Immunotherapy by Nivolumab After Prior Chemotherapy for HIV+ Patients With Advanced Non-small Cell Lung Cancer (NSCLC): IFCT-CHIVA2 Phase IIa Trial
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer Metastatic, Non Small Cell Lung Cancer Stage IIIB, HIV/AIDS
Sponsor: Intergroupe Francophone de Cancerologie Thoracique

 
 
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IFCT-1602 CHIVA2 
Immunotherapy by Nivolumab after prior Chemotherapy for 
HIV+ patients with Advanced non-small cell lung cancer 
(NSCLC): IFCT-CHIVA2 phase IIa trial 
N° EUDRACT : 2016-003796-22 
Sponsor 
 
10 rue de la Grange-Batelière 75009 PARIS – France 
Study Chair 
Dr Armelle LAVOLE, M.D. (Tenon Hospital, Paris) 
Study Co-chair 
Pr Jacques CADRANEL, MD, PhD (Tenon Hospital, Paris) 
 
The IFCT-1602 CHIVA2 study is part of the National OPDIVIH research program granted by 
the ANRS   
National Coordinator: Pr Jean Philippe SPANO, MD, PhD (CLIP² INCA early phase clinical trial 
center; Pitié-Salpêtrière Hospital, Paris, France) 
Immunology Coordinator: Dr Amélie GUIHOT, MD, PhD (Pitié-Salpêtrière Hospital, Paris, 
France) 
 
Partnership 
CancerVIH Group 
ANRS  

 
 
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Steering Committee 
Dr. Armelle LAVOLE, Hôpital Tenon, APHP Paris  
Pr. Jacques CADRANEL, Hôpital Tenon, APHP Paris  
Dr. Amélie GUIHOT, Hôpital de la Pitié-Salpêtrière, APHP Paris 
Pr. Jean-Philippe SPANO, Hôpital de la Pitié-Salpêtrière, APHP Paris 
Dr Laurent GREILLIER, APHM 
Pr Julien MAZIERES, CHU Toulouse 
Dr Isabelle MONNET, CHI Créteil 
Pr Jean-Charles SORIA, Gustave Roussy Villejuif 
Dr Caroline SOLAS, APHM 
Dr Alain MAKINSON, CHU Montpellier 
Franck MORIN, IFCT 
Alexandra LANGLAIS, IFCT 
Biological Steering Committee  
Amélie Guihot, Pitié Salpêtrière  
Brigitte Autran, Pitié Salpêtrière 
Jacques Cadranel, Hopital Tenon 
Vincent Calvez, Pitié Salpêtrière 
Constance Delaugerre, Hopital Saint Louis 
Olivier Lambotte, Hopital Kremlin Bicêtre 
Jean-Daniel Lelièvre, Hopital Henri Mondor, 
Anne-Geneviève Marcelin, Pitié Salpêtrière 
Jean Philippe Spano, Pitié Salpêtrière 
 

 
 
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PROTOCOL IFCT-1602 CHIVA2 APPROVAL AND SIGNATORIES 
Immunotherapy by Nivolumab after prior Chemotherapy for HIV+ patients with advanced 
non-small cell lung cancer (NSCLC): IFCT-CHIVA2 phase IIa trial 
SPONSOR 
IFCT 
Name 
Date 
(dd-mm-yy) 
Signature 
President 
Pierre-Jean 
Souquet 
 
 
Director 
Franck Morin 
 
 
Statistician 
Alexandra 
Langlais 
 
 
 
Responsibilities 
delegated by the 
sponsor 
Name 
Date 
(dd-mm-yy) 
Signature 
Study chair 
Armelle Lavole 
 
 
Study co-chair 
Jacques Cadranel 
 
 
Je reconnais avoir pris connaissance de l’ensemble du protocole et accepte de conduire 
cet essai en accord avec les Bonnes Pratiques Cliniques, la Loi de Recherche Biomédicale 
(4 aout 2004) et tel qu’il est décrit dans ce document. 
INVESTIGATEUR COORDINATEUR: 
Nom :     Armelle LAVOLE 
 
Date :  
Signature :    
 
 

 
 
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TABLE OF CONTENTS 
1 
Background Information ............................................................................ 5 
2 
Objectives ............................................................................................. 8 
3 
Regimen ............................................................................................... 9 
4 
Eligibity ............................................................................................... 10 
5 
Concomitant treatment ............................................................................ 12 
6 
Criteria for early termination, withdrawal from the trial or study termination ......... 13 
7 
Pre-treatment evaluation: ........................................................................ 14 
8 
Evaluation during and after protocol treatment .............................................. 15 
9 
Study treatment ..................................................................................... 18 
10 Treatment beyond disease progression ......................................................... 20 
11 Safety ................................................................................................. 21 
12 Dose toxicities and adjustement ................................................................. 27 
13 Data analysis and statistical considerations .................................................... 30 
14 Correlative biological studies (“Bio-CHIVA2”) ................................................. 33 
15 Administrative section ............................................................................. 35 
16 Final report and publications ..................................................................... 39 
              
 

 
 
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1 
BACKGROUND INFORMATION 
1.1 Anti-PD1 Antibody 
The anti-PD1 antibody nivolumab (OPDIVO, BMS®) has become the new standard of care 
after first-line platinum doublet chemotherapy in metastatic lung squamous cell 
carcinomas. The Phase III CheckMate 017 showed overall survival improvement with 
Nivolumab when compared to docetaxel in second line treatment (9.2 months vs. 6 
months, p = 0.00025, HR 0.59) and with a better safety. A planned subgroup exploratory 
analysis showed no difference in efficacy of nivolumab when compared to chemotherapy 
depending on PDL-1 tumor expression (Brahmer, july 9 NEJM 2015). The CheckMate 057 
phase III study showed similar overall survival improvement in non-squamous NSCLC 
treated by nivolumab compared to docetaxel in 2nd line treatment (12.2 months vs. 9.4 
months, p = 0.0015, OR: 0.73). However, in this study in a preplanned subgroup analysis, 
efficacy was similar between the two treatments when the threshold of PDL-1 expression 
was <1% (Borghaei NEJM 2015 373:1627). The prognostic and predictive role in the 
expression of PDL1 will have to be clarified by further studies (Barbee Annals of 
pharmacotherapy, august 17, 2015).    
1.2 Immunotherapy in patient living with HIV/AIDS 
Immune Checkpoints inhibitors administration is an efficient and innovative treatment in 
the general population with lung cancer. However, other populations, such as PLWHIV 
(People Living With HIV), may well benefit from anti-PD1 therapy, but no specific studies 
have been realized.  It is indeed essential to conduct studies dedicated to PLWHIV with 
non small cell lung cancer (NSCLC) as:  
- NSCLC is the most common of non-AIDS-related malignancy (Lanoy E Int j Cancer 
2011);and represents the leading cause of cancer-related death among  PLWHIV (Morlat 
AIDS 2014) 
- Some studies have shown that NSCLC prognosis is worse among PLWHIV (Sigel BJC 2013, 
Suneja AIDS 2013; Coghill JCO 2015); thus any therapeutic innovation in the general 
population must be applied quickly to PLWHIV population taking into account its 
specificities; 
- IFCT-1001 CHIVA phase II trial study of carboplatin plus pemetrexed followed by 
pemetrexed as first-line therapy for HIV infected patients with advanced non-squamous 
NSCLC was effective and reasonably well-tolerated, but the poor median overall survival 

 
 
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(7.6 months) suggested urgent unmet needs for investigations of others therapies than 
chemotherapy (Lavole Abst9076 ASCO 2016) 
- Toxicity profile is better with nivolumab than docetaxel with 7-10% vs 54-71% grade 3-4 
events (Borghaei NEJM 2015; Brahmer NEJM 2015)   
- Oncological cytotoxic treatments and antiretrovirals (ARV) can cause interactions 
because of common CYP450 metabolism, or additive adverse events, thus increasing 
incidence of haematological, hepatic and renal toxicities, (Makinson, JTO 2010 and 2011). 
By contrast, nivolumab is a monoclonal antibody and does not have hepatic metabolism 
and therefore probably won’t show interactions with antiretrovirals; 
- Oncogene addiction is rare in PLWHIV with NSCLC (Crequit Lung cancer 2015) due to the 
almost constant smoking status of the study population. Therefore, the use of specific 
inhibitors is exceptionally an option; by contrast nivolumab has showed an efficacy in  
smoking populations (Borghaei NEJM 2015; Brahmer NEJM 2015).  
- Standard chemotherapy reduces the number of CD4 altering the immunity of HIV 
patients.  
- Strong evidence suggests that blocking the PD-1/PD-L1 axis with monoclonal antibodies 
could be of highest interest during HIV-associated NSCLC  in order to 1°/ restore the HIV-
specific T cell responses for potential effect on the HIV reservoir and HIV replication, 
together with antiretroviral therapies.  (Trautmann Nat Med 2006 Nature Day 2006, Velu 
Nature 2009, Palmer J Immunol 2013) alongside ARVs and 2°/ thus contribute to the 
control of inflammation induced by HIV. Also, the high PD-1 expression levels on circulating 
CD8 during HIV infection (Day Nature 2006) suggests that blocking the PD-1/PD-L1 axis 
could restore tumor-specific cytotoxic T lymphocytes (CTL) functions – as much as in 
patients seronegative for HIV. 
- A phase I-II study of escalating doses of nivolumab in 47 patients with hepatocellular 
carcinoma, carriers of hepatitis B or C, showed a good toxicity profile and a sustainable 
response, which suggests the safety of this molecule in a given virological context (El 
Khoueriry ASCO 2015, abst LBA101). 
- To our knowledge, an ongoing phase I study is evaluating the association of nivolumab 
and ipilimumab in solid tumors including PLWHIV with lung cancer (NCT02408861), and 
another phase I study is evaluating pembrolizumab in PLWHIV with relapsed, refractory, or 
disseminated malignant neoplasms including lung cancer (NCT02595866). 

 
 
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- Therapeutic strategy is challenging in patients with advanced NSCLC and a poor 
performance status (PS≥2). In general PS is rather a prognostic factor than a predictive 
factor. Moreover, cytotoxic chemotherapy (particularly later lines of therapy) is associated 
with substantial toxicities, impaired quality of life, and a short lifespan in patients with a 
PS≥2. By contrast, immune checkpoint inhibitors (ICIs), particularly anti-PD1/PD-L1 
monotherapy, often have favorable toxicity profiles, even in patients with a poor PS 
(Johnson DB et al. Cancer June 1, 2017). There is very little published experience to guide 
oncologists in terms of whether to use ICIs in patients with a poor PS. One phase II study 
with atezolizumab in cisplatin-ineligible patients with urothelial carcinoma reported a 
response rate of 25% for patients with a PS=2 (vs 23% for all patients) (Balar AV et al, 
Lancet. 2017;389:67-76). In the French cohort IFCT CLINIVO (Girard N et al ESMO 2017) for 
treatment of advanced non-small cell lung cancer (NSCLC) by nivolumab reporting the 
efficacy/toxicity of more than 900 patients included in the ATU of Nivolumab in France, 
more than 70% of patients were treated in third line setting or more and 20% had a PS≥2. In 
this large cohort of fragilized patients, overall survival and progression free survival were 
similar to that reported in phase III trial including only highly selected patients. Moreover, 
phase II trial has been projected by the IFCT to evaluate ICIs in PS≥2 patients, however HIV 
patients will be excluded, as usual. On the other hand, docetaxel - the standard of care 
previously proposed before the era of ICIs, is associated in HIV patients with substantial 
toxicities additive to that of anti-retrovirals and with an increased risk of pharmacological 
interactions. Moreover, results of the phase II CHIVA1 trial (Lavolé A et al ASCO 2016) has 
shown that chemotherapy by carboplatin plus pemetrexed provides a poorer results than in 
the general population. Altogether, these findings suggest that HIV patients with advanced 
NSCLC should not be excluded for CHIVA2 phase II trial in case of PS2, although statistical 
analysis will be analyzed by subgroups. Finally, it is important that HIV patients can 
benefit from therapeutic innovations in the field of NSCLC. HIV-NSCLC population is 
inherently of poor prognosis and patients excluded from therapeutic trials. Moreover, it is 
aslo important that this access is secured by the administration of ICIs in the context of a 
therapeutic trial, such as CHIVA 2. 
1.3 Evaluation of risk-benefit ratio 
Two Phase III trials showed superiority in terms of efficacy and tolerance of nivolumab in 
second-line treatment compared to docetaxel in metastatic NSCLC in the general 
population, so it is important to evaluate this treatment in PLWHIV in maximum security 
conditions, taking into account their specificities and complex underlying immunological 
status. As NSCLC in PLWHIV is a rare tumour, a phase 2 trial, using DCR data, would be 

 
 
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able to recruit a sufficient number of patients, in a reasonable period of time, to provide a 
proof of concept of the safety and efficacy of nivolumab in this population. Therefore, we 
think that an open-label, one arm phase 2 trial, with a rapid accrual, would be currently a 
crucial approach and a window of opportunity to explore whether nivolumab could find its 
place in PLWHIV with NSCLC. Such a trial is typically a trial for an academic sponsor, 
experienced in PLWHIV with NSCLC, which previously showed its ability to recruit patients 
with such a rare disease as the IFCT did with the IFCT1001-CHIVA trial, testing carboplatin 
plus pemetrexed followed by pemetrexed.   
2 
OBJECTIVES AND ENDPOINTS 
2.1 Primary objective/endpoints 
 
Efficacy of the anti-PD1 antibody (nivolumab) as measured by DCR. 
2.2 Secondary objectives/endpoints 
 
tolerance: Adverse Events (AEs) grade (NCI-CTC 4.0), 
 
impact on HIV control and immunological (CD4, CD8, HIV viral load each 
evaluation), other associated chronic infection susceptible of reactivation (HHV8, 
CMV, EBV, tuberculosis) and potential occurrence of autoimmunity (organ specific 
i.e. thyroiditis, adrenalitis and hypophysitis, or non organ specific)  
 
duration of response 
 
Reponses rate according to tissue PD-L1 expression  
 
progression-free survival 
 
Overall survival 
 
Quality of life (LCSS) 
2.3 Exploratory objectives / endpoints  
 
Monitor HIV, CMV, EBV, HBV, HCV, HHV-8-specific T cell responses in PBMC under 
anti PD-1 therapy: quantification, polyfunctionality, expression of immune check 
points  
 
Monitor the HIV reservoirs (HIV-DNA) and the residual HIV replication by 
ultrasensitive viral load, as well as EBV, CMV, HBV, HCV, HHV-8 viral load 
 
Monitor T cell activation/ exhaustion/differentiation and immune check point 
expression by flow cytometry and ultrasensitive cytokine/chemokine plasma 
measurements. Explore the tumor somatic mutanome by RNA sequencing on 
paraffin initial biopsy or fresh new biopsy by studying normal tissue in parallel 

 
 
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before treatment in order to characterize neoepitopes; if normal tissue not 
available, explore somatic tumoral mutations by comparing whole tumor exome 
sequencing with whole PBMC exome sequencing; further characterization of neo-
epitope specific T cells in PBMC : polyfunctionality, expression of immune check 
points. 
 
Description of gene mutation that appear to be crucial for the response to 
immunotherapy or for adverse effects of immunotherapy, in particular MHC genes 
 
Immune monitoring of adverse effects: T cell phenotyping, cytokine/chemokine 
measurements, antibody dosage, auto-antibody dosage. 
 
Describe the tumoral microenvironment of NSCLC before nivolumab exposure (CD4, 
CD8, CD3 infiltrate, PD-1, PD-L1 expression). 
This will be done on a special 68 mL blood sample that will be done on C1, C2, C3, C9, 
C15, C27, C51, end of treatment and in case of immune related adverse event. This will 
also be done on initial FFPE biopsies that will be repatriated from the different centers. 
3 
REGIMEN 
Thirty eligible patients, previously treated by at least one line of platinum-based 
chemotherapy, will be included. 
TREATMENT:  
Nivolumab is administered intravenously (IV), over 30 minutes at 3 mg/kg every 2 weeks, 
until disease progression, death, limiting toxicity or patient refusal. 
Premedication is not required. 
Patients with tumoral progression will stop the treatment but will have a follow-up for the 
secondary endpoints of OS, and the toxicities assessment till a last study visit 4 weeks (± 1 
week) after the last injection of the drug. 
Twenty centers will be opened. 
 

 
 
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Schedule of the study design. 
4 
ELIGIBITY 
4.1 Inclusion Criteria 
1. 
Age ≥ 18 years old 
2. 
HIV1 or HIV2, regardless of CD4 cell count  
3. 
HIV Viral load <200   copies/mL  
4. 
Proven histologically and/or cytologically, stage IIIB-IV or metastatic relapse post-
surgery non-small cell lung cancer (NSCLC)  
5. Disease recurrence or progression during/after at least one prior platinum doublet-
based chemotherapy regimen for advanced or metastatic disease  
6. Measurable disease by Computed tomography (CT)/Magnetic resonance imaging (MRI) 
per RECIST 1.1 criteria 
7. Performance status (PS) 0, 1 or 2 
8. 
Written informed consent 
9. Patients must have adequate organ function: creatinine clearance > 40 mL/min 
(Cockroft, MDRD  or CKD-Epi formula or 24h Urine Calculate creatinine clearance from 
a 24h urine collection ), neutrophiles count > 1500/mm3; platelets > 100 000/mm3 ; 
hemoglobine > 9 g/dL; hepatic enzymes < 3N with total bilirubin ≤ 1.5 × ULN (upper 
limit of normal) except subjects with documented Gilbert’s syndrome (≤ 5 × ULN) or 
liver metastasis, who must have a baseline total bilirubin ≤ 3.0 mg/dL 
10. Patients must receive appropriate care and treatment for HIV infection including ART 
when clinically indicated and subjects should be under the care of a physician 
experienced in HIV management. In case of recent introduction of cART and CD4 levels 
<50 cells/ml, inclusion will be possible provided subjects had at least 4 weeks of 

 
 
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treatment prior to inclusion, to avoid clinical type IRIS (immune inflammatory 
syndrome reconstitution). All antiretroviral treatments are allowed. 
11. Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use a highly effective method of contraception for 28 days prior to the 
first dose of investigational product, and must agree to continue using such 
precautions for 6 months after the final dose of investigational product; cessation of 
contraception after this point should be discussed with the referent physician. Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. They must also refrain from egg cell donation for 6 months 
after the final dose of investigational product. Men receiving nivolumab  and who are 
sexually active with women of childbearing potential will be instructed to adhere to 
contraception  (appendix I) for a period of 31 weeks after the last dose of nivolumab.  
12. Persons deprived of liberty could be eligible because the expected benefice 
(improvement of disease control rate) justifies the foreseeable risk (adverse reaction 
of nivolumab). 
4.2 Exclusion Criteria: 
1. Concurrent malignancies requiring active intervention 
2. Active Infection 
3. Patient with known EGFR activating tumor mutation or known ALK or ROS1 gene 
rearrangement not treated with the appropriate targeted therapy. 
4. History of immunological events related to HIV: lymphoid interstitial pneumonitis (LIP), 
non-infectious uveitis, encephalitis and other manifestations of CD8 lymphocyte 
infiltration syndrome, HIV-associated nephropathy (HIVAN). 
5. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only 
requiring hormone replacement, or conditions not expected to recur in the absence of 
an external trigger are permitted to enroll. 
6. Active or history of inflammatory bowel disease (eg, diverticulitis, colitis, Crohn’s, 
coeliac disease or other serious gastrointestinal chronic conditions associated with 
diarrhea). Note that diverticulosis is permitted. 

 
 
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7. Symptomatic cerebral metastasis unless treated by brain radiotherapy which will be 
completed for at least 15 days before the beginning of the treatment; subjects with 
carcinomatous meningitis. 
8. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways. 
9. The last dose of prior chemotherapy or radiation therapy (with the exception of 
palliative radiotherapy) was received less than 3 weeks prior to inclusion; 
10. History of primary immunodeficiency, history of organ transplant that requires 
therapeutic immunosuppression and the use of immunosuppressive agents within 28 
days of inclusion or a prior history of severe (grade 3 or 4) immune mediated toxicity 
from other immune therapy. 
11. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 
days of inclusion. Intranasal/inhaled or topical steroids, and adrenal replacement 
steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of 
active autoimmune disease. 
12. Female subjects who are pregnant, breast-feeding or male or female patients of 
reproductive potential who are not employing an effective method of birth control. 
13. Legally protected adults. 
5 
Concomitant treatment 
5.1 Authorized concomitant treatment 
Subjects are permitted the use of topical,  ocular, 
intra-articular, 
intranasal, 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroids dosed < 
10 mg daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids 
>= for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions is permitted.  
Concomitant palliative and supportive care for disease related symptoms is allowed if 
initiated prior to first dose of study therapy. Prior palliative radiotherapy must have been 
completed at least 2 weeks prior to inclusion.  

 
 
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5.2 Prohibited concomitant treatment 
The following medications are prohibited during the study (unless required to treat a drug 
related adverse event):  
 
Immunosuppressive agents 
 
Immunosuppressive doses of systemic corticosteroids (>3 weeks of prednisone 10 mg 
per day or equivalent dose if administration of antiher corticosteroid) 
 
Any concurrent anti-neoplasic therapy (ie chemotherapy, hormonal therapy, 
immunotherapy, extensive, non-palliative radiation therapy, or standard or 
investigational agents for treatment of lung cancer) 
6 
 Criteria for early termination, withdrawal from the trial or study 
termination  
6.1 Withdrawal from the trial 
Reasons for withdrawal from the trial are: 
- Patient withdraws consent 
- Death 
Patients have the right to withdraw their consent and request to leave the study at any 
time for any reason (which they are not obligated to explain). This should not affect their 
right to future care.  
6.2 Early treatment termination 
The investigator may terminate a patient's participation early in the event of: 
- Tumour progression during treatment 
- Toxicity requiring termination of study treatments 
- Intercurrent illness 
- Protocol violation 
- Non-compliance (nivolumab) 
- Administrative reasons 
- Pregnancy 
 
 

 
 
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7 
PRE-TREATMENT EVALUATION: 
Investigations 
Timing 
History 
and 
Physical 
Exam 
including: 
• history including 
(occupational), smoking history 
• physical examination including 
height, weight, pulse, blood 
pressure 
• performance status (PS) 
Within 14 days of inclusion 
Haematology 
• CBC including haemoglobin, 
differential, platelet count 
Within 14 days of inclusion 
Biochemistry 
• AST (SGOT) and ALT (SGPT) 
• alkaline phosphatase 
• bilirubin 
• albumin  
• serum creatinine 
• lipase   
• fasting glucose 
• K, Cl, Na, Mg, Ca, P 
• LDH  
• CRP 
• TSH  (T3, T4 if TSH abnormal) 
• INR/APTT 
Within 14 days of inclusion 
Immunovirology 
• Serology EBV, HCV/HBV, CMV, 
Toxoplasmosis 
– 
TPHA-VDRL, 
HHV-8 
• Quantiferon 
Before inclusion 
• CD4/CD8 cell counts 
• HIV viral load (VL)  
• HCV/HBV VL, HHV-8 VL in the 
case of co-infection 
• EBV VL, CMV VL 
Within 28 days of inclusion ; those VL 
will be monitored further in case of 
positivity 
 
Radiology1 
• baseline CT brain, chest and 
abdomen (with iodine 
injection) (Wang 2004) 
• baseline PET-CT : highly 
recommended (but optional) 
(Ceresoli 2006b, von Schulthess 
2006, Francis 2007 ) 
Within 28 days of inclusion 
• other baseline imaging (e.g. 
bone scan,…) 
Required, within 28 days of inclusion, 
only if suspicious signs/symptoms are 
present  
Correlatives 
• tumour tissue for assessment of 
PD-L1 status 
From initial diagnosis block  

 
 
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• whole blood, serum, plasma for 
correlatives  
Prior to cycle 1, day 1 dosing 
Other 
Investigations 
• ECG 
Within 14 days of inclusion 
• pregnancy test if applicable 
 
Within 24hrs of first drug 
administration  
Adverse Event 
Baseline adverse event evaluation 
(to document residual adverse 
event from previous therapy and 
baseline symptoms) 
Within 14 days of inclusion 
Quality of Life 
LCSS questionnaire 
Within 14 days of inclusion 
8 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
8.1 Evaluation during Protocol Treatment 
Investigations 
Timing 
History and 
Physical Exam 
including: 
• physical examination including, pulse, 
blood pressure, weight 
• performance status 
Prior to each infusion until off 
protocol therapy 
 
Hematology 
• CBC including hemoglobin, differential, 
platelet count 
Prior to each infusion until off 
protocol therapy  
Biochemistry 
• 
AST (SGOT) and ALT (SGPT) 
• 
alkaline phosphatase, gamma GT 
• 
Bilirubin, LDH 
• 
albumin 
• 
creatinine, urea 
• 
lipase (and amylase if abnormal  
lipase) 
• 
fasting glucose 
• 
K, Cl, Na, Ca, Mg2+ 
• 
Urinary test 
Prior to each infusion until off 
protocol therapy 
• 
TSH (T3, T4 if TSH abnormal) 
• 
Antinuclear antibody and in case of 
positivity anti-ENA and anti-DNA; 
anti-thyroperoxydase, anti-
thyroglobulin 
Every 6 weeks,until off protocol 
therapy 
Immunolovirology 
(2) 
• 
Hbs antigen, HCV/HBV VL, HHV-8 VL 
in the case of co-infection 
• 
EBV VL, CMV VL,  
• 
 
Cycle 2, 3, 9, 15, 27, 51, end of 
treatment and in case of immune 
related adverse event. 
Every 3 cycles for Hbs antigen, 
HCV/HBV VL 

 
 
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Immunolovirology 
(1) 
• 
CD4/CD8 cell counts 
• 
HIV viral load (VL)  
 
Prior to each infusion until off 
protocol therapy 
Radiology* 
• CT-scan of chest and upper abdomen 
• Other imaging used for baseline tumoral 
assessment 
Every 8 weeks from randomization 
(CTs schedule must be maintained 
regardless of treatment delays) 
Other 
Investigations 
• ECG 
As clinically indicated 
• lung function tests: FEV1, FVC, TLCO and 
blood gas at room atmosphere 
Only if pulmonary symptoms or 
suspicion of pneumonitis  
• 
pregnancy test if applicable 
Every 3 cycles ± 1 weeks 
Correlatives  
• whole blood, serum, plasma 
Cycle 2, 3, 9, 15, 27, 51,  end of 
treatment and in case of immune 
related adverse event. 
Adverse Events 
patients must be evaluated at each visit for adverse events according to CTCAE 
v4 
Quality of Life 
• LCSS questionnaire 
Cycle 2, 3, 5, 7, 9  
* 
Radiology assessments must be kept to schedule irrespective of any delays in a treatment cycle. 
If the schedule cannot be kept all attempts must be made to undertake the required imaging as 
soon as possible. Thereafter, patients must be put back on original imaging schedule.  
8.2 Evaluation after protocol treatment 
Investigations 
Timing 
History and 
Physical Exam 
including: 
• physical examination including, pulse, 
blood pressure, weight 
• performance status 
Within 30 days following last 
treatment day 
 
Hematology 
• CBC including haemoglobin, 
differential, platelet count  
Within 30 days following last 
treatment day  
Biochemistry 
• 
AST (SGOT) and ALT (SGPT) 
• 
alkaline phosphatase 
• 
bilirubin 
• 
albumin 
• 
creatinine 
• 
lipase (and amylase if abnormal  
lipase) 
• 
fasting glucose 
• 
K, Cl, Na, Ca 
Within 30 days following last 
treatment day 
 
• 
TSH (T3, T4 if TSH abnormal) 
As clinically indicated 
Radiology* 
• CT-scan of chest and upper abdomen  Every 8 weeks  
Other 
• ECG 
As clinically indicated 

 
 
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Investigations 
• lung function tests: FEV1, FVC, TLCO 
and blood gas at room atmosphere 
As clinically indicated 
Adverse Events 
Patients must be evaluated for treatment related adverse events until 
resolution 
* Only for patients who have not yet discontinued the study treatment   
 
 

 
 
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9 
STUDY TREATMENT 
The study treatments are explained in table 1.  
Table 1. 
Active substance 
Nivolumab 
Commercial 
Name 
Opdivo© 
Pharmaceutical 
form 
Concentrate for solution for 
infusion 
Dosage 
10 mg/mL 
Posology 
3mg/kg 
Storage 
Store in refrigerator (2°C - 
8°C) in its original package in 
order to protect from light 
Laboratory 
BMS 
 
The treatment has to begin within 15 days following inclusion. 
These treatments will be labeled according to the regulation. These treatments will be 
administered until progression or limiting toxicities. 
Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial.   
Storage Conditions & Handling: 
 
Store at 2-8°C (36-46°F), protect from light, freezing, and shaking. 
 
If any temperature excursions are encountered during storage, please report these to 
IFCT for assessment via the Temperature Excursion Response Form.    
 
As with all injectable drugs, care should be taken when handling and preparing 
nivolumab. Whenever possible, nivolumab should be prepared in a laminar flow hood or 
safety cabinet using standard precautions for the safe handling of intravenous agents 
applying aseptic technique.  

 
 
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 
Partially used vials should be disposed at the site following procedures for the disposal 
of anticancer drugs.  
Use Time/Stability: Please refer to the appropriate section of the current Investigator 
Brochure or Addendum. Due to parameters surrounding the use time of nivolumab, the 
time of preparation should be noted in the Pharmacy Source documents [accountability 
logs] or in study files as required for investigator sponsored research [FDA and GCP] 
The administration of nivolumab infusion must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored up to 20 hours in 
a refrigerator at under refrigeration conditions (2°-°-8°C (, 36°-46°F) and used within 24 
hours, and a maximum of 4 hours of the total 24 hours can be at room temperature (20°-
25°C, 68°-77°F) and under room light. The maximum 4-hour period under room 
temperature and room light conditions for undiluted and diluted solutions of nivolumab 
injection in the IV bag includes the product administration period. 
 
Preparation and Administration: 
1. 
Visually inspect the drug product solution for particulate matter and discoloration prior 
to administration.  Discard if solution is cloudy, if there is pronounced discoloration 
(solution may have a pale-yellow color), or if there is foreign particulate matter other 
than a few translucent-to-white, amorphous particles. Note: Mix by gently inverting 
several times. Do not shake. 
2. 
Aseptically withdraw the required volume of nivolumab solution into a syringe, and 
dispense into an IV bag. If multiple vials are needed for a subject, it is important to use 
a separate sterile syringe and needle for each vial to prevent problems such as dulling 
of needle tip, stopper coring, repeated friction of plunger against syringe barrel wall. 
Do not enter into each vial more than once. Do not administer study drug as an IV push 
or bolus injection 
3. 
Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose 
Injection solution. It is acceptable to add nivolumab solution from the vials into an 
appropriate pre-filled bag of diluent. 
4. Note: Nivolumab infusion concentration must be at or above the minimum 
allowable concentration of 0.35 mg/mL [IBV15 Addendum Section 3.2.2] 
5. 
Note: It is not recommended that so-called “channel” or tube systems are used to 
transport prepared infusions of nivolumab. 
6. 
Attach the IV bag containing the nivolumab solution to the infusion set and filter. 

 
 
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7. 
At the end of the infusion period, flush the line with a sufficient quantity of approved 
diluents. 
10 TREATMENT BEYOND DISEASE PROGRESSION 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may 
have clinical benefits despite initial evidence of PD.  
Subjects treated with Investigational Treatment will be permitted to continue treatment 
beyond initial RECIST 1.1 defined PD – at 8 weeks CT scan assessment – if they meet all of 
the following criteria:  
 1. Investigator-assessed clinical benefit, and subjects do not have rapid disease 
progression  
 2. Continue to meet all other study protocol eligibility criteria  
 3. Good tolerance of study drug  
 4. Stable performance status  
After the 8 weeks CT-scan, a new CT-scan assessment should be performed within 4 weeks 
± 1 week from original PD scan to determine whether there has been a decrease in the 
tumour size or disease stabilization, or alternatively continued PD, which would terminate 
the trial treatment.  
 For the subjects who continue IP beyond progression, further progression is defined as an 
additional 10% increase in tumour volume from time of initial PD. This possibility has been 
introduced to take into account the pseudo-tumoral progressions sometimes observed 
under immune check-point inhibitors treatment. In case of the second evaluation would 
confirm disease progression and the clinical benefit no longer confirmed, the date of 
progression will be set at the date of the first CT-scan showing mRECIST criteria of 
progression (Wolchok 2009).  
In case of disease control, the experimental treatment will be given until disease 
progression (tumor assessment every 8 weeks ± 1 week). 
 
 

 
 
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11 SAFETY 
11.1  Definition of Adverse Events 
 
The term adverse event covers any unfavorable and unintended sign, symptom, syndrome, 
or illness that develops or worsens during the period of observation in the clinical study, 
reported for 100 days (3 months) post last treatment. 
Clinically relevant abnormal results of diagnostic procedures including abnormal laboratory 
findings (e.g., requiring unscheduled diagnostic procedures or treatment measures, or 
resulting in withdrawal from the study) are considered to be adverse events. 
Worsening of a sign or symptom of the condition under treatment will normally be 
measured by efficacy parameters. However, if the outcome fulfills the definition of 
“serious adverse event”, it must be recorded as such. 
The adverse event may be: 
• A new illness 
• Worsening of a concomitant illness 
• An effect of the study medication, including comparator 
• A combination of two or more of these factors 
No causal relationship with the study medication or with the clinical study itself is implied 
by the use of the term “adverse event”. 
Adverse events fall into the categories “non serious” and “serious”. 
Surgical procedures themselves are not adverse events; they are therapeutic measures for 
conditions that require surgery. The condition for which the surgery is required is an 
adverse event, if it occurs or is detected during the study period. Planned surgical 
measures permitted by the clinical study protocol and the condition(s) leading to these 
measures are not adverse events, if the condition(s) was (were) known before the start of 
study treatment. In the latter case the condition should be reported as medical history. 
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 participant to have study drug 
discontinued or interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
It is expected that wherever possible, the clinical rather than laboratory term would be 
used by the reporting investigator (eg, anemia versus low hemoglobin value). 

 
 
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11.2 Serious Adverse Events 
• Death. 
• Life-threatening.1 
• Unplanned hospitalization or prolongation of existing hospitalization (for > 24 hours). 2 
• Persistent or significant disability or incapacity.3 
• Pregnancy 
• Congenital anomaly or birth defect. 
• Is an important medical event.4 
• Drug-induced liver injury (DILI). 5 
1 “Life-threatening” means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe. 
2 The following hospitalizations are not considered SAEs: 
- 
Hospitalization < 24h 
- 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or to perform an efficacy measurement for the study) 
- 
Hospitalization for a preexisting condition, provided that all of the following 
criteria are met: 
o The hospitalization was planned prior to the study or was scheduled during 
the study when elective surgery became necessary because of the expected 
normal progression of the disease. 
o The patient has not experienced an adverse event. 
- 
Routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy) 
- 
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). 

 
 
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3 “Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions. 
4 Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred. 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above should also usually be considered 
serious. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse, 
or suspected transmission of an infectious agent (eg pathogenic or nonpathogenic) via the 
study drug, or overdose of treatment, or lab test abnormalities clinically significant. 
A diagnosis of cancer during the course of a treatment should be considered as medically 
important. The List of Critical Terms (1998 adaptation of World Health Organization 
Adverse Reaction Terminology Critical Terms List, provided in the “Instructions for 
completing the ‘Serious Adverse Event/Expedited Report from a Clinical Trial’ form”) 
should be used as guidance for adverse events that may be considered serious because 
they are medically important. 
5 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 DILI 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 se-rum 
alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and hyper-
bilirubinemia, 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. 
A hepatic AE management algorithm has been established according to nivolumab IB for 
appropriate management of DILI cases (cf; appendix II).  
 The following hospitalizations are not considered SAEs:  

 
 
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 
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). 
 
Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious”, which is based on the outcome or action criteria usually associated with events 
that pose a threat to life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
SAEs/AEs will be reported up to 100 days (3 months) for both study drugs, and SAEs 
notification will be made within 24 hours. 
11.3  Period of Observation 
For the purposes of this study, the period of observation for collection of adverse events 
extends from the date of signature of the informed consent until 100 days after the last 
day of study treatment except for adverse events related to study drug, which must be 
reported during follow-up period until resolution or initiation of further anti-tumor 
therapy. 
If an Investigator detects a serious adverse event in a study subject after the end of the 
period of observation, and considers the event possibly related to prior study treatment, 

 
 
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he or she should contact the Sponsor to determine how the adverse event should be 
documented and reported. 
At each visit/assessment AEs will be assessed from information collected from the source 
documents and information transcribed into the CRF. 
11.4  Documentation and Reporting of Adverse Events by Investigator 
All adverse events that occur during the observation period set in this protocol must be 
documented on the pages provided in the case report form in accordance with the 
instructions for the completion of adverse event reports in clinical studies. These 
instructions are provided in the case report form itself. 
The following approach will be taken for documentation: 
• All adverse events (whether serious or non-serious, or considered as an alert term) must 
be documented on the “Adverse Event” page of the case report form. 
• If the adverse event is serious, the investigator must complete, in addition to the 
“Adverse Event” page in the case report form, a “Serious Adverse Event/Expedited 
Report from a Clinical Trial” form at the time the serious adverse event is detected. 
This form will be filled in the eCRF. In case of unavailability of the eCRF, a paper form will 
be sent by email to sae@ifct.fr. 
Every attempt should be made to describe the adverse event in terms of a diagnosis. If a 
clear diagnosis has been made, individual signs and symptoms will not be recorded unless 
they represent atypical or extreme manifestations of the diagnosis, in which case they 
should be reported as separate events. If a clear diagnosis cannot be established, each sign 
and symptom must be recorded individually. 
All patients who have adverse events, whether considered associated with the use of the 
investigational products or not, must be monitored to determine the outcome. The clinical 
course of the adverse event will be followed up according to accepted standards of 
medical practice, even after the end of the period of observation, until a satisfactory 
explanation is found or the investigator considers it medically justifiable to terminate 
follow-up. All questions on the completion and supply of adverse event report forms and 
any further forms issued to the investigator at a later date to clarify unresolved issues 
should be addressed to the IFCT. 

 
 
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11.5  Immediate Reporting by Investigators to IFCT 
Serious adverse events and adverse events that fulfill a reason for expedited reporting to 
Pharmacovigilance must be documented on a “Serious Adverse Event/Expedited Report 
from a Clinical Trial” form in accordance with the “Instructions for completing the ‘Serious 
Adverse Event/Expedited Report from a Clinical Trial’ form”. This form must be completed 
and supplied to the Sponsor within 24 hours or at the latest on the following working day. 
The “Serious Adverse Event/Expedited Report from a Clinical Trial” form and the 
instructions are provided in the investigator’s study file. 
The initial report must be as complete as possible, including details of the current illness 
and (serious) adverse event, and an assessment of the causal relationship between the 
event and the investigational product(s). 
Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values received after the report) must be documented on a 
follow-up “Serious Adverse Event/Expedited Report from a Clinical Trial” form. 
The “Instructions for completing the ‘Serious Adverse Event/Expedited Report from a 
Clinical Trial’ form” give more detailed guidance on the reporting of serious adverse 
events, adverse events that comply with alert terms, and adverse events initially reported 
as non-serious that become serious. In the latter situation, when a non-serious event 
becomes serious, details must be forwarded immediately to the Sponsor on a “Serious 
Adverse Event/Expedited Report from a Clinical Trial” form. 
11.6 Pregnancy/Exposure Reporting 
If, following initiation of the investigational product, it is subsequently discovered that a 
study participant is pregnant or may have been pregnant at the time of investigational 
product exposure This means pregnancies occurring in female participants, female 
partners of male participants, or females exposed through direct contact with the agent 
during their pregnancy (for example, environmental exposure involving direct contact with 
the agent). Pregnancies occurring up to 6 months after the completion of nivolumab must 
also be reported. The investigational product will be permanently discontinued. 
The investigator is required to inform IFCT within 24 hours of learning of the pregnancy 
using the pregnancy reporting 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 reporting Form. 
 

 
 
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12 DOSE TOXICITIES AND ADJUSTEMENT 
12.1 Dose reductions 
There is no dose reduction for nivolumab. 
12.2 Dose Delay 
Nivolumab administration should be delayed for the following:  
 
Grade 2 pneumonitis 
 
Grade 2 or 3 diarrhea or colitis 
 
Grade 2 elevation in AST, ALT or total bilirubin 
 
Grade 2 or 3 creatinine elevation 
 
Symptomatic 
endocrinopathies 
(including 
hypothyroidism, 
hyperthyroidism, 
hypophysitis, adrenal insufficiency and diabetes) 
 
Grade 3 rash 
 
Any AE, laboratory abnormality or intercurrent illness which in the judgment of the 
investigator, warrants delaying the dose of study medication. 
Subjects who require delay of nivolumab should be re-evaluated weekly or more frequently 
if clinically indicated and resume nivolumab dosing when re-treatment criteria are met. 
12.3 Criteria to resume dosing 
Subjects may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤ 1 or baseline, with the following exceptions: 
 
Subjects may resume treatment in the presence of Grade 2 fatigue.  
 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity.  
 
Subjects 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.  
 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. Subjects with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible for retreatment 
if discussed with and approved by IFCT.  
 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with IFCT. 

 
 
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 
Subjects who delay study treatment due to any Grade ≥ 3 amylase or lipase 
abnormality that is not associated with symptoms or clinical manifestations of 
pancreatitis, may resume nivolumab when the amylase or lipase abnormality has 
resolved to Grade < 3. IFCT should be consulted prior to resuming nivolumab in such 
subjects. 
 
Dose delay of nivolumab which results in treatment interruption of > 6 weeks 
requires treatment discontinuation. 
12.4 Discontinuation of treatment 
Treatment with nivolumab should be permanently discontinued for any of the following: 
 
Any Grade ≥ 3 drug-related pneumonitis or interstitial lung disease 
 
Grade 4 colitis or diarrhea 
 
Grade ≥ 3 elevation in AST, ALT or total bilirubin 
 
Grade 4 creatinine elevation 
 
Grade 4 rash, grade 4 pruritus 
 
Grade 2 or 3 immune-related adverse reactions that persist despite treatment 
modifications or for inability to reduce corticosteroid dose to 10 mg prednisone or 
equivalent per day. 
 
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-
related reasons may be allowed if approved by IFCT. Prior to re-initiating treatment 
in a subject with a dosing delay lasting > 6 weeks, IFCT must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed. Periodic 
study visits to assess safety and laboratory studies should also continue or more 
frequently if clinically indicated during such dosing delays.  
 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing. 
12.5 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 is considered immuno-
oncology agents 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: 
o Gastrointestinal  

 
 
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o Renal  
o Pulmonary  
o Hepatic  
o Endocrinopathy  
o Skin  
o Neurological  
The above algorithms are found in Appendix II. 
12.6 Treatment of infusion reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to 
be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction was to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to IFCT and reported as an SAE if 
criteria are met. Infusion reactions should be graded according to NCI CTCAE (Version 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 subject until recovery from symptoms. The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg 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 (antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic 
medications indicateds for ≤ 24 hours). 
 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
subject 
with 
diphenhydramine 
50 
mg 
IV 
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor 
subject until resolution of symptoms. Corticosteroid and/or bronchodilator therapy 
may also be administered as appropriate. If the infusion is interrupted, then restart 

 
 
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the infusion at 50% of the original infusion rate when symptoms resolve; if no 
further complications ensue after 30 minutes, the rate may be increased to 100% of 
the original infusion rate. Monitor subject closely. If symptoms recur, then no 
further nivolumab will be administered at that visit. Administer diphenhydramine 
50 mg IV, and remain at bedside and monitor the subject until resolution of 
symptoms. The amount of study drug infused must be recorded on the electronic 
case report form (eCRF). 
 
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg should be administered at least 30 minutes before nivolumab infusions. If 
necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used. 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae [e.g., renal impairment, pulmonary infiltrates]. Grade 4: Life threatening; 
pressor or ventilatory support indicated) 
 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal 
saline and treat the subject as follows: Recommend bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg 
of 
a 
1:10,000 
solution 
injected 
slowly 
for 
IV 
administration, 
and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as 
needed. Subject should be monitored until the investigator is comfortable that the 
symptoms will not recur. Nivolumab will be permanently discontinued. Investigators 
should follow their institutional guidelines for the treatment of anaphylaxis. Remain 
at bedside and monitor subject until recovery of the symptoms. 
In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine or corticosteroids). 
13 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
13.1 Study design considerations 
The maximum sample size (N) is calculated based on α, β, and the expected effect size, 
using a test for single binomial proportion for a two-stage design with O’Brien-Fleming (OF) 

 
 
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stopping rules, allowing for early stopping for futility after Stage I. The software East 6.0 
was used 
13.2 Sample size assumption 
It is a phase II non randomized, multicenter, open study, assessing nivolumab efficacy. 
Tested hypothesis   
The hypothesis underscoring our study is that the disease is controlled (stable disease or 
response) in at least 57% of patients at first evaluation (8 weeks) of nivolumab therapy.   
H0: control rate ≤ 30% (unacceptable control rate) 
H1: control rate ≥ 57% (acceptable control rate) 
α=5% (one-sided), β=90% 
Step 1 (n=14 patients): ≤ 4 patients with a disease controlled  futility (H0 accepted) 
Final decision (n=28 patients): ≥ 13 patients with a disease controlled  rejected H0 
(positive trial) 
30 patients included, taking into account possible non eligible patients (5%) 
13.3 Analyzed Populations 
Subjects will be included according to the Intent-to-Treat (ITT) analysis. 
The safety population will comprise all patients included who receive at least one dose of 
treatment. 
The population of patients eligible will consist of patients ITT having no major deviation 
judged on the criteria of inclusion and non-inclusion. 
The protocol deviations will be reviewed by the principal investigators and classified minor 
or major deviations, and listed. 
13.4 Efficacy Analyses 
13.4.1 Primary endpoint analysis 
Analysis of the primary efficacy endpoint will be conducted on all eligible patients, based 
on the disease control rate after 8 weeks of treatment. Analysis of the primary efficacy 
endpoint will be also conducted on all patients (ITT analysis) as sensitivity analysis. 

 
 
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It will be presented associated with its 95% confidence interval. Patients for whom the 
answer cannot be evaluated will be considered as treatment failures. 
13.4.2 Secondary endpoints 
- Progression-free Survival (PFS) and Overall Survival (OS) 
PFS is defined as the time between the date of inclusion and the first date of documented 
progression or death due to any cause, whichever occurs first. Subjects who die without a 
reported progression will be considered to have progressed on the date of their death.  
Subjects who did not progress or die will be censored on the date of their last evaluable 
tumor assessment. 
The duration of overall survival is defined as the time elapsed between the date of 
inclusion and death. Subjects who did not die will be censored on the last date a subject 
was known to be alive. 
The median survival, 95% confidence intervals and an estimation of progression-free 
survival (PFS) and overall survival according to the Kaplan-Meier Method will be calculated 
using standard methods 
This analysis will be performed on all eligible patients. 
PFS and OS will be also conducted on all patients (ITT analysis) as a sensitivity analysis. 
- Tolerance 
The toxicity analysis will be performed on the safety population. 
13.5 Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be utilized to provide general oversight and safety 
considerations for this study. The DMC will provide advice to the Sponsor regarding actions 
the committee deems necessary for the continuing protection of subjects enrolled in this 
study. The DMC will be charged with assessing such actions in light of an acceptable 
risk/benefit profile for nivolumab. The DMC will act in an advisory capacity to IFCT and 
will monitor subject safety data for the study. 
The DMC will be advisory to the clinical study leadership team. The clinical study 
leadership will have responsibility for overall conduct of the study including managing the 
communication of study data.  

 
 
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The Intergroup 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 to the study conduct are 
required. 
A safety run will be done after the first 5 patients then every 10 patients (8 weeks follow 
up) and will be reviewed by the DMC in attempt to detect unexpected immunovirologic 
side effects, ie increase in HIV viral load, decrease of CD4 cell count or unexpected high 
frequency of IRIS. 
Details of the DMC responsibilities and procedures will be specified in the DMC charter. 
The DMC recommendations will be sent to ANSM for information. 
14 CORRELATIVE BIOLOGICAL STUDIES (“BIO-CHIVA2”) 
As for other trials previously conducted by the IFCT, several biological specimens will be 
centrally collected for correlative biological studies (BIO-CHIVA2). Two cores from archived 
or fresh paraffin embedded tissue specimens will be collected to perform IHC of PDL1 
expression on tumoral and immune cells and other phenotyping biomarkers associated with 
immune check point inhibitors efficacy (CD8, HLADR, interferon gamma and foxp3).  
Plasma will be also collected before treatment to evaluate the presence of circulating 
tumor DNA using a lung panel NGS approach. Presence, number of detected alterations and 
quantification of molecular alterations were correlated to the efficacy of nivolumab 
treatment.  
These analyses will be performed by the GRC-04 Theranoscan laboratory of P&M Curie Paris 
6 university (Pr Jacques Cadranel, Pr Marie Wislez, Dr Martine Antoine, Ms Nathalie 
Mathiot).  
 
Otherwise, the HLA class I restriction of CD8 T cell plays an important role in the antiviral 
response in term of both repertoire and avidity of the cellular response (Lissina AIDS. 2014 
Feb 20;28(4):477-86, Appay, Curr Opin HIV AIDS. 2011;6:157). But the efficacy of immune 
checkpoint inhibitors is based on the activation of the response of cytotoxic T cell.  This 
response could be modulated by the HLA class I restriction. The modulation by immune 
checkpoint inhibitors of CD4+ T cells antitumor function, restricted to HLA class II, has also 
been described (Pardoll Nature Reviews Cancer 2012 ; 12, 252 ; Kwek, Cancer Immunol 
Res. 2015;3:1008). A HLA class I and II typing by standard technique (PCR-SSO) with a 2-
digit resolution will be done in the biological study BIO-CHIVA-2 for all the patient and, 

 
 
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even more so, for patients experiencing immune related adverse events. This technique 
could be complemented by a technique with 4-digit alleles resolution.  
Furthermore, all genes which have a major interest in the response to immune check point 
inhibitor or in the occurrence of an event will be sequenced after the registration of a 
significant number of patients. For that purpose, a dried cell pellet of 5 to 10 millions of 
PMBC will be stored for the genetic study of relationships between cancer and HIV 
infection. 
14.1 Protocol for Immunology and Virology (Pitié Salpêtrière);  
Samples for cell bank, plasma and serum analysis will be made by a 68 mL blood sample 
before first nivolumab infusion, at cycle 2, 3, 9, 15, 27, 51, at the end of treatment , and 
in the case of immune adverse effect. The following tubes will be collected and sent to the 
centralized laboratory within 24h: 
- 
6 acid Citrate Dextrose tubes of 9 mL 
- 
2 EDTA tubes of 7 mL 
The plasma bank will measure the concentration of anti PD1 / PDL-1 and optionally the 
anti-antibody levels, and the residual HIV replication. The plasma dosage will also measure 
cytokines / chemokines and other inflammation markers based on scientific knowledge on 
the subject. The cell bank will: 1°/ assess the size of the HIV reservoir (cell-associated 
DNA), 2°/ assess the anti-HIV immune response (quantitative and qualitative study of 
antiviral T cells: count, polyfonctionality, expression of immune checkpoints ...), 3°/ 
assess the state of differentiation / activation of T cells expressing immune checkpoints, 
4°/ evaluate the immune responses against the other virus (EBV, CMV, hepatitis B and C, 
HHV-8) if co-infected, and 5°/ finally assess the anti-neoepitope CTL directed against 
tumor neoantigens. Finally, paraffin embedded tumor and peritumoral biopsies will be 
punched in centers in order to sample tumoral and healthy tissue; those punches will be 
rerouted to the immunology laboratory (Pitié Salpêtrière) in order to perform RNAseq 
studies, then identification of tumoral neo-epitopes by sequence alignment, HLA typing, 
and finally neoepitope prediction. If punch sample is not available, FFPE tumor slides will 
be rerouted to the Pitie Salpetrière hospital: 20µm thickness or 4x10µm thickness, for 
tumoral whole exome sequencing and definition of neoepitopes. 
 
 
 

 
 
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15 ADMINISTRATIVE SECTION  
15.1 Sponsor obligations 
Before the trial 
The sponsor will: 
 
Ensure regulatory requirements are met before the trial is implemented 
 
Ensure that all administrative procedures are in place for each department in the 
associated establishments 
 
Provide centres with the complete protocol and its appendices, the adverse event report 
form, CPP (Independent ethics committee) permission, statement of insurance and 
authorization from the French health authority (ANSM). 
The sponsor and their representatives will: 
 
Provide centres with the instructions and documents needed to conduct the trial 
properly (protocol, data collection form and investigator file) 
 
Organise an orientation session to train study investigators and coordinators (during 
this session, all protocol sections will be reviewed and how to fill out case report 
forms and study procedures will be explained) 
During the trial 
The sponsor and their representatives will: 
 
Regularly visit the investigating centres 
 
Be available at all times for consultation and remain in contact with the personnel 
of the investigating centre by email, telephone and/or fax 
 
Examine and evaluate the data in the case report form and look for possible errors 
in data collection 
In cooperation with the principal investigator, the sponsor will provide all of the 
investigators involved with the study with any new information that may interfere with 
conducting the trial. 
In terms of the trial 
It is the sponsor's responsibility to make sure that the procedures are completed at the end 
of the trial. 

 
 
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15.2 Investigator obligations 
The investigator agrees to conduct the study in compliance with the 1974 Declaration of 
Helsinki, revised in 1975 and 1989, good clinical practice, and French current regulations. 
In regards to the French law of 9 August 2004, the investigator from each centre agrees to 
collect the informed written consent from each patient participating in the trial. One copy 
of the consent form will be given to the patient and the other will be kept in the patient's 
clinical file. Patients must be able to give their informed consent freely and not be under 
guardianship or suffer from any type of mental impairment that may affect their 
judgement.  
The investigator also agrees to fill out the case report form needed for study follow-up. 
The investigator also agrees to: 
 
Inform the sponsor of any serious or unexpected adverse event occurring during 
the trial within the time periods described in chapter 7.1 using the appropriate 
form  
 
Agree to monitoring with access to source documents to validate data from the 
case report forms and if needed, agree to an internal or external audit by the 
sponsor or a representative from the regulatory authorities 
 
Archive trial documents (copies of case report forms, written consent forms) for 
a period of at least 15 years 
 
Include at least one patient during the first six months following the trial's 
implementation 
 
Make sure that there is no interference with another trial for the same 
indications 
 
Respect the confidentiality of the documents provided 
15.3 Ethical considerations 
Participant information and consent 
Before conducting this biomedical research on a person, they must provide their free, 
informed and express consent (including consent for genetic studies) after being informed 
of the purpose of the research, the study procedures and duration, the benefits, and 
potential risks and constraints of the study, as well as the type of product being 
researched and the opinion of the CPP (art. L.1122-1). 

 
 
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The patient and investigator or representing physician will personally date and sign the 
consent form (original copy archived by the investigator, a copy will be given to the patient or 
their legal representative). 
 
Request for CNIL authorisation for automated data processing 
This biomedical research will produce scientific information. This coded, directly or 
indirectly personal information is part of the legal framework of file use (Law n° 78-17 
from 6 January 1978 and law n° 94-548 from 1 July 1994) 
The sponsor (IFCT) has authorisation (n°1227585) to process personal data for the purpose of 
Biomedical Research on medication and diseases under the law of 20 December 1988 
modified by law n° 2004-806 of 9 August 2004. 
To the extent that this biomedical research is conducted within the strict regulatory and legal 
requirements (the "Huriet-Sérusclat" law of 20 December 1988 modified by law n° 2004-806 
of 9 August 2004) and according to standard methods, the CNIL has adopted a standard 
method (MR001 according to article 54 from the law of 6 January 1978 modified), which 
now covers all personal data processing conducted as part of biomedical research - 
including pharmacogenetic trials - as defined in the public health code, and commitment 
to comply with said method. 
15.4 Amendment and additional clauses procedures 
The study's principal investigator or sponsor will suggest any substantial change in the 
protocol, and will then inform the other party. This will be an amendment submitted to 
the CPP and AFSSAPS. No change can be made without agreement from the committee. The 
sponsor will inform each investigator and send them the amendment and related statement 
of intent. 
15.5 Quality control and assurance 
Regulatory considerations: medical procedures for this trial comply with the most recent 
recommendations from the Declaration of Helsinki and public health law no. 2004-806 of 9 
August 2004 related to the protection and safety of humans. 
Confidentiality: the protocol and its appendixes, as well as all of the data, are confidential 
as noted at the beginning of the protocol. 
Data monitoring: The IFCT's Clinical Research Unit will monitor this trial in order to ensure 
accurate, complete and reliable data collection. It will also provide logistical support to 

 
 
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investigating centres. An inspection by an employee obligated to professional secrecy 
mandated by Regulatory Authorities may be required to ensure that all of the source 
documents needed are available and that the clinical trial is being conducted according to 
Good Clinical Practices and the law from 9 August 2004.  
15.6 Study schedule 
The protocol should begin in June 2017. The trial recruitment period is expected to be 42 
months. The study will be ended one year after the last treatment of the last patient. The 
trial should be ended by December 2021.  
15.7 Early study termination 
The sponsor and coordinating investigator will issue any early termination of the study. The 
sponsor will provide written notification. This letter will be sent to the Agence Nationale 
de Sécurité du Médicament (French agency for the safety of health products) and to each 
investigator, as well as the CPP. 
15.8 Statement of commitment 
New investigators 
Investigators can only participate in the trial after submitting a written request to the 
sponsor. It should include the following items: 
 
A statement of commitment indicating the expected number of patients that 
the investigator can include in the protocol per year 
 
A recent CV with French medical board registration number 
Site opening 
Before inclusions can begin, a site must be officially opened; in other words, the 
investigator's name, institution, telephone and fax number, and email address must be 
duly issued to the sponsor, CPP and Ministry (initial and additional authorization statement). 
The investigator must have all of the documents needed to conduct the trial properly 
(protocol, investigator brochure, case report form). He must have obtained agreement from 
the facility's pharmacist to distribute treatments and resolve any problems with the study 
coordinator. He must have informed the director of his facility by letter of his participation. 
An agreement must be signed between the director of his facility and the sponsor. 

 
 
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15.9 Study organization 
The Steering Committee makes all of the decisions concerning the study's implementation, 
execution, analysis and reporting. It meets three times per year two times, and 
periodically sends information on the study's progress to investigators.  
It is comprised of members of the editorial board, study statisticians and a sponsor 
representative. 
The Coordination Centre will be the Clinical Research Unit (Unité de Recherche Clinique - 
URC) of the IFCT, located at 10 rue de la Grange-Batelière, 75009 PARIS. Its purpose is to 
ensure that the trial is being conducted as intended in the protocol: patient inclusion 
management, data collection, data management, SAE management, organization of 
investigator and committee meetings. It informs the Steering Committee of any issues 
concerning the trial's progress. 
Moreover, the Steering Committee can organize regular investigator meetings during which 
the files of included patients will be reviewed. The purpose of this review panel will be to 
jointly verify compliance and understanding of the eligibility criteria and treatment methods 
dictated by the protocol. In addition, it will conduct a progress analysis for retrospective 
validation.  
16 FINAL REPORT AND PUBLICATIONS 
Once the study is finished, a clinical trial report will be published by the study's principal 
investigators and statistician. The coordinating investigator will sign the final version of 
the clinical trial report for this study, and by doing so will indicate his approval of the 
report's analyses, results and conclusions.  
The key participants in a clinical study are the principal investigator, investigators, IFCT-
employee team members, and members of the management and scientific boards who all 
collaborate to various degrees from designing the trial to writing the final report. 
1. The coordinator can choose between first and last place. In both cases, he must have 
participated significantly in designing the trial, inclusions and writing the article. 
2. If the investigator chooses the first place, last place goes to the president, one of the 
secretaries, or one of the other elected members of the Management Board or 
Scientific Council. The person must be chosen based on their participation in 
designing the trial, inclusions and writing the article. If there is difficulty in 
choosing this person, a secret vote by the management board will decide. 

 
 
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3. If the investigator chooses the last place, the next-to-last place goes to the 
president, one of the secretaries, or another elected member of the Management 
Board or Scientific Council under the same conditions, unless he/she takes the first 
position if, in agreement with the principal investigator, he writes the article. If 
there is difficulty in choosing this person, a secret vote by the management board 
will decide. 
4. Investigators appear by the order in which eligible patients were included. All other 
investigators must appear in a list in the appendix. 
5. Two members of the same team cannot sign the same article unless one of them 
appears as a principal investigator (coordinator?), Management Board member, or 
Scientific Council member signing as such in first, second, or next-to-last place. 
6. Members of the IFCT employee team play a vital role in clinical studies. For this 
reason, those who were involved in designing the trial, managing it or writing the 
article must systematically appear in the acknowledgements or as signatories. The 
director will provide their names to the principal investigator (coordinator). If they 
appear as signatories, they cannot be included in the first six or last two positions. 
There can be no more than two if the number of signatories is more than 10, and 
only one if the number is equal to or less than 10. 
7. If a university statistician has worked on developing or processing trial data, he can 
sign with the approval of the principal investigator (coordinator) in a place on 
which they both agree (generally 3rd or 4th place). 
8. Under no circumstances can someone sign for having provided a patient with 
routine care that was unrelated to the research. 
9. All investigators (one per IFCT investigating centre) will be listed after each article 
in a table that may also include pathologists, surgeons and radiation therapists from 
the centre based on the article, so that this citation appears on Medline. 
10. For ancillary studies (biological, radiology, or others), if the article or abstract has 
a maximum of 10 signatures, the principal investigator (coordinator) of the 
biological study can choose between first and last position. In both cases, he must 
have participated widely in the study's design, financing, inclusions and writing the 
article. The rules above apply to last position if he chooses last position. Next-to-
last place can go to the research lab director who contributed most to the study. 
The last but two places can go to the study's principal investigator (coordinator) if it is 
not taken by the biological study's principal investigator. The first four places can 

 
 
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be taken by scientists or physicians, with the IFCT or not, who contributed the most 
to the ancillary study. This may also include the university statistician if suggested by 
the coordinating investigator and management board office, and validated by the 
management board. If there are a maximum of 10 signatures, three to four places in 
the middle will be reserved for the best clinical contributors (in the sense that they 
contributed the most in terms of pathology specimens). In the case of articles with 
20 signatures, two to three places will be reserved for pathologists who contributed 
the most to the study (either in collecting specimens or reviewing the IFCT's 
pathology panel). All of the labs that participated in the study shall be represented 
by one signatory, the remaining signatory places must be attributed to clinicians 
according to the rules above, including one permanent member of the IFCT team 
who contributed the most to the study (decision made by the CI + Director + 
President), as well as the CI for the clinical study. 
11. All articles should include the mention "…on behalf of IFCT" at the end of the 
signatories list, and include the acronym IFCT-XXYY in the title of the clinical trial 
to which the ancillary study is related. 
12. The IFCT can receive assistance with the English formatting of an article, but can 
never delegate the writing itself to an agency or industry. 
 
These rules were created and validated by the IFCT Management Board in September 2010. 
 
 

 
 
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APPENDIX I 
Exigences concernant la contraception 
Votre médecin investigateur a connaissance des différentes méthodes de contraception 
acceptables et pourra vous donner les conseils appropriés sur la meilleure méthode 
contraceptive vous concernant. 
Le tableau ci-dessous liste les différentes méthodes de contraception. 
 
Méthode de contraception 
Hautement efficace 
Contraceptif hormonal uniquement progestatif associé à 
l'inhibition de l'ovulation 
Méthodes hormonales de contraception, comprenant les 
pilules contraceptives orales combinées (estrogène + 
progestérone), anneau vaginal, produits injectables, les 
implants et les dispositifs intra-utérins (DIU) (ex: stérilet tel 
que  Mirena®) 
Parfois, 
les 
niveaux 
hormonaux 
des 
méthodes 
de 
contraception peuvent être affectés par le(s) produit(s) à 
l'étude. Votre médecin vous précisera quelles formes de 
contraception hormonales sont autorisées dans le cadre de  
cette étude 
Dispositif intra-utérin (DIU) non-hormonal (ex : stérilet 
ParaGard®) 
Ligature bilatérale des trompes 
Partenaire ayant subi une vasectomie 
Système hormonal intra-utérin (SIU) 
Abstinence totale 
Préservatif masculin pour les hommes ayant des partenaires 
susceptibles d’avoir des enfants 
Méthodes non autorisées 
Abstinence 
périodique 
(méthodes 
du 
calendrier, 
symptothermale, post-ovulation) Retrait (coït interrompu) 
Spermicides seuls  
Méthode de l'aménorrhée lactationnelle (MAMA) 
 
Vous devez utiliser une méthode de contraception hautement efficace (taux d’échec de 
moins d’1% par an), et en discuter avec votre médecin investigateur si vous débutez cette 
méthode pendant l’étude. 
Vous devez informer votre médecin investigateur si vous débutez une méthode de 
contraception non-autorisée pendant l’étude. 
 
 

 
 
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APPENDIX II 
 
  
 
 

 
 
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