
215-503-9893 
 
Grace Lu Yao, PhD 
Department of Medical Oncology 
233 South 10th Street, Suite 812 
Philadelphia, PA 19107 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 3 of 127 
 
 
215-503-7970 
 
 
Abington: 
 
Melanie J. Nordlinger, MD 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
 
Willard G. Andrews, III, MD 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
 
Anthony P. Scarpaci, MD 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
 
Pooja Suresh, MD 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
 
Christian J. Fidler, MD 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
 
Steven Cohen, MD 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
 
Sheel Patel, MD 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
 
Seema Sethi, DO 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
 
Meghan Coleman, DNP 
1200 Old York Rd, 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 4 of 127 
 
 
Abington, PA 19001 
Phone: 215-481-2400 
 
Walter Scott, MD 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
Karon Martyn, CRNP 
1200 Old York Rd, 
Abington, PA 19001 
Phone: 215-481-2400 
 
Statistician: 
Benjamin Leiby, PhD 
Department of Pharmacology and Experimental Therapeutics 
1015 Chestnut Street, Suite 520 
Philadelphia, PA 19107 
215-503-9876 
Funding: 
 
Thomas Jefferson University with funding support and drug from 
Bristol-Myers Squibb 
IND/IDE Holder: 
Rita Axelrod, MD 
IND/IDE Number: 
137162 
Study Product: 
Nivolumab (100,052) 
 
Protocol IDs: 
JeffTrial # 11371 
PRC # 2017-129 
IRB Control # 17P.556 
 
Version Number: 
Version Date: 
1.0 
5/10/2017 
2.0 
10/27/2017 
3.0 
12/04/2017 
3.1 
04/11/2018 
4.0 
11/14/2018 
5.0 
04/08/2019 
6.0 
07/24/2019 
6.1 
08/07/2019 
7.0 
11/05/2019 
7.1 
12/27/2019 
 
CONFIDENTIAL 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 5 of 127 
 
 
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. 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 6 of 127 
 
 
Table of Contents 
Signature Page .........................................................................................................................12 
Statement of Compliance ..........................................................................................................12 
List of Abbreviations ..................................................................................................................13 
Study Summary ........................................................................................................................15 
1 
Introduction .........................................................................................................................18 
1.1 
Background Information ..............................................................................................18 
1.2 
Rationale for the Proposed Study ...............................................................................22 
1.3 
Potential Risks and Benefits .......................................................................................32 
1.4 
Objectives ...................................................................................................................36 
1.5 
Endpoints/Outcome Measures ....................................................................................37 
2 
Study Design ......................................................................................................................39 
2.1 
Characteristics ............................................................................................................39 
2.2 
Duration of Therapy ....................................................................................................41 
2.3 
Duration of Follow Up .................................................................................................41 
2.4 
Study Timeline ............................................................................................................41 
3 
Study Enrollment and Withdrawal .......................................................................................41 
3.1 
Eligibility Criteria .........................................................................................................41 
3.2 
Gender/Minority/Pediatric Inclusion for Research........................................................44 
3.3 
Strategies for Recruitment and Retention ...................................................................44 
3.4 
Affiliate Site Enrollment Procedures ............................................................................44 
3.5 
Participant Withdrawal ................................................................................................45 
3.6 
Premature Termination or Suspension of Study ..........................................................46 
4 
Study Intervention ...............................................................................................................46 
4.1 
Study Products: ..........................................................................................................46 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 7 of 127 
 
 
4.2 
Study Product Description ...........................................................................................46 
4.3 
Dosage, Preparation, and Administration ....................................................................48 
4.4 
Study Product Accountability ......................................................................................49 
4.5 
Cisplatin ......................................................................................................................50 
4.6 
Pemetrexed ................................................................................................................51 
4.7 
Gemcitabine................................................................................................................54 
4.8 
Carboplatin .................................................................................................................56 
4.9 
Treatment Schedules Nivolumab/Cisplatin/Pemetrexed and 
Nivolumab/Cisplatin/Gemcitabine ..........................................................................................56 
4.10 
Dose Modifications and Dosing Delays .......................................................................58 
4.10..3 
Cisplatin/Gemcitabine and Cisplatin Pemetrexed Dose Modifications: ....................66 
4.11 
Assessing Participant Compliance with Study Product Administration ........................72 
4.12 
Concomitant Medications/Treatments .........................................................................72 
4.13 
Dietary Restrictions .....................................................................................................74 
5 
Study Schedule ..................................................................................................................74 
5.1 
Baseline/Screening (for both nonsquamous and squamous NSCLC cohorts) .............80 
5.2 
Treatment Period (for both nonsquamous and squamous NSCLC cohorts) ................82 
5.3 
Post-surgical/Follow-Up ..............................................................................................84 
5.4 
End of Treatment Study Procedures ...........................................................................85 
5.5 
Post-treatment/Follow-Up ...........................................................................................85 
5.6 
Withdrawal Visit/Discontinuation of Therapy ...............................................................86 
5.7 
Surgery .......................................................................................................................86 
5.8 
Study Procedures/Evaluations ....................................................................................86 
5.9 
Laboratory Procedures/Evaluations ............................................................................87 
5.10 
Patient Assessments ..................................................................................................87 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 8 of 127 
 
 
6 
Evaluation of Safety ............................................................................................................88 
6.1 
Specification of Safety Parameters .............................................................................88 
6.2 
Safety Assessment and Follow-Up .............................................................................89 
6.3 
Recording Adverse Events ..........................................................................................90 
6.4 
Safety Reporting .........................................................................................................91 
Reporting to IRB .................................................................................................................91 
6.5 
Reporting to SKCC DSMC ..........................................................................................93 
6.6 
Reporting to Funding Supporter ..................................................................................94 
6.7 
Reporting to FDA ........................................................................................................94 
6.8 
Reporting of Pregnancy ..............................................................................................96 
6.9 
Laboratory Test Result Abnormalities .........................................................................96 
6.10 
Overdose ....................................................................................................................97 
6.11 
Potential Drug Induced Liver Injury (DILI) ...................................................................97 
6.12 
Halting Rules ..............................................................................................................97 
7 
Study Oversight ..................................................................................................................97 
8 
Clinical Site Monitoring and Auditing ...................................................................................98 
9 
Statistical Considerations ...................................................................................................98 
9.1 
Study Hypotheses .......................................................................................................98 
9.2 
Analysis Plans ............................................................................................................98 
9.3 
Interim Analyses and Stopping Rules..........................................................................99 
9.4 
Sample Size Considerations ..................................................................................... 100 
10 
Source Documents and Access to Source Data/Documents ........................................ 100 
11 
Quality Control and Quality Assurance ......................................................................... 101 
12 
Ethics/Protection of Human Participants ....................................................................... 101 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 9 of 127 
 
 
12.1 
Ethical Standard ....................................................................................................... 101 
12.2 
Institutional Review Board ......................................................................................... 101 
12.3 
Informed Consent Process ........................................................................................ 101 
12.4 
Exclusion of Women, Minorities, and Children (Special Populations) ........................ 102 
12.5 
Participant Confidentiality.......................................................................................... 102 
12.6 
Future Use of Stored Specimens and Other Identifiable Data ................................... 102 
13 
Data Handling and Record Keeping ............................................................................. 102 
13.1 
Data Management Responsibilities ........................................................................... 102 
13.2 
Data Capture Methods .............................................................................................. 103 
13.3 
Types of Data ........................................................................................................... 103 
13.4 
Study Records Retention .......................................................................................... 103 
13.5 
Protocol Deviations ................................................................................................... 103 
14 
Study Finances ............................................................................................................. 103 
14.1 
Funding Source ........................................................................................................ 104 
14.2 
Conflict of Interest ..................................................................................................... 104 
14.3 
Participant Stipends or Payments ............................................................................. 104 
15 
Publication and Data Sharing Policy ............................................................................. 104 
16 
References ................................................................................................................... 105 
20. 
Pataer A, Kalhor N, Correa AM, et al. Histopathologic response criteria predict survival of 
patients with resected lung cancer after neoadjuvant chemotherapy. J Thorac Oncol 2012 
May;7(5):825-32. doi: 10.1097/JTO.0b013e318247504a. ....................................................... 106 
Appendices ............................................................................................................................. 109 
APPENDIX A: ECOG Performance Status: ............................................................................. 110 
APPENDIX B: AJCC 8th Edition Staging System ..................................................................... 111 
Appendix C: Management Algorithms ..................................................................................... 112 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 10 of 127 
 
 
APPENDIX D: UNANTICIPATED PROBLEM FORM

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 11 of 127 
 
 
 ............................................................................................................................................... 125 
APPENDIX E: SERIOUS ADVERSE EVENT PROBLEM FORM ............................................ 126 
APPENDIX F: Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Criteria for 
Evaluating Response in Solid Tumors ..................................................................................... 126 
 
 Staging NSCLC 
 
 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 12 of 127 
 
 
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 Harmonization 
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 
 
 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 13 of 127 
 
 
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 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTO 
Clinical Trials Office 
CTOC 
Clinical Trials Oversight Committee 
DSF 
DSMC 
Disease Free Survival 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 
FWA 
Federal wide 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 Harmonization 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
IRC 
Institutional Review Board 
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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 14 of 127 
 
 
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 
 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 15 of 127 
 
 
Study Summary 
Title: 
Nivolumab plus Cisplatin/Pemetrexed or Cisplatin/Gemcitabine as 
Induction in Resectable Non-Small Cell Lung Cancer 
Précis: 
Patients with NSCLC who are candidates for curative intent surgery will be 
treated with a combination of induction cisplatin/pemetrexed or 
cisplatin/gemcitabine plus nivolumab, to assess the rate of major pCR 
over historical control with induction chemotherapy alone. 
Lead Site: 
Thomas Jefferson University 
Phase: 
Phase II 
Number of 
Sites: 
• 3: Thomas Jefferson University (lead site), Abington Memorial 
Hospital, Main Line Health 
Objectives: 
 
Primary: 
• The primary objective of the study is to estimate major pathologic 
response (mpCR) at the in patients with newly diagnosed and 
untreated NSCLC Stage I-IIIA treated with three courses of 
induction Nivolumab added to either cisplatin/pemetrexed or 
cisplatin/gemcitabine prior to surgery.  
 
Secondary: 
• Safety 
• Complete Pathologic Response  
• 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-
gamma, IL-4, IL10, etc.) or cell subset frequencies (M2 monocytes, 
myeloid-derived suppressor cells, etc.) within a patient’s peripheral 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 16 of 127 
 
 
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 
• PD-L1 assessment in tumor. Blood correlatives for immune 
markers before and after treatment. 
 
Blood correlatives of immune function before, during, and after 
treatment.   
 - Flow Cytometry 
   - White blood cell subset: CD3, CD4, CD8, CD11c, CD14, CD15, 
CD19, CD56, CD123 
  - White blood cell activation: CD25, CD163, CD204, CD206, PD1, 
PDL1 
  - Luminex, multiplex ELISA – Millipore human cytokine panel I 
(HCYTOMAG-60K-PX41) 
 
Population: 
Men and women, 18 and above, resectable non-squamous and squamous 
NSCLC who will have planned surgery. 
 
 
Statistics: 
A Simon two-stage design will be used. The null hypothesis is that the true 
major pathologic response rate at the primary tumor site is ≤ 0.19 and will 
be tested against the alternative that it is >0.19. After testing the regimen 
on 21 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 34 patients will 
be studied. If the total number responding is less than or equal to 9, the 
regimen is rejected.  This design yields a type I error rate of 9.5% and 
power of 80% when the true response rate is 0.35.  The mpCR 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 cisplatin/pemetrexed 
or cisplatin/gemcitabine to which nivolumab is added as induction therapy 
prior to planned surgery for the definitive management of non-squamous 
and squamous NSCLC respectively. 
TREATMENT PLAN 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 17 of 127 
 
 
Non-squamous NSCLC 
Nivolumab 360mg q 3w  x 3  
Cisplatin  75mg/m2 q 3w x 3 
Pemetrexed 500 mg/m2 q 3w  x 3 
 
Squamous NSCLC 
Nivolumab 360mg q 3w  x 3  
Cisplatin 75mg/m2 q 3w x 3 
Gemcitabine 1250mg/m2   d1, d8   x 3  
 
 
 
Study 
Treatment 
Duration: 
9 weeks  
 
Patient 
Participation 
Duration: 
8 months from study entry  
Estimated 
Time to 
Complete 
Enrollment: 
24 months 
Estimated 
Time to 
Study 
Completion 
32 months 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 18 of 127 
 
 
Schematic of Study Design: 
 
 
1 Introduction 
1.1 Background Information 
Lung cancer is the second most common cancer in both men and women in North 
America [Siegel 2017]. Worldwide, 1.8 million cases of lung cancer are diagnosed 
annually [Ferlay 2013]. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all 
pulmonary neoplasms [Travis 2000]. Although incidence and death rates have stabilized 
and are falling slowly, lung cancer is still the leading cause of cancer related-deaths in 
the US, with an overall all-stage 5-year survival of 18% [Siegel 2017]. The primary 
treatment of early stage (I-IIIA) NSCLC is curative surgery. Currently only ~30% of 
patients present with stages I-IIIA lung cancer [Datta 2003], however, with the advent of 
lung cancer screening this percentage is expected to increase [The National Lung 
Screening Trial Research Trial 2011]. Although patients treated with curative surgery 
have a better prognosis, the 5-year survival for patients treated with surgery alone 
remains low, ranging from 67% (stage IA) to 23% (stage IIIA) [Mountain 1997].  
 
The poor survival rates following surgical resection for patients with stage II and III 
disease have led several groups to investigate the utility of adjuvant chemotherapy in 
improving lung survival outcomes. Five large randomized trials have been done to 
determine if adjuvant platinum-based chemotherapy after curative surgery for NSCLC 
confers a survival advantage: ALPI [Scaggliotti 2003]; IALT [Arriagada 2004]; JBR10 
[Winton 2005]; CALGB 9633 [Strauss 2008]; and ANITA [Douillard 2006]. Three of 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 19 of 127 
 
 
these five trials showed statistically significant improvements in overall survival, ranging 
from 4% [IALT] to 15% [JBR10] at 5 years, corresponding to an absolute improvement 
in relapse-free survival from 49% to 61%. Of the two trials that did not demonstrate 
improved survival, one [ALPI] suffered from poor compliance to the treatment regimen 
(69%), and the second, CALGB 9633,  was a smaller trial (n=344) limited to patients 
with stage IB disease [Strauss 2008], which was likely underpowered to detect a 20% 
reduction in hazard ratio (HR=0.8)  statistically significant improvement in overall 
survival. Interestingly, despite being limited to patients with stage IB disease, CALGB 
9633 did demonstrate an overall survival hazard ratio comparable to the other adjuvant 
trials (HR=0.8) that included patients with more advanced disease, despite not 
achieving statistical significance [Strauss 2008].  
 
Since the publication of original adjuvant chemotherapy trials, a number of meta-
analyses have confirmed the benefit of adjuvant platinum-based chemotherapy after 
surgical resection for NSCLC [Pignon 2008; NSCLC Meta-analysis Collaborative Group 
2010] (figure 1). In these meta-analyses, all-stage (IB-IIIa) hazard ratios were in the 
range of HR=0.86, corresponding to an absolute benefit of chemotherapy on overall 
survival of 4-5% at 5 years [Pignon 2008; NSCLC Meta-analysis Collaborative Group 
2010]. The benefit of adjuvant chemotherapy, however, was demonstrated to be stage 
dependent (although using older staging criteria versions), with the benefit only reaching 
statistical significance for stages II and III [Pignon 2008]. While the role of adjuvant 
chemotherapy in stage I disease has historically been controversial [Wakelee 2007], 
subgroup analyses in a number of trials in high-risk patients with stage IB disease 
(tumors > 4cm) suggests that there may be an overall survival advantage with adjuvant 
chemotherapy in this subgroup of patients, comparable to those observed in stage II 
and III disease [Strauss 2008]. Neoadjuvant chemotherapy has also become accepted 
in some countries [NSCLC Meta-analysis Collaborative Group 2014].  
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 20 of 127 
 
 
 
Figure 1 
 
 
 
Figure 2 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 21 of 127 
 
 
 
Preoperative induction chemotherapy is also an established option [NCCN 2016].  A  
meta-analysis of 15 randomized controlled trials (2385 individual patients analyzed) of 
preoperative chemotherapy vs. surgery alone in patients with stage IB-IIIA showed 
significant OS HR 0.87 comparable to postoperative adjuvant chemotherapy [NSCLC 
Meta-analysis Collaborative Group 2014].   However, the addition of both pre- or post-
operative adjuvant platinum doublet chemotherapy increases overall survival (OS) by 
only 5% [Pignon 2008; NSCLC Meta-analysis Collaborative group 2014; Strauss 2008] 
(figure 2).  .   
Despite the established benefit of adjuvant and induction chemotherapy with curative 
surgery for NSCLC, 30-60% of patients, depending on stage, will eventually relapse and 
die of their disease [Hotta 2004]. Furthermore, not all patients with early stage disease 
are eligible or willing to undergo chemotherapy following complete surgical resection. As 
such, the long-term prognosis of patients with NSCLC, even among those with early 
stage disease, remains poor. Novel therapies are, therefore, required to improve the 
clinical outcomes of completely resected NSCLC.  Among these, are the checkpoint 
inhibitors.  
Immune Therapy 
Immunotherapy with checkpoint inhibitors has demonstrated clinical efficacy in several 
solid tumors types, including melanoma, renal cell carcinoma, Head and Neck Cancer, 
bladder cancer among others. Early success was achieved with the CTLA4 antagonist 
ipilimumab in the treatment of advanced melanoma.7  Nivolumab, a PD-1 checkpoint 
inhibitor, is approved as second line therapy in both squamous and non-squamous 
NSCLC regardless of PD-L1 status.  Pembrolizumab, also a PD-1 checkpoint inhibitor, 
is approved in as second line therapy in squamous and non-squamous NSCLC in 
patients whose tumors show PD-L1 of 1% or more.  It is also approved as first line 
therapy in advanced NSCLC in patients whose tumors show >50% PD-L1.  
Atezolizumab, a PD-L1 inhibitor, is approved as second line therapy in squamous and 
non-squamous NSCLC irrespective of PD-L1 status.   
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 factors may interfere with the function of T cells 
and other effector immune cells critical to tumor 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 combination approaches  to “boost” the responses seen with nivolumab 
monotherapy. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 22 of 127 
 
 
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). Nivolumab 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, as second line therapy in advanced recurrent squamous Head 
and Neck cancer, and advanced renal cell carcinoma who have received prior anti-
angiogenic therapy.  Nivolumab is established as second line therapy in both squamous 
and nonsquamous NSCLC based on results from Checkmate 017 and 057 respectively.  
To further improve outcomes in the advanced disease setting, multiple combination 
studies in first and latter line therapy are in various stages of investigation. In addition, 
nivolumab is being evaluated in earlier stage disease in various combinations and 
sequences with surgery and radiation.    
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 
For patients with localized NSCLC, 5 year post-surgical survivals for stage pIIA-IIIA  
have been modest at 46% - 24% [Goldstraw 2007].  Though, post-operative adjuvant 
chemotherapy is more the default standard, preoperative induction chemotherapy is 
also an established option [NCCN 2016].  A  meta-analysis of 15 randomized controlled 
trials (2385 individual patients analyzed) of preoperative chemotherapy vs. surgery 
alone in patients with stage IB-IIIA showed significant OS HR 0.87 comparable to 
postoperative adjuvant chemotherapy [NSCLC Meta-analysis Collaborative Group 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 23 of 127 
 
 
2014].   However, the addition of both pre- or post-operative adjuvant platinum doublet 
chemotherapy increases overall survival (OS) by only 5% [Pignon 2008; NSCLC Meta-
analysis Collaborative group 2014; Strauss 2008].  Thus, there remains a large unmet 
need to improve outcomes.   
Potential advantages of induction include the higher rate of chemotherapy delivery 
compared to when chemotherapy is postoperatively administered.  It does so without 
decreasing the rate of surgery compared to postoperative adjuvant chemotherapy 
[Westeel2013;Felip 2010].  Moreover, given the protracted length of time required to 
assess OS in the surgical population, induction strategy is an important opportunity to 
speed discovery of promising regimens by using response as a surrogate endpoint for 
OS.  Use of major pathological response defined as < 10% viable tumor is a promising 
endpoint.  In a retrospective analysis of 192 patients stages I-IV (4% had stage IV) who 
had received induction (89% with a platinum doublet) with a median of three cycles, 36 
patients (19%) of samples showed major pathologic response defined as having < 10% 
viable cells averaged across 10 slides [Pataer 2012].  Patients whose tumors showed a 
major pathologic response had a 5 year OS of 85% versus 40% (p<0.0001) and 5 year 
DFS, 78% vs. 35% (p<0.001).  Of interest, from the same retrospective study, in a set of 
166 patients who had not had induction therapy, none of the patients’ tumor specimens 
showed < 10% viable cells.   Thus major pathologic response is both predictive and 
common enough to serve as a strong surrogate for OS [Hellmann 2014].   
PD-1/PD-L1 axis checkpoint inhibitors (nivolumab and pembrolizumab (PD-1) and 
atezolizumab (PD-L1))  are established as second line therapy for squamous and 
nonsquamous NSCLC [Brahmer 2015; Borghei 2015; Herbst 2016; Barlesi 2016]. 
Pembrolizumab is FDA approved as first line therapy in patients who have tumor 
proportion score for PD-L1 >50% [Reck 2016].  They all have the property of equal or 
superior median survivals depending on PD-L1 status, very sustained responses, and 
tolerability superior to standard chemotherapy.   
There are also preliminary single agent nivolumab data in early stage disease in a 
window trial.  In a small study, patients with stage I-IIIa NSCLC were treated 4 and 2 
weeks before surgery with 3mg/kg  nivolumab [Forde 2016].   There were reportedly no 
significant safety concerns or delays to surgery in the 16 analyzed for safety, and 12 of 
15pt (80%) showed some regression.  Forty percent had major pathological response 
manifested by tumor specimens with either complete pathologic response or isolated 
remaining tumor cells with the specimens  dense  with an infiltration of immune cells  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 24 of 127 
 
 
including T cells which were not detected in the pre-treatment biopsy.  These data 
suggest the potential efficacy and safety of inclusion of nivolumab as induction therapy. 
There is preclinical evidence supporting the addition of PD-1/PD-L1 axis checkpoint 
inhibitors to standard cytotoxic agents [Hato 2014; Nowak 2002].  Clinical data include a 
randomized carboplatin and pemetrexed plus/minus pembrolizumab phase II in first-line 
advanced non-squamous NSCLC.  Response rates were 55% vs. 29% (p=0.0016) in 
the triplet vs. doublets arms and median PFS was 13.0 vs. 8.1 (HR 0.53; p=0.01) 
[Langer 2016] (figure 3).  Numerically improved response and PFS were seen in all PD-
L1 subsets though numbers of patients were small.  Severe adverse events were similar 
with 39% and 26% grade 3 in the triplet vs. doublet with 1 and 2 treated related deaths 
in the respective arms.   In a multi-arm study of four nivolumab containing triplets 
including 10mg/kg nivolumab with cisplatin/ gemcitabine, cisplatin-pemetrexed or 
carboplatin-paclitaxel or nivolumab 5mg/kg with carboplatin-paclitaxel in first line 
advanced NSLCC, response rates were 33%, 47%, 47%, and 43% with efficacy seen 
irrespective of PD-L1 expression [Rizvi 2016].  Forty-five percent had > grade 3 toxicity 
with only 2/56 (4%) discontinuing therapy due to toxicity during the triplet treatment (and 
another 10/56 during maintenance nivolumab).  These NSCLC data support the safety 
and efficacy of standard chemotherapy combined with PD-1 inhibitors.     
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 25 of 127 
 
 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 26 of 127 
 
 
 
Figure 3 
 
PFS 
Chemo + 
Pembro 
Chemo + 
Pembro 
Chemo 
Chemo 
OS 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 27 of 127 
 
 
Given the single agent efficacy and relative safety of nivolumab in both squamous and 
nonsquamous NSCLC in advanced disease and preliminary evidence in pre-surgical 
disease, and the promising data with platinum-based doublets and immune checkpoint 
inhibitors in advanced NSCLC, we propose to study cisplatin and gemcitabine  plus 
nivolumab in squamous and cisplatin pemetrexed plus nivolumab in non-squamous 
NSCLC as an induction regimen in resectable stage Ib (>4cm) – IIIa NSCLC.  It is tenable 
that the addition of nivolumab to these doublets will be both well tolerated and improve 
efficacy including major pathologic response, and long term disease control.  The 
induction setting is especially appealing to study nivolumab added to platinum doublets 
in resectable NSCLC given the ability to rapidly reach an endpoint, major pathological 
response, which is predictive of OS.  Moreover, it affords the opportunity to obtain repeat 
tissue sampling for pharmacodynamics endpoint evaluation.    
Hypothesis: 
The addition of nivolumab to induction cisplatin pemetrexed or cisplatin gemcitabine will 
increase the rate of major pathologic response over historical control with induction 
chemotherapy alone. 
Immunotherapy in NSCLC 
Indications in squamous and non-squamous NSCLC as second line therapy irrespective 
of PD-L1 status was supported by two large studies.  In Checkmate 017, a phase III study 
in 272 patients with advanced squamous NSCLC who had recurrence after a platinum 
doublet were randomized to docetaxel (75mg/m2 q 3 wks) or nivolumab (3mg/kg q 2wks).  
The median overall survivals (OS) were 9.2 and 6.0 months for nivolumab and docetaxel 
respectively  (HR 0.59; p<0.001) [Brahmer 2015].  Responses were 19% vs. 12% 
(p=0.02) in nivolumab and docetaxel treated patients respectively with the median 
duration of response for nivolumab not reached (range 2.9-20.5+) and in the docetaxel 
group the median was 8.4 months (1.4+-15.2+).  Treated related adverse events grade 3 
or 4 were 7% in nivolumab vs. 55% of patients treated with docetaxel with a lower rate of 
both grade 3 and 4 hematologic and non-hematologic toxicities.   
In a very similar phase III study, Checkmate 057, 582 patients with advanced squamous 
NSCLC who had recurrence after a platinum doublet were randomized to docetaxel 
(75mg/m2 q 3 wks) or nivolumab (3mg/kg q 2wks).  The median OS were 12.2 and 9.4 
months for nivolumab and docetaxel respectively  (HR 0.73; p<0.002) [Borghaei 2015].  
Responses were 20% vs. 9% (p=0.008) in nivolumab and docetaxel treated patients 
respectively with the median duration of response for nivolumab 17.2 months (range 1.8-
22.6+) and in the docetaxel group the median was 5.6 months (1.2+-15.2+).  Notably, 
patients with EGFR mutated cancer did not have improved OS and had a numerically 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 28 of 127 
 
 
worse PFS than docetaxel.  Unlike 017, patients randomized to nivolumab whose tumors 
had <10, 5 or 1% PD-L1 expression at baseline did not have superior OS, but rather equal 
OS.  Treated related adverse events grade 3 or 4 were 10% in nivolumab vs. 54% of 
patients treated with docetaxel with a lower rate of both grade 3 and 4 hematologic and 
non-hematologic toxicities.  In conclusion, nivolumab was at least as effective as 
docetaxel in patients irrespective of baseline PD-L1 expression and better tolerated and 
thus approved by the FDA for advanced second line NSCLC without requiring PD-L1 
assessment.   
Combination of Nivolumab and chemotherapy 
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 [Rizvi 2016]. 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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 29 of 127 
 
 
 
 
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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 30 of 127 
 
 
 
 
 
 
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.   
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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 31 of 127 
 
 
expression in these different cell subsets by immunohistochemistry and flow cytometry 
at various stages of treatment and look for association with clinical outcome.  
Analysis of peripheral blood mononuclear cells and cytokines 
 
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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 32 of 127 
 
 
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 [32]. 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[33] .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 [34]. Prevalence rates of depression in cancer patients differ extensively across 
studies [35, 36]. Previous studies have also shown that depression might affect behavior and 
adherence to medical treatment [37].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 
[38].  The diagnostic validity of the PHQ was established in two large studies in primary care and 
obstetrics [39].   
 
Additional Lab tests and waist to hip ratio: 
C - reactive protein (CRP) is an acute phase reactant [40], which reflects tissue injury .It is also a 
well-established marker for inflammation[10]. However, in recent literature it has also been shown 
to be a predictive biomarker for immunotherapy[41], elevated CRP also predicted prognosis and 
treatment response[42]. 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[43]. New onset autoimmune Diabetes 
Mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare [44, 45]. 
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[46, 47].  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[48, 
49]. 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. 
 
1.3 Potential Risks and Benefits 
Potential Risks 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 33 of 127 
 
 
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.  
 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 34 of 127 
 
 
 
• The safety of this drug combination with chemotherapy in Non-small cell lung 
cancer has shown the following. 18 
 
 
 
 
 
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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 35 of 127 
 
 
 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 36 of 127 
 
 
Benefits 
In this population, the safety profile of nivolumab was shown to be favorable as 
compared to standard of care chemotherapy.  In the case of pembrolizumab, the 
addition of this agent to platinum doublets in NSCLC improved response and 
progression free survival compared to chemotherapy alone and in the case of 
nivolumab plus platinum doublets, also appeared more active compared to historical 
controls.  Given the activity of both cisplatin pemetrexed and cisplatin gemcitabine, the 
known sustained responses of single agent nivolumab and the promising combination 
platinum doublet PD-1 inhibitor data in advanced disease in NSCLC, the proposed 
regimens offer is substantial promise of improved major pathologic response which in 
turn historically implies improved long term survival outcomes when given as induction 
prior to surgery in stage I-IIIa. 
 
Study Objectives 
1.4 Objectives 
Primary 
The primary objective of the study is to estimate major pathologic response (mpCR) in 
patients with newly diagnosed and untreated NSCLC Stage I-IIIA treated with three 
courses of induction Nivolumab added to either cisplatin/pemetrexed or 
cisplatin/gemcitabine prior to surgery.  
Secondary 
• Safety 
• Complete Pathologic Response at all sites of disease 
• Major pathologic response rate at primary site 
• 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-gamma, IL-4, 
IL10, etc.) or cell subset frequencies (M2 monocytes, myeloid-derived 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 37 of 127 
 
 
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 
• PD-L1 assessment in tumor. Blood correlatives for immune markers before and 
after treatment. 
 
Blood correlatives of immune function before, during, and after treatment.   
 - Flow Cytometry 
   - White blood cell subset: CD3, CD4, CD8, CD11c, CD14, CD15, CD19, CD56, 
CD123 
  - White blood cell activation: CD25, CD163, CD204, CD206, PD1, PDL1 
  - Luminex, multiplex ELISA – Millipore human cytokine panel I (HCYTOMAG-60K-
PX41) 
 
• 
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; to 
describe the longitudinal pattern of quality of life and depression from baseline to end of 
treatment; and evaluate the physical and psychosocial needs of cancer survivors.   
Patient Reported Outcomes Measures-: Depression: PHQ2 and PHQ9, Quality 
of Life: FACT-G and FACT-L 
 
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.   
 
 
 
1.5 Endpoints/Outcome Measures 
Primary 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 38 of 127 
 
 
The primary objective of the study is to estimate major pathologic response (mpCR 
defined as < 10% viable tumor) in patients with newly diagnosed and untreated NSCLC 
Stage I-IIIA treated with three courses of induction Nivolumab added to either 
cisplatin/pemetrexed or cisplatin/gemcitabine prior to surgery. 
Secondary 
Safety will be continually assessed using the CTCAE version 5.0. 
Progression Free Survival (PFS) is defined as the time between the date of study entry 
and the date of either documented progression (by RECIST v1.1- Appendix F) or death 
whichever comes first.  PFS at one year will be the percent of patients who have PFS by 
1 year.  For patients without documentation of death or evaluation of tumor status, PFS 
will be censored on the last date the subject was known to be alive or had documented 
tumor status assessment, whichever comes first. 
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. 
 
Exploratory 
• 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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 39 of 127 
 
 
• Exosomes  
We will look for changes in exosome quantity and content following nivolumab 
and chemotherapy therapy. 
 
Blood correlatives of immune function before, during, and after treatment.   
 - Flow Cytometry 
   - White blood cell subset: CD3, CD4, CD8, CD11c, CD14, CD15, CD19, CD56, 
CD123 
  - White blood cell activation: CD25, CD163, CD204, CD206, PD1, PDL1 
  - Luminex, multiplex ELISA – Millipore human cytokine panel I (HCYTOMAG-60K-
PX41) 
 
2 Study Design 
2.1 Characteristics 
This is a phase II trial looking at the either cisplatin/pemetrexed or cisplatin/gemcitabine 
to which nivolumab is added  as induction therapy prior to planned surgery  for the 
definitive management of NSCLC. 
TREATMENT PLAN 
Non-squamous NSCLC 
Nivolumab 360mg q 3w  x 3 
Cisplatin  75mg/m2 q 3w x 3 
Pemetrexed 500 mg/m2 q 3w  x 3 
 
Squamous NSCLC 
Nivolumab 360mg q 3w  x 3 
Cisplatin 75mg/m2 q 3w x 3 
Gemcitabine 1250mg/m2 d1, d8 x 3 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 40 of 127 
 
 
 
If in the opinion of the treating physician, the cisplatin is not tolerated Well, the patient may be 
switched to standard carboplatin (AUC 5) for both squamous and nonsquamous for the 
remaining courses.  
Nonsquamous for the remaining courses: 
Carboplatin AUC 5 
Pemetrexed 500mg/m2 
Nivolumab 360mg 
 
Squamous for the remaining courses: 
Carboplatin AUC 5 
Gemcitabine 1250mg/m2 
Nivolumab 360mg 
Evaluation of Response to Chemotherapy 
Clinical response to chemotherapy will be measured by repeat CT of thorax.  PET/CT 
and MRI brain will be obtained during the initial staging work-up for all patients (if not 
PET/CT then baseline CT chest abdomen and pelvis with bone scan). If the treating 
medical oncologist determines that there is evidence the patient is progressing while on 
treatment, the appropriate repeat imaging will be obtained. 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 at the discretion of their treating oncologist and surgeon. Finally, the level 
of pathologic response will be assessed in the final tumor specimen, and attainment of 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 41 of 127 
 
 
major pathologic response will be determined by pathologic review.  Assessment of 
pathologic 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 3 weeks after the last dose of platinum doublet (last dose of 
gemcitabine can be 2 weeks before surgery).  
Number of Participants 
34 total subjects. 24 subjects will be enrolled at Thomas Jefferson University, 5 subjects 
will be enrolled at Abington Memorial Hospital, and 5 subjects will be enrolled at Main 
Line Health.  
2.2 Duration of Therapy 
9 weeks  
2.3 Duration of Follow Up 
6 months after surgery or about 8 months after enrollment on trial. 
2.4 Study Timeline 
Primary Completion 
We anticipate accrual of 34 patients to the study over  24 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. 
Study Completion 
We anticipate completion of the study in 32 months. 
3 Study Enrollment and Withdrawal 
3.1 Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug 
and must meet all inclusion and exclusion criteria. 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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 42 of 127 
 
 
3.1..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 NSCLC, not previously treated, with a plan to undergo 
surgery 
3. Stage I-IIIA (stage I tumors must be >4cm) per AJCC 8th edition 
4. Tumor sample must be available for PD-L1 testing. Archival tissue within 3 
months of study enrollment will be used. If archival tissue is unavailable, a fresh 
biopsy will be taken.  
5. ECOG Performance status 0-1. 
6. 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 
7. 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 the study enrollment. 
8. 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 more 
than 40 mIU/mL. 
9. 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. 
10. Informed Consent:  All subjects must be able to comprehend and sign a written 
informed consent document.  
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 43 of 127 
 
 
3.1..2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation 
in this study: 
1. Patients who have participated in a study with an investigational agent or device 
within 2 weeks of enrollment 
2. Any prior radiotherapy to the lung. 
3. Any prior treatment for NSCLC.  
4. EGFR or ALK activating alteration 
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 that has undergone potentially curative therapy.  Patients with a 
history of other prior malignancy must have been treated with curative intent and 
must have remained disease-free for 3years post-diagnosis. 
9. Participants with an active autoimmune disease or any other condition requiring 
systemic treatment with either corticosteroids within 14 days (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 30 days 
of randomization. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of 
active autoimmune disease.  
10. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll. 
11. Patients with evidence of interstitial lung disease or active, non-infectious 
pneumonitis. Patients with a history of interstitial lung disease or non-infectious 
pneumonitis requiring treatment with steroids are also excluded.  
12. 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). 
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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 44 of 127 
 
 
abuse disorder(s) that would interfere with cooperation with the requirements of 
the trial. 
16. Women must not be pregnant (as above) or breastfeeding. 
 
3.2 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 squamous cell and nonsquamous cell lung 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 Lung 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. 
3.3 Strategies for Recruitment and Retention 
Thirty-four subjects will be recruited. No advertisement will be conducted. 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, image 
studies etc. 34 patients will be enrolled (see Statistical Analysis Plan) with replacement 
of patients who do not begin therapy. 
3.4 
Affiliate Site Enrollment Procedures 
When a potential patient is identified at the Affiliate Site, the Thomas Jefferson 
University (TJU) Study Site Contact should 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 Affiliate Site will send the following to the TJU Study Site 
Contact 
1. Notify them of the pending patient registration 
2. Confirm the method of sending registration documents (i.e. fax, email, 
etc.). Registration documents should include at least a completed eligibility 
checklist and supporting documentation to confirm eligibility.  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 45 of 127 
 
 
3. Communicate the desired timeline of the registration. 
Once eligibility has been confirmed, TJU will email the Research Coordinator at the 
Affiliate Site to confirm . 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 Affiliate Site Research Nurse/Coordinator will enter patients enrolled at the Affiliate 
Site into the protocol management system, JeffTrial, within 5 business days of 
enrollment.  
A master study enrollment log will be maintained by the study team at Thomas 
Jefferson University. The Affiliate 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 Affiliate Site will need to contact the TJU Study Site Contact 
by Friday at noon at the latest.   
If a patient is enrolled at the Affiliate Site without approval from the lead site, TJU will: 
1)  Temporarily suspend the Affiliate Site 
2)  Complete mandatory re-training of staff at the Affiliate Site on the enrollment 
process.  This training will be fully documented. 
If enrollment without approval occurs a second time, the Affiliate Site will not be able to 
continue to participate in this study. 
3.5 Participant Withdrawal 
3.5..1 
Reasons for Withdrawal 
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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 46 of 127 
 
 
3.5..2 
Handling of Participant Withdrawals and Participant Discontinuation of Study 
Intervention 
Patients who are discontinued from the study prior to initiation of radiation will not be 
considered as evaluable for this study and will be replaced. 
3.6 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 Investigational New Drug (IND) sponsor 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. 
4 Study Intervention 
4.1 Study Products: 
• Nonsquamous cohort 
o Nivolumab 
o Cisplatin 
o Pemetrexed 
• Squamous cohort 
o Nivolumab 
o Cisplatin  
o Gemcitabine 
4.2 If in the opinion of the treating physician, the cisplatin is not tolerated well, 
the patient may be switched to standard carboplatin (AUC 5) for both 
squamous and nonsquamous for the remaining courses. Study Product 
Description 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 47 of 127 
 
 
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). 
 
4.2..1 
Acquisition 
Nivolumab will be supplied by Bristol-Myers Squibb directly to each site involved in the 
research (Thomas Jefferson University and Affiliate Sites). 
Chemotherapy (cisplatin, pemetrexed, gemcitabine, and carboplatin) at each site will be 
supplied commercially.  
4.2..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 
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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 48 of 127 
 
 
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. 
4.2..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 
4 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 4-hour period under room temperature and room light 
conditions includes the product administration period. 
 
4.3 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. 
 
Dosage & Administration Time of Nivolumab 
The dose of nivolumab is a flat dose 360mg 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.  
 
 
Frequency of Treatment: 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 49 of 127 
 
 
For the duration of the study, nivolumab is to be administered on a Q3 weeks and  
cisplatin/pemetrexed or cisplatin/gemcitabine Q 3 weeks, all agents on the same day.  
Nivolumab administration will precede chemotherapy administration. 
 
 
4.4 Study Product Accountability 
Table 1 
Product Description 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packagi
ng 
(Volume)
/ Label 
Type 
Secondary 
Packaging 
(Qty) /Label 
Type 
Appearance 
Storage 
Conditions 
(per label) 
Nivolumab BMS-
936558-01 
Solution for 
Injection 
100 mg 
(10 
mg/mL) 
10 mL 
vial 
5-vials per 
carton/ Open-
label 
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. 
• 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.  
• If conditions for destruction cannot be met, please contact BMS.  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 50 of 127 
 
 
• 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. 
 
4.5 Cisplatin 
Please see package insert for detailed information regarding side effects related to this 
drug.  
 
Other Names  
Cisdiaminedichloroplatinum, Cis-diaminedichloroplatinum (II), diaminedichloroplatinum, 
cis-platinum, platinum, Platinol, Platinol-AQ, DDP, CDDP, DACP, NSC 119875. 
Classification  
Alkylating agent  
 
Mode of Action  
Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. Other possible 
mechanisms include chelation of DNA and binding to cell membranes thereby 
stimulating immune mechanisms.  
 
Storage and Stability  
Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. Other possible 
mechanisms include chelation of DNA and binding to cell membranes thereby 
stimulating immune mechanisms.  
 
Preparation  
The desired dose of cisplatin is diluted with 250-1000 mL of saline and/or dextrose 
solution. Varying concentrations of 0.225-5% sodium chloride and 5% dextrose may be 
used. To maintain stability of cisplatin, a final sodium chloride concentration of at least 
0.2% is recommended.  
 
Administration  
Cisplatin solution must be administered over a 60 to 120 minute period.  
 
Dosage 
75mg/m2 on day 1 of each 3 week cycle for three cycles.  
Incompatibilities  
Amsacrine, cefepime, gallium nitrate, mesna, piperacillin, sodium bicarbonate, and 
thiotepa. Cisplatin may react with aluminum which is found in some syringe needles or 
IV sets, forming a black precipitate.  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 51 of 127 
 
 
 
Availability  
Commercially available as a mg/mL solution in 50 and 100 mg vials.  
 
Side Effects  
Please see package insert for detailed information regarding side effects related to this 
drug.  
A dose-related ototoxicity, manifested by high-frequency hearing loss and tinnitus, 
occurs in about 30% of subjects. Mild leukopenia and thrombocytopenia occur in 25-
30% of subjects, but are rarely dose-limiting. Nausea and vomiting occur in almost 
100% of subjects unless adequate antiemetic prophylaxis is given. Allergic reactions are 
reported in up to 20% of subjects. Symptoms include: rash, facial edema, wheezing, 
hypotension, and tachycardia. 
 
4.6 Pemetrexed 
Availability  
Pemetrexed is commercially available and is approved for this indication.  
 
Chemical Name  
Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-
amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, 
heptahydrate.  
 
Classification  
An antifolate antineoplastic agent  
 
Molecular Formula  
C20H19N5Na2O6•7H2O Molecular Weight: 597.49  
 
Mode of Action  
Pemetrexed is an antifolate antineoplastic agent that exerts its action by disrupting 
folate-dependent metabolic processes essential for cell replication.  
 
How Supplied  
Pemetrexed is supplied as a sterile lyophilized powder for intravenous infusion available 
in single-dose vials. The product is a white to either light yellow or green-yellow 
lyophilized solid. Pemetrexed is supplied in 100mg and 500 mg vials. Each 500-mg vial 
of pemetrexed contains pemetrexed disodium equivalent to 500 mg pemetrexed and 
500 mg of mannitol. Each 100-mg vial of pemetrexed disodium contains equivalent to 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 52 of 127 
 
 
100mg pemetrexed and 106mg of mannitol. Hydrochloric acid and/or sodium hydroxide 
may have been added to adjust pH.  
NDC 0002-7623-01 (VL7623): single-use vial with flip-off cap individually packaged in a 
carton (500 mg vial).  NDC 0002-7640-01 (vl7640); single use vial with flip-off cap 
individuality packaged in a carton (100 mg vial). 
 
Storage and Stability  
Pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-
30°C (59-86°F) [see USP Controlled Room Temperature]. Chemical and physical 
stability of reconstituted and infusion solutions of pemetrexed were demonstrated for up 
to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C (36-46°F), or 
at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room 
Temperature]. When prepared as directed, reconstituted and infusion solutions of 
Pemetrexed contain no antimicrobial preservatives. Discard unused portion. 
Pemetrexed is not light sensitive.  
 
Dose Specifics and Administration  
All patients on Arm B or Arm C of Maintenance Phase of protocol treatment will receive 
pemetrexed at 500 mg/m2 IV over 10 minutes every 21-day cycle.  
 
Preparation  
1. Use aseptic technique during the reconstitution and further dilution of pemetrexed for 
intravenous infusion administration.  
2. Calculate the dose and the number of pemetrexed vials needed. Each vial contains 
500 mg or 100mg of Pemetrexed. The vial contains an excess of Pemetrexed to 
facilitate delivery of label amount.  
3. Reconstitute 500-mg vials with 20 mL of 0.9% Sodium Chloride Injection 
(preservative free) to give a solution containing 25 mg/mL Pemetrexed. Gently swirl 
each vial until the powder is completely dissolved, Reconstitute 100mg vials with 4.2 ml 
of 0.9% Sodium Chloride injection (preservative free) to give a Solution containing 4.3 
mg/ml pemetrexed.  The resulting solution is clear and ranges in color from colorless to 
yellow or green-yellow without adversely affecting product quality. The pH of the 
reconstituted pemetrexed solution is between 6.6 and 7.8. FURTHER DILUTION IS 
REQUIRED.  
4. Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. If particulate matter is observed, do not administer.  
5. The appropriate volume of reconstituted Pemetrexed solution should be further 
diluted to 100 mL with 0.9% Sodium Chloride Injection (preservative free) and 
administered as an intravenous infusion over 10 minutes.  
6. Chemical and physical stability of reconstituted and infusion solutions of pemetrexed 
were demonstrated for up to 24 hours following initial reconstitution, when stored at 
refrigerated or ambient room temperature [see USP Controlled Room Temperature] and 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 53 of 127 
 
 
lighting. When prepared as directed, reconstitution and infusion solutions of pemetrexed 
contain no antimicrobial preservatives. Discard any unused portion. Reconstitution and 
further dilution prior to intravenous infusion is only recommended with 0.9% Sodium 
Chloride Injection (preservative free). Pemetrexed is physically incompatible with 
diluents containing calcium, including Lactated Ringer’s Injection, USP and Ringer’s 
Injection, USP and therefore these should not be used. Coadministration of pemetrexed 
with other drugs and diluents has not been studied, and therefore is not recommended.  
 
Route of Administration  
Intravenous Infusion.  
 
Incompatibilities and Potential Drug Interactions  
Chemotherapeutic Agents — Cisplatin does not affect the pharmacokinetics of 
pemetrexed and the pharmacokinetics of total platinum is unaltered by pemetrexed.  
 
Vitamins — Coadministration of oral folic acid or intramuscular vitamin B12 does not 
affect the pharmacokinetics of pemetrexed.  
 
Drugs Metabolized by Cytochrome P450 Enzymes — Results from in vitro studies with 
human liver microsomes predict that pemetrexed would not cause clinically significant 
inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, 
and CYP1A2. No studies were conducted to determine the cytochrome P450 isozyme 
induction potential of pemetrexed, because Pemetrexed used as recommended (once 
every 21 days) would not be expected to cause any significant enzyme induction.  
 
Aspirin — Aspirin, administered in low to moderate doses (325 mg every 6 hours), does 
not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on 
pemetrexed pharmacokinetics is unknown.  
 
Ibuprofen — Daily ibuprofen doses of 400 mg QID reduce pemetrexed’ s clearance by 
about 20% (and increase AUC by 20%) in patients with normal renal function. The effect 
of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown. 
Pemetrexed is primarily eliminated unchanged renally as a result of glomerular filtration 
and tubular secretion. Concomitant administration of nephrotoxic drugs could result in 
delayed clearance of pemetrexed. Concomitant administration of substances that are 
also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of 
pemetrexed. Although ibuprofen (400 mg QID) can be administered with pemetrexed in 
patients with normal renal function (creatinine clearance (80 mL/min), caution should be 
used when administering ibuprofen concurrently with pemetrexed to patients with mild 
to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients 
with mild to moderate renal insufficiency should avoid taking NSAIDs with short 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 54 of 127 
 
 
elimination half-lives for a period of 2 days before, the day of, and 2 days following 
administration of pemetrexed. In the absence of data regarding potential interaction 
between pemetrexed and NSAIDs with longer half-lives, all patients taking these 
NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days 
following pemetrexed administration. If concomitant administration of an NSAID is 
necessary, patients should and gastrointestinal toxicity.  
 
Side Effects  
Renal: creatinine elevation (10%)  
Neurologic: neuropathy-sensory (9%), taste disturbance (8%)  
Hematologic: anemia (33%), neutropenia (29%), leucopenia (18%), thrombocytopenia 
(10%)  
Gastrointestinal: nausea (56%), vomiting (40%), anorexia (27%), constipation (21%), 
stomatitis/pharyngitis (14%), diarrhea (12%), dyspepsia/heartburn (5%)  
Dermatology/skin: alopecia (12%), rash/desquamation (7%)  
Other: fatigue, febrile neutropenia, infection, pyrexia, dehydration, increased AST, 
increased ALT, creatinine clearance decrease, renal failure, conjunctivitis, arrhythmia, 
chest pain, increased GGT, motor neuropathy  
 
Pregnancy  
Category D 
 
Nursing/Patient Implications  
1. Monitor CBC’s and chemistries.  
2. Administer Adequate Antiemetics.  
3. Monitor renal toxicity: Calculate Creatinine Clearance prior to administering 
pemetrexed.  
a. Patient use of Ibuprofen: Refer to precautionary guidelines  
4. Administer 1000 micrograms Vitamin B12 intramuscularly within 1 week of first dose 
of pemetrexed and repeat every 3 cycles until the end of treatment.  
5. 400-1000 micrograms of folate (folic acid) beginning at least 5-7 days prior to initial 
dose of pemetrexed and continuing for at least 3 weeks after last dose.  
6. Monitor for adequate hydration.  
7. Patients may receive dexamethasone 4mg orally twice daily (or equivalent 
corticosteroid) on the day before, day of, and day after each dose of pemetrexed to 
prevent the occurrence of rash. 
4.7 Gemcitabine 
Please see package insert for detailed information regarding this medication  
 
Other Names  
2'-Deoxy-2',2'-difluorocytidine monohydrochloride, Gemzar  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 55 of 127 
 
 
 
Classification  
Antimetabolite (nucleoside pyrimidine analogue)  
 
Mode of Action  
Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA 
synthesis (S phase) and also blocking the progression of cells through the G1/S phase 
boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to the active 
diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of 
gemcitabine is attributed to a combination of two actions of the diphosphate and the 
triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, gemcitabine 
diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the 
reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition 
of this enzyme by the diphosphate nucleoside causes a reduction in the concentrations 
of deoxynucleotides, including dCTP. Second, gemcitabine triphosphate competes with 
dCTP for incorporation into DNA. The reduction in the intracellular concentration of 
dCTP (by the action of the diphosphate) enhances the incorporation of gemcitabine 
triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is 
incorporated into DNA, only one additional nucleotide is added to the growing DNA 
strands. After this addition, there is inhibition of further DNA synthesis. DNA polymerase 
epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA 
strands (masked chain termination).  
Storage and Stability  
Unreconstituted drug vials are stored at controlled room temperature (15ºC to 30ºC, 
59ºF to 86ºF). Reconstituted solution should be stored at controlled room temperature 
and used within 24 hours. Solutions of gemcitabine should not be refrigerated; as 
crystallization may occur. The unused portion should be discarded.  
 
Preparation  
Gemcitabine may be further diluted with normal saline as per institutional standards. 
 
Route of Administration  
IV infusion.  
 
Dosage 
Gemcitabine 1250mg/m2   on Day 1 and Day 8 of each 3 week cycle.  
 
Availability  
Gemcitabine is commercially available in 200 mg and 1 gm vials  
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 56 of 127 
 
 
Side Effects  
Please see package insert for detailed information regarding side effects related to this 
drug.  
 
Below are some common side effects related to Gemcitabine  
Neutropenia, anemia, thrombocytopenia, and leukopenia are reported. Rash with pruritus and 
injection-site reactions are can occur. Nausea and vomiting, diarrhea, constipation and mucositis 
have been reported. Abnormalities of hepatic transaminase enzymes occur in two-thirds of 
subjects, but they are usually mild, non-progressive, and rarely necessitate stopping treatment. 
Bronchospasm and/or dyspnea within a few hours of infusion of the drug, cough, rhinitis, 
pneumonitis may occur. Somnolence, insomnia, paresthesia, pain. Peripheral edema is reported 
in about 30% of subjects. Flu-like symptoms are reported for about 20% of subjects. This 
includes fever, headache, back pain, chills, myalgia, asthenia, and anorexia. 
 
4.8  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 mg/mL, and the pH of a 1% solution is 5-7. It is virtually insoluble in ethanol, 
acetone, and dimethylacetamide. 
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. 
Preparation and administration must be performed per standard of care. 
 
4.9 Treatment Schedules Nivolumab/Cisplatin/Pemetrexed and 
Nivolumab/Cisplatin/Gemcitabine 
Nivolumab/Cisplatin/Pemetrexed  
On days 1, 22 and 42, the medicine administration  sequence will be nivolumab, 
pemetrexed, cisplatin.  Pegfilgrastim or filgrastim will be administered per standard of 
care schedule. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 57 of 127 
 
 
 
 
  Day 1 
Day 22 
Day 42 
Nivolumab 
360 mg IV 
360 mg IV 
360 mg IV 
Pemetrexed 
500 mg/m2 IV 
500 mg/m2 IV 
500 mg/m2 IV 
Cisplatin 
75 mg/m2 IV 
75 mg/m2 IV 
75 mg/m2 IV 
 
4.9..1 
Nivolumab Administration 
Nivolumab will be administered as a flat dose of 360mg IV over approximately 30 
minutes  in NS 100 mL. on day 1 of each 3 week cycle. Premedication not 
required.  
 
4.9..2 
Pemetrexed Administration:  
Pemetrexed 500/m2, will be administered  on Days 1 of each 3 wk cycle in NS, 
100 mL, IV over 10 minutes.   
 
4.9..3 
Cisplatin Administration:  
Cisplatin 75mg/m2, will be administered Q 3 weeks in D5/NS, 250 -1000mL, IV 
over 1 – 2 hours on day 1 of each 3 week cycle 
 
Nivolumab/Cisplatin/Gemcitabine 
On days 1, 22 and 42, the medicine administration sequence will be nivolumab, 
gemcitabine, cisplatin. Pegfilgrastim or filgrastim will be administered per standard of 
care schedule. 
 
  Day 1 
Day 8 
Day 22 
Day 29 
Day 42 
Day 49 
Nivolumab 
360 mf IV 
 
360 mg IV 
 
360 mg IV 
 
Gemcitabine 
1250 mg/m2 
IV 
1250 mg/m2 
IV 
1250 mg/m2 
IV 
1250 mg/m2 IV 
1250 mg/m2 
IV 
1250 mg/m2 
IV 
Cisplatin 
75 mg/m2 IV 
 
75 mg/m2 IV 
 
75 mg/m2 IV 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 58 of 127 
 
 
4.9..4 
Nivolumab Administration 
Nivolumab will be administered as a flat dose of 360mg IV over approximately 30 
minutes  in NS 100 mL.  on day 1 of each 3 week cycle Premedication not 
required.  
 
4.9..5 
Gemcitabine Administration:  
Gemcitabine, 1250mg/m2, will be administered  on Days 1 and 8 of each 3 wk 
cycle in NS, 250 mL, IV over 30 minutes.   
 
4.9..6 
Cisplatin Administration:  
Cisplatin 75mg/m2, will be administered Q 3 weeks in D5/NS, 250 -1000mL, IV 
over 1 – 2 hours on day 1 of each 3 week cycle 
4.10 Dose Modifications and Dosing Delays 
The following sections detail the allowable dose modifications and dose delays for the study 
treatment.  
 
If a patient discontinues one of the drugs in the three drug regimen 
(Nivolumab/Cisplatin/Pemtrexed or Nivolumab/Cisplatin/Gemcitabine), the patient will 
discontinue all drugs in the regimen.  
 
If in the opinion of the treating physician, the cisplatin is not tolerated well, the patient may be 
switched to standard carboplatin (AUC 5) for both squamous and nonsquamous for the remaing 
courses. 
Thus: 
 
Nonsquamous: 
Carboplatin auc 5, pemetrexed 500mg/m2 and nivolumab (current dose) 
 
Squamous 
Carboplatin auc5, gemcitabine (current dose) and nivolumab (current dose). 
4.10..1 Nivolumab: 
 
There will not be dose modifications 
 
Dose Delays: 
Dose delay criteria apply for all drug-related AEs. Treatment delay is up to 2 weeks for 
nivolumab and up to 2 weeks for either cisplatin/pemetrexed of cisplatin/gemcitabine; 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 59 of 127 
 
 
the maximum prior to the last planned dose before surgery (any dose delays greater 
than these will require review and approval from the TJU PI). 
 
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  
• 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 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 
toxicity range, delay dosing for drug-related Grade ≥ 3 toxicity 
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 cisplatin/pemetrexed of 
cisplatin/gemcitabine dose.  
 
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, diarrhea, or colitis 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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 60 of 127 
 
 
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. 
o Dose delay of nivolumab which results in treatment interruption of > 2 
weeks requires treatment discontinuation. 
 
 
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: 
o Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation. 
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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 61 of 127 
 
 
• 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. 
• 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. Prior to re-initiating 
treatment in a subject with a dosing delay lasting > 6 weeks, the TJU PI must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such 
dosing delays. 
• 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 the Appendix 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  
• 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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 62 of 127 
 
 
• 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 are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 63 of 127 
 
 
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). 
 
The assessment of a dose delay or discontinuation is to be made independently of the 
consideration of radiation treatments, please see below. 
 
4.10..2 Cisplatin pemetrexed 
(for cisplatin alterations please see below in the section describing cisplatin gemcitabine 
 
 
Pemetrexed  
In the event of toxicity, patient should be enquired about compliance with intake of folic 
acid. Administration of vitamin B12 every 3 cycles of therapy should be ensured.  
 
Hematological toxicity  
Before initiation of a new cycle of therapy, the following hematological indices must be 
met: 
• ANC ≥ 1500/mm3  
• Platelets ≥ 100,000/mm3  
 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 64 of 127 
 
 
If the indices have not improved to this level, pemetrexed should be delayed until 
recovery. Upon recovery, patients should be treated using the guidelines below. The 
complete blood count should be checked at least once a week when the pemetrexed is 
held. Pemetrexed should be discontinued if a patient experiences any hematologic 
Grade 3 or 4 toxicity after 2 dose reductions.  
 
Dose Reduction for Pemetrexed and Cisplatin- Hematologic Toxicities 
ANC <500/mm3 and platelets 
≥50,000/m3 
75% of full dose 
Platelets <50,000/mm3 without 
bleeding, regardless of ANC 
75% of full dose 
Platelets <50,000/mm3 with 
bleeding, regardless of ANC 
50% of full dose 
 
 
For febrile neutropenia: 
 
Grade 3 or 4 Febrile 
neutropenia 
Pemetrexed 
1st occurrence 
375mg/m2 
2nd occurrence 
250mg/m2 
3rd occurrence 
Off study 
 
 
Leucovorin can be considered for grade 4 leukopenia lasting > 3 days, grade 4 
neutropenia lasting > 3 days, and immediately for grade 4 thrombocytopenia, or 
bleeding associated with grade 3 thrombocytopenia. The following intravenous doses 
and schedules of leucovorin are recommended if it is used: 100mg/m², intravenously 
once, followed by leucovorin, 50 mg/m², intravenously every 6 hours for 8 days. 
 
Non-hematological toxicity  
For non-hematologic toxicities (considered related to pemetrexed) ≥ grade 3, 
pemetrexed should be delayed until resolution to less than or equal to the patient’s 
baseline value by the start of the cycle, before proceeding. If treatment is delayed for > 
3 weeks for any pemetrexed related toxicity, the patient should be treated as follows: 
Discontinue all protocol treatment. 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 65 of 127 
 
 
  
Dose Reduction for Pemetrexed and Cisplatin- NonHematologic Toxicities 
 
Dose of Pemetrexed 
(mg/m2) 
Dose of cisplatin 
(mg/m2) 
Any Grade 3 or 4 toxicities except 
mucositis 
75% of dose 
75% of dose 
Any diarrhea requiring 
hospitalization (irrespective of 
Grade) or Grade 3 or 4 diarrhea 
75% of dose 
75% of dose 
Grade 3 or 4 mucositis 
50% of dose 
1000% of dose 
 
Pemetrexed should be discontinued if a patient experiences any non-hematologic 
Grade 3 or 4 toxicity after 2 dose reductions.  
 
Neurotoxicity 
In the event of neurotoxicity, the recommended dose adjustments for pemetrexed and 
cisplatin are described below. Patients should discontinue therapy immediately if Grade 
3 or 4 neurotoxicity is experienced. 
 
Dose Reduction for Pemetrexed and Cisplatin- Neurotoxiticy 
Grade 
Dose of Pemetrexed 
(mg/m2) 
Dose of cisplatin 
(mg/m2) 
0-1 
100% of dose 
100% of dose 
2 
100% of dose 
50% of dose 
 
 
Renal Toxicity  
Caution should be used when administering ibuprofen concurrently with pemetrexed to 
patients with mild to moderate renal insufficiency (CrCl < 45mL/min). Patients with mild 
to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-
lives for a period of 2 days before, the day of, and 2 days following administration of 
pemetrexed. All patients taking NSAIDs with longer elimination half-lives should 
interrupt dosing for at least 5 days before, the day of, and 2 days following pemetrexed 
administration. If concomitant administration of an NSAID is necessary, patients should 
be monitored closely for renal toxicity. 
 
Stomatitis  
Leucovorin may be considered for grade 3 or 4 stomatitis and can be given on the 
following schedule: 100mg/m², intravenously once, followed by leucovorin, 50 mg/m², 
intravenously every 6 hours for 8 days.  
 
Clinically Significant Effusions  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 66 of 127 
 
 
For patients who develop or have baseline clinically significant pleural or peritoneal 
effusions (on the basis of symptoms or clinical examination) before or during initiation of 
pemetrexed therapy, consideration should be given to draining the effusion prior to 
dosing. However, if, in the investigator's opinion, the effusion represents progression of 
disease, the patient should be discontinued from study therapy after confirmation of 
progression of disease. 
 
Upon resolution, pemetrexed treatment will resume as follows:  
• In the event of grade 3 nausea or vomiting, and/or grade 4 vomiting, pemetrexed 
may resume without dose reduction. Grade 3 nausea or vomiting and/or Grade 4 
vomiting should be managed with appropriate changes in antiemetic regimen.  
 
• In the event of grade 3 or 4 mucositis, pemetrexed should be resumed at 50% of 
the previous level.  
 
• In the event of grade 4 transaminase elevation, grade 3 or 4 diarrhea, or any 
grade diarrhea requiring hospitalization, a 25% dose reduction of pemetrexed is 
mandatory. Thus, pemetrexed should resume at 75% of the previous dose level.  
 
• For other grade 3 or 4 non-hematologic toxicities, treatment should resume at 
75% of the previous dose level, if deemed appropriate by the treating physician. 
 
4.10..3 Cisplatin/Gemcitabine and Cisplatin Pemetrexed Dose Modifications: 
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 will be 
used to grade adverse events.  
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study as specified in 
the Schedule of Events.  
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and 
adverse events requiring study drug interruption or discontinuation at each study visit 
during the treatment portion of the study.  
 
 
Subjects discontinued from the treatment phase of the study for any reason will be 
evaluated at least 30 days (± 7) after the last dose of study drug. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 67 of 127 
 
 
Dose Level 
Gemcitabine 
0 
1250mg/m2 
-1 
1000mg/m2 
-2 
750mg/m2 
Subjects who require more than two permanent dose reductions will be removed from 
gemcitabine treatment 
 
 
 
 
 
 
Subjects who require more than two permanent dose reductions will be removed from 
cisplatin treatment 
Hematologic Toxicity: gemcitabine-cisplatin  
Gemcitabine and cisplatin doses may be modified separately based on individual 
toxicity according to the rules outlined below. There is no dose reduction below level -2 
for gemcitabine or cisplatin. If dose reduction below level -2 is required, gemcitabine 
and/or cisplatin should be discontinued.  
 
Recommended Dose Reductions for Gemcitabine in Non-Small Cell Lung 
Cancer 
Absolute 
granulocyte count 
(x109/L) 
 
Platelet Count 
(x106/L) 
% of full dose 
≥1000 
And 
≥100,000 
100% 
500-999 
OR 
50,000-99,999 
75% 
<500 
OR 
<50,000 
Hold 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 68 of 127 
 
 
 
Recommended Dose Modifications for Cisplatin in Non-Small Cell Lung Cancer 
Grade 4 neutropenia lasting >5 days 
w/Grade 1-2 thrombocytopenia 
15% of dose 
Grade 3 neutropenia and 
thrombocytopenia 
15% of dose 
Grade 4 neutropenia w/Grade 3 
thrombocytopenia 
25% of dose 
Grade 4 thrombocytopenia 
50% of dose 
If a patient requires more than two dose reductions for hematologic toxicity, treatment 
should be discontinued.  
 
Non-Hematologic Toxicity 
Please see section 4.9.2 for cisplatin dose modifications for non-hematologic toxicity. 
 
Neurotoxicity 
Please see section 4.9.2 for cisplatin dose modifications for neurotoxicity. 
 
Criteria for initiation of a new cycle with gemcitabine-cisplatin:  
 
For Day 1 of each cycle, subjects must have an ANC ≥ 1,500 AND platelets ≥ 100,000 
before receiving treatment with gemcitabine-cisplatin or nivolumab. Subjects that do not 
meet these values on Day 1 will have their cycle start delayed and any nivolumab doses 
during that cycle will be similarly delayed. Resume the gemcitabine-cisplatin new cycle 
and nivolumab dosing once the ANC improves to ≥1,500 AND platelets ≥100,000 (see 
5.10.2.3 for nivolumab guidelines).  
If treatment is/was delayed:  
 
• For up to 1 week, resume treatment at the previous doses of gemcitabine-
cisplatin. After the delay, nivolumab dosing and interval should resume to stay 
“in-sequence” with gemcitabine-cisplatin cycle.  
• For more than 1 week and less than 4 weeks, reduce gemcitabine and cisplatin 
by one dose level for this and all subsequent cycles. Once the cycle is resumed, 
nivolumab dosing and its’ interval should resume to stay “in-sequence” with 
gemcitabine-cisplatin cycle. No nivolumab dosing interval change.  
• If a second treatment delay of more than one week and less than 4 weeks 
occurs, reduce gemcitabine and cisplatin an additional dose level. Nivolumab 
dosing should restart on the planned cycle day (for Cohort I, this is generally 
Day8), however the nivolumab dosing interval should be permanently increased 
by 1 week for subsequent doses.  
• Greater than 4 weeks due to hematologic toxicity, discontinue all therapy and 
initiate workup to optimize the subject for surgical consideration.  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 69 of 127 
 
 
 
Workup of cytopenia etiology beyond bone marrow suppression is encouraged at any 
time, and per treating physician judgment.  
 
Febrile Neutropenia  
For febrile neutropenia (defined here as temperature ≥ 38.5° C [101° F] sustained for 
more than one hour concomitant with ANC ≤ 500/mm3) reduce gemcitabine and 
cisplatin by one dose level for this and subsequent cycles. Consider filgrastim or peg-
filgrastim in subsequent cycles.  
 
Hepatic Dysfunction (See Table 6 below)  
Hepatic dysfunction should prompt consideration of workup for etiology such as 
medication and supplement review, infection, imaging, pancreatico-biliary evaluation, 
and amylase, lipase. Consideration should be given to evaluation of concomitant 
pancreatitis in the appropriate setting. This evaluation and workup is at the treating 
physician discretion. 
 
For bilirubin > 1.5 x ULN (or > 3 x ULN for subjects with Gilbert’s syndrome), delay 
nivolumab treatment until bilirubin ≤ 1.5 x ULN (< 3 x ULN for subjects with Gilbert’s 
syndrome), then resume with one dose level reduction of gemcitabine and at the 
previous dose of cisplatin.  
 
If bilirubin is > 1.5 x ULN despite two gemcitabine dose reductions, gemcitabine should 
be discontinued but cisplatin. For subjects with Gilbert's syndrome, if bilirubin is > 3 x 
ULN despite two gemcitabine dose reductions, gemcitabine and cisplatin should be 
permanently discontinued.  
 
 
Guidelines for 
Dose 
Modifications 
due to LFT 
abnormalities. 
LFT  
Gemcitabine 
Cisplatin 
AST/ALT >ULN to 
2xULN  
and  
Total bilirubin >1.5 
xULN OR  
>3 xULN for 
subjects with 
Gilbert’s 
syndrome1  
delay treatment 
until AST/ALT ≤2 
xULN and total 
bilirubin ≤ 1.5 
xULN (≤3 xULN for 
subjects with 
Gilbert’s 
syndrome1), then 
resume with one 
dose level 
delay treatment 
until AST/ALT ≤2 
xULN and total 
bilirubin ≤ 1.5 
xULN (≤3 xULN for 
subjects with 
Gilbert’s 
syndrome1), then 
resume at 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 70 of 127 
 
 
reduction of 
gemcitabine.  
After 2 dose level 
reductions, 
gemcitabine 
should be 
discontinued.  
previous dose of 
cisplatin.  
For subjects with 
Gilbert’s, 
discontinue both 
gemcitabine and 
cisplatin after 2 
occurrences of 
total bili >1.5.  
AST/ALT >2 xULN 
to ≤8 xULN  
and  
Total bilirubin ≤1.5 
xULN OR  
≤3 for subjects 
with Gilbert’s 
syndrome1  
delay treatment 
until AST/ALT ≤2 
xULN and total 
bilirubin ≤ 1.5 
xULN (≤3 xULN for 
subjects with 
Gilbert’s 
syndrome1), then 
resume with one 
dose level 
reduction of 
gemcitabine.  
Consider 
hepatologist 
consult.  
delay treatment 
until AST/ALT ≤2 
xULN and total 
bilirubin ≤ 1.5 
xULN (≤3 xULN for 
subjects with 
Gilbert’s 
syndrome1), then 
resume at 
previous dose of 
cisplatin.  
Consider 
hepatologist 
consult.  
AST/ALT>2 xULN 
to ≤8 xULN  
and  
Total bilirubin >1.5 
xULN OR  
>3 for subjects 
with Gilbert’s 
syndrome1  
delay treatment 
until AST/ALT ≤2 
xULN and total 
bilirubin ≤ 1.5 
xULN (≤3 xULN for 
subjects with 
Gilbert’s 
syndrome1), then 
resume with one 
dose level 
reduction of 
gemcitabine.  
After 2 dose level 
reductions, 
gemcitabine 
should be 
discontinued.  
Consider 
hepatologist 
consult.  
delay treatment 
until AST/ALT ≤2 
xULN and total 
bilirubin ≤ 1.5 
xULN (≤3 xULN for 
subjects with 
Gilbert’s 
syndrome1), then 
resume at 
previous dose of 
cisplatin.  
For subjects with 
Gilbert’s, 
discontinue both 
gemcitabine and 
cisplatin after 2 
occurrences of 
total bili >1.5.  
Consider 
hepatologist 
consult.  
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 71 of 127 
 
 
AST/ALT >8 x 
ULN  
and  
Total Bilirubin any 
level  
delay treatment 
until AST/ALT ≤2 
xULN and total 
bilirubin ≤ 1.5 
xULN (≤3 xULN for 
subjects with 
Gilbert’s 
syndrome1), then 
resume with one 
dose level 
reduction of 
gemcitabine.  
Consider 
hepatologist 
consult.  
delay treatment 
until AST/ALT ≤2 
xULN and total 
bilirubin ≤ 1.5 
xULN (≤3 xULN for 
subjects with 
Gilbert’s 
syndrome1), then 
resume at 
previous dose of 
cisplatin.  
For subjects with 
Gilbert’s, 
discontinue both 
gemcitabine and 
cisplatin after 2 
occurrences of 
total bili >1.5.  
Consider 
hepatologist 
consult.  
 
 
 
For grade 3 sensory or motor neuropathy, skip cisplatin until the toxicity resolves to 
≤grade 2 and then resume therapy with one dose level reduction of cisplatin on Day 1 of 
the next scheduled cycle. If cisplatin is skipped for two consecutive cycles, permanently 
discontinue cisplatin. Treatment with gemcitabine and nivolumab may continue.  
 
For grade 4 sensory or motor neuropathy, skip gemcitabine and cisplatin therapy until 
resolution to ≤ grade 2. If sensory neuropathy improves to grade 3, but not grade 2 or 
better, within 4 weeks, resume gemcitabine at the previous dose without cisplatin. If the 
sensory neuropathy remains at grade 4 within 4 weeks, discontinue gemcitabine and 
cisplatin, then prepare the subject for surgery within 2-7 weeks. 
 
Gastrointestinal Toxicity  
For grade 3 or 4 nausea or vomiting despite maximal antiemetic therapy (including 5HT-
3 antagonist, corticosteroids up to 5 days, and aprepitant), discontinue cisplatin. 
Continue gemcitabine at the previous dose when symptoms resolve to ≤ grade 1. 
 
Kidney Dysfunction –  
A Ccr from properly collected timed (24 hours; 18-24 hours acceptable) urine 
supersedes a calculated value for determination of cisplatin eligibility and dosing. 
Accuracy of timed urine collection, however, is dependent on patient compliance; proper 
collection adherence should be confirmed with the patient. Improper collection methods 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 72 of 127 
 
 
disqualify use of the timed collection results and a calculated serum value should be 
used.  
 
For creatinine clearance < 50 mL/min (measured or calculated) on Day 1 of a cycle, 
delay all treatment until creatinine clearance improves to ≥ 50 mL/min as follows:  
• If creatinine clearance improves to ≥ 60 mL/min within 1 week, resume with one 
dose level reduction for cisplatin and gemcitabine for all subsequent dose.  
• If creatinine clearance improves to ≥ 50 and < 60 mL/min within 1 week, resume 
with one dose level reduction of cisplatin for this and all subsequent cycles. 
Administer cisplatin as a split dose on Days 1 and 2 (preferred) or Days 1 and 8 
of this cycle. Resume gemcitabine at the same dose.  
 
If creatinine clearance does not improve to ≥ 50 mL/min within 1 week, skip cisplatin for 
this cycle only. Treat with cisplatin at one lower dose level for this and all subsequent 
cycles with split dosing over Days 1&2 (or Days 1 and 8, per treating physician 
discretion as previously described) ule. For a subsequent cycle, if creatinine clearance 
is again < 50 mL/min, discontinue cisplatin   
 
Gemcitabine Non-Hematologic 
Toxicity Grade  
Dose Modification  
0-2  
Full dose  
3-4  
Hold until resolution to ≤ Grade 2, 
then decrease by 1 dose level from 
current dose. This dose reduction is 
not permanent. If toxicity does not 
resolve within 4 weeks, discontinue 
gemcitabine treatment.  
 
4.11 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. 
4.12 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 Sponsor. 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, the Sponsor, and the subject 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 73 of 127 
 
 
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 must 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. 
• The use of amifostine is not permitted. 
• The use of hematopoietic growth factors (erythropoietin) 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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 74 of 127 
 
 
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 chemo-radiotherapy is there is local and / or 
regional progression of disease.   
 
4.13 Dietary Restrictions 
There are no dietary restrictions. 
 
 
5 Study Schedule  
Nonsquamous NSCLC 
Study Period 
Baseline 
Treatment 
Observation 
(d) 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 75 of 127 
 
 
Week 
 
1 
4 
7 
10 
12 
Monthly 
Treatment 
 
Pemetrexed + 
Cisplatin 
Nivolumab  
Surgery 
(q) 
 
Standard of 
care (d)  
Nivolumab 
 
X 
X 
X 
 
 
 
Pemetrexed 
 
X 
X 
X 
 
 
 
Cisplatin(t) 
 
X 
X 
X 
 
 
 
Consent form signed by 
patient 
X 
 
 
 
 
 
 
History and physical 
exam (including vital 
signs, weight, BMI, 
height) 
X(o) 
 
X(n) 
X 
X 
X(o) 
 
X 
ECOG Performance 
Status 
X 
X 
(n) 
X 
X 
X 
 
X 
Assessment of 
concurrent medications 
X 
X(n) 
X 
X 
X 
X 
X 
PET/CT or CT chest, 
abdomen, pelvis and 
bone scan. (l) 
X 
Within 4 
weeks 
 
 
 
X(j) 
 
X (e) 
MRI brain (l) 
X 
 
 
 
 
 
 
CBC, differential, platelet 
count  
X 
Within 21 
days 
X(n) 
X 
X 
X (r) 
 
X 
CMP (m) 
X 
X(n) 
X 
X 
X (r) 
 
X 
Serum chemistries (m) 
X 
X(n) 
X 
X 
 
 
 
C-reactive protein (CRP), 
HbA1c, lipid panel (s) 
X 
 
 
 
 
X 
 
PT/PTT 
X 
X(n) 
 
 
X (p) 
 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 76 of 127 
 
 
Endocrine (TSH, T4, T3, 
cortisol) 
X 
X(n) 
X 
X 
X (p) 
 
X(u) 
Pregnancy test (women 
of childbearing potential) 
X 
Within 21 
days 
X 
(k) 
X 
(k) 
X 
(k) 
 
 
 
Viral studies (HepB, 
HepC) 
X 
Within 28 
days 
 
 
 
 
 
 
Assessment of cardiac 
function EKG  
X 
Within 2 
weeks 
 
 
 
X (h) 
 
 
Blood Draw for CTCs 
(correlative studies) 
              X 
 
 
X 
 
X (b) 
X(c) 
X(c) 
Patient Reported 
Outcomes (s) 
              X 
 
 
 
 
X 
 
Adverse Event 
Assessment + PRO-
CTCAE 
              X 
 
X 
X 
X 
X (p) 
 
X 
Tumor Biopsy  
X (a) 
 
 
 
X (f, g) 
 
 
(a) Five cores or excisional biopsy (to be processed as in appendix). If available, archival 
tissue within 3 months of study enrollment will be used. If archival tissue is unavailable, a 
fresh biopsy will be taken. Tissue sample will be assessed for PD-L1 expression.  
(b) Must be drawn on the morning of surgery 
(c) At least a week after surgery and less than 4 weeks after surgery.  If post-operative 
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 6 months s/p surgery. Patient’s medical 
records will be reviewed every 3 months for 6 months to obtain survival and disease 
recurrence information.  
(e) Timing of  post-operative repeat as per standard of care, chest CT only   
(f) Specimen to be processed as in appendix.   
(g) Formal assessment and documentation of degree of pathologic response (as in 
appendix) 
(h) EKG alone  
(i)  
(j) Standard CT thorax within a week prior to planned surgery date 
(k) Must be done within 24 hours of receiving each dose of Nivolumab 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 77 of 127 
 
 
(l) Scans must be done with contrast, unless otherwise contraindicated for a patient. MRI 
brain must be performed with and without contrast. 
(m) Serum chemistries and CMP includes: Albumin, LDH, AST, ALK Phos, T. Bili, BUN, 
Creatinine, Calcium, Mag, Phos, Na, Cl, Glucose, Amylase, Lipase. Drawn within 7 days 
of first administration and within 3 days of subsequent administration 
(n) Performed within 7 days of first dose of nivolumab/cisplatin/pemetrexed 
(o) Physical examination at baseline and end of treatment must include BMI and waist hip 
ratio (WHR) only for patients enrolled at the lead site.  
(p) Procedures including PRO-CTCAE must be completed within 1 week prior to planned 
surgery date.  
(q) Patients must meet with the surgeon within 1 week of planned surgery date. Surgery can 
occur no later than 90 days from enrollment.  
(r) Must be performed the morning of surgery 
(s) Performed only for patients enrolled at the lead site (only one PRO is needed, either 
before or on the day of treatment) 
(t) If in the opinion of the treating physician, the cisplatin is not tolerated well, the patient 
may be switched to standard carboplatin (AUC 5) for the remaining courses. 
(u) TSH, T4, T3, cortisol will be collected every 3 months during follow up visits    
 
 
Squamous NSCLC 
Study Period 
Baseline 
 
Treatment 
 
Observation 
(d) 
Week 
 
 
1 
4 
7 
10 
 
12 
Monthly 
Treatment 
 
 
Gemcitabine + 
Cisplatin 
Nivolumab  
Surgery 
(q) 
  
Standard of 
care (d)  
Nivolumab 
 
 
X 
X 
X 
 
 
 
 
Gemcitabine 
(j) 
 
 
X(j) 
X(j) X(j) 
 
 
 
 
Cisplatin(u) 
 
 
X 
X 
X 
 
 
 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 78 of 127 
 
 
Consent form 
signed by 
patient 
X 
 
 
 
 
 
 
 
 
History and 
physical exam 
(including vital 
signs, weight, 
BMI, height)  
X (s) 
 
 
X(o) 
X 
X 
X (s) 
 
 
X 
Performance 
Status 
X 
 
X 
(o) 
X 
X 
X 
 
 
X 
Assessment of 
concurrent 
therapies 
X 
 
X(o) 
X 
X 
X 
 
X 
X 
PET/CT or CT 
chest, 
abdomen, 
pelvis and 
bone scan.(m)  
X 
Within 4 
weeks 
 
 
 
 
X(k) 
 
 
X (e) 
MRI brain(m) 
X 
 
 
 
 
 
 
 
 
C-reactive 
protein (CRP), 
HbA1c, lipid 
panel (t) 
X 
 
 
 
 
 
 
 
X 
 
CBC, 
differential, 
platelet count 
X 
Within 21 days 
 
X(j, 
o) 
X(j, 
o) 
X(j, 
o) 
X (r) 
 
 
X 
CMP (n) 
X 
 
X(j, 
o) 
X(j) X(j) 
X (r) 
 
 
X 
Serum 
chemistries (n) 
X 
 
X 
X 
X 
 
 
 
 
PT/PTT 
X 
 
X(n) 
 
 
X (p) 
 
 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 79 of 127 
 
 
Endocrine 
(TSH, T4, T3, 
cortisol) 
X 
 
X(n) 
X 
X 
X (p) 
 
 
X(v) 
Pregnancy test 
(women of 
childbearing 
potential) 
X 
Within 21 days 
 
X(l) 
X(l) X(l) 
 
 
 
 
Assessment of 
cardiac 
function EKG  
X 
Within 4 
weeks 
 
 
 
 
X (h) 
 
 
 
Viral studies 
(HepB, HepC) 
X 
Within 28 days 
 
 
 
 
 
 
 
 
Blood Draw for 
CTCs 
(correlative 
studies) 
                   X 
 
 
X 
 
X (b) 
 X(c) 
X(c) 
Patient 
Reported 
Outcomes (t) 
                 X 
 
 
 
 
 
 
X 
 
Adverse Event 
Assessment + 
PRO-CTCAE 
   X  
 
X 
X 
X 
X (p) 
 
 
X 
Tumor Biopsy  
X (a) 
 
 
 
 
X 
 
X 
(f,g) 
 
(a) Five cores or excisional bx (to be processed as in appendix) . If available, archival tissue 
within 3 months of study enrollment will be used. If archival tissue is unavailable, a fresh 
biopsy will be taken. Tissue sample will be assessed for PD-L1 expression. 
(b) Must be drawn on the morning of surgery 
(c) At least a week after surgery and less than 4 weeks after surgery.  If post-operative 
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 6 months s/p surgery 
(e) Timing of post-operative repeat as per standard of care, chest CT only  
(f) Specimen to be processed as in appendix.   

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 80 of 127 
 
 
(g) Formal assessment and documentation of degree of pathologic response (as in 
appendix) 
(h) EKG  
(i)  
(j) Weeks 2, 5, 8 patients to get single agent gemcitabine and accompanying CBC, CMP 
(k) Standard CT thorax within a week prior to planned surgery date 
(l) Must be done within 24 hours of receiving each dose of Nivolumab 
(m) Scans must be done with contrast, unless otherwise contraindicated for a patient. MRI 
brain must be performed with and without contrast. 
(n) Serum chemistries and CMP includes: Albumin, LDH, AST, ALK Phos, T. Bili, BUN, 
Creatinine, Calcium, Mag, Phos, Na, Cl, Glucose, Amylase, Lipase. Drawn within 7 days 
of first administration and within 3 days of subsequent administration 
(o) Performed within 7 days of first dose of nivolumab/cisplatin/gemcitabine. Subsequent 
labs are performed within 3 days of administration of nivolumab/cisplatin/gemcitabine. 
(p) Procedures including PRO-CTCAE must be completed within 1 week prior to planned 
surgery date.  
(q) Patients must meet with the surgeon within 1 week of planned surgery date. Surgery can 
occur no later than 90 days from enrollment.  
(r) Must be performed the morning of surgery 
(s) Physical examination at baseline and end of treatment must include BMI and waist hip 
ratio (WHR) for patients enrolled at the lead site only 
(t) Performed only for patients enrolled at the lead site (only one PRO is needed, either 
before or on the day of treatment) 
(u) If in the opinion of the treating physician, the cisplatin is not tolerated well, the patient 
may be switched to standard carboplatin (AUC 5) for the remaining courses. 
(v) TSH, T4, T3, cortisol will be collected every 3 months during follow up visits    
 
 
5.1 Baseline/Screening (for both nonsquamous and squamous NSCLC 
cohorts) 
 Screening window for laboratory tests and scans (unless otherwise indicated) is days -
28 to -1. 
Enrollment/Baseline Visit (Visit 1, Day 0) 
• Obtain and document consent from potential participant on study consent form. 
• Review medical history to determine eligibility based on inclusion/exclusion 
criteria. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 81 of 127 
 
 
• Review medications history to determine eligibility based on inclusion/exclusion 
criteria. 
• Verify collection of baseline tumor tissue specimen.  
o Tumor sample prior to therapy is mandatory to confirm the presence of 
squamous or non-squamous non-small cell lung cancer, 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. 
Archival tissue can be FFPE or frozen.  
*Note: If a fresh tissue sample is taken, need adequate tumor to assess PD-L1 
testing for all patients ideally 5 cores or excisional.  If tumor sample is not 
available at screening, a fresh biopsy will be taken prior to enrollment. 
• PET/CT or CT chest, abdomen, pelvis and bone scan. must be completed within 
28 days of initiation of therapy. Scan must be performed with contrast, unless 
otherwise contraindicated for the patient.  
• MRI brain with and without contrast must be completed within 28 days of 
initiation of therapy. 
• Verify inclusion/exclusion criteria. 
• Obtain demographic information, medical, medication history, alcohol, and 
tobacco use history. 
• Record results of physical and ECOG Performance Status, Vital Signs, Complete 
Physical Exam  
• 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, Glucose, Amylase, Lipase, TSH, 
Free T4, Free T3, cortisol), blood counts with differential, viral studies (HepB 
surface antigen and hepatitis C antibody or hepatitis C RNA) serum or urine 
pregnancy test for women of childbearing potential within 21 days of study 
enrollment. 
• 
Schedule study visits for individuals who are eligible and available for the initial 
treatments of the trial- either cisplatin/pemetrexed/nivolumab or 
cisplatin/gemcitabine/nivolumab, based on histology 
The following procedures are only to be performed for patients enrolled at the lead site: 
• Body Mass Index with Waist Hip Ratio (WHR) 
• C-reactive protein (CRP), glycated hemoglobin (HbA1c), and lipid panel  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 82 of 127 
 
 
• Patient Reported Outcomes (PROs): 
o PHQ2 
o PHQ9 
o FACT-G 
o FACT-L 
 
5.2 Treatment Period (for both nonsquamous and squamous NSCLC cohorts) 
Study Procedures: Administration of cisplatin/pemetrexed/nivolumab or      
cisplatin/gemcitabine/nivolumab and Surgery 
 
Cycle 1-3 (Medical Oncologist): Each cycle is 3 weeks long.  Full medical  history, 
general physical exam, comprehensive metabolic panel (CMP), CBC, height, weight. 
Intravenous administration of cisplatin/pemetrexed/nivolumab or      
cisplatin/gemcitabine/nivolumab. On week 10, surgery. 
 
Non-squamous NSCLC 
Nivolumab 360mg q 3w  x 3  
Cisplatin  75mg/m2 q 3w x 3 
Pemetrexed 500 mg/m2 q 3w  x 3 
 
Squamous NSCLC 
Nivolumab 360mg q 3w  x 3  
Cisplatin 75mg/m2 q 3w x 3 
Gemcitabine 1250mg/m2 d1 & d8  x 3  
 
If in the opinion of the treating physician, the cisplatin is not tolerated well, the patient may be 
switched to standard carboplatin (AUC 5) for both squamous and nonsquamous for the 
remaining courses. The doses of Nivolumab, pemetrexed and gemcitabine will be given as 
describe aboved. 
 
Visit 2, Week 1, Day 1  
• Targeted physical examination within 7 days 
• Review entry labs, performed within 7 days of first administration of either 
cisplatin/pemetrexed/nivolumab or cisplatin/gemcitabine/nivolumab. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 83 of 127 
 
 
• Review concomitant medications within 7 days 
• Ensure that surgery dates and treatment planning are scheduled 
• Women of childbearing potential must have a pregnancy test done within 24 
hours of receiving study drug 
• Administer the either cisplatin/pemetrexed/nivolumab or      
cisplatin/gemcitabine/nivolumab. 
 
Visit 3 , Week 4, Days  ±4 days-  
• Record adverse events as reported by participant or observed by investigator. 
• Targeted physical examination. 
• CBC, CMP, Mag, Phos prior to administration of the study drug; to be drawn 
within 3 days of administration. 
• Women of childbearing potential must have a pregnancy test done within 24 
hours of receiving study drug 
• Draw CTCs (correlative blood draws) 
• Review concomitant medications. 
• Administer the either cisplatin/pemetrexed/nivolumab or      
cisplatin/gemcitabine/nivolumab. 
 
Visit 4, Week 7± 4 days 
• Record adverse events as reported by participant or observed by investigator. 
• Targeted physical examination. 
• CBC, CMP, Mag, Phos prior to administration of the study drug; to be drawn 
within 3 days of administration. 
• Women of childbearing potential must have a pregnancy test done within 24 
hours of receiving study drug 
• Review concomitant medications. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 84 of 127 
 
 
• Administer the either cisplatin/pemetrexed/nivolumab or      
cisplatin/gemcitabine/nivolumab. 
 
Visit 5, Week 10  - 4 days or + 20 days(Surgery scheduled) 
• CT scan Preop (within a week prior to planned surgery date) 
• Record adverse events as reported by participant or observed by investigator. 
• Targeted physical examination. 
• Correlative labs 
• Safety Assessment: 
o CBC and Complete Metabolic Panel (CMP) on the morning of surgery 
o Endocrine (TSH, T4, T3, cortisol), PT/PTT completed within a week prior 
to planned surgery date 
• Intraoperative specimens sent fresh on ice for correlative studies.  
Surgery will be performed by surgeons Board Certified in Thoracic Surgery.  
Surgeons will have expertise in lung cancer and significant experience in minimally 
invasive lung resection as well as resection after induction therapy as determined by 
the Surgical PI. 
Surgery will be performed approximately 3 weeks (Week 10) after the last dose of 
study treatment. Surgery is to be performed no later than 90 days after enrollment. 
5.3 Post-surgical/Follow-Up 
Visit 6, Week 12 ± 4 days 
• Postop evaluation and exam 
• Correlative labs 
• Wound assessment 
• Safety assessment 
 
• The following procedures are for patients enrolled at the lead site only: 
o Body Mass Index with Waist and Hip Ratio (WHR) 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 85 of 127 
 
 
o C-reactive protein (CRP), glycated hemoglobin (HbA1c), and lipid panel  
o Patient Reported Outcomes (PROs): 
▪ PHQ2 
▪ PHQ9 
▪ FACT-G 
▪ FACT-L 
 
 
Visit 7, 3 months  ± 2 weeks post- operative completion 
• Evaluation and exam 
• Correlative labs 
• Wound assessment 
• Safety assessment includes PRO-CTCAE, CBC, and CMP, TSH, T4, T3, cortisol 
• CT thorax 
 
5.4 End of Treatment Study Procedures 
Final Study Visit (Visit 8, 6 months ± 3 weeks post-surgical completion) 
• Record adverse events as reported by participant or observed by investigator. 
• Complete Physical Exam 
• Review concomitant medications. 
• Wound assessment 
• CT thorax 
 
5.5 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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 86 of 127 
 
 
Follow Up Imaging is to be completed per the institutional standards. 
5.6 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. 
5.7 
Surgery 
The resection plans will be 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.  
5.8 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 
• Obtain histologic confirmation of disease 
• Standard presurgical assessments including lung function and staging 
• Vital Signs 
The following procedures are only for patients enrolled at the lead site: 
• PROs are self-administered 
 
PRO assessment completed at baseline will be conducted before any treatment or 
procedures. 
 
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  
• 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. 
• Hip circumference should be measured around the widest portion of the 
buttocks, with the tape parallel to the floor.  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 87 of 127 
 
 
Body Mass Index (BMI) to calculated as kg/m2 
5.9 Laboratory Procedures/Evaluations 
5.9..1 
Clinical Laboratory Evaluations 
• Pregnancy Test: WOCBP must have serum or urine pregnancy test performed 
within 24 hours prior to dosing chemotherapy with nivolumab.  
• A serum or urine pregnancy testing is required for WOCBP within 21 days. of 
study enrollment.. 
• 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, 
Phos, Na, K, Cl, LDH, Glucose, amylase, lipase.  Within 72 hours prior to re-
dosing- TSH (with reflexive Free T4 and Free T3, cortisol) 
Special Assays or Procedures 
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, Room 606. 
Correlative samples collected at sub-site(s) should be shipped to Thomas Jefferson 
University: 
Attn: Larry Harshyne, PhD 
233 South 10th Street, Room 606 
Philadelphia, PA 19147 
 
See Laboratory Manual for additional information. 
 
5.10 Patient Assessments  
Patients must be offered the opportunity to participate in patient-reported outcomes 
(PROs) assessments as a component of the study. One instrument. will be used to 
measure patient reported outcomes PRO-CTCAE.  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 88 of 127 
 
 
This assessment will be completed prior to start of treatment (baseline), at completion of 
nivolumab and chemotherapy, before surgery (during follow-up) and post-treatment 
follow-up. 
PRO-CTCAE 
To integrate the patient perspective into adverse event reporting, the National Cancer 
Institute developed a patient-reported outcomes version of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE. It is designed for patient reporting of 
symptomatic adverse events with an item bank of questions derived from the CTCAE 
adverse event items and is meant to be complimentary to the CTCAE. 
6 Evaluation of Safety 
6.1 Specification of Safety Parameters 
6.1..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. 
6.1..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. 
6.1..3 
Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• Results in death 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 89 of 127 
 
 
• Is life-threatening (places the participant at immediate risk of death from the 
event as it occurred) 
• 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. Potential drug 
induced liver injury (DILI) is also considered an important medical event 
• 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.  
 
Nonserious Adverse Event Collection and Reporting 
• The collection of nonserious AE information should begin at initiation of study drug. 
All nonserious adverse events (not only those deemed to be treatment-related) 
should be collected continuously during the treatment period and for a minimum of 
100 days following the last dose of study treatment.  
 
6.2 Safety Assessment and Follow-Up 
Adverse event reporting will begin after study treatment, unless the 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, 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 90 of 127 
 
 
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. 
6.3 Recording Adverse Events 
The following subsections detail what information must be documented for each 
adverse event occurring during the time period specified in Section 6.2.  
6.3..1 
Relationship to Study Intervention 
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. 
6.3..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. 
6.3..3 
Severity of Event 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 91 of 127 
 
 
Adverse events will be graded for severity according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. 
6.3..4 
Intervention 
Any intervention implemented to treat the adverse event must be documented for all 
adverse events. 
6.4 Safety Reporting 
Reporting to IRB 
6.4..1 
Unanticipated Problems 
All incidents or events that meet criteria for unanticipated problems (UAPs) as defined in 
Section 6.1..1Unanticipated 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.  
6.4..1.1 
Affiliate Site Unanticipated Problems Reporting 
Unanticipated problems (UAPs) occurring at the Affiliate Site are to be reported to the 
TJU Study Site Contact using the Unanticipated Problems Form (see Appendix D). The 
TJU study site contact will submit the UAPs occurring at the sub-site to the TJU IRB. . 
6.4..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.  
6.4..3 
Serious Adverse Events 
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.  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 92 of 127 
 
 
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. 
SAEs occurring at the sub-site are to be reported to the TJU IRB per above guidelines.  
6.4.3.1 Sub-Site SAE Reporting Procedures 
All SAEs occurring at the Affiliate Site must be reported to the TJU Study Site Contact 
within 24 hours of notification. This initial notification can take place via email, followed 
by the submission of a formal report. 
SAEs occurring at the Affiliate Site that are reportable to BMS should be reported to 
TJU Study Site Contact using the BMS SAE Reporting Form or Pregnancy Surveillance 
Form, 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.   
SAEs occurring at the Affiliate Site that are reportable to both the FDA and BMS should 
be reported to TJU Study Site Contact using 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 SAE reporting form in Appendix E.  
A reportable AE is any adverse event NOT identified in the IB or consent form as a risk.  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 93 of 127 
 
 
Any non-reportable AE must be kept by the Affiliate Site on an ongoing tracking log to 
be reviewed by TJU quarterly. 
6.5 
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 DSMP. The report to DSMC will also 
include any unanticipated problems that in the opinion of the PI should be reported to 
the DSMC. 
See the table below for the DSMC AE/SAE Reporting Requirements: 
 
The Affiliate 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 DSMC. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 94 of 127 
 
 
6.6 
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 TJU Study Site Contact is responsible for submitting all SAE reports occurring at 
TJU and the Affiliate Site to the study funder. 
6.7 
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) 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 95 of 127 
 
 
as soon as possible 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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 96 of 127 
 
 
The TJU Study Site Contact is responsible for submitting all SAE reports occurring at 
TJU and the Affiliate Site to the FDA. 
6.8 
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 24 hours 
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. 
6.9 
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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 97 of 127 
 
 
• 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 
6.10 Overdose 
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. 
 
6.11 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: 
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase), AND 
3. 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. 
 
6.12 Halting Rules 
Please see Section 11.3 for stopping rules. 
7 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 DSMC 
operates in compliance with a Data and Safety Monitoring Plan (DSMP) that is 
approved by the Clinical Trials Oversight Committee (CTOC).  

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 98 of 127 
 
 
8 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 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 DSMP. 
9 Statistical Considerations 
9.1 Study Hypotheses 
 
The addition of nivolumab to induction cisplatin pemetrexed or cisplatin gemcitabine will 
increase the rate of major pathologic response over historical control with induction 
chemotherapy alone. 
The primary objective of the study is to estimate major pathologic response (mpCR) in 
patients with newly diagnosed and untreated NSCLC Stage I-IIIA treated with three 
courses of induction Nivolumab added to either cisplatin/pemetrexed or 
cisplatin/gemcitabine prior to surgery. The null hypothesis is that the mpCR rate is ≤ 
0.19 vs. the alternative that it is >0.19. We have powered under the specific alternative 
that the true rate is 0.35 or greater (section 9.4).   
9.2 Analysis Plans 
 
Primary Endpoint Evaluation: A minimax Simon two-stage design will be used. After 
testing the regimen on 21 patients in the first stage, the trial will be terminated if 3 or fewer 
have a mpCR of the primary tumor. If the trial goes on to the second stage, a total of 34 
patients will be studied. If the total number having a mpCR of the primary tumor is less 
than or equal to 9, the regimen is rejected.  The mpCR rate and its associated score 95% 
confidence interval will be estimated using the methods of Tsai et al (2008) which 
appropriately account for the two-stage design in the estimation process.  
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 99 of 127 
 
 
 
Secondary Endpoint Analyses:  
 
Safety data will be summarized descriptively.   
 
Response rates for secondary outcomes (i.e.,clinical: CR, PR, SD, PD, UE, ND and 
pathologic including CR at all sites of disease and, mpCR at primary site) will be 
estimated along with appropriate 95% confidence intervals.   
 
The distribution of progression-free survival and overall survival will be estimated using 
the Kaplan-Meier method.  Estimates of 1-year PFS and OS will be obtained from the 
Kaplan-Meier analysis.   
 
 
Exploratory Endpoint Analyses (CORRELATIVE STUDIES):  
 
Changes in markers will be summarized descriptively.  Primary and secondary 
endpoints will be summarized by PD-L1 status.  Baseline marker values and changes in 
markers will be summarized by response status.  Association of continuous baseline 
marker levels with response will be evaluated using logistic regression.  Differences 
between response groups with respect to change in markers 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.   
 
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. 
9.3 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 21 patients.   
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 100 of 127 
 
 
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 2 of the first 10 patients or 3 of the first 21 patients experience 
excessive toxicity due to study treatment, leading to delays in definitive surgery greater 
than 90 days from enrollment.  
 
Toxicity leading to delays in definitive surgery will be assessed after the first 10 patients 
have undergone treatment, and will be re-assessed after the first 21 enrolled patients.  
 
9.4 Sample Size Considerations 
A minimax Simon two-stage design will be used. The null hypothesis is that the true 
mpCR response rate at the primary site is ≤ 0.19 and will be tested against the 
alternative that it is >0.19. After testing the regimen on 21 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 34 patients will be studied. If the total number responding is less than or equal to 
9 the regimen is rejected.  This design yields a type I error rate of 9.5% and power of 
80% when the true response rate is 0.35.   
 
Replacement Policy 
Patients who do not have surgery will be replaced on the study. 
10 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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 101 of 127 
 
 
11 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 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.  
12 Ethics/Protection of Human Participants 
12.1 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. 
12.2 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. 
12.3 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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 102 of 127 
 
 
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. 
12.4 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. 
12.5 Participant Confidentiality 
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. 
 
12.6 Future Use of Stored Specimens and Other Identifiable Data 
No identifiable data will be retained. 
13 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. 
13.1 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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 103 of 127 
 
 
accurate and complete.  Unanticipated problems and adverse events must be reviewed 
by the investigator or designee. 
13.2 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.  
 
13.3 Types of Data 
Data that will be collected include patient history and physical examination data, safety, 
laboratory studies, pathology staging studies, and immunohistochemistry as determined 
in the laboratory. 
13.4 Study Records Retention 
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. 
13.5 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. 
14 Study Finances 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 104 of 127 
 
 
14.1 Funding Source 
Bristol-Myers Squibb, who is providing the investigational products, Nivolumab, for this 
study. 
14.2 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). 
14.3 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.   
15 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 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 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 105 of 127 
 
 
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. 
16 References 
1. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients 
with completely resected non-small-cell lung cancer. N Eng J Med 2004; 350: 351-60. 
2. Barlesi F, Park K, Ciardiello F, et al. Primary analysis from oak, a randomized phase III 
study comparing atezolizumab with docetaxel in 2L/3L nsclc. ESMO, Annals of Onc. 
2016;27(Supplement 6): vi552-vi587. 
3. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced 
nonsquamous non-small-cell lung cancer. N Engl J Med, 2015;373:1627-39. 
4. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced 
squamous-cell non-small-cell lung cancer. N Engl J Med, 2015;373:123-35. 
5. Datta D, Lahiri B. Preoperative evaluation of patients undergoing lung resection surgery. Chest 
2003; 123: 2096-103. 
6. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation 
in patients with completely resected stage IB-IIIA non-small cell lung cancer (Adjuvant 
Navelbine International Trialist Association [ANITA]): a randomized controlled trial [published 
erratum appears in Lancet Oncol 2006; 7: 797]. Lancet Oncol 2006; 7: 719-27. 
7. Felip E, Rosell R, Maestre JA, et al. Preoperative chemotherapy plus surgery versus surgery 
plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. 
J Clin Oncol 2010;28;3138-45. 
8. Ferlay J, Soerjomataram I, Ervik M et al. GLOBOCAN 2012 v1.0, Cancer Incidence and 
Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency 
for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 
07/06/2014. 
9. Forde PM, Smith KN, Chaft JE, et al. Neoadjuvant anti-PD1, nivolumab in early stage 
resectable non-small lung cancer. ESMO: Annals Onc., 2016;27(supplement):1-36 
10. Goldstraw P, Crowley J, Chansky K, et al. The IASLC lung cancer staging project: proposals 
for the revision of the TNM stage groupings in  the forthcoming (seventh) edition of the TNM 
classification of  malignant tumours. J Thorac Oncol 2007;2:706-14. 
11. 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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 106 of 127 
 
 
12. Hellmann MD, Chaft JE, William WN Jr, et al. Pathological response after neoadjuvant 
chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major 
pathological response as a surrogate endpoint. Lancet, 2014;15:e42-e50. 
13. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, 
PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized 
controlled trial. Lancet,2016;387:1540-50. 
14. Hotta K, Matsuo K, Ueoka H et al. Role of adjuvant chemotherapy in patients with resected 
non-small cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J 
Clin Oncol 2004; 22: 3860-7. 
15. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomized, 
phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol, 2016;Oct 10 (Epub 
ahead of print). 
16. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997; 111: 
1710-7. 
17. The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-
dose computed tomography screening. N Eng J Med 2011; 365: 395-409. 
18. Nowak AK, Robinson BW, Lake RA. Gemcitabine exerts a selective effect on the humoral 
immune response: implications for combination chemo-immunotherapy. Cancer Res, 
2002;62:2353-8. 
19. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell 
lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 
2014;383:1561-71. 
20. Pataer A, Kalhor N, Correa AM, et al. Histopathologic response criteria predict survival of 
patients with resected lung cancer after neoadjuvant chemotherapy. J Thorac Oncol 2012 
May;7(5):825-32. doi: 10.1097/JTO.0b013e318247504a. 
21. Pignon JP, Tribodet H, Scaliotti GV, et al. Lung adjuvant cisplatin evaluation: A pooled 
analysis by the LACE collaborative group. J Clin Oncol. 2008 ;26:3552-59.  
22. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for 
PD-L1 positive non-small-cell lung cancer.  N Engl J Med, 2016;375:1823-33. 
23. 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. 
24. Scagliotti GV, Fossati R, Torri V et al. Randomized study of adjuvant chemotherapy for 
completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003; 95: 
1453–61. 
25. Siegel RL, Miller KD, Jemal A,. Cancer Statistics 2017. CA Cancer J Clin 2017; Jan;67(1):7-
30. doi: 10.3322/caac.21387. Epub 2017 Jan 5.. 
26. Strauss GM, Herndon II JE, Maddaus JA. Adjuvant paclitaxel plus carboplatin compared 
with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the cancer and 
leukemia group B, radiation therapy oncology group, and north central cancer treatment 
group study groups. J Clin Oncol. 2008;26:5043-51. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 107 of 127 
 
 
27. Travis W, Linder J, Mackay B. Classification, histology, cytology and electron microscopy, in 
Lung Cancer: Principles and Practice (2 ed). Philadelphia, PA, Lippincott Williams & Wilkins, 
2000. 
28. 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.   
29. Wakelee H, Dubey S, Gandara D et al. Optimal adjuvant therapy for non-small cell lung cancer 
– how to handle stage I disease. Oncologist 2007; 12: 331-7. 
30. Westeel V, Quoix E, Puyraveau, et al. A randomized trial comparing preoperative to 
perioperative chemotherapy in early-stage non-small-cell lung cancer (IFCT 0002 trial). Eur 
J Cancer 2013;49:2654-64. 
31. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs observation in resected 
non-small-cell lung cancer. N Eng J Med 2005; 352: 2589-97. 
 
32. 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. 
33. 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. 
34. Massie, M.J., Prevalence of depression in patients with cancer. J Natl Cancer Inst Monogr, 
2004(32): p. 57-71. 
35. 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. 
36. 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. 
37. Spiegel, D. and J. Giese-Davis, Depression and cancer: mechanisms and disease 
progression. Biol Psychiatry, 2003. 54(3): p. 269-82. 
38. 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. 
39. 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. 
40. 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. 
41. Pepys, M.B. and G.M. Hirschfield, C-reactive protein: a critical update. Journal of Clinical 
Investigation, 2003. 111(12): p. 1805. 
42. 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. 
43. 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. 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 108 of 127 
 
 
44. 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. 
45. 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. 
46. Merino, S.M., et al., Lipid metabolism and lung cancer. Critical reviews in 
oncology/hematology, 2017. 112: p. 31. 
47. Beloribi-Djefaflia, S., S. Vasseur, and F. Guillaumond, Lipid metabolic reprogramming in 
cancer cells. Oncogenesis, 2016. 5(1): p. e189. 
48. 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. 
49. Cerhan, J.R., et al. A pooled analysis of waist circumference and mortality in 650,000 adults. 
in Mayo Clinic proceedings. 2014. Elsevier. 
 

CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Based on SKCC Interventional Protocol Template v.20151019 
page 109 of 127 
 
 
Appendices 
The following documents are officially affiliated with the protocol and will be submitted to the IRB 
as a part of the protocol. As such, changes to these items require a protocol amendment. 
APPENDIX A: ECOG Performance Status: 
APPENDIX B: AJCC 8th Edition Staging System  
APPENDIX C: Management Algorithms 
• 
Gastrointestinal 
• 
Renal 
• 
Pulmonary 
• 
Hepatic 
• 
Endocrinopathy 
• 
Skin 
• 
Neurological

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
 
APPENDIX A: 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 
 
 
 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
APPENDIX B: AJCC 8th Edition Staging System  
 
Staging NSCLC 
 
 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
 
Appendix C: 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. 
 
 
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. 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
 
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. 
 
Grade of Diarrhea/ 
Colitis 
(NCI CTCAE v5) 
 
 
Management 
 Follow-up 
 
 
Grade 1 
Diarrhea:< 4 stools/day over baseline; 
Colitis: asymptomatic 
 
• Continue  I-O therapy per 
protocol 
• Symptomatic treatment 
• Close monitoring for worsening symptoms. 
• Educate patient to report worsening immediately 
If worsens: 
• Treat as Grade 2 or 3/4 
 
 
 
Grade 2 
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated <24 hrs; 
not interfering with ADL 
Colitis: abdominal pain; blood in stool 
 
 
 
 
• Delay I-O therapy per protocol 
• Symptomatic treatment 
If improves to grade 1: 
•  Resume I-O therapy per protocol 
If persists > 5-7 days or recur: 
•  0.5-1.0 mg/kg/day methylprednisolone  or oral equivalent 
•  When symptoms improve to grade 1, taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol. 
If worsens or persists > 3-5 days with oral steroids: 
•  Treat as grade 3/4 
 
 
Grade 3-4 
Diarrhea (G3): ≥7 stools per day over 
baseline; incontinence; IV fluids ≥24 
hrs; interfering with ADL 
Colitis (G3):  severe abdominal pain, 
medical intervention indicated, 
peritoneal signs 
G4: life-threatening, perforation 
• Discontinue I-O therapy per 
protocol 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone  IV or  IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider lower endoscopy 
 
If improves: 
• Continue steroids until grade 1, then taper over at 
least 1 month 
If persists > 3-5 days, or recurs after improvement: 
• Add infliximab 5 mg/kg (if no contraindication). 
Note: Infliximab should not be used in cases of 
perforation or sepsis 
 
 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Renal Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy 
 
 
Grade of Creatinine 
Elevation 
(NCI CTCAE v5) 
 
Management 
 Follow-up 
 
 
Grade 1 
Creatinine > ULN and  > 
than baseline but  ≤ 1.5x 
baseline 
 
• Continue I-O therapy per protocol 
• Monitor creatinine weekly 
If returns to baseline: 
•Resume routine creatinine monitoring per protocol 
If worsens: 
•Treat as Grade 2 or 3/4 
 
 
 
 
Grade 2-3 
Creatinine > 1.5x baseline 
to ≤ 6x ULN 
• Delay I-O therapy per protocol 
• Monitor creatinine every 2-3 days 
• 0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or oral 
equivalent 
• Consider renal biopsy with 
nephrology consult 
If returns to Grade 1: 
•Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume I-O therapy 
and routine creatinine monitoring per protocol 
 
If elevations persist > 7  days or worsen: 
•Treat as Grade 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 4 
Creatinine > 6x ULN 
 
• Discontinue I-O therapy per 
protocol 
• Monitor creatinine daily 
• 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Consult nephrologist 
• Consider renal biopsy 
 
 
 
 
 
If returns to Grade 1  :  Taper steroids over at least 1 month and 
add prophylactic antibiotics for opportunistic infections 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
 
 
 
 
 
 
 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 

corticosteroids. 
Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
 
 
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. 
 
Grade of 
Pneumonitis 
(NCI CTCAE v5) 
Management 
 Follow-up 
 
 
 
 
Grade 1 
Radiographic changes only 
• Consider delay of I-O therapy 
• Monitor for symptoms every 2-3 
days 
• Consider Pulmonary and ID 
consults 
 
• Re-image at least every 3 weeks 
If worsens: 
• Treat as Grade 2 or 3-4 
 
 
 
 
 
Grade 2 
Mild to moderate  new 
symptoms 
 
 
 
 
 
 
 
 
Grade 3-4 
Severe new symptoms; 
New/worsening hypoxia; 
Life-threatening 
• Delay I-O therapy per protocol 
• Pulmonary and ID consults 
• Monitor symptoms daily, consider 
hospitalization 
• 1.0 mg/kg/day methyl- 
prednisolone IV or oral equivalent 
• Consider  bronchoscopy , lung 
biopsy 
 
• Discontinue  I-O therapy per 
protocol 
• Hospitalize 
• Pulmonary and ID consults 
• 2-4  mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider bronchoscopy, lung 
biopsy 
• Re-image every 1-3 days 
If improves: 
• When symptoms return to near baseline, taper steroids over 
at least 1 month and then resume I-O therapy per protocol 
and consider prophylactic antibiotics 
If not improving after 2 weeks  or worsening: 
• Treat as Grade 3-4 
 
 
 
 
 
 
If improves to baseline: 
• Taper steroids over at least 6 weeks 
If not improving after 48 hours or worsening: 
• Add additional immunosuppression 

corticosteroids. 
Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
 
 
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. 
 
Grade of Liver 
Test Elevation 
(NCI CTCAE v5) 
 
Management 
 Follow-up 
 
 
Grade 1 
AST or ALT > ULN to 3.0 x 
ULN and/or T. bili > ULN 
to 1.5 x ULN 
 
 
• Continue I-O therapy per protocol 
 
• Continue LFT monitoring per protocol 
If worsens: 
• Treat as Grade 2 or 3-4 
 
 
 
 
Grade 2 
AST or ALT > 3.0 to ≤ 5 x 
ULN and/or T. bili > 1.5 
to ≤ 3 x ULN 
 
 
 
• Delay I-O therapy per protocol 
• Increase frequency of monitoring 
to every 3 days 
If returns to baseline: 
•Resume routine monitoring, resume I-O therapy per protocol 
 
If elevations persist > 5-7 days or worsen : 
• 0.5-1 mg/kg/day methylprednisolone or oral equivalent and 
when LFT returns to grade 1 or baseline, taper steroids over at 
least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per protocol 
 
 
 
 
 
Grade 3-4 
AST or ALT > 5 x ULN  or 
T.bili >3 x ULN 
• Discontinue  I-O therapy* 
• Increase frequency of monitoring 
to every 1-2 days 
•  1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent** 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consult gastroenterologist 
 
If returns to grade 2: 
• Taper steroids over at least 1 month 
 
 
If does not improve in >3-5 days, worsens or rebounds: 
• Add  mycophenolate mofetil 1 g BID 
• If no response within an additional 3-5 days, consider other 
immunosuppressants per local guidelines 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral corticosteroids. 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
*I-O therapy may be delayed rather than discontinued if AST/ALT ≤ 8 x ULN or T.bili ≤ 5 x ULN. 
**The recommended  starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Suspicion of 
crisis (e.g. 
hypotension, 
out 
of proportion 
current 
 
• Delay or discontinue I-O therapy per 
 
• Rule out 
 
• Stress dose of IV steroids with mineralocorticoid 
 
• IV 
 
• Consult 
 
• If adrenal crisis ruled out,  then 
treat as above for 
 
 
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. 
 
Asymptomatic 
TSH elevation 
• Continue I-O therapy per protocol 
• If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 2 subsequent measurements: include fT4 at 
subsequent cycles as clinically indicated; consider endocrinology consult 
 
 
 
 
 
 
 
Symptomatic 
endocrinopathy 
 
• Evaluate endocrine function 
• Consider pituitary scan 
 
Symptomatic with abnormal lab/pituitary scan: 
• Delay I-O therapy per protocol 
•  1-2 mg/kg/day methylprednisolone IV or  PO equivalent 
• Initiate appropriate hormone therapy 
 
No abnormal lab/pituitary MRI scan but symptoms persist: 
• Repeat labs in 1-3 weeks / MRI in 1 month 
If improves  (with or without 
hormone replacement): 
• Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
infections 
• Resume I-O therapy per protocol 
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component 
 
 
 
 
 
 
 
 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, 
once sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
 
 
Skin Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 
 
 
Grade of 
Rash 
(NCI CTCAE v5) 
 
 
Management  
Follow-up 
 
 
 
 
 
Grade 1-2 
Covering  ≤ 30% 
BSA* 
 
 
 
 
• Symptomatic therapy (e.g. antihistamines, 
topical steroids) 
• Continue I-O therapy per protocol 
If persists > 1-2 weeks or recurs: 
• Consider skin biopsy 
• Delay I-O therapy per protocol 
• Consider 0.5-1.0 mg/kg/day methylprednisolone IV or 
oral  equivalent. Once improving , taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol 
If worsens: 
• Treat as Grade 3-4 
 
 
 
Grade 3-4 
Covering >30% BSA; 
Life threatening 
consequences*^ 
• Delay or discontinue I-O therapy per 
protocol 
• Consider skin biopsy 
• Dermatology consult 
• 1.0-2.0 mg/kg/day IV methylprednisolone 
IV or IV equivalent 
 
 
If improves to Grade 1: 
• Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic infections 
• Resume I-O therapy per protocol 
 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*Refer to NCI CTCAE v4 for term-specific grading criteria. 
^If SJS/TEN is suspected, withhold I-O therapy and refer patient for specialized care for assessment and treatment. If SJS or TEN is diagnosed, permanently 
discontinue I-O therapy. 

Updated 05-Jul-2016 
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
Neurological Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 
Grade of 
Neurological 
Toxicity 
(NCI CTCAE v5) 
 
 
Management 
 Follow-up 
 
 
Grade 1 
Asymptomatic or 
mild symptoms; 
Intervention not 
indicated 
 
 
 
• Continue I-O therapy per protocol 
 
Continue to monitor the patient. 
If worsens: 
• Treat as Grade 2 or 3-4 
 
 
Grade 2 
Moderate symptoms; 
Limiting instrumental 
ADL 
• Delay I-O therapy per protocol 
• Treat symptoms per local guidelines 
• Consider  0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or  PO 
equivalent 
 
If improves to baseline: 
•Resume I-O therapy per protocol when improved to baseline 
If worsens: 
• Treat as Grade 3-4 
 
 
 
Grade 3-4 
Severe symptoms; 
Limiting self-care 
ADL; 
Life-threatening 
• Discontinue I-O therapy per protocol 
• Obtain neurology consult 
• Treat symptoms per local guidelines 
•  1.0-2.0 mg/kg/day IV 
methylprednisolone  IV or IV equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
 
If improves to Grade 2: 
• Taper steroids over at least 1 month 
 
If worsens or atypical presentation: 
• Consider IVIG or other immunosuppressive therapies per 
local guidelines 

Update
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral 
corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained 
clinical improvement is observed.  Lower bioavailability of oral corticosteroids 
should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
 
 
 

Update
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
APPENDIX D: UNANTICIPATED PROBLEM FORM
 
 
 

Update
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
APPENDIX E: SERIOUS ADVERSE EVENT PROBLEM FORM 
 

Update
CA209-9HP Induction Nivolumab with cisplatin/pemetrexed or cisplatin/gemcitabine in NSCLC 
Version 7.1 
Protocol IRB# 17P.556 
 
27 December2019 
 
 
 
APPENDIX F: Response Evaluation Criteria in Solid Tumors (RECIST) v1.1  
Criteria for 
Evaluating Response in Solid Tumors 
 
http://recist.eortc.org/wp-content/uploads/2015/03/RECISTGuidelines.pdf