Randomized Phase III Study Testing Nivolumab and Ipilimumab Versus a Carboplatin Based Doublet in First Line Treatment of PS 2 or Elderly (More Than 70 Years Old) Patients With Advanced Non-small Cell Lung Cancer
Phase: PHASE3
Conditions: Advanced Non Small Cell Lung Cancer
Sponsor: Rennes University Hospital

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ENERGY 
 
Randomised phase III study testing nivolumab and ipilimumab versus a carboplatin 
based doublet in first line treatment of PS 2 or elderly (more than 70 years old) 
patients with advanced non-small cell lung cancer. 
 
 
Sponsor 
CHU de Rennes - 2, rue Henri le Guilloux, 35033 Rennes cedex 9 
 
Coordinating investigator  
Dr Herve LENA, Service de Pneumologie - CHU de Rennes - Hôpital de Pontchaillou - 2, rue Henri le Guilloux 35033 
Rennes cedex 9.  
 
Pharmacovigilance 
Catherine Mouchel, Service de Pharmacologie et Centre d’Investigation Clinique - INSERM 1414 - CHU de Rennes – 
Hôpital de Pontchaillou – 2, rue Henri le Guilloux 35033 Rennes cedex 9.  
 
Pharmacy 
Dr Catherine Hamon, Pharmacie - CHU de Rennes – Hôpital de Pontchaillou – 2, rue Henri le Guilloux 35033 Rennes 
cedex 9 
 
Methodology and Data management Centre 
Methodologist:  
Dr David Pérol Unité de Biostatistique et d'Evaluation des Thérapeutiques, Direction de la Recherche et de l’Innovation -  
Centre Léon Bérard - 28, rue Laënnec  - 69373 Lyon cedex 08 
Biostatistician:  
Sylvie Chabaud, Unité de Biostatistique et d'Evaluation des Thérapeutiques, Direction de la Recherche et de l’Innovation 
- Centre Léon Bérard - 28, rue Laënnec  - 69373 Lyon cedex 08 
 
Coordination and monitoring of study 
Direction de la Recherche et de l’Innovation, CHU de Rennes - 2, rue Henri le Guilloux, 35033 Rennes cedex 9 
Groupe Français de Pneumo-Cancérologie 
 
 
 
Version history log 
Version submitted to the authorities: Version 1.0 du 03/07/2017 
Version accepted to the authorities: Version 2.0 du 06/11/2017 
 

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SPONSOR : 
CHU Rennes (Rennes University Hospital Centre) 
TRIAL CODE : 
SPONSOR 35RC16_9734 
GFPC 08-2015 
BMS CA209-449 
EudraCT no. : 
2017-002842-60 
PRODUCT/COMPOUND 
Nivolumab / Ipilimumab 
COMPLETE TITLE 
 
Etude randomisée de phase III testant l’association du 
nivolumab et de l’ipilimumab versus un doublet à base de 
carboplatine dans le traitement de première ligne du CBNPC 
chez des patients PS 2 ou de plus de 70 ans. 
Randomised phase III study testing nivolumab and ipilimumab 
versus a carboplatin based doublet in first line treatment of PS 2 
or elderly (more than 70 years old) patients with advanced non-
small cell lung cancer. 
CLINICAL PHASE 
III 
INDICATION(S) (TARGET) 
Advanced non small cell lung cancer  
COORDINATING  INVESTIGATOR 
Dr Herve Lena 
Service de pneumologie 
CHU of Rennes - Hôpital Pontchaillou 
2 rue Henri Le Guilloux 
35033 Rennes Cedex 9 
France 
PROTOCOL VERSION NO. 
2.0 
DATE OF PROTOCOL 
06/11/2017 
CPP 
Approved on 28/09/2017 
By the Committee for the Protection of Persons SOOM IV of 
Limoges  
ANSM 
Date of authorisation: 12/09/2017 
Authorisation no.: 170472A-12 
THIS CONFIDENTIAL DOCUMENT IS THE PROPERTY OF CHU RENNES. NO UNPUBLISHED 
INFORMATION CONTAINED IN THIS DOCUMENT CAN BE DISCLOSED WITHOUT THE PRIOR 
WRITTEN AUTHORISATION OF CHU RENNES. 

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TABLE OF CONTENTS 
 
1 
GENERAL INFORMATION .................................................................................................................. 17 
1.1. Title ............................................................................................................................................................ 17 
1.2. 
Sponsor ................................................................................................................................................. 17 
1.3. 
Coordination and monitoring of study .................................................................................................. 17 
1.4. 
Investigators .......................................................................................................................................... 17 
1.5. 
Pharmacy............................................................................................................................................... 17 
1.6. 
Pharmacovigilance ................................................................................................................................ 17 
1.7. 
Methodologist – biostatistician ............................................................................................................. 18 
1.10. 
Efficacy evaluation committee ............................................................................................................. 18 
1.11. 
Data monitoring committee .................................................................................................................. 18 
2 
SCIENTIFIC RATIONALE AND GENERAL DESCRIPTION OF STUDY .................................... 19 
2.1. Name and description of investigational medicinal products .................................................................... 19 
2.2. Summary of results of non-clinical trials and clinical trials available and relevant regarding the 
research involving the human person study concerned .................................................................................... 19 
2.3 Summary of benefits and of foreseeable and known risks for the person who is a Patient in the research 
study ............................................................................................................................................................... 25 
2.3.1 Benefits ................................................................................................................................................. 25 
2.3.1.1 Individual benefits ......................................................................................................................... 25 
2.3.1.2 Collective benefit .......................................................................................................................... 25 
2.3.2 Risks ..................................................................................................................................................... 25 
Individual risks.......................................................................................................................................... 25 
2.4. Description and rationale for route of administration, dosage, administration regimen and duration of 
treatment ........................................................................................................................................................... 25 
2.5. Statement indicating that the study will be conducted in compliance with the protocol as well as with 
good clinical practices and legislative and regulatory conditions in force ....................................................... 26 
2.6. Description of the studied population ........................................................................................................ 26 
2.7. References to the scientific literature and to relevant data used as a reference for the study .................... 26 
3 
STUDY OBJECTIVES ............................................................................................................................. 27 
3.1. Primary objective ....................................................................................................................................... 28 
3.2. Secondary objectives ................................................................................................................................. 28 
4 
STUDY DESIGN ....................................................................................................................................... 28 
4.1 Evaluation criteria ....................................................................................................................................... 28 
4.1.1 Primary evaluation criteria ................................................................................................................. 28 
4.1.2. Secondary evaluation criteria ............................................................................................................. 28 
4.2. Description of study methodology ............................................................................................................. 28 
4.2.1. Experimental design............................................................................................................................ 28 
4.2.2. Conduct of study ................................................................................................................................. 28 
4.2.2.1. Inclusion Assessments and Procedures ....................................................................................... 30 
4.2.2.2. On-Study Assessments and Procedures ........................................................................................ 30 
4.2.2.3 Post progression Assessments and Procedures............................................................................. 31 
4.2.2.4 Study Flow-chart ........................................................................................................................... 32 
4.3. Description of the measures taken to reduce and prevent bias .................................................................. 34 
4.3.1. Randomisation .................................................................................................................................... 34 
4.3.2. Methods of blinding ............................................................................................................................ 34 
4.4. Description of dosage and methods of administration of the investigational medicinal products. 
Description of dose unit form, packaging and labelling of the investigational medicinal product(s) .............. 34 
4.5. Expected duration of participation of persons and description of chronology and of duration of all 
study periods including monitoring .................................................................................................................. 34 

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4.6. Description of rules for permanent or temporary discontinuation ............................................................. 34 
4.6.1. Discontinuation of participation of a person in study ........................................................................ 34 
4.6.2. Discontinuation of part or of the entire study ..................................................................................... 34 
5 
SCREENING AND EXCLUSION OF PERSONS FROM THE STUDY ........................................... 35 
5.1. Inclusion criteria for persons who are Patients in the study ...................................................................... 35 
5.2. Non-inclusion criteria for persons who are patients in the study ............................................................... 36 
5.3. Methods of recruitment .............................................................................................................................. 36 
6 
TREATMENTS ADMINISTERED TO PERSONS WHO ARE PATIENTS IN THE STUDY ....... 37 
6.1. Description of the treatments necessary for conduct of the study ............................................................. 37 
6.1.1. Nivolumab - Ipilimumab ..................................................................................................................... 37 
6.1.1.1 Description .................................................................................................................................... 37 
6.1.1.2 Dosing schedule and Administration ............................................................................................ 37 
6.1.1.3 Dosage adjustment ........................................................................................................................ 38 
6.1.2. Comparator ......................................................................................................................................... 38 
6.1.2.1 Dose Reductions for Investigator’s Choice Chemotherapy .......................................................... 39 
 
Carboplatin/pemetrexed ................................................................................................................ 40 
 
Carboplatin-paclitaxel ................................................................................................................... 42 
6.2. Packaging and labelling ............................................................................................................................. 44 
6.3 Drug ordering and accountability ............................................................................................................... 44 
6.4 Authorised and unauthorised medicinal products and treatments in the setting of the protocol, 
including emergency medicinal products ......................................................................................................... 44 
6.4.1. Authorised treatments ......................................................................................................................... 44 
6.4.2. Unauthorised treatments ..................................................................................................................... 44 
6.4.3. Interaction with other medicinal products .......................................................................................... 44 
6.4.4. Emergency treatment .......................................................................................................................... 45 
6.5. Conditions for storage of the investigational medicinal product ............................................................... 45 
6.6. Management of Nivolumab and Ipilumumab, resupply and dispensing of Nivolumab and Ipilumumab . 46 
6.6.1 Initial Orders ....................................................................................................................................... 46 
6.6.2 Re-Supply ............................................................................................................................................. 46 
6.6.3 Drug Excursions .................................................................................................................................. 46 
6.6.4 Handling and Dispensing .................................................................................................................... 46 
6.6.5 Destruction ........................................................................................................................................... 46 
7 
EVALUATION OF SAFETY .................................................................................................................. 46 
7.1 Definitions ................................................................................................................................................... 46 
7.1.1 Adverse event (AE) ............................................................................................................................... 46 
7.1.2 Adverse reaction of an investigational medicinal product (AR) .......................................................... 47 
7.1.3 Serious adverse event or serious adverse reaction (SAE/SAR) ........................................................... 47 
7.2 Investigator’s role ....................................................................................................................................... 47 
7.2.1 Adverse Events to be immediately notified to the sponsor ................................................................... 47 
7.2.1.1 Serious Adverse Events ................................................................................................................. 47 
7.2.1.2. Potential Drug Induced Liver Injury (DILI) ................................................................................ 47 
7.2.1.3 Suspected transmission of an infectious agent.............................................................................. 48 
7.2.1.4 Non serious adverse event but critical to safety evaluation ......................................................... 48 
7.2.2 Notification to the sponsor and time frame reporting ......................................................................... 48 
7.2.2.1 Events not to be notified immediately to the sponsor ................................................................... 49 
 
Specific hospitalizations ............................................................................................................... 49 
 
Specific events related to non-small cell lung cancer progression ............................................... 49 
 
Non serious adverse events ........................................................................................................... 49 
7.3 Sponsor’s role ............................................................................................................................................. 49 
7.3.1 Analysis of serious adverse events ....................................................................................................... 49 

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7.3.2 Method of relationship assessment ...................................................................................................... 49 
7.3.3 Declaration of unexpected serious adverse events .............................................................................. 50 
7.3.4 Transmission of annual safety reports ................................................................................................. 50 
7.3.5 Declaration of other safety data .......................................................................................................... 50 
7.4 Expected adverse reactions specific to the present study ........................................................................... 50 
7.4.1 Adverse reactions related to Nivolumab or Ipilimumab ...................................................................... 50 
7.4.2 Adverse reactions related to Carboplatin ............................................................................................ 55 
7.4.3 Adverse reactions related to Pemetrexed ............................................................................................ 56 
7.4.4 Adverse reactions related to Paclitaxel ............................................................................................... 56 
8 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ........................................... 56 
Sample size consideration ................................................................................................................................. 56 
Definition of population .................................................................................................................................... 57 
Endpoints .......................................................................................................................................................... 57 
9 
RIGHT OF ACCESS TO DATA AND SOURCE DOCUMENTS ...................................................... 58 
9.1. Access to data ............................................................................................................................................ 58 
9.2. Source documents ...................................................................................................................................... 58 
9.3. Confidentiality of data ............................................................................................................................... 58 
10 
QUALITY CONTROL AND ASSURANCE.......................................................................................... 59 
11 
ETHICAL CONSIDERATIONS ............................................................................................................. 59 
11.1. Regulatory and institutional review ......................................................................................................... 59 
11.2. Substantial changes .................................................................................................................................. 59 
11.3. Information for patients and written informed consent form ................................................................... 59 
12 
DATA PROCESSING AND RETENTION OF DOCUMENTS AND DATA .................................... 59 
12.1. Case report forms and data entry ............................................................................................................. 59 
12.2. CNIL ........................................................................................................................................................ 60 
12.3. Archiving ................................................................................................................................................. 60 
13 
INSURANCE ............................................................................................................................................. 60 
14 
STUDY FEASIBILITY ............................................................................................................................ 60 
15 
RULES PERTAINING TO PUBLICATION ......................................................................................... 60 
16 
LIST OF APPENDIX ............................................................................................................................... 60 

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SIGNATURES 
 
INVESTIGATOR’S SIGNATURE 
 
I have read all pages of this clinical trial protocol for which the CHU of Rennes is the sponsor. I 
confirm that it contains all information necessary for the correct conduct of the study. I agree to 
conduct the study in compliance with the protocol and terms of conditions which are defined in it. 
I agree to conduct the study while complying with the conditions of: 
 
- 
Principles of the “Declaration of Helsinki”, 
- 
The rules and recommendations of international good clinical practice ((ICH-E6) and 
French good clinical practice (rules of good clinical practice for biomedical research 
studies of medicinal products for human use - decisions of 24 November 2006), 
- 
National legislation and regulations pertaining to clinical trials, 
- 
Compliance with the Clinical Trials Directive of the EU [2001/20/EC]. 
 
I also agree that investigators and other qualified members of my team may have access to copies 
of this protocol and documents pertaining to the correct conduct of the study enabling them to 
work in compliance with conditions contained in these documents. 
 
 
NAME : Docteur Hervé Léna 
 
Signature : 
 
 
 
 
 
 
Date : 6 novembre 2017 
 
 
SPONSOR’S SIGNATURE 
 
Sponsor : CHU de Rennes 
 
NAME : Monsieur Pascal Gaudron 
 
Signature : 
 
 
 
 
 
 
Date : 6 novembre 2017 

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SYNOPSIS 
 
TITLE 
eNERGY Nivolumab Ipilimumab EldeRly GFPC 08-2015 
Etude randomisée de phase III étudiant l’association du nivolumab et de l’ipilimumab 
versus un doublet à base de carboplatinedans le traitement de première ligne du 
CBNPC avancé chez des patients PS 2 ou de plus de 70 ans. 
Randomized phase III study testing nivolumab and ipilimumab versus a carboplatin 
based doublet in 1st line treatment of PS 2 patients or elderly (more than 70 years old) 
with advanced non-small cell lung cancer. 
SPONSOR 
CHU of Rennes 
COORDINATING 
INVESTIGATOR  
Dr Hervé Lena 
Service de pneumologie 
CHU de Rennes - Hôpital Pontchaillou 
2 rue Henri Le Guilloux 
35033 Rennes Cedex 9 
France 
PROTOCOL VERSION 
2.0 
RATIONALE / CONTEXT  
Lung cancer is the most common cancer in the world and the leading cause of cancer-
related deaths in Western countries (1). Unfortunately, at the time of diagnosis, the 
majority of patients already have metastatic disease and a systemic, palliative 
treatment is the primary therapeutic option.  
Guidelines for PS 2 patients or older than 75 years old patients at the time of diagnosis 
recommend for fit patients a carboplatin doublet chemotherapy. 
Nivolumab has proven efficacy in 3rd line squamous cell lung carcinoma and is 
superior to chemotherapy in 2nd line treatment of squamous and non-squamous lung 
cancer in term of overall survival.  
In 1st line, nivolumab failed to show superiority compared to a platin based doublet in 
terms of progression free survival and overall survival in tumors ≥ 5% PD-L1 
expression. The association Nivolumab plus Ipilimumab showed encouraging results 
in first line setting in phase 1 study. 
We think that with regard to the manageable toxicity of nivolumab in lung cancer 
population and the possibility to obtain long responses, this association could be a 
valid option for this population of elderly and/or PS2 patients in term of overall 
survival. 
ORIGINALITY AND 
INNOVATIVE ASPECTS 
It will be the first trial to test the efficacy of the association nivolumab and ipilimumab 
in PS2 and elderly in advanced NSCLC patients. 
PRIMARY OBJECTIVE  
To compare overall survival of patients in experimental arm versus chemotherapy 
SECONDARY OBJECTIVES 
 To evaluate :  
 
survival at one year of patients treated with nivolumab and ipilimumab versus 
patients treated with chemotherapy, 
 
the objective response rate,  
 
the progression free survival, 
 
the safety and the tolerability of nivolumab and ipilimumab versus 
chemotherapy, 
 
the QOL, 
 
the prognostic impact of PD-L1 expression by immunochemistery (IHC) on 
OS and PFS, 
 
the predictive impact of a geriatric mini data set on OS, PFS and toxicity and 
its evolution under treatment, this analysis will be restricted to patients ≥70 
years old. 
PRIMARY EVALUATION 
CRITERION  
Overall survival 
SECONDARY EVALUATION 
CRITERIA  
 
Percentage of patients alive one year after inclusion in the trial, 

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 
Objective response rate according to Recist 1.1, 
 
Progression free survival time,  
 
Safety tolerability according to CTCAE 4.0, 
 
QOL evaluated by EQ5D and EORTC QLQ-ELD14 every 6 weeks, 
 
PD-L1 testing by immunochemistery assessed by a central laboratory, 
 
Geriatric mini data set (restricted to patients ≥70 years old) 
METHODOLOGY / STUDY 
SCHEDULE 
Open label Phase III randomized study  
CRITERIA FOR INCLUSION 
OF PATIENTS  
 
Signed written informed consent 
 
Cytologically or histologically proven NSCLC (adenocarcinoma, squamous 
cell carcinoma, large-cell carcinoma) 
 
Stage IV or non-treatable by radiotherapy or surgery stage III (7th 
classification) 
 
No previous systemic chemotherapy for lung cancer, except in case of relapse 
after adjuvant treatment for localized disease with 6 months or more between 
end of previous chemotherapy and relapse 
 
Patients less than 70 years old and PS 2 or 70 years older PS 0 to 2 
 
Judged fit enough to receive a carboplatin based doublet according to ESMO 
guidelines 
 
Presence of at least one measurable target lesion (RECIST 1.1 rules) in a non-
irradiated region and analysable by CT 
 
Life expectancy >12 weeks 
 
Prior radiation therapy is authorized if it involved less than 25% of the total 
bone marrow volume and finished 14 days before D1 of planned treatment 
 
Screening laboratory values must meet the following criteria and should be 
obtained within 14 days prior to randomization/registration 
 
WBC   
≥ 2000/μL 
 
Neutrophils  
≥ 1500/μL 
 
Platelets 
 ≥ 100 x103/μL 
 
Hemoglobin  > 10.0 g/dL 
 
Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) 
≥ 45 mL/min (if using the Cockcroft-Gault formula below):  
Female CrCl = [(140 - age in years) x weight in kg x 0.85] / 
[72 x serum creatinine in mg/dL] 
Male CrCl = [(140 - age in years) x weight in kg x 1.00] / [72 
x serum creatinine in mg/dL] 
 
AST/ALT ≤ 3 x ULN  
 
Total Bilirubin ≤ 1.5 x ULN (except Patients with Gilbert 
Syndrome, who can have total bilirubin < 3.0 mg/dL)  
 
Availability of adequate FFPE tumor-derived material (tumor blocks or slides) 
from a biopsy, surgery or fine needle aspirate for analysis of PD-L1 testing by 
IHC 
 
Age and Reproductive Status 
 
Women of childbearing potential (WOCBP) must use appropriate method(s) 
of contraception during treatment. 
WOCBP should use an adequate method to avoid pregnancy : 
o For 23 weeks (30 days plus the time required for nivolumab to 
undergo five half-lives) after the last dose of nivolumab + ipilimumab,  
o For 4 weeks after the last dose of carboplatine + pemetrexed, 
o For 5 weeks after the last dose of carboplatine + paclitaxel. 
 
Women of childbearing potential must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) 

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within 24 hours prior to the start of treatment 
 
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 during treatment 
Men will be instructed to adhere to contraception for a period of 31 weeks 
after the last dose of nivolumab + ipilimumab and with carboplatine 
+pemetrexed or carboplatine + paclitaxel up to 6 months thereafter. 
NON-INCLUSION CRITERIA 
OF PATIENTS 
 
Patients with other severe concurrent disorders that occurred during the prior 
six months before enrollment (myocardial infection, severe or unstable angor, 
coronarian or peripheric arterial bypass operation, NYHA class 3 or 4 
congestive heart failure, transient or constituted cerebral ischemic attack, at 
least grade 2 peripheral neuropathy, psychiatric or neurological disorders 
preventing the patient from understanding the trial, uncontrolled infections) 
are not eligible. 
 
Serious or uncontrolled systemic disease judged as incompatible with the 
protocol by the investigator 
 
Another previous or concomitant cancer, except for basocellular cancer of the 
skin or treated cervical cancer in situ, or appropriately treated localized low-
grade prostate cancer (Gleason score < 6), unless the initial tumor was 
diagnosed and definitively treated more than 5 years previously, with no 
evidence of relapse. 
 
Known activating mutation of EGFR (del LREA exon 19, mutation L858R or 
L861X of exon 21, mutation G719A/S in exon 18) or EML4-ALK or ROS-1 
translocation 
 
Superior caval syndrome 
 
Uncontrolled infectious status 
 
All concurrent radiotherapy 
 
Concurrent administration of one or several other anti-tumor therapies. 
 
Psychological, familial, social or geographic difficulties preventing follow-up 
as defined by the protocol. 
 
Protected person (adults legally protected (under judicial protection, 
guardianship or supervision), person deprived of their liberty, pregnant 
woman, lactating woman and minor), 
 
Concurrent participation in another clinical trial 
 
Patients are excluded if they have active brain metastases or leptomeningeal 
metastases. Patients with brain metastases are eligible if metastases have been 
treated and there is no magnetic resonance imaging (MRI) evidence of 
progression for [lowest minimum is 4 weeks or more]  after treatment is 
complete and within 28 days prior to the first dose of nivolumab and 
ipilimumab administration. There must also be no requirement for 
immunosuppressive doses of systemic corticosteroids (> 10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration. 
 
Patients should be excluded if they have an active, known or suspected 
autoimmune disease. Patients are permitted to enroll if they have vitiligo, type 
I diabetes mellitus, residual hypothyroidism due to autoimmune condition 
only requiring hormone replacement, psoriasis not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external 
trigger 
 
Patients should be excluded if they have a condition requiring systemic 
treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or 
other immunosuppressive medications within 14 days of study drug 
administration. Inhaled or topical steroids and adrenal replacement doses > 10 
mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease. 

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 
Patients should be excluded if they are positive test for hepatitis B virus 
surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV 
antibody) indicating acute or chronic infection 
 
Patients should be excluded if they have known history of testing positive for 
human immunodeficiency virus (HIV) or known acquired immunodeficiency 
syndrome (AIDS) 
 
Patients should be excluded if they have a lung disease that is symptomatic or 
may interfere with the detection or management of suspected drug-related 
pulmonary toxicity 
 
Allergies and Adverse Drug Reaction 
 
History of allergy to study drug components 
 
Severe spinal hypoplasia and / or hemorrhagic tumors 
TREATMENTS/STRATEGIES/
PROCEDURES 
The investigator will declare before randomization the treatment in control arm (ie the 
choice of the second drug associated to carboplatin).  
Patients will be randomized 1:1 into one of the two treatment arms and stratified by 
age (70 years old versus less than 70 years old), by PS (PS 0/1 versus PS2) and by 
histology (squamous versus non-squamous). 
 
Experimental arm: 
          Nivolumab (BMS-936558) dosed intravenously over 30 minutes at 240 mg 
every 2 weeks combined with Ipilimumab dosed intravenously over 30 minutes at 1 
mg/kg every 6 weeks until disease progression, unacceptable toxicity, or other reasons 
specified in the protocol. Nivolumab and Ipilimumab can be continued beyond 
progression according to RECIST 1.1 if the investigator assesses a clinical benefit 
(defined paragraph) 
 
Control arm : the investigator will declare before randomization the treatment 
among: 
 
Doublet of chemotherapy according to standard of care carboplatin (AUC 5) 
with a dose that will be capped to 700 mg and pemetrexed (500 mg/m²) over 4 to 6 
hours every three weeks (restricted to non-squamous histology) or carboplatin (AUC 
6) with a dose that will be capped to 700 mg and paclitaxel (90 mg/m²) D1 D8 D15 
over 4 to 6 hours every 4 weeks, with a maximum of 4 cycles of carboplatin based 
doublet, and the possibility to use maintenance with pemetrexed. 
           
Follow up will be done over 30 minutes every 6 weeks in both arms, until progression. 
Patients treated by the association nivolumab plus ipilimumab in experimental arm 
and who did not discontinue for progression or toxicity will be treated up to 2 years. In 
case of subsequent progression a rechallenge with additional one year of treatment by 
the association nivolumab plus ipilimumab will be proposed. 
For patients treated by chemotherapy in control arm, after progression, a second line 
therapy will be proposed according to standard of care.  
OS will be followed continuously while patients are on the study drug and every 3 
months via in-person or phone contact after patients discontinue the study drug. All 
randomized patients will be evaluated. Subsequent therapies will be recorded during 
one year after inclusion. 
NUMBER OF PATIENTS  
The primary endpoint of the phase III is overall survival. The study is calibrated to 
detect a treatment effect hazard ratio (HR) of 0.65, translating in an improvement of 1-
year OS rate from 40% (control arm) to 55% (Nivolumab and Ipilimumab arm). 
A total of 199 events observed at the time of the final analysis would have 85% power 
to show statistically significant log-rank test at a 2-sided alpha level of 5%. 
Considering a recruitment duration of 24 months and a18 months follow-up for the 
last included patient (estimated total duration of the study: 42 months), 242 patients 
will be randomized in the study (121 by arm).  

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Randomization ratio 1:1 will be stratified according to Age (< 70 vs. ≥ 70 
years),ECOG-PS status (0/1 vs. 2) and histology status (squamous vs non-squamous). 
 
Interim analysesDuring the trial, one interim analysis for futility will be performed, 
permitting to early stop the trial, if no sufficient efficacy is shown. This analysis will 
be performed after that 33% of the expected events have occurred. Using planned 
enrollment rate, this analysis should be performed after inclusion of 171 patients (17 
months after first included patient). No adjustment of type I error was required. 
Stopping boundaries were defined according to Lan-DeMets spending function to 
control type II error. Table 1 shows the futility boundaries. 
An independent Data Safety Monitoring Board will be organized to discuss the 
conduct of the study after analysis performed. 
Sample size calculation and interim analysis planning were performed using East® 
software (Cytel Inc. 1994-2014), version 6.3.1 
 
Table1: Futility boundaries 
 
 
Table1: Futility boundaries 
 
Look 
Fraction 
of 
information 
Cumulative 
 
P value 
HR futility bound 
1 
0.33 
0.012 
0.698 
1.137 
2 
1 
0.15 
0.0025 
 
 
 
DURATION OF STUDY  
Recruitment period : 24 months 
Duration of patient monitoring : 18 months or until end of study treatment in both 
arms 
Estimated total duration of study : 42 months 
EXPECTED FINDINGS AND 
IMPACT  
Superiority of nivolumab and ipilimumab versus a carboplatin based-doublet in 
specific populations of elderly or PS2 NSCLC 
 

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LIST OF ABBREVIATIONS 
 
Term 
Definition 
21CFR50 
United States Code of Federal Regulations, Title 21, Part 50 
ANC 
absolute neutrophil count 
AIDS 
acquired immunodeficiency syndrome 
aPTT 
activated partial thromboplastin time 
AE 
adverse event 
ALT 
alanine aminotransferase 
AT 
aminotransaminases 
ANOVA 
analysis of variance 
ADA 
Anti-drug antibody 
APC 
Antigen Presenting Cell 
AUC 
area under the concentration-time curve 
AUC(INF) 
area under the concentration-time curve from time zero extrapolated to infinite time 
AUC(0-T) 
area under the concentration-time curve from time zero to the time  of the last quantifiable 
concentration 
AUC(TAU) 
area under the concentration-time curve in one dosing interval 
AST 
aspartate aminotransferase 
A-V 
atrioventricular 
TR_AUC(0-T) 
AUC(0-T) treatment ratio 
TR_AUC(INF) 
AUC(INF) treatment ratio 
Cavg 
average concentration 
BLQ 
below limit of quantification 
BOR 
best overall response 
b-HCG 
beta-human chorionic gonadotrophin 
HCO3- 
bicarbonate 
BA/BE 
bioavailability/bioequivalence 
BID, bid 
bis in die, twice daily 
BP 
blood pressure 
BUN 
blood urea nitrogen 
BMI 
body mass index 
BMS 
Bristol-Myers Squibb 
Ca++ 
calcium 
CBNPC 
cancer bronchique non-à-petites cellules 
CRF 
Case Report Form, paper or electronic 
C 
celcius 
cm 
centimeter 
CNS 
central nervous system 

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Cl- 
chloride 
CL 
clearance 
CRC 
clinical research center 
TR_Cmax 
cmax treatment ratio 
CFR 
code of federal regulations 
CV 
coefficient of variation 
CTCAE v4 
common terminology criteria for adverse events version 4 
CBC 
complete blood count 
CR 
complete response 
CT 
computed tomography 
Ctau 
concentration in a dosing interval (eg, concentration at 24 hours, concentration at 12 hours, 
etc.) 
CI 
confidence interval 
CrCl 
creatinine clearance 
C 
cycle 
CMV 
cytomegalovirus 
CTLA-4 
cytotoxic t lymphocyte-associated antigen 4 
D 
day 
dL 
deciliter 
D/C 
discontinue 
ECOG 
eastern cooperative oncology group 
T-HALFeff_AUC 
effective elimination half life that explains the degree of auc accumulation observed 
T-HALFeff_Cmax 
effective elimination half life that explains the degree of cmax accumulation observed) 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EP 
endpoint 
EGFR 
epidermal growth factor receptor 
q 
every 
eg 
exempli gratia (for example) 
Ct 
expected concentration at a certain time, usually at the end of an expected future dosing 
interval (eg, concentration at 24 hours, concentration at 12 hours, etc.) 
ESR 
expedited safety report 
FISH 
fluorescent in situ hybridization 
FSH 
follicle stimulating hormone 
FDA 
food and drug administration 
FFPET 
formalin fixed paraffin embedded tissue 
FFPE 
formalin fixed paraffin-embedded 
GGT 
gamma-glutamyl transferase 

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GFPC 
groupe français de pneumo-cancérologie 
GFR 
glomerular filtration rate 
GCP 
good clinical practice 
g 
gram 
T-HALF 
half life 
HR 
hazard ratio 
HIPAA 
health information portability and accountability act 
HR 
heart rate 
HBsAg 
hepatitis b surface antigen 
HBV 
hepatitis b virus 
HCV AB 
hepatitis c antibody 
HCV RNA 
hepatitis c rna 
HCV 
hepatitis c virus 
HRT 
hormone replacement therapy 
h 
hour 
HCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
ie 
id est (that is) 
IHC 
immunohistochemistry 
IEC 
independent ethics committee 
IRRC 
independent radiology review committee 
ICF 
informed consent form 
IRB 
institutional review board 
IVRS 
interactive voice response system 
ICH 
international conference on harmonisation 
IU 
international unit 
IU/L 
international unit per liter 
IU/mL 
international unit per milliliter 
IV 
intravenous 
IMP 
investigational medicinal products 
IND 
investigational new drug exemption 
IB 
investigator brochure 
KM 
kaplan-meier 
kg 
kilogram 
LDH 
lactate dehydrogenase 
L 
liter 
LCSS 
lung cancer symptom scale 
Mg++ 
magnesium 

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MRI 
magnetic resonance maging 
Cmax, CMAX 
maximum observed concentration 
MTD 
maximum tolerated dose 
mCRPC 
metastatic castration-resistant prostate cancer 
m 
meter 
mcg 
microgram 
miRNA 
microrna (micro ribonucleic acid) 
mg 
milligram 
mL 
milliliter 
mL/min 
milliliters per minute 
mm 
millimeter 
mmHg 
millimeters of mercury 
MIC 
minimum inhibitory concentration 
min 
minute 
mo 
month 
MDSC 
myeloid derived suppressor cells 
NIMP 
non-investigational medicinal products 
NSCLC 
non-small cell lung cancer 
NSAID 
nonsteroidal anti-inflammatory drug 
N/A 
not applicable 
NE 
not evaluable 
N 
number of patients or observations 
ORR 
overall response rate 
OS 
overall survival 
PR 
partial response 
PRO 
patient reported outcomes 
PBMC 
peripheral blood mononuclear cells 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PPK 
population pharmacokinetic 
K+ 
potassium 
K3EDTA 
potassium ethylenediaminetetraacetic acid 
PD-1 
programmed death-1 
PD-L1 
programmed death-ligand 1 
PD-L2 
programmed death-ligand 2 
PFS 
progression free survival 
PD 
progressive disease 
PS 
performance status 

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QC 
quality control 
QOL 
Quality of life 
QPCR 
quantitative polymerase chain reaction 
QD, qd 
quaque die, once daily 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
CLR 
renal clearance 
RECIST 1.1 
response evaluation criteria in solid tumors version 1.1 
SAE 
serious adverse event 
SNP 
single nucleotide polymorphism 
Na+ 
sodium 
SD 
stable disease 
SD 
standard deviation 
SOP 
standard operating procedures 
SmPC 
summary of product characteristics 
t 
temperature 
TID, tid 
ter in die, three times a day 
TSH 
thyroid stimulating hormone 
T 
time 
Tmax, TMAX 
time of maximum observed concentration 
TAO 
trial access online, the bms implementation of an edc capability 
Cmin, CMIN 
trough observed concentration 
TILs 
tumor infiltrating lymphocytes 
UV 
ultraviolet 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
WHO 
world health organization 
 

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1 
GENERAL INFORMATION 
1.1. Title 
eNERGY 
Etude randomisée de phase III testant l’association du nivolumab et l’ipilimumab versus un doublet à base de platine dans 
le traitement de première ligne du CBNPC chez des patients PS 2 ou de plus de 70 ans. 
 
Randomised phase III study testing nivolumab and ipilimumab versus a carboplatin based doublet in first line treatment of 
PS 2 or elderly (more than 70 years old) patients with advanced non-small cell lung cancer. 
 
1.2. Sponsor 
Identification 
CHU of Rennes 
2, rue Henri le Guilloux 
35033 Rennes cedex 9 
 
Signature of protocol on behalf of the sponsor  
Pascal Gaudron, Director of Research 
CHU of Rennes 
2, rue Henri le Guilloux 
35033 Rennes cedex 9 
 
Person responsible for study on the side of the sponsor 
Pascal Gaudron, Director of Research 
CHU of Rennes 
2, rue Henri le Guilloux 
35033 Rennes cedex 9 
 
1.3. Coordination and monitoring of study 
Direction of Research 
CHU of Rennes 
2, rue Henri le Guilloux 
35033 Rennes cedex 9 
 
1.4. Investigators 
Coordinating investigator 
Dr Hervé Léna 
Service de pneumologie 
CHU of Rennes- Hôpital de Pontchaillou 
2 rue Henri Le Guillou 
35033 Rennes Cedex 9 
 
Associated investigators (see appendix 1) 
 
1.5. Pharmacy 
Dr Catherine Hamon 
Pharmacie 
CHU of Rennes – Hôpital de Pontchaillou 
2 rue Henri le Guilloux 
35033 Rennes cedex 9 
 
1.6. Pharmacovigilance 
Dr Catherine Mouchel 
Service de Pharmacologie et Centre d’Investigation Clinique - INSERM 0203 
CHU of Rennes – Hôpital de Pontchaillou 

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2 rue Henri le Guilloux 
35033 Rennes cedex 9 
 
1.7. Methodologist – biostatistician 
- 
Methodologist : 
Dr David Pérol  
Unité de Biostatistique et d'Evaluation des Thérapeutiques 
Direction de la Recherche et de l’Innovation 
Centre Léon Bérard 
28, rue Laënnec  - 69373 Lyon Cedex 08 
 
- 
Biostatistician : 
Sylvie Chabaud 
Biostatisticienne - Responsable pôle statistique 
Unité de Biostatistique et d'Evaluation des Thérapeutiques 
Direction de la Recherche et de l’Innovation 
Centre Léon Bérard 
28, rue Laënnec  - 69373 Lyon Cedex 08 
 
1.8. Referent for geriatric analysis based on mini data set assessment 
Pr Elena Paillaud 
Département de gériatrie CHU Henri Mondor 
51 Avenue du Maréchal de Lattre de Tassigny 
94010 Créteil Cedex 
 
1.9. Referent for PD-L1 testing by immunochemistery (IHC) assessed by the central laboratory  
Pr Diane Damotte 
Service d’anatomie et cytologie pathologiques 
HU-PARIS OUEST SITE G.POMPIDOU APHP 
20 Rue Leblanc 
75015 Paris 
 
1.10. 
Efficacy evaluation committee 
The efficacy evaluation committee will review all available tumor assessment scans to determine response (RECIST 1.1). 
The determined response will be used in the analyses of ORR and PFS. 
 
The members are: 
Dr Gilles Robinet, service d’oncologie thoracique, CHU Brest 
Dr Maurice Pérol, service d’oncologie médicale, Centre Léon Bérard Lyon 
Pr Christos Chouaid, service de pneumologie Centre Hospitalier Intercommunal Créteil 
Pr Alain Vergnenègre, service de pneumologie, CHU Limoges 
Dr Hervé Léna, service de pneumologie, CHU Rennes 
 
This committee will meet three times a year to follow inclusion rates, primary and secondary endpoints of the study. 
Conference call will be organized if necessary. 
 
1.11. 
Data monitoring committee 
A Data Monitoring Committee (DMC) will be established to provide oversight of safety and efficacy considerations in 
protocol Energy, and to provide advice to the Sponsor regarding actions the committee deems necessary for the 
continuing protection of patients enrolled in the trial. The DMC will monitor patient safety and evaluate the available 
efficacy data for the study. The group will be responsible for promptly reviewing the DMC recommendations, for 
providing guidance regarding the continuation or termination of the study, and for determining whether amendments to 
the protocol or changes in study conduct are required. After meeting, the DMC will notify the clinical study leadership 
group that it has met and will provide recommendations about the study by telephone or email. Any recommendation by 

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the DMC regarding study modification will be submitted to the clinical study leadership team within pre-specified 
business days of the DMC meeting. 
 
Members of the DMC are:  
Thoracic oncologists :  
Pr A Cortot, Service de pneumologie, CHU Lille  
Dr B Mennecier, Service de pneumologie, CHU Strasbourg 
 
Pharmacovigilance :  
Dr Sophie Duranton, Direction de la Recherche, CHU Poitiers 
 
Méthodologist : 
Bruno Giraudeau, CIC Inserm 1415, CHU Tours 
 
 
2 
SCIENTIFIC RATIONALE AND GENERAL DESCRIPTION OF STUDY 
2.1. Name and description of investigational medicinal products 
 
Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype mAb that binds PD-1 on activated immune cells and 
disrupts engagement of the receptor with its ligands PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273), thereby 
abrogating inhibitory signals and augmenting the host antitumor response.  
 
Ipilimumab is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset of T cells from 
human and nonhuman primates. CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody 
that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been 
shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-
effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a 
general increase in T-cell responsiveness, including the anti-tumor response. 
 
2.2. Summary of results of non-clinical trials and clinical trials available and relevant regarding the research 
involving the human person study concerned 
 
Control arm 
Chemotherapy is feasible and beneficial for elderly NSCLC patients with advanced/metastatic disease [1–4]. On the 
other hand, it should be noted that elderly had higher rates of adverse events during chemotherapy compared with 
patients younger than 55 years and this observation was independent of comorbidity [5]. This could be the reason for the 
significant under-treatment of elderly patients in clinical practice.  
Prospective trials support the use of carboplatin-based doublets in fit elderly patients [6-7]. For less fit patients, single-
agent treatment (gemcitabine, vinorelbine, taxanes) represents a valid option according to ESMO guidelines published in 
2014 [8]. There are no data to support any single agent offering an OS benefit, very limited data are available for 
octogenarians and, therefore, no specific recommendations can be made for this group. Performance status, 
comorbidities, life expectancy and patient’s preference should be taken into account when developing a treatment 
strategy.  
For patients PS 2 with advanced NSCLC, the updated systematic review performed by the ASCO clinical practice 
guideline update and published in oct 2015 [9] identified two small trials specifically comparing single agent versus 
combination chemotherapy in patients with PS 2. The first trial which included 205 participants, compared carboplatin 
plus pemetrexed with pemetrexed alone[10]. In the results, OS and PFS were statistically significantly longer with the 
combination. Adverse events were slightly more frequent with the combination, but the results were not statistically 
significant. One trial with 56 participants compared cisplatin plus gemcitabine with gemcitabine and found that OS and 
QoL was also higher; however, the study was stopped early and had few participants [11]. The Cochrane systematic 
review on chemotherapy and supportive care, updated in 2012, continued to show that chemotherapy and best supportive 
care versus supportive care alone benefit patients, including those who have PS 2 [12]. PFS were statistically 
significantly longer with the combination.  

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Trials limited to patients with PS 2 have typically not reported the cause for designation of PS 2 (ie, cancer-related 
symptoms secondary to large tumor burden v poor PS designation because of multiple chronic conditions). That’s why 
ASCO guidelines concluded in 2015, that the data informing chemotherapy decisions for patients with PS 2 are 
insufficient to make a strong recommendation favoring combination chemotherapy. Patients and clinicians should 
discuss the risks and benefits of combination chemotherapy. Some patients may choose single-agent chemotherapy if 
their perception of risk outweighs perceived benefits of combination therapy. There is no effective tool to determine 
which patients will tolerate doublet therapy and experience an improvement in PS with a reduction of symptoms and 
which patients will experience an acceleration of their decline with treatment [9]. 
 
Experimental arm 
Immunotherapeutic approaches recently have demonstrated clinical efficacy in several cancer types, including melanoma 
and hormone-refractory prostate cancer [13]. Tumors may modulate and evade the host immune response through a 
number of mechanisms, including down regulation of tumor-specific antigen expression and presentation, secretion of 
anti-inflammatory cytokines, and upregulation of inhibitory ligands. T cell checkpoint regulators such as CTLA-4 and 
programmed death-1 (PD-1, CD279) are cell surface molecules that, when engaged by their cognate ligands, induce 
signaling cascades down-regulating T cell activation and proliferation. One proposed model by which therapeutic T cell 
checkpoint inhibitors derive antitumor activity is through breaking of immune tolerance to tumor cell antigens. 
Nivolumab is now approved in Europe to treat patients with metastatic squamous cell NSCLC with progression on or after 
platinum-based chemotherapy. 
The approval was based on the results of CA209017 [14], a randomized trial of nivolumab versus docetaxel. The median 
overall survival (OS) for Patients in the nivolumab arm was 9.2 months versus 6 months for those in the docetaxel arm 
(HR = 0.59). Improvement in survival was observed for nivolumab regardless of PD-L1 expression, though there was a 
trend for better efficacy for those with PD-L1 expressing tumors. A single arm trial (CA209063) of 117 Patients with 
metastatic squamous cell NSCLC, with progression after platinum-based chemotherapy and at least one additional 
systemic regimen, showed a 15% overall response rate (ORR), of whom 59% had response durations of 6 months or 
longer [15]. 
A second phase 3 study, CA209057 [16], stopped at a preplanned interim analysis by the independent Data Monitoring 
Committee (DMC), met its primary endpoint of superior overall survival of nivolumab versus docetaxel in Patients with 
previously-treated non-squamous NSCLC. Patients in the nivolumab arm had a 27% reduction in risk of death (HR = 
0.73; P = 0.0015). Interaction p-values, reported for PD-L1 expression subgroups by each of the predefined expression 
levels, suggested a clinically important signal of a predictive association. Nivolumab also significantly improved ORR vs 
docetaxel (P=0.0246), with ORR as high as 36% in Patients with PD-L1 expressing tumors. OS approximately doubled 
with nivolumab vs docetaxel across the PD-L1 expression continuum. In contrast, no difference in OS was seen between 
nivolumab and docetaxel when PD-L1 was not expressed in the tumor. Nivolumab monotherapy has also been evaluated 
in first-line NSCLC, where it showed promising activity regardless of histology. As in pretreated NSCLC, activity with 
nivolumab monotherapy is pronounced in PD-L1 expressing NSCLC. The recruitment of the trial comparing nivolumab 
to chemotherapy in 1st line at the investigator’s choice is closed to inclusions. In general, nivolumab also has been well 
tolerated to date, with a favorable safety profile relative to anticipated toxicities based on an immunostimulatory 
mechanism of action. 
 
Nivolumab monotherapy has also been evaluated in first-line NSCLC, where it showed promising activity regardless of 
histology [17]. But study Checkmate 026 failed to demonstrate a PFS nor OS benefit in favor of Nivolumab versus a 
platin-based doublet in first line treatment of stage IV NSCLC ≥ 5% PD-L1 expression [18]. 
 
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may improve antitumor activity. In 
vitro combinations of nivolumab plus ipilimumab increase IFN-ɤ production 2- to 7-fold over either agent alone in a 
mixed lymphocyte reaction. Increased antitumor activity of the combination was also observed in 3 of 5 syngeneic murine 
cancer models. In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodiesincreased the 
proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and dual blockade increased 
tumor infiltration of T effector cells and decreased intratumoral T regulatory cells, as compared to either agent alone [19]. 
 
The combination of nivolumab and ipilimumab was evaluated in CA209004 (MDX1106-04), a phase 1b multiple 
ascending dose study in Patients with treatment-naive and previously treated advanced melanoma. Results showed 
promising activity, with higher, but tolerable toxicity than ipilimumab alone [20]. Based on these data, CA209069, a 

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phase 2 study, compared the combination to ipilimumab alone in treatment-naïve patients with advanced melanoma: 
nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks x4 followed by nivolumab 3 mg/kg every 2 weeks versus 
ipilimumab 3 mg/kg every 3 weeks x 4 [21]. In patients with BRAF wild type tumors, the ORR was 61% (44/72), 
including 22% (16/72) complete responses (CR) in the group treated with the combination, compared to 11% (4/37) with 
0 CRs in those treated with ipilimumab alone. The median PFS was not reached in the combination versus 4.4 months for 
ipilimumab alone (HR=0.4). It should be noted that in the combination group, the ORR was independent of PD-L1 
expression. In this group, ORR was 58% among patients with PD-L1+ tumors and 55% among those with PD-L1- tumors. 
In contrast, in the ipilimumab alone group, the ORR was numerically higher among patients with PD-L1+ tumors (18%) 
compared to those with PD-L1- tumors (4%). Grade 3-4 treatment-related AEs were reported in 54% of patients receiving 
the combination compared to 24% for ipilimumab alone.  
Ipilimumab has been shown to have activity in lung cancer. A Phase 2 study (CA184041) in Patients with NSCLC or 
small cell lung cancer (SCLC) investigated the addition of ipilimumab to carboplatin and paclitaxel using 2 different 
schedules (concurrent and phased). The phased schedule demonstrated a significant improvement of immune-related 
progression-free survival as well as progression-free survival by modified WHO criteria compared to chemotherapy alone, 
in both NSCLC and SCLC [22]. 
Based on the initial data in melanoma, and the activity observed with nivolumab and ipilimumab in lung cancer, the 
nivolumab plus ipilimumab combination has been also evaluated as first-line therapy in patients with advanced NSCLC. 
In CA209012, early combination cohorts evaluated 2 dosing schedules that were studied in the CA209004 study in 
melanoma: 
- nivolumab 1 mg/kg + ipilimumab 3 mg/kg, q 3 weeks x4, followed by nivolumab 3 mg/kg q 2 weeks (arms G and H, 
n=24); 
-nivolumab 3 mg/kg + ipilimumab 1 mg/kg, q 3 weeks x4, followed by nivolumab 3 mg/kg q 2 weeks (arms I and J, 
n=25) 
These regimens resulted in significant toxicity, with 39% of patients discontinuing treatment due to a treatment-related 
adverse event. 
Thus, additional combination cohorts were initiated, using lower doses of both nivolumab and ipilimumab, or less 
frequent dosing of ipilimumab. Data from these cohorts demonstrate that both nivolumab 1 mg/kg + ipilimumab 1 mg/kg 
q 3 weeks with nivolumab maintenance 3 mg/kg q2w (arm N in study CA209012), as well as ipilimumab at 1 mg/kg q6w 
is tolerable, when given with nivolumab 3 mg/kg q2w (arm Q in study CA209012). Overall, the safety data are not 
dissimilar to what has been observed in the nivolumab arm (arm F in CA209012). Of particular note, the rate of 
discontinuation due to drug-related AEs was 13% in arm N and 11% in arm Q compared to 10% in the nivolumab 
monotherapy arm (arm F) [17]. 
 
Table1:  Treatment-related immune adverse events from selected cohorts in C209012 [17]. 

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The toxicity rate was higher with the combination compare to nivolumab alone. Nevertheless it was a majority of grade 1-
2 toxicities. 
 
Table 2: Clinical activity of nivolumab/ipilimumab combination and nivolumab alone[17]. 
  
 
Table 3: Clinical activity of nivolumab/ipilimumab combination compared to nivolumab alone by PD-L1 status, using 1% 
cutoff [17]. 

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Flat dose regimens of nivolumab 
The safety and efficacy of 240 mg Q2W flat dose of nivolumab is expected to be similar to3 mg/kg Q2W dosing regimen. 
A flat dose of nivolumab 240 mg Q2W was selected since it is identical to a dose of 3 mg/kg for patients weighing 80 kg, 
the observed median body weight in nivolumab treated cancer patients. Using a PPK model, the overall distributions of 
nivolumab exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are comparable after treatment with either 3 mg/kg or 240 
mg nivolumab. The predicted range of nivolumab exposures (median and 90% prediction intervals) resulting from a 240 
mg flat dose across the 35 to 160 kg weight range is maintained well below the corresponding exposures observed with 
the well tolerated 10 mg/kg nivolumab Q2W dosage. Across the various tumor types in the clinical program, nivolumab 
has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab 
exposure produced by 3 mg/kg and efficacy and safety has been found to be relatively flat. Given the similarity of 
nivolumab PK across tumor types and the similar exposures predicted following administration of 240 mg flat dose 
compared to 3 mg/kg Q2W regimen, it is expected that the safety and efficacy profile of 240 mg Q2W nivolumab will be 
similar to that of 3 mg/kg nivolumab. Hence, a flat dose of 240 mg nivolumab is under investigation. 
 
Shorter Infusion Duration 
Establishing that nivolumab can be safely administered using a shorter infusion time (30 minutes) is under investigation. 
Previous clinical studies of nivolumab monotherapy have used a 60-minute infusion duration wherein, nivolumab has 
been safely administered up to 10 mg/kg over long treatment periods. Infusion reactions including high-grade 
hypersensitivity reactions have been uncommon across nivolumab clinical program. In CA209010, a dose association was 
observed for infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 
mg/kg). All the events were Grade 1-2 and were manageable. An infusion duration of 30 minutes for 3 mg/kg nivolumab 
(30% of the dose provided at 10 mg/kg) is not expected to present any safety concerns compared to the prior experience at 
10 mg/kg nivolumab dose infused over a 60-minute duration. The safety of nivolumab 3 mg/kg administered as a 30-min 
infusion was assessed in CA209153 in patients (n=322) with previously treated advanced NSCLC. Overall, there were no 
clinically meaningful differences in the frequency of hypersensitivity/infusion-related reactions (of any cause or 
treatment-related) in patients administered nivolumab over a 30 min infusion compared with that reported for patients 
with the 60 min infusion. Thus, it was shown that nivolumab can be safely infused over 30 min. 
 
Based on these data, the following schedule will be evaluated in Inergy: 
- Nivolumab (3 mg/kg every 2 weeks) + ipilimumab (1 mg/kg every 6 weeks) will be evaluated in both PD-L1+ and PD-
L1- patients. 
 
Of note, all patients included in the trials with nivolumab and ipilimumab were in good general status PS 0 to 1 (inclusion 
criteria). Number of elderly patients included in CA209 057 and CA 209 017 was very low even if there was no limitation 
of age in inclusion criteria. Median age for example in 057 study was 61 years old with only 7% older than 75. 

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Energy is planned to compare the efficacy and safety of nivolumab and ipilimumab versus carboplatin-based doublet in 
advanced NSCLC in first line in patients ≥70 years old or PS2. 
 
2.3 Summary of benefits and of foreseeable and known risks for the person who is a Patient in the research study 
 
2.3.1 Benefits 
2.3.1.1 Individual benefits 
Regard to the low toxicity of nivolumab and ipilimumab in lung cancer population, the possibility to obtain long 
responses, nivolumab and ipilimumab could be a valid option for this frail population of patients. 
 
2.3.1.2 Collective benefit 
Evaluation of new treatments in these specific populations of frail or elderly lung cancer patients will potentially increase 
the therapeutic possibilities for these specific populations. 
 
2.3.2 Risks 
Individual risks 
 
Physical risks and constraints 
The main risk in this frail population could be the delay to cytotoxic chemotherapy. First evaluation will be done at 6 
weeks, allowing a rapid crossover in case of progression under nivolumab and ipilimumab. In case of clinical progression, 
a rapid evaluation will be asked to confirm progression and beginning of chemotherapy. The association of nivolumab and 
ipilimumabincrease toxicity compared to nivolumab alone but at the doses of nivolumab plus ipilimumab that will be used 
in this study we don’t expect to observe a higher rate of discontinuation due to drug-related AEs than with nivolumab 
alone. This association appears tolerable even for a frail population. 
 
 
Psychological risks and constraints 
Not applicable. Cancer patients benefit of specific support according to plans cancers 1 to 3. All research sites have an 
agreement for treatment of advanced cancer patients and psychological support is part of this agreement. 
 
 
Socio-economic risks and constraints 
Nivolumab and ipilimumab will be supplied by BMS. All other drugs are registered and used in this indication and are 
included in national and international recommendations.  
 
2.4. Description and rationale for route of administration, dosage, administration regimen and duration of 
treatment 
Experimental arm:  
 
Patients will receive treatment with nivolumab as a 30 minutes infusion at 240 mg every 2 weeks and ipilimumab as a 30 
minutes infusion at 1 mg/kg every 6 weeks, starting on Day 1, until disease progression, unacceptable toxicity, or other 
reasons specified in the protocol section 4.6. 
All decisions to continue treatment beyond initial progression documented in the study record, discussed and agreed to by 
the study coordinator. Patients should be re-consented with an ICF describing any reasonably foreseeable risks or 
discomforts. 
Accumulating evidence indicates a minority of Patients treated with immunotherapy may derive clinical benefit despite 
initial evidence of PD.   
Patients will be permitted to continue treatment beyond initial RECIST 1.1 defined PD as long as they meet the following 
criteria determined by the investigator: 
• 
Investigator-assessed clinical benefit and Patient is tolerating study drug. 
• 
Tolerance of study drug 
• 
Stable performance status 
The assessment of clinical benefit should take into account whether the Patient is clinically deteriorating and unlikely to 
receive further benefit from continued treatment.  
Treatment beyond progression will not delay an imminent intervention to prevent serious complications of disease 
progression (eg, CNS metastases). 

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A radiographic assessment/ scan should be performed within 6 weeks of initial investigator-assessed progression to 
determine whether there has been a decrease in the tumor size or continued PD. The assessment of clinical benefit should 
be balanced by clinical judgment as to whether the patient is clinically deteriorating and unlikely to receive any benefit 
from continued treatment with nivolumab + ipilimumab. 
For the patients who continue nivolumab + ipilimumab study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden from time of initial PD. This includes an increase in the sum of diameters 
of all target lesions and/ or the diameters of new measurable lesions compared to the time of initial PD. Nivolumab+ 
ipilimumab treatment should be discontinued permanently upon documentation of further progression. 
New lesions are considered measureable at the time of initial progression if the longest diameter is at least 10 mm (except 
for pathological lymph nodes which must have a short axis of at least15 mm). Any new lesion considered non-
measureable at the time of initial progression may become measureable and therefore included in the tumor burden if the 
longest diameter increases to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to inclusion of new lesions 
which become measurable, these new lesions must demonstrate an absolute increase of at least 5 mm. 
For statistical analyses, this will need to be described in patient population information. E.g. Patients who continue 
treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be considered to have investigator-
assessed progressive disease at the time of the initial progression event. 
 
Control arm: 
Patients will receive according to standard practice and local guidelines: 
-  carboplatine AUC 5 with a dose that will be capped to 700 mg I.V D1 and pemetrexed (500 mg/m²) I.V D1 over 
4 to 6 hours every 3 weeks for 4 cycles (restricted to non-squamous histology) 
- or carboplatine AUC 6 with a dose that will be capped to 700 mg I.V D1 and paclitaxel (90 mg/m²) I.V D1 D8 
D15 over 4 to 6 hours every 4 weeks for 4 cycles (allowed in squamous and  non-squamous histologies). 
 
 
Premedication (steroids for pemetrexed and paclitaxel, folic acid and vitamin B12 for pemetrexed) and emesis prevention 
therapy are required and will be used as standard practice. Treatment will be given for 4 cycles except in case of 
progression or toxicity. 
See chapter 6 for more detailed description.  
 
In cases of patient with a body surface area≥2m², all the chemotherapies doses will be capped at 2m² of body surface area. 
2.5. Statement indicating that the study will be conducted in compliance with the protocol as well as with good 
clinical practices and legislative and regulatory conditions in force 
The sponsor and the investigator also agree that this study will be conducted: 
 
in compliance with the protocol, 
 
in compliance with local and international good clinical practice currently in force, 
 
in compliance with legislative and regulatory conditions currently in force in participating countries. 
 
2.6. Description of the studied population  
Patients with untreated non-small cell lung cancer, patients less than 70 years old with PS2 or older than 70 years old with 
PS 0, 1 or 2 or at diagnosis. The selection procedures are described in chapter 5. 
 
2.7. References to the scientific literature and to relevant data used as a reference for the study 
1. Gridelli C, Brodowicz T, Langer CJ et al. Pemetrexed therapy in elderly patients with good performance status: 
analysis of two phase III trials of patients with nonsquamous non-small-cell lung cancer. Clin Lung Cancer 2012; 13: 
340–346. 
2. Kawaguchi T, Tamiya A, Tamura A et al. Chemotherapy is beneficial for elderly patients with advanced non-small-cell 
lung cancer: analysis of patients aged 70–74, 75-79, and 80 or older in Japan. Clin Lung Cancer 2012; 13: 442–447. 
3. Davidoff AJ, Tang M, Seal B et al. Chemotherapy and survival benefit in elderly patients with advanced non-small-cell 
lung cancer. J Clin Oncol 2010; 28: 2191–2197. 
4. Zhu J, Sharma DB, Chen AB et al. Comparative effectiveness of three platinumdoublet chemotherapy regimens in 
elderly patients with advanced non-small cell lung cancer. Cancer 2013; 119: 2048–2060. 

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5. Chrischilles EA, Pendergast JF, Kahn KL et al. Adverse events among the elderly receiving chemotherapy for advanced 
non-small-cell lung cancer. J Clin Oncol 2010; 28: 620–627. 
6- Quoix E, Zalcman G, Oster JP et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with 
monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet 
2011; 378: 1079–1088. 
7- Socinski MA, Langer CJ, Okamoto I et al. Safety and efficacy of weekly nab(R)- paclitaxel in combination with 
carboplatin as first-line therapy in elderly patients with advanced non-small-cell lung cancer. Ann Oncol 2013; 24: 314–
321. 
8- Pallis AG, Gridelli C, Wedding U, et al. Management of elderly patients with NSCLC; updated expert’s opinion paper: 
EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology. Ann Oncol Off J Eur 
Soc Med Oncol ESMO 2014; 25: 1270–83. 
9- Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S Jr, Brahmer JR, Ellis PM, Gajra A, Rackear N, Schiller JH, 
Smith TJ, Strawn JR, Trent D, Johnson DH; American Society of Clinical Oncology Clinical Practice. Systemic Therapy 
for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J 
Clin Oncol. 2015 Oct 20;33(30):3488-515. 
10- Zukin M, Barrios CH, Pereira JR, et al: Randomized phase III trial of single-agent pemetrexed 
versus carboplatin and pemetrexed in patients with advanced non–small-cell lung cancer and Eastern Cooperative 
Oncology Group performance status of 2. J Clin Oncol 31:2849-2853, 2013. 
11- Morabito A, Gebbia V, Di Maio M, et al: Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine 
alone in patients with advanced non-small cell lung cancer and a performance status of 2: The CAPPA-2 study. Lung 
Cancer 81:77-83, 2013 
12- Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy and supportive care versus supportive care alone 
for advanced non-small cell lung cancer. Cochrane Database Syst Rev 5:CD007309, 2010 
13- Mellman I, Coukos G & Dranoff G. Cancer immunotherapy comes of age. Nature 2011 Dec 22;29 4 8 0:480-89. 
14- Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, 
Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, 
Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced 
Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. 
15- Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, 
Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, 
Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, 
Ramalingam SS. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, 
refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.Lancet Oncol. 2015 
Mar;16(3):257-65. 
16- Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi 
F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi 
N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab 
versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. 
17- Hellmann MD et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; 
I) in advanced (adv) NSCLC. J Clin Oncol 34, 2016 (suppl; abstr 3001). 
18- Socinski M. CheckMate 026: A Phase 3 Trial of Nivolumab vs Investigator's Choice (IC) of Platinum-Based Doublet 
Chemotherapy (PT-DC) as First-Line Therapy for Stage IV/Recurrent Programmed Death Ligand 1 (PD-L1) − Positive 
NSCLC’ Abstract LBA7_PR, ESMO2016. 
19- Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and 
reduces regulatory T and myeloid cells within B16 melanoma tumors. PNAS 2010; 107: 4275-80. 
20- Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. New Engl J Med 
2013; 369: 122-33. 
21- Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N 
Engl J Med 2015; 372:2006-2017. 
22- Ipilimumab (BMS-734016) Investigator Brochure, version 17, 2014. 
 
 
3 
STUDY OBJECTIVES 

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3.1. Primary objective 
To compare overall survival of patients treated with nivolumab + ipilimumab versus patients treated with chemotherapy. 
 
3.2. Secondary objectives 
To compare:  
 
survival rate at one year of patients treated with nivolumab + ipilimumab versus patients treated with 
chemotherapy, 
 
the objective response rate,  
 
the Progression free survival, 
 
the safety and the tolerability of nivolumab + ipilimumab versus chemotherapy, 
 
the QOL, 
 
the prognostic impact of  PD-L1 expression by immunochemistery (IHC) on OS and PFS, 
 
the prognostic impact of a geriatric mini data set on OS, PFS and toxicity and its evolution under treatment 
restricted to patients ≥70 years old. 
 
 
4 
STUDY DESIGN 
4.1 Evaluation criteria 
4.1.1 Primary evaluation criteria 
Overall survival 
 
4.1.2. Secondary evaluation criteria 
 
Survival rate at one year, 
 
Objective response rate according to RECIST 1.1, 
 
Progression free survival, 
 
Safety tolerability according to CTCAE version 4.0, 
 
Quality of life according to EQ-5D and EORTC QLQ-ELD14 questionnaires every 6 weeks, 
 
PD-L1 expression by immunochemistery (IHC) as a predictive factor of OS and PFS, 
 
Geriatric mini data set restricted to patients ≥70 years old. 
 
4.2. Description of study methodology  
4.2.1. Experimental design 
Open label phase III randomised study 
 
4.2.2. Conduct of study 
 
 

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Figure 1: Study Schema 
 
 
 
 
 
 
 
                      
 
Nivolumab + Ipilimumab possible at progression as 
recommended by health authorities 
Follow-up for survival 
Non-Small Cell Lung Cancer 
 
 
Stage IV or recurrent 
 
Squamous or Non-Squamous 
 
No prior systemic therapy for 
advanced disease 
 
EGFR and ALK wild-type or 
unknown 
 
ECOG PS 2 or age over 70 PS0-2 
Randomize 1:1 
Stratified by : 
 
Age ≥ or < 70 years 
 
PS 0/1 versus 2 
 
Histology: squamous/non-squamous 
Arm A 
Nivolumab 240 mg every 2 weeks + 
Ipilimumab 1mg/kg every 6 weeks until 
PD or unacceptable toxicity with a 
maximum of two years of therapy 
Arm B 
Investigator’s Choice Chemotherapy 
 
 paclitaxel (90 mg/m2) D1 D8 D15 with carboplatin 
(AUC 6 with a dose that will be capped to 
700 mg) D1 
 pemetrexed (500  mg/m2)D1 with carboplatin 
(AUC 5 with a dose that will be capped to 700 
mg) D1; (only non-squamous) 
 
 
Post-Chemotherapy 
Follow-Up 
Optional Continuation 
Maintenance by 
pemetrexed 
Until PD or unacceptable 
toxicity (non-squamous 
only) 

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4.2.2.1. Inclusion Assessments and Procedures 
 
Within 28 days before treatment: 
 
Informed consent must be obtained prior to any specific procedure to the trial  
 
Checking inclusion/ exclusion criteria 
 
A complete medical history and concomitant medications 
 
Physical measurements including height, and weight (calculated BMI, calculated BSA for Patients randomized to 
treatment Arm B). Focused physical examination may be performed as clinically indicated 
 
ECOG performance status 
 
Vital signs  (including  heart  rate, blood  pressure)  within  72 hours of dosing 
 
Oxygen saturation by pulse oximetry at rest, (also monitor amount of supplemental O2 if applicable) within 72 
hour of dosing 
 
A serum or urine pregnancy testing for WOCBP will be collected within 24 hours prior to start of study therapy 
 
Laboratory tests include (performed within 7 days prior to randomization unless otherwise specified) 
 Blood for complete blood count (CBC) with differential, including neutrophil and lymphocyte count 
 Serum chemistry tests : urea level, serum creatinine, sodium, potassium, calcium, phosphate, chloride, glucose, 
LDH) 
 AST, ALT, albumin, total bilirubin, alkaline phosphatase 
 TSH, free T3 and free T4 (within 28 days of randomization) 
 Hepatitis B surface antigen (HBV sAG), Hepatitis C antibody (HCV Ab) or Hepatitis C RNA (HCV 
RNA),HIV and CMV serology testing within 28 days prior to randomization 
 
Signs and symptoms present prior to randomization (regardless of relationship to disease) will be recorded.  
Additionally, record any concomitant medications taken within 14 days of randomization. 
 
Disease evaluation (chest abdomen CT scan, PET scan or bone scan if suspicion of bone disease, brain or MRI if 
clinically indicated)  
 
QOL evaluated with EQ5D and EORTC QLQ-ELD14 
 
Geriatric mini data set only for patients ≥70 years old (appendix 9) 
 
Electrocardiogram 
 
Availability of adequate FFPE tumor-derived material (tumor blocks or slides) from a biopsy, surgery or fine needle 
aspirate for analysis of PD-L1 testing by IHC. The tumor blocks or slides will be secondary sent to Pr Diane 
Damotte, service d’anatomie et cytologie pathologiques Hôpital Européen Georges-Pompidou H.E.G.P. 20 Rue 
Leblanc (Paris 15 - Vaugirard) 75015 Paris. 
 
4.2.2.2. On-Study Assessments and Procedures 
Before every infusion of treatment (experimental and control arm):  
 
 
Adverse Events and Serious Adverse Events 
 
Concomitant medications taken through course of study should be recorded 
 
Blood for CBC with differential, including WBC, lymphocyte count, ANC, hemoglobin, hematocrit, and platelet 
count (results to be obtained within 72 hours prior to dosing on infusion days). 
 
Serum chemistry tests: urea level, serum creatinine, albumin, sodium, potassium, calcium, phosphate, chloride, 
glucose, and LDH.  
 
Liver function tests including AST, ALT, total bilirubin, and alkaline phosphatase 
 
Vital signs (heart rate, blood pressure) 
 
Physical measurements including weight (and calculated BSA for Patients randomized to treatment Arm B), and 
ECOG performance status 
 
For nivolumab + ipilimumab arm, oxygen saturation by pulse oximetry at rest (obtained within 72 hours of dosing 
and at any time a Patient has any new or worsening respiratory symptoms. also monitor amount of supplemental 
oxygen if applicable) If a Patient shows changes on pulse oximetry or other pulmonary-related signs (hypoxia, 
fever) or symptoms (eg. dyspnea, cough, fever) consistent with possible pulmonary adverse events, the patient 

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should be immediately evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity  
management algorithm contained within the Investigator’s Brochure.  
 
Every 6 weeks :  
 
• 
Tumor evaluation with chest and abdmen CT scan until disease progression even if study treatment is discontinued. 
If a cycle is delayed, tumor evaluation must not be delayed. 
If clinical progression occurs outside tumor evaluation, all efforts must be made to document this progression by CT 
scan or appropriate imaging methods.  
 
Thyroid function testing should be done every 6 weeks (every 3 cycles) for patients receiving nivolumab: free T3 
and T4 if TSH is abnormal or if pts have symptoms. 
 
A serum or urine pregnancy testing is required every 6 weeks. 
 
QOL evaluated with EQ5D and EORTC QLQ-ELD14. 
At 8 weeks or before in case of progression or withdrawal of the study and restricted to patients ≥70 years old: 
 
Geriatric mini data set 
 
4.2.2.3 Post progression Assessments and Procedures 
 
 
After discontinuation from nivolumab + ipilimumab, a serum or urine pregnancy testing should be repeated at 
approximately 30 days and approximately 70 days. 
 
Chemotherapy / nivolumab + ipilimumab according to INCA standards should be proposed according to the patient’s 
condition and decision. The data on post progression therapy will be recorded in the CRF. 
 
AE possibly related to nivolumab and/or ipilimumab must be followed 100 days after last dosing. 
 
OS will be followed every 3 months via in-person or phone contact after patients discontinue the study drug. All 
randomized patients will be evaluated. Patients will be followed for one year after inclusion. 
 Initial follow-up visits 1 and 2 
 After discontinuation from treatment, the patient will come to the hospital for the first 2 follow-up visits. 
The first visit will take place approximately one month after cessation of treatment and the second 
approximately two months later. During this time, the patient's condition will be assessed. 
 Additional follow-up visits (after the follow-up visit 2) 
 This monitoring will be followed every 3 months via in-person or phone. During this time, the patient's 
condition will be assessed. 

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4.2.2.4 Study Flow-chart 
 
Procedure 
Screening visit 
(Within 28 days 
before treatment) 
On-treatment 
(D1 of each cycle 
if not otherwise 
specified) 
Post 
progression 
 
Eligibility 
Assessments 
 
 
 
 
Informed Consent 
x 
 
 
 
Inclusion/Exclusion 
Criteria 
x 
 
 
 
Medical History 
x 
 
 
 
Safety Assessments 
 
 
 
 
Vital Signs and 
Oxygen saturation 
x 
 
 
Vital signs include heart rate, blood pressure. 
For Nivolumab + ipilimumab arm only, oxygen saturation by pulse oximetry at 
rest (also monitor amount of supplemental oxygen if applicable) should be 
assessed at each on-study visit prior to dosing. 
Physical 
Measurements 
(including 
Performance Status) 
x 
x 
 
Physical measurements include height (at screening only), weight (calculated 
BSA for Patients randomized to treatment Arm B) and Performance Status. 
Focused physical examination may be performed as clinically indicated 
ECG 
x 
 
 
 
Hepatitis B,C, HIV 
and CMV testing 
x 
 
 
Within 28 days before treatment: Hepatitis B,C (HBV sAg and HCV Ab or HCV 
RNA), HIV and CMV testing 
Complete blood counts 
(CBCs) 
x 
x 
 
Within 7 days before C1D1, and within 72 hours before each cycle: 
Includes WBC count with differential, ANC, lymphocyte count, hemoglobin, 
hematocrit, and platelet count 
Serum Chemistry 
Tests 
x 
x 
 
Within 7 days before C1D1, and within 72 hours before each cycle: 
serum urea level, creatinine, Ca, Na, K, Cl, LDH, Glucose 
Liver Function testing 
x 
x 
 
Within 7 days before C1D1, and within 72 hours before each cycle: 
ALT, AST, total bilirubin, alkaline phosphatase 
Endocrine testing 
x 
x 
 
Within 28 days before treatment and every 6 weeks (every 3 cycles) for Patients 
receiving nivolumab+ ipilimumab : TSH (with Free T4 and Free T3) 
Pregnancy Test 
x 
x 
x 
A serum or urine pregnancy testing is required within 24 hrs of study enrollment 
or randomization, then every 6 weeks for WOCBP prior to dosing nivolumab + 
ipilimumab. 
After discontinuation from nivolumab + ipilimumab these should be repeated at 
approximately 30 days and approximately 70 days. 
 

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Adverse Events 
(AE) and Serious 
Adverse Event 
(SAE) assessment 
(of signs and 
symptoms) 
x 
x 
x 
AE possibly related to nivolumab and/or ipilimuamb must be followed 100 days 
after last dosing 
Concomitant 
Medication collection 
x 
x 
x 
Post-progression therapy should be recorded in CRF 
Efficacy Assessments 
 
 
 
 
Radiographic Tumor 
Assessment (Chest and 
abdomen) 
x 
x 
 
Within 28 days before treatment: chest abdomen CT scan, PET scan or bone 
scan if suspicion of bone disease, brain or MRI if clinically indicated 
Every 6 weeks: tumor evaluation with chest and abdomen CT scan until disease 
progression. 
If clinical progression occurs outside tumor evaluation, all efforts must be made 
to document this progression by CT scan or appropriate imaging methods 
EQ5D and EORTC 
QLQ-ELD14 
questionnaires 
x 
x 
 
At screening and then Every 6 weeks until disease progression 
Collection of Survival 
Information 
 
 
x 
Every 3 months, until death, lost to follow-up, or withdrawal of study consent. 
May be performed by phone contact or office visit. 
Geriatric assessment 
 
 
 
 
Geriatric mini data set 
(restricted to patients 
≥70 years old.) 
x 
x 
At week 8 
 
To repeat at 8 weeks or before in case of progression or withdrawal of the study 
Clinical Drug 
Supplies 
 
 
 
 
Study drug 
administration 
 
x 
 
 
Tumor blocks or 
slides 
 
 
 
 
 
 
x 
 
Sent to Pr Diane Damotte, service d’anatomie et cytologie pathologiques Hôpital 
Européen Georges-Pompidou H.E.G.P. 20 Rue Leblanc (Paris 15 - Vaugirard) 
75015 Paris for PDL1 testing by IHC 

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4.3. Description of the measures taken to reduce and prevent bias 
4.3.1. Randomisation 
After the Patient’s eligibility is established and informed consent has been obtained, the Patient will be enrolled and a 
number will be assigned through the eCRF. Every Patient who signs informed consent must be assigned a Patient 
number in eCRF.  
The investigator (or designee) will register the Patient for enrollment by following the enrollment procedures established 
by the CHU de Rennes. The following information is required for enrollment: 
 
Date of informed consent 
 
Date of birth 
 
Gender at birth 
 
Once enrolled in eCRF, enrolled Patients that have signed informed consent and met all eligibility criteria will be ready 
to be randomized through the eCRF. The following information is required for Patient randomization: 
 
Patient number 
 
Date of birth 
 
Gender at birth 
 
Diagnosis 
 
Date of informed consent 
 
PS  
 
4.3.2. Methods of blinding  
Not applicable 
 
4.4. Description of dosage and methods of administration of the investigational medicinal products. Description of 
dose unit form, packaging and labelling of the investigational medicinal product(s) 
The description of the medicinal product (Dosage and methods of administration, Unit form, packaging and labelling) is 
detailed in Section 6.  
 
4.5. Expected duration of participation of persons and description of chronology and of duration of all study 
periods including monitoring 
- Recruitment period: 24 months 
- Duration of patient monitoring: 18 months or until end of study treatment in both arms 
- Estimated total duration of study: 42 months  
 
Starting with inclusion of the first patient, the sponsor has to inform without delay the local health agency and the ethics 
committee of the actual date of start-up of the study. The actual date of start-up = date of signature of consent form by the 
first person who is a Patient in the study. 
The date of end of the study will be transmitted by the sponsor to the ethics committee and to the local health agency 
within 90 days or earlier according to local regulations. The date of end of the study corresponds to the last visit of the last 
person who is a Patient in the study. 
 
4.6. Description of rules for permanent or temporary discontinuation  
4.6.1. Discontinuation of participation of a person in study 
Patients can withdraw their consent and ask to withdraw from the study at any time and for whatever reason. If a Patient 
discontinues the study before its completion, the investigator must document the reasons as completely as possible.  
In fact, the investigator can temporarily or permanently discontinue the study treatment for any reason which is in the best 
interest of the Patient. 
If a Patient is lost to follow-up, the investigator will make every effort to resume contact with that person. 
 
4.6.2. Discontinuation of part or of the entire study 
Unexpected events or new information pertaining to the product, in light of which the study objectives or clinical 
programme probably would not be achieved, can lead the sponsor to terminate the study. 

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In case of early permanent discontinuation of the study, the information will be sent by the sponsor within 15 days to the 
relevant country health agency and to the ethics committee or earlier according to local regulations. 
 
 
5 
SCREENING AND EXCLUSION OF PERSONS FROM THE STUDY 
5.1. Inclusion criteria for persons who are Patients in the study 
 
Target Population 
 
Signed written informed consent 
 
Cytologically or histologically proven NSCLC (adenocarcinoma, squamous cell carcinoma, large-cell carcinoma) 
 
Stage IV or non-treatable by radiotherapy or surgery stage III (7th classification) 
 
No previous systemic chemotherapy for lung cancer, except in case of relapse after adjuvant treatment for 
localized disease with 6 months or more between end of previous chemotherapy and relapse 
 
Patients PS 2 less than 70 years old or 70 years older PS 0 to 2 
 
Judged fit enough to receive a carboplatin-based doublet according to ESMO guidelines 
 
Presence of at least one measurable target lesion (RECIST 1.1 rules) in a non-irradiated region and analysable by 
CT 
 
Life expectancy >12 weeks 
 
Prior radiation therapy is authorized if it involved less than 25% of the total bone marrow volume and finished 14 
days before D1 of planned treatment 
 
Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to 
randomization/registration 
 
WBC   
≥ 2000/μL 
 
Neutrophils  
≥ 1500/μL 
 
Platelets 
 ≥ 100 x103/μL 
 
Hemoglobin  > 10.0 g/dL 
 
Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 45 mL/min (if using the 
Cockcroft-Gault formula below):  
Female CrCl = [(140 - age in years) x weight in kg x 0.85] / [72 x serum creatinine in mg/dL] 
Male CrCl = [(140 - age in years) x weight in kg x 1.00] / [72 x serum creatinine in mg/dL] 
 
AST/ALT ≤ 3 x ULN  
 
Total Bilirubin ≤ 1.5 x ULN (except Patients with Gilbert Syndrome, who can have total bilirubin 
< 3.0 mg/dL)  
Age and Reproductive Status 
 
Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception during treatment. 
WOCBP should use an adequate method to avoid pregnancy :  
o For 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose 
of nivolumab + ipilimumab,  
o For 4 weeks after the last dose of carboplatine + pemetrexed, 
o For 5 weeks after the last dose of carboplatine + paclitaxel. 
 
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 treatment 
 
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 during treatment  
 
Men will be instructed to adhere to contraception for a period of 31 weeks after the last dose of nivolumab + 
ipilimumab and with carboplatine + pemetrexed or carboplatine + paclitaxel up to 6 months thereafter 
 
Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as 
azoospermic men do not require contraception 
 

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5.2. Non-inclusion criteria for persons who are patients in the study 
 
Patients with other severe concurrent disorders that occurred during the prior six months before enrollment 
(myocardial infection, severe or unstable angor, coronarian or peripheric arterial bypass operation, NYHA class 3 
or 4 congestive heart failure, transient or constituted cerebral ischemic attack, at least grade 2 peripheral 
neuropathy, psychiatric or neurological disorders preventing the patient from understanding the trial, uncontrolled 
infections) are not eligible 
 
Serious or uncontrolled systemic disease judged as incompatible with the protocol by the investigator 
 
Another previous or concomitant cancer, except for basocellular cancer of the skin or treated cervical cancer in 
situ, or appropriately treated localized low-grade prostate cancer (Gleason score < 6), unless the initial tumor was 
diagnosed and definitively treated more than 5 years previously, with no evidence of relapse. 
 
Known activating mutation of EGFR (del LREA exon 19, mutation L858R or L861X of exon 21, mutation 
G719A/S in exon 18) or EML4-ALK or ROS-1 translocation 
 
Superior caval syndrome 
 
Uncontrolled infectious status 
 
All concurrent radiotherapy 
 
Concurrent administration of one or several other anti-tumor therapies 
 
Psychological, familial, social or geographic difficulties preventing follow-up as defined by the protocol. 
 
Protected person (adults legally protected (under judicial protection, guardianship or supervision), person 
deprived of their liberty, pregnant woman, lactating woman and minor) 
 
Concurrent participation in another clinical trial 
 
Patients are excluded if they have active brain metastases or leptomeningeal metastases. Patients with brain 
metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) 
evidence of progression for [lowest minimum is 4 weeks or more]  after treatment is complete and within 28 days 
prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive 
doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug 
administration 
 
Patients should be excluded if they have an active, known or suspected autoimmune disease. Patients are 
permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune 
condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger 
 
Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug 
administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents 
are permitted in the absence of active autoimmune disease 
 
Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C 
virus ribonucleic acid (HCV antibody) indicating acute or chronic infection 
 
Patients should be excluded if they have known history of testing positive for human immunodeficiency virus 
(HIV) or known acquired immunodeficiency syndrome (AIDS) 
 
Patients should be excluded if they have a lung disease that is symptomatic or may interfere with the detection or 
management of suspected drug-related pulmonary toxicity 
 
Allergies and Adverse Drug Reaction 
 
History of allergy to study drug components 
 
Severe spinal hypoplasia and / or hemorrhagic tumors 
 
5.3. Methods of recruitment 
Recruitment will come from GFPC centers. Treatment decision for new cancers patients are made in multidisciplinary 
meetings and proposal for inclusion in clinical trials are part of these meetings.  
 
 
 
 
 
 

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6 
TREATMENTS ADMINISTERED TO PERSONS WHO ARE PATIENTS IN THE STUDY 
6.1. Description of the treatments necessary for conduct of the study 
6.1.1. Nivolumab - Ipilimumab 
6.1.1.1 Description  
NIVOLUMAB AND IPILIMUMAB INFORMATION TABLE: Please also see Drug Information (Appendix 7) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended safety measures for preparation 
and handling of nivolumab and ipilimumab include laboratory coats and gloves. 
For additional details on prepared drug storage and use time of nivolumab and ipilimumab under room temperature/light 
and refrigeration, please refer to the BMSInvestigator Brochure section for “Recommended Storage and Use Conditions”  
The product storage manager should ensure that the study drug is stored in accordance with the environmental conditions 
(temperature, light, and humidity) as determined by BMS. If concerns regarding the quality or appearance of the study 
drug arise, the study drug should not be dispensed and contact BMS immediately. Study drug not supplied by BMS will 
be stored in accordance with the package insert. 
Investigational product documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, administration and, as 
applicable, storage temperatures, reconstitution, and use of required processes (eg, required diluents, administration sets). 
Infusion-related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) will not be supplied by the sponsor and should 
be purchased locally if permitted by local regulations. 
For nivolumab and ipilimumab, please refer to the current version of the Investigator Brochures and/or pharmacy 
reference sheets for complete storage, handling, dispensing, and infusion information 
 
6.1.1.2 Dosing schedule and Administration 
 
Week 1 
+/- 3 days 
Week 2 
Week 3 
+/- 3 days 
Week 4 
Week 5 
+/- 3 days 
Week 6 
Nivolumab 
240 mg q2 
weeks 
+ Ipilimumab  
1 mg/kg q 6 
weeks 
Day 1 
Nivolumab  
+  
Ipilimumab 
 
Day 1 
Nivolumab 
 
Day 1 
Nivolumab 
 
Product 
Description / 
Class and 
Dosage Form 
Potency 
IP/Non-
IMP 
Blinded or 
Open Label 
Packaging / Appearance 
Storage 
Conditions 
(per label) 
Nivolumab 
Solution for 
Injection 
100 mg 
(10 mg/ml) 
 
IP 
Open label 
Clear to opalescent colorless 
to pale yellow liquid. May 
contain particles. 
240 mg kit contains: 2 x 100 
mg vials (10 mL/vial) and 1 
x 40 mg vial (4 mL/vial) or 
carton containing 5 vials 
of  100 mg 
2-8°C. 
Protect 
from light 
and 
freezing. 
Ipilimumab 
Solution for 
Injection 
200mg 
(5mg/mL) 
IP 
Open label 
Clear to slightly opalescent 
colorless to pale yellow 
liquid. May contain particles. 
Carton containing 4 vials of 
200mg  
2-8°C. 
Protect 
from light 
and 
freezing. 

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Patients randomized to experimental arm will receive treatment with Nivolumab as a 30 minutes infusion 240 mg every 2 
weeks and ipilimumab as a 30 minutes infusion 1 mg/kg every 6 weeks, starting on Day 1, until progression, unacceptable 
toxicity, withdrawal of consent, or the study ends, whichever occurs first. When nivolumab and ipilimumab are to be 
administered on the same day, separate infusion bags and filters must be used for each infusion. Nivolumab is to be 
administered first. The second infusion will always be ipilimumab and will start no sooner than 30 minutes after 
completion of the nivolumab infusion.  
Nivolumab and ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution.  
Dosing calculations should be based on the body weight assessed as per Table 5.1-4. If the patient’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the prior dose, the dose must be recalculated. All doses should 
be rounded to the nearest milligram. There will be no dose modifications allowed.  
Patients may be dosed with nivolumab no less than 12 days from the previous dose. There are no premedications 
recommended.  
Patients should be carefully monitored for infusion reactions. If an acute infusion reaction is noted, Patients should be 
managed according to Protocol Section 4.5.11. 
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued depending on how well the Patient 
tolerates the treatment. See Sections 4.5.5, 4.5.7, and 4.5.8, for more details regarding dose delays, retreatment, and 
discontinuations. 
 
6.1.1.3 Dosage adjustment 
Dose reductions or dose escalations are not permitted. 
 
6.1.2. Comparator 
 
Table 6.1.2-1: 
Product Description - 
Treatment Phase 
 
 
 
Product 
Description 
and Dosage 
F
Potency 
Primary 
Packaging 
(Volume)/ 
L b l T
Secondary 
Packaging 
(Qty) /Label 
T
Appearance 
Storage 
Conditio
ns (per 
l b l)
Carboplatin 
Solution for 
Injection 
450 
mg/vial 
(10 mg/mL) 
45 mL 
per 
vial/ 
O
4 vials per 
carton/Open-
label 
Clear, colorless or 
slightly yellow 
solution 
Store at or 
below 25°C. 
Protect from 
li ht
Pemetrexed 
Powder for 
Concentrate for 
Solution for 
Infusion
 
500 
mg/vial 
500 mg 
per 
vial/ 
Open-
label
1 vial per 
carton/ Open- 
label 
White to 
either 
light 
yellow or 
green
Store at 
25°C. 
Excursions 
permitted 
(15 30°C)
Paclitaxel 
Solution for 
Injection 
 
100 
mg/vial 
(6 
16.7 mL 
vial/ 
Open-
label 
4 vials 
per 
carton/Open-
label 
Clear, colorless or 
slightly yellow 
viscous 
solution 
Store at 15°C-
30°C. Protect 
from light. 

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6.1.2.1 Dose Reductions for Investigator’s Choice Chemotherapy 
To receive chemotherapy patient must have: 
Neutrophils count >= 1500/mm3 
Platelets >=100000/mm3 
Back to grade≤1 non-hematological toxicity  
A maximum delay of two weeks is accepted. If D1 cannot be administered, chemotherapy will be stopped. Some 
exceptions can be discussed with the principal investigator 
 
Dose reductions of investigator’s choice chemotherapy may be required, and will be performed according to Table 
6.1.2-2. Chemotherapy dose reductions are permanent; once the dose of any chemotherapy agent is reduced, it may 
not be re-escalated in subsequent combination cycles. The dose reductions for each agent in the investigator’s choice 
chemotherapy regimen are not linked and may be adjusted independently as summarized below. 
 
Table 6.1.2-2 
Dose Modifications of Chemotherapeutic Agents 
Dose Level 
 Pemetrexed 
Carboplatin 
 Paclitaxel 
Starting dose 
500 mg/m² 
AUC 6 (with Paclitaxel) 
AUC 5 (with 
Pemetrexed) 
 
90 mg/m² 
First dose reduction 
375 mg/m² 
AUC 5 (with paclitaxel) 
AUC 4 (with 
Pemetrexed) 
 
 
80 mg/m² 
Second dose reduction 
185 mg/ m² 
AUC 4 (with paclitaxel) 
AUC 3 (with 
Pemetrexed) 
 
70 mg/m² 
Third dose reduction 
Discontinue 
Discontinue 
Discontinue 
 
Any Patients with two prior dose reductions for one agent who experiences a toxicity that would cause a third dose 
reduction must be discontinued from that agent. 
 
Investigator’s Choice Chemotherapy - Dose Reductions for Hematologic Toxicity 
Dose adjustments are based on nadir blood counts (assessed as per local standards) since the preceding drug 
administration. Dose level adjustments for investigator’s choice chemotherapy are relative to that of the preceding 
administration. Generally, both chemotherapy agents in the investigator’s choice chemotherapy regimen should be 
dose reduced together for hematologic toxicity. After the first cycle, growth factors may be used to assist hematologic 
recovery. Use local standards of care in the use of these supportive measures. Additionally, prophylactic antibiotics 
may be used according to local standards of care. Please report any antibiotic or growth factor use on the eCRF. 
 
Table 6.1.2-3: 
Dose Modifications for Hematologic Toxicity (Based on Nadir Counts) 
Toxicity 
Pemetrexed 
Cisplatin 
 
Paclitaxel 
Neutrophil Count Decreased 
Grade 4 durig at least 7 days (< 500/mm3 or < 
0.5 x 109/L) 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Grade 3 or 4 febrile neutropenia (< 1000/mm3 or 
< 1.0 x 109/L and fever≥ 
38°5C) 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Anemia 

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Grade 4 (< 6,5 g/dl) 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Platelet Count Decreased 
Grade 3 
Reduce one 
Reduce one 
 
Reduce one 
(25,000 - 
dose level 
dose level 
 
dose level 
< 50,000/mm3; 
 
 
 
 
 
25.0 -< 50.0 x 109/L) 
or bleeding requiring transfusion 
 
 
 
 
 
Grade 4 
(< 25,000/mm3; < 25.0 x 109/L) 
or bleeding requiring transfusion 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
 
Investigator’s Choice Chemotherapy – Dose Reductions for Non-Hematologic Toxicities 
Dose adjustments for investigator’s choice chemotherapy for non-hematologic toxicities during treatment are 
described in Table 4.3.4.3-1. All dose reductions should be made based on the worst grade toxicity. Patients 
experiencing any of the toxicities detailed in Table 6.1.2-4  during the previous cycle should have their chemotherapy 
delayed until retreatment criteria are met (per Section 4.3.5.2) and then reduced for all subsequent cycles by 1 dose 
level or discontinued as appropriate. Dose levels for the two drugs in the investigator’s choice chemotherapy regimen 
are not linked and may be reduced independently, as summarized in the table below. 
 
Table 6.1.2-4: Dose Modifications for Non-hematologic Toxicity 
 
Toxicity 
 
Pemetrexed 
Carboplatin 
Paclitaxel 
Diarrhea 
Grade  3 
Reduce one dose 
level 
No change 
Reduce one dose 
level 
Allergic 
reaction 
Grade  3 
Discontinue 
Discontinue 
Discontinue 
Neuropathy 
Grade 2 
No change 
No change 
Reduce one dose 
level 
Neuropathy 
Grade  3 
Discontinue 
Discontinue 
Discontinue 
Calculated creatinine 
clearance 
< 45 mL/min 
Discontinue 
No change 
No change 
Other Grade 
 3 toxicity (except for fatigue 
and transient arthralgia and 
myalgia) 
Adjust as 
medically 
indicated 
Adjust as 
medically 
indicated 
Adjust as 
medically 
indicated 
a Only the drug(s) causing the hypersensitivity reaction or acute infusion reaction (
 Grade 3) require(s) 
discontinuation. All other drugs may be continued 
 
 
Carboplatin/pemetrexed 

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Pemetrexed 500 mg/m² on D1 + carboplatin AUC 5 with a dose that will be capped to 700 mg on D1, the cycles being 
repeated every 21 days. The reconstitution of the cytostatics should be ideally realized in central units. In all cases, the 
traceability of the products must be assumed for all enrolled patients. The drugs will be administered as follows. 
Pemetrexed will be given at a dose of 500 mg/m² as an IV infusion lasting about 10 min on D1 of each 21-day cycle. 
 
Premedication regimen 
To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, 
and the day after pemetrexed administration. The corticosteroid should be equivalent to 4 mg of dexamethasone 
administered orally twice a day. 
To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation (see section 4.4). 
Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1000 micrograms) on a daily basis. At 
least five doses of folic acid must be taken during the seven days preceding the first dose of pemetrexed, and dosing 
must continue during the full course of therapy and for 21 days after the last dose of pemetrexed. Patients must also 
receive an intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first dose of 
pemetrexed and once every three cycles thereafter. Subsequent vitamin B12 injections may be given on the same day 
as pemetrexed.  
 
Pemetrexed should not be administered to dehydrated patients. 
 
Dosage adjustment 
The dose at the beginning of each cycle will be adjusted to the polymorphonuclear neutrophil (PNN) nadir and the 
platelet nadir of the previous cycle. 
The PNN must be >1500/mm³ and the platelet count >100 000/mm³ before starting each treatment cycle. 
 
Dose adjustment according to cell counts during each previous cycle 
 
CBC D22, D43, D64 
 
Polymorphonuclear 
neutrophils (/mm 
3) 
Platelets 
(/mm3) 
Doses and postponements 
 
 1500 
 100 000 
Treatment dates as planned, dose adjustment according to the nadir 
< 1 500 
and/or < 100 
000 
Treatment postponed for a week*, dose adjusted to the nadir of the 
previous cycle 
* no more than two one-week postponements are authorized; otherwise, treatment will be stopped. 
 
Dose adjustment according to the nadir during each cycle: cf Table 6.1.2-3 
 
Dose adjustment of the carboplatin–pemetrexed combination for non-hematologic toxicity 
Diarrhea 
In case of grade III or IV diarrhea (CTCAE), the following measures are authorized: hydration, octreotide and 
antidiarrhoeal agents. A 25% reduction in the dose of the two drugs is recommended. 
In case of severe diarrhea necessitating IV rehydration and/or associated with fever or severe grade III or IV 
neutropenia, broad-spectrum antibiotic therapy must be prescribed. Patients with severe diarrhea or diarrhea associated 
with nausea or vomiting must be hospitalized for IV hydration and correction of electrolytic imbalance. 
In the case of diarrhea necessitating hospitalization, chemotherapy must not be administered until the diarrhea has 
resolved, and the dose must be reduced to 75% of the previous dose. 
 
Other non-hematologic toxicity 
In case of grade >3 toxicity (excepting neurotoxicity), treatment must be interrupted until the disorder subsides to 
grade <1 or to the grade observed at enrollment in the study. A 25% reduction in the dose of the two drugs can be 
made if considered appropriate by the clinician. 
 
Stomatitis: in case of stomatitis, only the pemetrexed dose will be adjusted, as described in the following table: 
 

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CTCAE 
Pemetrexed 
Carboplatin 
CTC Grade 0 – 2 
100% of the planned dose 100% of the planned dose 
CTC Grade 3-4 
50% of the planned dose 
100% of the planned dose 
Recurrent grade >3 stomatitis after two dose reductions 
Study exit 
Study exit 
 
Neurotoxicity: in case of neurotoxicity, only the carboplatin dose will be adjusted, as described in the following table: 
 
CTCAE grade 
Carboplatin dose 
Pemetrexed dose (mg/m2) 
0-1 
100% of the planned dose 
100% of the planned dose 
2 
50% of the previous dose 
100% of the planned dose 
3–4 
Study exit 
Study exit 
 
Renal failure: Before beginning a new cycle, creatinine clearance, calculated with the Cockcroft-Gault formula, must 
be >45 ml/min. Chemotherapy can be postponed up to 2 weeks while waiting for the adverse event to resolve. Beyond 
D36, if the creatinine clearance is not >45 ml/min, the patient will leave the study. 
All other grade III or IV toxicity: the dose must be reduced to 75% of the previous dose. Treatment must be postponed 
until the adverse event resolves. The patient will leave the study after a maximum of two dose reductions. 
Protocol rescue 
In case of severe hematologic toxicities like grade IV leucopenia, neutropenia, myelosuppression during more than 3 
days and with complications, or grade IV thrombopenia with bleeding or grade III or IV mucitis, the following 
protocol can be used: 
- 
Ac Folinic (leucovorin®) 100 mg/m² IV followed by 
- 
Ac Folinic (leucovorin®) 50 mg/m² IV every 6 hours during 8 days. (an oral form can also be used) 
 
 
Carboplatin-paclitaxel 
4 cycles of carboplatin AUC6 D1 + paclitaxel 90 mg/m² D1, D8, D15 4 cycles every 28days. Carboplatin dosage will 
be made according to Calvert formula. 
 
All patients should be premedicated prior to Paclitaxel administration in order to prevent severe hypersensitivity 
reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours 
before Paclitaxel, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to Paclitaxel, and cimetidine 
(300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes before Paclitaxel. 
The reconstitution of the cytostatics should be ideally realized in central units. In all cases, the traceability of the 
products must be assumed for all enrolled patients. The drugs will be administered as follows. 
Institutions should follow their standard administration regimens for paclitaxel. In general, paclitaxel will be 
administered intravenously at a dose of 90 mg/m2 over 3 hours followed by carboplatin at day one. At day 8 and day 
15, paclitaxel alone will be administered. 
 
Dosage adjustment 
The dose at the beginning of each cycle will be adjusted to the polymorphonuclear neutrophil (PNN) nadir and the 
platelet nadir of the previous cycle. 
At D1, the PNN must be >1500/mm³ and the platelet count >100 000/mm³ before starting each treatment cycle. 
 
Dose adjustment at D1 according to cell counts during each previous cycle 
 
CBC D22, D43, D64 
 
Polymorphonuclear 
neutrophils (/mm 
3) 
Platelets 
(/mm3) 
Doses and postponements 
 
 1500 
 100 000 
Treatment dates as planned, dose adjustment according to the nadir 
< 1 500 
and/or < 100 
000 
Treatment postponed for a week*, dose adjusted to the nadir of the 
previous cycle 
* no more than two one-week postponements are authorized; otherwise, treatment will be stopped 
 
Dose adjustment according to the nadir during each cycle: cf Table 6.1.2-3 
 
Dose adjustment of the carboplatin–paclitaxel combination for non-hematologic toxicity 

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ORGANS 
TOXICITIES 
GRADE 
ACTIONS 
Ears 
hearing/inner ear 
≥2 
Discontinue carboplatin 
Pursue paclitaxel according to investigator’s 
choice 
Cardiovascular 
Asymptomatic sinus bradycardia 
Asymptomatic ventricular 
arrhythmia 
1 
No dose change 
ECG before each cycle 
Asymptomatic ventricular 
arrhythmia 
Atrio ventricular block (except of 
first degree) 
Other blocks 
≥2 
Discontinue chemotherapy 
Gastrointestinal 
mucositis 
≥3 
Reduce one dose level for the two drugs 
Liver 
Bilirubin>3× ULN 
AST/ALT>2.5× ULN 
In cas of liver metastasis:≥5× ULN 
≥3 
≥2 
Discontinue chemotherapy 
Infection 
Infection without neutropenia 
≥3 
Reduce one dose level for the two drugs 
Neurological 
Sensitive neuropathy 
1 
 
2 
 
 
*2 
 
≥3 
No change 
 
Reduce one dose level for the two drugs 
 
If persistence despite dose reduction,  one more 
level reduction 
 
Discontinue chemotherapy 
Pain 
Arthralgia/myalgia 
 
 
During more than 7 days 
≥3 
 
≥3 
Reduce one dose level for paclitaxel only 
 
Discontinue chemotherapy 
Kidneys 
Creatinin>1.5 × ULN 
≥2 
Discontinue carboplatin 
Pursue paclitaxel according to investigator’s 
choice 
Other toxicities excluding nausea, vomiting and 
asthenia 
≥3 
Reduce two doses levels or stop according to 
investigator’s choice 
 
Dose adjustment at day 8 and 15 of paclitaxel  
At D8 and D15 infusions of paclitaxel will be done only if ANC is≥1500/mm3, platelets ≥100000/mm3. Infusion 
will be omitted if CBC does not allow infusion. If D8 and D15 must have been cancelled, next cycle will start at D29 
in respect of planned dose level reduction. 
The dose of paclitaxel will be the same at D8 or D15 than at D1 except if a non-hematological toxicity requiring a 
dose level reduction is occurred between D1 and D8 or D8 and D15. 
 
- 
Allergic Reaction/Hypersensitivity (Paclitaxel Only)  
CAUTION: Patients who had a mild to moderate hypersensitivity reaction have been successfully rechallenged, but 
the administration of prophylactic medication (see below) and intensive monitoring of vital signs is recommended.  
 
• Mild symptoms: Complete paclitaxel infusion. Supervise at bedside. No treatment required.  
• Moderate symptoms: Stop paclitaxel infusion. Give IV diphenhydramine 25−50 mg and IV dexamethasone 10 mg. 
Resume paclitaxel infusion after recovery of symptoms at a low rate, 20 mL/hour for 15 minutes, then 40 mL/hour for 
15 minutes, then if no further symptoms, at full-dose rate until infusion is complete. If symptoms reoccur, stop 
paclitaxel infusion. Paclitaxel treatment will be discontinued.  
• Severe life-threatening symptoms: Stop paclitaxel infusion. Give IV diphenhydramine and dexamethasone as above. 
Add epinephrine or bronchodilators if indicated. Paclitaxel treatment will be discontinued.  
 
Moderate or severe hypersensitivity reactions should be recorded as an adverse event. 
 

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6.2. Packaging and labelling 
 The reconstitution of the cytostatics should be ideally realized in central units a specific label for a clinical trial in 
compliance with applicable regulatory requirements including European regulations; mentioning at least: 
 
Name of study 
 
Name of product, 
 
Dosage, 
 
Route of administration, 
 
Conditions for storage, 
 
The expiry date for use, 
 
Batch number, 
 
Sponsor’s name and address, 
 
“for clinical trial use only” 
Labels will be translated in French. The sponsor ensures a proper labelling and the sponsor ensures via the clinical 
research organization the good distribution of the drugs to all sites. 
 
6.3 Drug ordering and accountability  
BMS is supplying study drug.  
The sponsor is responsible for ensuring that the investigational product is stored under the appropriate environmental 
conditions (temperature, light, and humidity). 
If concerns regarding the quality or appearance of the investigational product arise, do not dispense the investigational 
product, and contact BMS immediately. If commercial investigational product is used, it should be stored in 
accordance with the appropriate local labeling. 
If the study drug(s) are to be destroyed on site, it is the investigator’s responsibility to ensure that arrangements have 
been made for disposal, and that procedures for proper disposal have been established according to applicable 
regulations, guidelines, and institutional procedures. 
 
6.4 Authorised and unauthorised medicinal products and treatments in the setting of the protocol, including 
emergency medicinal products 
6.4.1. Authorised treatments 
Experimental arm: Patients 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 (eg, contrast 
dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by 
contact allergen) is permitted. 
As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition to hepatoxicity should be used 
with caution. 
Control arm: all support treatment (emesis prevention, GCSF if judged necessary by investigato) are allowed as 
standard of care. 
 
6.4.2. Unauthorised treatments 
The following medications are prohibited during the study (unless utilized to treat a drug-related adverse event): 
 
Immunosuppressive agents 
 
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 6.4.1) 
 
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, extensive, non-
palliative radiation therapy, or standard or investigational agents for treatment of NSCLC) 
 
Investigators should refer to the local product labeling for the chemotherapy drugs selected for use in each Arm B 
Patient for additional prohibited and restricted concomitant medications. 
Except for the permitted procedures specified as palliative local therapies, all other radiation therapy or surgery to any 
tumor lesion is not permitted during study treatment. Patients who require such non-palliative procedures must be 
discontinued from study treatment. 
 
6.4.3. Interaction with other medicinal products 
Pemetrexed 
Concomitant use contraindicated: Yellow fever vaccine: risk of fatal generalised vaccinale disease 

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Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) should avoid taking 
non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, and aspirin (> 1.3 g daily) for 2 days before, on 
the day of, and 2 days following pemetrexed administration. 
In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy NSAIDs with long elimination 
half-lives should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed 
administration. 
 
Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent by glomerular filtration. 
Concomitant administration of nephrotoxic drugs (e.g. aminoglycoside, loop diuretics, platinum compounds, 
cyclosporin) could potentially result in delayed clearance of pemetrexed. This combination should be used with 
caution. If necessary, creatinine clearance should be closely monitored. 
 
Carboplatin 
Concomitant use contraindicated: Yellow fever vaccine: risk of generalised disease mortal 
Concomitant use not recommended:  
- Live attenuated vaccines (except yellow fever): Risk of systemic, possible fatal disease. This risk is increased in 
patients who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where this exist 
(poliomyelitis). 
- Phenytoin, fosphenytoin: Risk of exacerbation of convulsions (resulting from the decrease of phenytoin digestive 
absorption by the cytotoxic drug), risk of toxicity enhancement or loss of efficacy of the cytotoxic drug (due to 
increased hepatic metabolism by phenytoin). 
 
6.4.4. Emergency treatment 
Carboplatin pemetrexed 
In case of severe hematologic toxicities like grade IV leucopenia, neutropenia, myelosuppression during more than 3 
days and with complications, or grade IV thrombopenia with bleeding or grade III or IV mucitis, the following 
protocol can be used: 
 
Ac Folinic (leucovorin®) 100 mg/m² IV followed by 
 
Ac Folinic (leucovorin®) 50 mg/m² IV every 6 hours during 8 days. (an oral form can also be used) 
Carboplatin paclitaxel 
 
Cases of severe hypersensitivity characterized by hypotension, dyspnea, angioedema or generalized urticaria 
have been reported in 2% of patients receiving paclitaxel. 
In case of hypersensitivity reactions, appropriate measures must be taken by the investigator based on the severity of 
the event. 
 
CTC Grade 1: transient rash, fever <38 ° C: further infusion monitoring. No treatment needed. 
 
CTC Grade 2: hives, fever> = 38 ° C and / or symptomatic bronchospasm: stopping the paclitaxel infusion, 
administration of 2.5 mg of methylprednisolone dexchloropheniramine and 60 mg. Resume paclitaxel infusion 
after sedation of symptoms at a slower rate: 20 ml / h for 15 min and 50 ml / h for 15 minutes then there are 
no other symptoms at the initial pace until the end of infusion. Particular attention monitored should be 
monitored during the next administration of paclitaxel. 
 
CTC Grade 3 or 4: severe symptoms and even life threatening: Major bronchospasm requiring intravenous 
treatment, with or without urticaria, edema / angioedema, anaphylactic shock: stopping the paclitaxel infusion. 
Administration of diphenhydramine and methylprednisolone as above. Add adrenaline if necessary. Mention 
the incident as a Junk Grave Event (SAE). Definitely stop chemotherapy. 
 
6.5. Conditions for storage of the investigational medicinal product 
The investigator should ensure that the study drug is stored in accordance with the environmental conditions 
(temperature, light, and humidity) as per product information and the Investigator Brochure and per local regulations. 
It is the responsibility of the investigator to ensure that investigational product is only dispensed to study Patients. The 
investigational product must be dispensed only from official study sites by authorized personnel according to local 
regulations. If concerns regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately. 
Please refer to the current version of the Investigator Brochure and/or shipment reference sheets for additional 
information on storage, handling, dispensing, and infusion information for nivolumab and ipilimumab. 
Treatments used in the study will be stored at the pharmacies of participating center.  
 

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6.6. Management of Nivolumab and Ipilumumab, resupply and dispensing of Nivolumab and Ipilumumab 
Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial.  Ten or five vials are provided in a 
carton. 
Ipilimumab has a concentration of 5 mg/mL and is provided in a 40 mL vial. Four vials are provided in a carton. 
 
6.6.1 Initial Orders  
Following submission and approval of the required regulatory documents, a supply of nivolumab and/or Ipilimumab 
may be ordered from by completing a Drug Request Form provided by BMS for this specific trial. The first request 
may take place upon screening of the first patient.  
The initial order should be limited to 20 vials. Allow 5 business days for shipment of drug from BMS receipt of the 
Drug Request Form. Drug is protocol specific, but not patient specific. All drug product will be shipped by courier in a 
temperature-controlled container. It is possible that sites may have more than one nivolumab or ipilimumab clinical 
study ongoing at the same time. It is imperative that only drug product designated for this protocol number be used for 
this study. 
Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents, In-line filters and infusion 
tubing. 
 
6.6.2 Re-Supply 
Drug re-supply request form should be submitted electronically business days before the expected delivery date.  
Deliveries will be made Tuesday through Friday. 
When assessing need for resupply, institutions should keep in mind the number of vials used per treatment dose, and 
that shipments may take 14 business days from receipt of request. Drug is not patient-specific. Be sure to check with 
your pharmacy regarding existing investigational stock to assure optimal use of drug on hand. 
 
6.6.3 Drug Excursions 
Drug excursions should be reported immediately to BMS on the form provided with the study-specific drug order 
form. 
 
6.6.4 Handling and Dispensing 
The investigator should ensure that the study drug is stored in accordance with the environmental conditions 
(temperature, light, and humidity) as per product information and the Investigator Brochure and per local regulations. 
It is the responsibility of the investigator to ensure that investigational product is only dispensed to study Patients. The 
investigational product must be dispensed only from official study sites by authorized personnel according to local 
regulations. If concerns regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and contact BMS immediately. 
Please refer to the current version of the Investigator Brochure and/or shipment reference sheets for additional 
information on storage, handling, dispensing, and infusion information for nivolumab and ipilimumab. 
 
6.6.5 Destruction  
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 can be consulted by 
sponsor upon request. 
•             Records are maintained that allow for traceability of each IP, including the date disposed of, quantity 
disposed, and identification of the person disposing the IP. The method of disposal must be documented.  
•            Accountability and disposal records are complete, up-to-date, and available for sponsor to review throughout 
the clinical trial period as per the study agreement.  
Please refer to the most recent version of the Investigator Brochure for additional information. 
 
 
7 
EVALUATION OF SAFETY  
7.1 Definitions 
7.1.1 Adverse event (AE)  
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical 
condition in a clinical investigation Patient administered an investigational (medicinal) product and that does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 

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sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
investigational product, whether or not considered related to the investigational product. 
 The causal relationship to study drug is determined by a physician and should be used to assess all adverse 
events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
Not related: There is not a reasonable causal relationship between study drug administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
 
7.1.2 Adverse reaction of an investigational medicinal product (AR)  
Any untoward and unintended responses to an investigational medicinal product related to any dose administered. In 
other wise, that means all adverse events judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to a medicinal product, qualify as adverse reactions. 
 
7.1.3 Serious adverse event or serious adverse reaction (SAE/SAR)  
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
 
results in death 
 
is life-threatening (defined as an event in which the Patient was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more severe) 
 
requires inpatient hospitalization or causes prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
is a congenital anomaly/birth defect  
 
is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or 
result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize 
the Patient or may require intervention [eg, medical, surgical] to prevent one of the other serious outcomes 
listed in the definition above.)  
 
Potential drug induced liver injury (DILI) is also considered as an important medical event. 
 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug is an SAE.  
 
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these events must be 
handled as SAEs. 
 
A Serious Adverse Reaction (SAR) is a serious adverse event with a causal relationship to an investigational 
medicinal product. 
 
7.2 Investigator’s role  
7.2.1 Adverse Events to be immediately notified to the sponsor 
7.2.1.1 Serious Adverse Events 
Every serious adverse event, related to study drugs or not, must be reported immediately by the investigator to the 
sponsor on a “SAE form” mentioning  the date of occurrence, criterion of seriousness, relationship with the study 
drugs  (or the study), and the outcome. 
Follow-up information must be completed if needed and sent to the sponsor as soon as new relevant information is 
obtained. Copies of the patient’s medical record must be attached as well as results of laboratory tests. Whenever a 
serious event persists at the end of the study, the investigator must follow the patient until the event is considered 
resolved. 
 
7.2.1.2. Potential Drug Induced Liver Injury (DILI) 
Potential Drug Induced Liver Injury (DILI) is considered as an important medical event and must be reported 
immediately by the investigator to the sponsor on a “SAE form”. 
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) 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 

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3) No other immediately apparent possible causes of AST/ALT 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. 
 
7.2.1.3 Suspected transmission of an infectious agent  
Suspected transmission of an infectious agent (pathogenic or nonpathogenic) must be reported immediately by the 
investigator to the sponsor on a “SAE form”. 
 
7.2.1.4 Non serious adverse event but critical to safety evaluation 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study Patient is pregnant or 
may have been pregnant at the time of investigational product exposure, including during at least 6 half lives after 
Nivolumab or Ipilimumab administration, the investigational product will be permanently discontinued in an 
appropriate manner (eg, dose tapering if necessary for Patient safety).  
The investigator must immediately notify the sponsor of this event via the Pregnancy Surveillance Form.  
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, where 
applicable, offspring information must be reported on the Pregnancy Surveillance Form. 
 Any pregnancy that occurs in a female partner of a male study participant should be reported to the sponsor. 
Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
 
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. 
 
Laboratory Test Abnormalities considered as SAE 
All laboratory test results captured as part of the study should be recorded following institutional procedures. Test 
results that constitute SAEs should be documented and reported as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
- 
any laboratory test result that is clinically significant or meets the definition of an SAE 
- 
any laboratory abnormality that required the Patient to have study drug discontinued or interrupted 
- 
any laboratory abnormality that required the Patient to receive specific corrective therapy.  
 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, x-rays, and any 
other potential safety assessments, whether or not these procedures are required by the protocol, should also be 
recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
 
7.2.2 Notification to the sponsor and time frame reporting 
• Following the Patient’s written consent to participate in the study, all SAEs and other events listed above, 
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.  
• The investigator should report any SAE that occurs after these time periods that is believed to be related to study 
drug or protocol-specified procedure.  
• All SAE and other events listed above must be reported to the sponsor immediately or within 24 hours from the 
time the investigator becomes aware of them.  
• The Investigator must complete, sign, and date the SAE form, verify the accuracy of the information recorded on 
the SAE form with the corresponding source documents, and send a copy via fax to Sponsors’ Clinical Trial 
Vigilance Office (Catherine Mouchel - catherine.mouchel@chu-rennes.fr) which contacts information provided 
below: 
Fax number: 02 99 28 40 10/ Phone number: 02 99 28 91 96 
E-mail: vigilance.essais@chu-rennes.fr  
• When further information or additional follow-up information becomes available, the SAE form should be updated 
with the new information and reported to the sponsor immediately or within 24 hours via the same contacts 
information.  
• All SAEs should be followed to resolution or stabilization. 
 

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7.2.2.1 Events not to be notified immediately to the sponsor 
 
Specific hospitalizations 
The following hospitalizations are not considered SAEs and will not be collected:  
- 
a visit to the emergency room or other hospital department < 24 hours, that does not result in admission 
(unless considered an important medical or life-threatening event) 
- 
elective surgery, planned prior to signing consent 
- 
admissions as per protocol for a planned medical/surgical procedure 
- 
routine health assessment requiring admission for baseline/trending of health status (eg, routine colonoscopy) 
- 
medical/surgical admission other than to remedy ill health and planned prior to entry into the study. 
Appropriate documentation is required in these cases 
- 
admission encountered for another life circumstance that carries no bearing on health status and requires no 
medical/surgical intervention (eg, lack of housing, economic inadequacy, caregiver respite, family 
circumstances, administrative reason). 
 
 
Specific events related to non-small cell lung cancer progression 
Disease progression can be considered as worsening of a patient’s condition attributable to the disease for which the 
investigational product is being studied. It may be an increase in the severity of the disease under study and/or 
increases in the symptoms of the disease. The development of a new or progression of existing metastasis to the 
primary cancer under study should be considered as disease progression and not AE. 
 Events, which are unequivocally due to disease progression, should not be reported as an Adverse Event (AE) 
during the study and will not be collected. 
 
 
Non serious adverse events 
• The collection of non-serious AEs information should begin at initiation of study drug. The information regarding 
non-serious AE must be reported in the CRF. 
 
• All non-serious AEs (not only those deemed to be treatment-related) should be collected continuously during the 
treatment period and for a minimum of 30 days following the last dose of study treatment.  
 
• Seven specific types of non-serious AEs must be collected that occur within 100 days of discontinuation of dosing:  
 
Renal adverse event 
 
Endocrinopathy 
 
Gastro-intestinal adverse event 
 
Hepatic adverse event 
 
Neurological adverse event 
 
Pulmonary adverse event 
 
Skin adverse event 
 
• Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious.  
 
• Follow-up is also required for non-serious AEs that cause interruption or discontinuation of study drug and for 
those present at the end of study treatment as appropriate.  
 
7.3 Sponsor’s role 
7.3.1 Analysis of serious adverse events 
The sponsor must evaluate the following: 
- 
the causal relationship of serious adverse events (all adverse events for which the investigator or the sponsor 
considers that a causal relationship with the investigational medicinal products can be reasonably considered, are 
considered as suspected adverse reactions. If the sponsor’s evaluation of the event differs from the investigator’s, 
both opinions are mentioned in the statement sent to the competent authority if this statement is necessary), 
- 
and their expected or unexpected feature, using the reference document in force. All SAEs will be followed to 
resolution or stabilization. 
 
7.3.2 Method of relationship assessment 
The method used by the sponsor in evaluating the relationship of the event is as follows: 
- 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
- 
Not related: There is not a reasonable causal relationship between study drug administration and the AE.  

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The term "reasonable causal relationship" means there is evidence to suggest a causal relationship; the adverse event is 
therefore qualified as an adverse reaction. 
If the adverse reaction is unexpected, it is qualified as being Suspected Unexpected SAR (SUSAR) and must be 
declared in a report by the sponsor to the competent authorities and to the ethic committee. 
 
7.3.3 Declaration of unexpected serious adverse events 
The sponsor reports all suspected unexpected serious adverse reactions (SUSAR) to Eudravigilance (European 
pharmacovigilance database), to local regulatory agency (ANSM), to the ethic committee and to investigators within 
the regulatory time periods for reporting. 
  
7.3.4 Transmission of annual safety reports 
On the anniversary date of authorisation of the study delivered by the Health Authorities, the sponsor writes a Data 
Safety Update Report (DSUR) report containing: 
- 
the list of serious adverse events which may be related to the investigational medicinal products studied, including 
expected and unexpected serious effects, 
- 
a critical analysis of safety of patients who are Patients in the study. 
It is sent to local regulatory agency and to the ethics committee within 60 days following the anniversary of 
authorisation of the trial. 
 
7.3.5 Declaration of other safety data 
Every safety finding that can alter the benefit/risk ratio of an investigational medicinal product or sufficient to 
consider changes in administration of the study product or changes in conduct of the trial must immediately be 
notified to the sponsor. The former will be the Patient of a report to the competent authorities and ethic committee. 
 
7.3.6 Transmission of Safety Data to BMS 
SAEs and pregnancies will be reported to BMS within 24 hours. SAEs will be recorded on CIOMS Form; pregnancies 
will 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 will be 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 will be sent within 24 hours to BMS using the same procedure used for transmitting the initial 
SAE report. 
 
7.4 Expected adverse reactions specific to the present study 
7.4.1 Adverse reactions related to Nivolumab or Ipilimumab 
 
Infections and infestations  
Uncommon  
bronchitis, upper respiratory tract infection  
Neoplasms benign, malignant and unspecified (including cysts and polyps)  
Uncommon  
histocytic necrotising lymphadenitis (Kikuchi lymphadenitis)  
Immune system disorders  
Uncommon  
anaphylactic reaction, hypersensitivity, infusion related reaction  
Endocrine disorders  
Common  
hypothyroidism  
Uncommon  
adrenal insufficiency, thyroiditis  
Metabolism and nutrition disorders  
Very common  
decreased appetite  
Nervous system disorders  
Common  
peripheral neuropathy, headache, dizziness  
Uncommon  
myasthenic syndrome, polyneuropathy  
Cardiac disorders  
Uncommon  
tachycardia  
Vascular disorders  
Uncommon  
vasculitis  
Respiratory, thoracic and mediastinal disorders  
Common  
pneumonitis, dyspnoea, cough  

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Uncommon  
lung infiltration  
Gastrointestinal disorders  
Very common  
nausea  
Common  
diarrhoea, stomatitis, vomiting, abdominal pain, constipation, 
dry mouth  
Uncommon  
colitis, duodenal ulcer  
Skin and subcutaneous tissue disorders  
Common  
rash, pruritus  
Uncommon  
urticaria  
Musculoskeletal and connective tissue disorders  
Common  
musculoskeletal pain,a arthralgia  
Uncommon  
polymyalgia rheumatica  
Renal and urinary disorders  
Uncommon  
tubulointerstitial nephritis, renal failure  
General disorders and administration site conditions  
Very common  
fatigue  
Common  
pyrexia, oedema  
Investigations  
Very common  
increased 
AST,bincreased 
ALT,b 
increased 
alkaline 
phosphatase,b increased creatinine,b decreased lymphocytes,b 
decreased 
platelet 
count,b 
decreased 
haemoglobin,b 
hypercalcaemia,b 
hypocalcaemia,b 
hyperkalaemia,b 
hypokalaemia,b hypomagnesaemia,b hyponatraemiab  
Common  
increased total bilirubin,b decreased absolute neutrophil count,b 
hypermagnesaemia,b, hypernatraemiab  
Uncommon  
Increased lipase, increased amylase  
a Musculoskeletal pain is a composite term which includes back pain, bone pain, musculoskeletal chest pain, 
musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, spinal pain.  
b Frequencies reflect the proportion of patients who experienced a worsening from baseline in laboratory 
measurements. See “Description of selected adverse reactions; laboratory abnormalities” below. 
 
Management Algorithms for Immuno-Oncology Agents 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration than AEs caused by 
other therapeutic classes. Nivolumab and ipilimumab are considered an immuno-oncology agent in this protocol. 
Early recognition and management of AEs associated with immuno-oncology agents may mitigate severe toxicity. 
Management algorithms have been developed to assist investigators in assessing and managing the following groups 
of AEs: 
Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, Neurological. 
While the ipilimumab investigator brochure contains very similar safety management algorithms for these adverse 
events, the recommendation is to follow the nivolumab algorithms for immune-oncology agents (I-O) in order to 
standardize the safety management across the three blinded treatment arms. 
The algorithms are found in the Nivolumab IB and in Appendix 8 of this protocol.  
 
Dose Delay for experimental Arm (Nivolumab plus Ipilimumab) 
Tumor assessments for all Patients should continue as per protocol even if dosing is delayed. 
Nivolumab and ipilimumab administration should be delayed for the following: 
Any Grade ≥ 2 non-skin, drug-related AE except forfatigue or laboratory abnormalities  
• 
Any Grade 3 skin, drug-related AE 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions AST, ALT, total bilirubin, or 
asymptomatic amylase or lipase: 
• 
 
• 
If a Patient has a baseline AST, ALT, or total bilirubin that is within normal limits, delay dosing for drug-
related Grade ≥ 2 toxicity. 
• 
If a Patient has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, delay dosing for drug-
related Grade ≥ 3 toxicity. 
• 
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.  

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Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the investigator, warrants delaying 
the dose of study medication. 
 
Patients that have drug-related toxicities that meet the criteria for dose delay, should have both drugs (ipilimumab and 
nivolumab) delayed until retreatment criteria are met. 
 
Criteria to Resume Nivolumab and Ipilimumab Dosing 
Patients may resume treatment with study drug when the drug-related AE(s) resolve to Grade ≤1 or baseline value, 
with the following exceptions: 
• 
Patients may resume treatment in the presence of Grade 2 fatigue 
• 
Patients who have not experienced a Grade 3 drug-related skin AE may resume treatment in the presence of 
Grade 2 skin toxicity. 
• 
Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons other than a 2-
grade shift in AST/ALT or total bilirubin may resume treatment in the presence of Grade 2 AST/ALT or total 
bilirubin. 
• 
Patients with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation parameters 
(Section 4.5.8.2) should have treatment permanently discontinued. 
• 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before treatment is 
resumed. 
• 
Patients 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. 
• 
Drug-related endocrinopathies adequately controlled with only physiologic hormone replacement may resume 
treatment after consultation with the BMS Medical Monitor. 
• 
Dose delay of ipilimumab which results in no ipilimumab dosing for > 12 weeks requires ipilimumab 
discontinuation, with exceptions as noted in Section 6.1.1.7.  
 
Ipilimumab may not be resumed sooner than 6 weeks (+/- 5days) after the prior ipilimumab dose. 
In general, Patients who meet criteria to resume ipilimumab will also have met criteria to resume nivolumab, so it 
should be feasible to synchronize dosing of both drugs when resuming ipilimumab. In order to facilitate this, the 
dosing days of nivolumab and ipilimumab may be adjusted within the permitted +/- 5 day window, as long as 
consecutive nivolumab doses are given at least 12 days apart. 
One exception to note is when ipilimumab and nivolumab doses are delayed due to drug related Grade ≥3 amylase or 
lipase abnormalities not associated with symptoms or clinical manifestations of pancreatitis. If the investigator 
assesses the Grade ≥3 amylase or lipase abnormality to be related to ipilimumab and not related to nivolumab, 
nivolumab may be resumed when the amylase or lipase abnormality resolves to Grade < 3 but ipilimumab may only 
be resumed when the amylase or lipase abnormality resolves to Grade 1 or baseline. 
Investigator attribution of this toxicity to the ipilimumab dosing must be clearly noted in the patient’s medical chart. 
The Medical Monitor should be consulted prior to resuming nivolumab in such Patients. 
 
Nivolumab and Ipilimumab discontinuation 
Nivolumab Dose Discontinuation 
Treatment with nivolumab should be permanently discontinued for 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 3 non-skin, drug-related adverse event lasting > 7 days, with the following exceptions for drug-
related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, and infusion 
reactions, and endocrinopathies: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or infusion 
reaction of any duration requires discontinuation 
o Grade 3 drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement do not require discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except those 
noted below 
 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
 
Any drug-related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation:  
• 
AST or ALT > 8 x ULN  

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• 
Total bilirubin > 5 x ULN 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following events which do 
not require discontinuation: 
 
Grade 4 neutropenia ≤7 days  
 
Grade 4 lymphopenia or leucopenia 
 
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 Medical Monitor 
should be consulted for Grade 4 amylase or lipase abnormalities 
 
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 
 
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 BMS 
Medical Monitor. 
 Dosing interruptions or delays lasting > 6 weeks that occur for non-drug-related reasons may be allowed if 
approved by the Investigator. Prior to re-initiating treatment in a Patient with a dosing interruption lasting > 6 
weeks, the BMS medical monitor must be consulted. Tumor assessments should continue as per protocol even 
if dosing is interrupted 
 Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the Investigator, 
presents a substantial clinical risk to the Patient with continued nivolumab dosing.  
The assessment for discontinuation of nivolumab should be made separately from the assessment made for 
discontinuation of ipilimumab. Although there is overlap among the discontinuation criteria, if discontinuation criteria 
are met for ipilimumab but not for nivolumab, treatment with nivolumab may continue if ipilimumab is discontinued. 
If a patient meets the criteria for discontinuation of ipilimumab but not nivolumab prior to completion of the first 4 
cycles, treatment with nivolumab may not resume until the adverse event has fully resolved, and the patient has 
discontinued steroids, if they were required for treatment of the adverse event. The relationship to ipilimumab should 
be well documented in the source documents. Nivolumab should be resumed at 240 mg every 2 weeks. 
If a patient in any of the nivolumab/ipilimumab combination arms meets criteria for discontinuation and investigator is 
unable to determine whether the event is related to both or one study drug, the patient should discontinue both 
nivolumab and ipilimumab and be taken off the treatment phase of the study. 
 
Ipilimumab Dose Discontinuation 
Ipilimumab should be permanently discontinued if any of the following criteria are met: 
 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 2 weeks OR requires systemic treatment; 
 Any Grade ≥ 3 bronchospasm or other hypersensitivity reaction; 
 Any other Grade 3 non-skin, drug-related adverse with the following exceptions for laboratory abnormalities, 
grade 3 nausea and vomiting, grade 3 neutropenia and thrombocytopenia, and symptomatic endocrinopathies 
which resolved (with or without hormone substitution); 
 Any drug-related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation: 
 
AST or ALT > 8x ULN 
 
Total bilirubin > 5 x ULN 
 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following events, which do 
not require discontinuation: 
 
Grade 4 neutropenia ≤7 days 
 
Grade 4 lymphopenia or leukopenia 
 
Isolated Grade 4 amylase or lipase abnormalities which are not associated with symptoms or clinical 
manifestations of pancreatitis. The BMS Medical Monitor should be consulted for Grade 4 amylase or 
lipase abnormalities. 
 
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 

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 
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 BMS 
Medical Monitor. 
 Any treatment delay resulting in no ipilimumab dosing for > 12 weeks with the following exceptions: Dosing 
delays to manage drug-related adverse events, such as prolonged steroid tapers, are allowed. Prior to re-
initiating treatment in a patient with a dosing delay lasting > 12 weeks, the medical monitor must be 
consulted. Tumor assessments should continue as per protocol even if dosing is delayed. 
 Dosing delays resulting in no ipilimumab dosing for > 12 weeks that occur for non-drugrelated reasons may 
be allowed if approved by the BMS medical monitor. Prior to reinitiating treatment in a patient with a dosing 
delay lasting > 12 weeks, the BMS medical monitor must be consulted. Tumor assessments should continue as 
per protocol even if dosing is delayed. 
 Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the Investigator, 
presents a substantial clinical risk to the patient with continued nivolumab dosing. 
 The assessment for discontinuation of ipilimumab should be made separately from the assessment made for 
discontinuation of nivolumab. Although there is overlap among the discontinuation criteria, if discontinuation 
criteria are met for ipilimumab but not for nivolumab, treatment with nivolumab may continue if ipilimumab 
is discontinued. 
 If a patient meets the criteria for discontinuation of ipilimumab but not nivolumab, treatment with nivolumab 
may not resume until the adverse event has fully resolved and the patient has discontinued steroids, if they 
were required for treatment of the adverse event. The relationship to ipilimumab should be well documented 
in the source documents. Nivolumab should be resumed at 240 mg every 2 weeks. If a patient in any of the 
nivolumab/ipilimumab combination arms meets criteria for discontinuation and investigator is unable to 
determine whether the event is related to both or one study drug, the patient should discontinue both 
nivolumab and ipilimumab and be taken off the treatment phase of the study. 
 
Treatment Beyond Disease Progression 
Accumulating evidence indicates a minority of Patients treated with immunotherapy may derive clinical benefit 
despite initial evidence of progressive disease (PD). Patients will be permitted to continue treatment beyond initial 
RECIST 1.1 defined PD as long as all of the following criteria are met and clearly documented: 
• Investigator-assessed clinical benefit and no rapid disease progression; 
• Tolerating blinded study drug(s); 
• Stable performance status; 
• Treatment beyond progression will not delay an imminent intervention to prevent serious complications of disease 
progression (eg, CNS metastases); 
• Patient provides written informed consent prior to receiving additional study therapy, using an ICF describing any 
reasonably foreseeable risks or discomforts, or other alternative treatment options 
The assessment of clinical benefit should be balanced by clinical judgment as to whether the patient is clinically 
deteriorating and unlikely to receive any benefit from continued study therapy. 
A radiographic assessment should be performed within 6 weeks of original PD to determine whether there has been a 
decrease in the tumor size, or continued PD. For the Patients who continue study therapy beyond progression, further 
progression is defined as an additional 10% increase in tumor burden from time of initial PD. This includes an 
increase in the sum of all target lesions and/ or the development of new measurable lesions. For Patients with 
evaluable disease only, further progression is defined as unequivocal disease progression of non-target lesions or the 
development of new lesions from time of initial PD. Treatment should be discontinued permanently upon 
documentation of further disease progression. 
New lesions are considered measurable at the time of initial progression if the longest diameter is at least 10 mm 
(except for pathological lymph nodes, which must have a short axis of at least 15 mm). Any new lesion considered 
non-measurable at the time of initial progression may become measurable and therefore included in the tumor burden 

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measurement if the longest diameter increases to at least 10 mm (except for pathological lymph nodes, which must 
have an increase in short axis to at least 15 mm). 
For statistical analyses that include the investigator-assessed progression date, Patients who continue treatment beyond 
initial investigator-assessed, RECIST 1.1-defined progression will be considered to have investigator-assessed 
progressive disease at the time of the initial progression event. 
For Patients in all treatment arms, global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic deterioration’. Every effort 
should be made to document. 
 
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions 
Since nivolumab and ipilimumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were to occur, it might 
manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other 
symptoms of allergic-like reactions.  
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 (Insert version e.g.: 4.0) 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 Patient 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 [eg, 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 Patient with diphenhydramine 50 mg 
IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and monitor Patient until 
resolution of symptoms. Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms resolve; if no 
further complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
Patient 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 Patient until resolution of symptoms. The amount 
of study drug infused must be recorded on the electronic case report form (eCRF). The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 
325 to 1000 mg (acetaminophen) should be administered at least 30 minutes before additional nivolumab 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) 
may be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion]; recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae [eg, 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 Patient 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. Patient 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 Patient until 
recovery from symptoms.  
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized pruritis within 1 
week after treatment), symptomatic treatment may be given (eg, oral antihistamine, or corticosteroids). 
 
7.4.2 Adverse reactions related to Carboplatin 
The reference document for definition of expectedness is the the European Union (EU) Summary of Product 
Characteristics (SPC) CARBOPLATINE HOSPIRA 10 mg/ml sol inj p perf. The expected adverse reactions related to 
Carboplatin are listed in this document. 
 

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7.4.3 Adverse reactions related to Pemetrexed 
The reference document for definition of expectedness is the the European Union (EU) Summary of Product 
Characteristics (SPC) ALIMTA 100 mg pdre p sol diluer p perf. The expected adverse reactions related to Pemetrexed 
are listed in this document. 
 
7.4.4 Adverse reactions related to Paclitaxel 
The reference document for definition of expectedness is the the European Union (EU) Summary of Product 
Characteristics (SPC) TAXOL 6 mg/ml sol diluer p perf. The expected adverse reactions related to Paclitaxel are 
listed in this document. 
 
 
8 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
A comprehensive Statistical analysis plan (SAP) for the trial will be prepared before any statistical analysis. It will 
include detailed information on the analysis of primary and secondary outcome measures and the definitions of major 
protocol deviations. 
 
Sample size consideration 
The primary endpoint of the phase III is overall survival. The study is calibrated to detect a treatment effect hazard 
ratio (HR) of 0.65, translating in an improvement of 1-year OS rate from 40% (control arm) to 55% (Nivolumab + 
Ipilimumab arm). 
A total of 199 events observed at the time of the final analysis would have 85% power to show statistically significant 
log-rank test at a 2-sided alpha level of 5%. Considering a recruitment duration of 24 months and a 18 months follow-
up for the last included patient (estimated total duration of the study: 42 months), 242 patients will be randomized in 
the study (121 by arm).  
Randomization ratio 1:1 will be stratified according to Age (< 70 vs. ≥ 70 years),ECOG-PS status (0/1 vs. 2) and by 
histology (squamous versus non-squamous). 
 
Interim analyses 
During the trial, one interim analysis for futility will be performed, permitting to early stop the trial, if no sufficient 
efficacy is shown. This analysis will be performed after that 33% of the expected events have occurred. Using planned 
enrollment rate, this analysis should be performed after inclusion of 171 patients (17 months after first included 
patient) (fig. 1). No adjustment of type I error was required. Stopping boundaries were defined according to Lan-
DeMets spending function to control type II error. Table 1 shows the futility boundaries. 
An independent Data Safety Monitoring Board will be organized to discuss the conduct of the study after analysis 
performed. 
Sample size calculation and interim analysis planning were performed using East® software (Cytel Inc. 1994-2014), 
version 6.3.1 
 
Table1: Futility boundaries 
 
Look Fraction of information 
 P value HR futility bound 
1 
0.33 
0.012 
0.698 
1.137 
2 
1 
0.15 
0.0025 
 
 

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Figure 1:  Estimated Sample size / events during study period. 
 
Definition of population 
• 
The Intent-to-treat (ITT) population is defined as all patients randomized in the trial, regardless of whether 
they actually received treatment. The treatment groups will be analyzed as randomized. 
• 
The Per Protocol (PP) population is a subgroup of the ITT population containing all patients who do not have 
any major protocol violation and received study treatment at least once. Major protocol violations will be 
defined in the Statistical Analysis Plan (SAP). 
• 
The Safety population will include all randomized patients having received at least one dose of study 
treatment and one safety follow-up, whether withdrawn prematurely or not. 
 
All efficacy analysis will be performed on the ITT population. The safety data will be analyzed on the safety analysis 
set  
 
Endpoints 
• 
Primary endpoint : Overall survival 
Overall survival is defined as the time from the date of randomization until death due to any cause. Any patient not 
known to have died at the time of analysis will be censored based on the last recorded date on which the patient was 
known to be alive. 
OS will be estimated using the Kaplan-Meier method, and will be compared between arms at a 2-sided significance 
level of 5% (Log-Rank test supported by a stratified Cox regression adjusted on randomization strata).  Median OS per 
arm associated with its 95% confidence interval with be presented. 
 
• 
Secondary endpoint :  
• 
Survival rate at one year will be presented per arm. Associated 2-sided 95% CI will be provided. 
• 
Objective response rate according to RECIST 1.1: ORR is defined as the rate of patients with an observed 
tumor response (CR or PR) as best response seen during all over the study treatment period and evaluated 
according to RECIST 1.1.  Patients   without any tumor assessment following study treatment initiation and not 
died of neoplasic cause will be considered as non-evaluable patients.  ORR rate will be presented by arm 
associated with its corresponding 95% CI and compared between arms using chi² or Fisher exact test if needed. 
Definition RECIST 1.1: Appendix 4. 
• 
Progression free survival: PFS is defined as the time from randomization until the date of the first progression 
assessment according to RECIST version 1.1 or death (by any cause in the absence of progression). Patients who 
have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment 
from their last evaluable RECIST assessment.  

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The first progression assessment will be based on investigator-recorded assessments. or on central review  of the 
radiological scans. 
As for OS, PFS will be estimated using the Kaplan-Meier method, and will be compared between arms at a 2-
sided 5% significance level Log-Rank test. 
• 
Safety tolerability according to CTCAE version 4.0: The assessment of safety will be based mainly on the 
frequency of adverse events (AE). 
Descriptive statistics will be provided to evaluate the number of patients with at least: 
• 
One adverse events and the number of adverse events by arm,  
• 
One Serious AE, 
• 
One AE with grade 3 or above. 
Comparison between arms will be performed using chi² test or fisher exact test if needed. 
Adverse events of special interest should be described in addition to safety analysis based on system organ class 
and preferred term classifications 
• 
Quality of life according to EQ-5D and EORTC QLQ-ELD14 questionnaires every 6 weeks: Quality of Life 
will be analyzed descriptively and according to the scoring manual. Absolute and relative variation compared to 
randomization time point will be calculated by patient. Evolution during time will be compared between treatment 
arms 
• 
PD-L1 testing by immunochemistery (IHC) by local and central laboratories: Pronostic impact of PD-L1 on 
OS and PFS will be tested. Univariate and multivariate analysis will be implemented. Sub group analysis 
depending on PD-L1 level will be performed. 
• 
Geriatric mini data set (restricted to patients ≥70 years old.): predictive impact of geriatric mini data set and its 
evolution over time on OS, PFS and toxicity. Univariate and multivariate analysis will be implemented. This 
analysis will be performed, using baseline geriatric characteristics included in the geriatric mini data set as 
stratification variables. To identify factors potentially influencing OS, PFS or toxicity, a multivariate Cox model 
will be constructed with stepwise variable selection. We’ll use univariate Cox models to select baseline variables 
(p=0·20) for the multivariate analysis. 
 
 
9 
RIGHT OF ACCESS TO DATA AND SOURCE DOCUMENTS 
9.1. Access to data 
In compliance with GCP: 
- 
the sponsor is in charge of obtaining the agreement of all parties involved in the study to ensure direct access to all 
sites of study conduct, source data, source documents and reports with the aim of checking quality and of an audit 
by the sponsor, 
- 
investigators will make available to persons in charge of monitoring, checking of quality or audit of the study 
documents and individual data which are strictly necessary for such checking, in compliance with legislative and 
regulatory conditions in force (articles L.1121-3 and R.5121-13 of the French public health code). 
 
9.2. Source documents  
Source data defined as all documents or original items which make it possible to demonstrate the existence or 
accuracy of data or of a finding recorded in the clinical study will be kept for 15 years by the investigator or by the 
hospital if it involves a hospital medical dossier. 
Source documents consist of a medical dossier, originals of laboratory test results, imaging examination reports, etc. 
 
9.3. Confidentiality of data 
In compliance with conditions concerning confidentiality of data to which persons in charge of quality control of the 
research involving the human person study have access (article L.1121-3 of the French public health code), in 
compliance with conditions pertaining to confidentiality of information in particular concerning the type of 
investigational medicinal products, the tests, persons who are Patients in the study and results obtained (article R. 
5121-13 of the French public health code), persons having direct access will take all necessary precautions with the 
aim of ensuring confidentiality of information pertaining to the investigational medicinal products, tests, the persons 
who are Patients in the study and in particular concerning their identity as well as that of results obtained. 
These persons, in the same capacity as the investigators themselves, are Patient to professional secrecy (according to 
conditions defined by articles 226-13 and 226-14 of the French penal code). 
During the study or at its end, data collected on persons who are Patients in the study and forwarded to the sponsor by 
the investigators (or all other specialised participants) will be made anonymous (deletion of Patients’ names). 
They must not in any event clearly reveal the names of the persons concerned or their address.  

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Only the first letter of the surname and of the first name of the Patient are recorded, together with the code number 
specific for the study indicating the order of inclusion of Patients.  
The sponsor will make certain that each person who is a Patient in the study has provided his or her written agreement 
for access to his/her personal individual data and strictly necessary for quality control of the study. 
 
 
10 
QUALITY CONTROL AND ASSURANCE 
A Clinical Research Associate (CRA) designated by the sponsor will ensure proper conduct of the study and the 
quality of data collected, in agreement with the Standard Operating Procedures applied in the CHU of Rennes and in 
compliance with Good Clinical Practice as well as legislative and regulatory conditions in force. 
The investigator and members of his team agree to make themselves available at Quality Control visits carried out at 
regular intervals by the Clinical Research Associate. At these visits the following items will be reviewed: 
- 
informed consent, 
- 
compliance with study protocol and procedures defined in it, 
- 
quality of data collected in the case report forms: accuracy, missing data, consistency of data with "source" 
documents (medical dossiers, appointment diaries, originals of laboratory test results, etc.), 
- 
management of possible products. 
In addition, the investigators agree to receive quality assurance audits performed by the sponsor as well as inspections 
performed by the Competent Authorities. All data, all documents and reports can be Patiented to audits and regulatory 
inspections without being opposed by medical secrecy. 
 
 
11 
ETHICAL CONSIDERATIONS 
11.1. Regulatory and institutional review 
The protocol, information form and certificate of consent of the study will be submitted to the relevant independent 
ethics committee (IEC) for review. 
Notification of a favourable opinion from the IEC will be transmitted to the sponsor of the study and to the competent 
Authority. An application for authorisation will be sent by the sponsor to local regulatory authority prior to start of 
study. 
 
11.2. Substantial changes 
In case of a substantial change made to the study protocol by the investigator, it will be approved by the sponsor. The 
latter must obtain prior to start of study a favourable opinion from the ethics committee and authorisation from the 
relevant health authority in the setting of their respective competence. Additional consent from persons participating 
in the study will be collected if necessary. 
 
11.3. Information for patients and written informed consent form 
Patients will be completely and truly informed in terms which are understandable to them of the objectives and 
constraints of the study, the possible risks incurred measures of supervision and safety necessary, of their right to 
refuse to participate in the study or of the possibility of retracting their agreement at any time. 
All this information is contained in an information and consent form given to the patient. Free, informed and written 
consent from the patient will be collected by the investigator, or a doctor representing him prior to final inclusion in 
the study. A copy of the information and consent form signed by both parties will be given to the patient; the 
investigator will keep the original of it.  
 
 
12 
DATA PROCESSING AND RETENTION OF DOCUMENTS AND DATA 
12.1. Case report forms and data entry 
All information required by the study protocol must be recorded in the case report forms and an explanation must be 
provided for any missing data. Data must be collected progressively as obtained and recorded explicitly in the case 
report forms.  
An electronic case report form (e-CRF) will be made available and data entry will be made in centres through a WEB 
interface (Clinsight software, Ennov, Paris (75), France). It solely requires an internet connection and a browser. An 
aid document for use of this tool will be provided to investigators. The interface between the CRA and the investigator 
thus will be promoted, making possible the collection and control of data at a distance. Tests of control of consistency 
of data will be incorporated in electronic format. An audit function is incorporated in the e-CRF thus making it 
possible to follow any change in study data. This function also makes it possible to clearly identify the person who 
made a change as well as the date. A justification possibly can be incorporated in comment. 

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If requested, a paper copy will be printed at the end of the study, authenticated (dated and signed) by the investigator 
and a copy will be sent to the sponsor and archived. 
Data analysis will be carried out by statisticians of the Biostatistics Unit Department of Pharmacoly of Rennes. 
 
12.2. CNIL 
This study falls within the scope of the “Methodology of Reference” (MR-001) in application of conditions of article 
54 line 5 of French law no. 78-17 of 6 January 1978 modified pertaining to data processing, computer files and 
liberties. This change has been authorised by the decision of 5 January 2006. The CHU of Rennes, sponsor of the 
study, has signed an agreement of compliance with this “Methodology of Reference”. 
 
12.3. Archiving 
The following documents will be kept in the respective departments until the end of the period of practical utility. 
These documents are:  
- 
The study protocol and its annexes, and possible amendments, 
- 
The original signed informed information and consent forms, 
- 
Individual data (authenticated copies of raw data), 
- 
Monitoring documents, 
- 
Statistical analyses, 
- 
The study final report. 
At the end of the period of practical utility, the documents will be archived by the sponsor for at least 25 years after 
the end of the study or its early discontinuation, in compliance with institutional practices. 
Archived documents cannot be moved or destroyed without agreement of the sponsor. All data, all documents and 
reports can be patiented to an audit or inspection. 
 
 
13 
 INSURANCE 
The Sponsor will take out, for the duration of the study, insurance covering his own civil responsibility as well as that 
of all doctors involved in conduct of the study. He will also insure the total compensation of all harmful consequences 
of the study for persons who are Patients in it and his heirs, except for evidence to be provided that the harm is not 
causally related to his fault or that of any participant, without it being possible to oppose the intervention of a third 
party or the voluntary withdrawal of a person who had initially consented to be a Patient in the study. 
 
 
14 
STUDY FEASIBILITY 
The Groupe Français de Pneumocancérologie performed multiples studies in non small cell lung cancer, some of them 
focused on elderly patients. ESOGIA, a phase III randomized study included 495 patients in less than 3 years, 
TARSEQ, randomized phase II 132 inclusions in 1 year.   
 
 
15 
RULES PERTAINING TO PUBLICATION 
Scientific presentations and reports corresponding to the study will be written under the responsibility of the 
coordinating investigator of the study with the agreement of the responsible investigators. The co-authors of the report 
and of publications will be the investigators and clinicians involved, on a pro rata basis of their contribution in the 
study, as well as the biostatistician and associated researchers.  
Rules on publication will follow international recommendations (N Engl J Med, 1997; 336:309-315). 
The study will be recorded on a freely accessible website (Clinical Trials) prior to inclusion of the first patient in the 
study. 
 
16 
LIST OF APPENDIX 
Appendix 1 : List of investigators 
Appendix 2: Notes d’information et formulaires de consentement 
Appendix 3: American Joint Committee on Cancer Staging Criteria for Lung Cancer  
Appendix 4: RECIST (version 1.1) for Tumor Response  
Appendix 5: Eastern Cooperative Oncology Group Performance Status 
Appendix 6 : Echelles de qualité de vie EQ5D et EORTC QLQ-ELD14 
Appendix 7 : Information on NIVOLUMAB 
Appendix 8 : Nivolumab and Ipilimumab Management Algorithms 
Appendix 9: Geriatric mini data set