Perioperative Treatment in Resectable Gastric Cancer With Spartalizumab (PDR001) in Combination With Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel (FLOT): A Phase II Study (GASPAR)
Phase: PHASE2
Conditions: Gastric Cancer by AJCC V8 Stage, Resectable Carcinoma
Sponsor: Centre Francois Baclesse

 
 
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Document référence DRCI CFB  V du 14/11/2019 
 
GASPAR TRIAL 
 
Perioperative 
Treatment 
in 
Resectable 
Gastric 
Cancer 
with 
Spartalizumab (PDR001) in Combination with fluorouracil, leucovorin, 
oxaliplatin, and docetaxel (FLOT): A phase II study (GASPAR) 
 
N°Eudract : 2020-004497-21 
Version 3.1 /2022 03 23 
 
This trial is granted by the French Cancer Institute  
(INCa reference CLIPPNo19-022, INCa_14824) 
 
REGLEMENTARY CLASSIFICATION OF TRIAL: RIPH 1 
 
SPONSOR 
Centre François Baclesse 
3 avenue du Général Harris 
14076 CAEN cedex 5 
Tél. : 02 31 45 50 50 – Fax : 02 31 45 51 58 
 
COORDONNATOR 
INVESTIGATOR 
 
Dr Mélanie DOS SANTOS 
Centre François Baclesse 
3 avenue du Général Harris 
14076 CAEN cedex 5 
 
 
COMPETENT 
AUTHORITY 
Agence Nationale de Sécurité 
des Médicaments (ANSM) 
Date of authorization:2021-01-20 
 
ETHIC COMMITTEE 
CPP of Ile de France VII 
Date of approval : 2021-01-18 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is the property of Centre François Baclesse and therefore is 
provided to you in confidence for review by you, your team, an applicable Ethics Committee/Institutional 
Review and regulatory authorities. It is understood that the information will not be disclosed to third 
parties without prior written approval from Centre François Baclesse, except to the extent necessary to 
obtain informed consent from those persons to whom the medication may be administered. 
 
 

 
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TABLE DES MATIERES 
1 
LIST OF ABBREVIATIONS .......................................................................................................................................... 4 
2 
SYNOPSIS ................................................................................................................................................................. 5 
3 
STUDY FLOW CHART ................................................................................................................................................ 9 
4 
SCIENTIFIC RATIONALE OF THE STUDY ................................................................................................................... 10 
4.1 
DISEASE EPIDEMIOLOGY ....................................................................................................................................... 10 
4.2 
CURRENT TREATMENTS ........................................................................................................................................ 10 
4.3 
MECHANISM OF ACTION OF PRODUCT ................................................................................................................. 10 
4.4 
STUDY RATIONALE AND PURPOSE ........................................................................................................................ 11 
4.5 
ANCILLARY STUDIES .............................................................................................................................................. 11 
5 
STUDY OBJECTIVES ................................................................................................................................................ 13 
5.1 
PRIMARY OBJECTIVE ............................................................................................................................................. 13 
5.2 
SECONDARY OBJECTIVES ...................................................................................................................................... 13 
5.3 
FURTHER ANCILLARY STUDIES .............................................................................................................................. 13 
6 
ENDPOINTS ............................................................................................................................................................ 13 
6.1 
PRIMARY ENDPOINT ............................................................................................................................................. 13 
6.2 
SECONDARY ENDPOINTS ...................................................................................................................................... 13 
7 
STUDY DESIGN ....................................................................................................................................................... 14 
7.1 
METHODOLOGY .................................................................................................................................................... 14 
7.2 
STUDY DURATION ................................................................................................................................................. 14 
7.3 
SUBJECTS SELECTION ............................................................................................................................................ 14 
7.3.1 
Inclusion criteria ............................................................................................................................................... 14 
7.3.2 
Non-inclusion criteria ....................................................................................................................................... 15 
7.4 
STUDY PLAN .......................................................................................................................................................... 15 
7.4.1 
Consent sign ..................................................................................................................................................... 15 
7.4.2 
Inclusion procedure .......................................................................................................................................... 15 
7.4.3 
Drug administration ......................................................................................................................................... 16 
7.4.4 
Surgery ............................................................................................................................................................. 16 
7.4.5 
Premedication .................................................................................................................................................. 17 
7.5 
SCHEDULE OF ASSESSMENT .................................................................................................................................. 17 
7.5.1 
Inclusion Assessments ...................................................................................................................................... 17 
7.5.2 
Assessments during treatment ......................................................................................................................... 17 
7.5.3 
End of treatment assessments ......................................................................................................................... 19 
7.5.4 
Follow-up assessments ..................................................................................................................................... 19 
7.6 
CRITERIA FOR PREMATURE WITHDRAWAL ........................................................................................................... 19 
7.7 
CONCOMITANT MEDICATION ............................................................................................................................... 20 
8 
PHARMACEUTICAL FORM OF STUDY MEDICATION: SPARTALIZUMAB ................................................................... 21 
8.1 
PRESENTATION OF THE PRODUCT ........................................................................................................................ 21 
8.2 
PACKAGING AND LABELLING ................................................................................................................................ 21 
8.3 
STORAGE CONDITIONS ......................................................................................................................................... 21 
8.4 
METHOD OF ADMINISTRATION ............................................................................................................................ 21 
8.5 
LABEL .................................................................................................................................................................... 21 
9 
DOSE ADJUSTMENTS OF ANTICANCER PRODUCTS ................................................................................................. 21 
9.1 
GENERAL RULES .................................................................................................................................................... 21 
9.2 
DOSE LEVELS ......................................................................................................................................................... 22 
9.3 
ADJUSTEMENT FOR FLOT REGIMEN...................................................................................................................... 22 
9.3.1 
Dose Modifications for hematologic toxicity .................................................................................................... 22 
9.3.2 
Dose Modifications for oxaliplatin neurologic toxicity ..................................................................................... 23 
9.3.3 
Dose modifications for diarrhea ....................................................................................................................... 23 
9.3.4 
Dose modification for liver toxicity ................................................................................................................... 24 
9.3.5 
Dose modification for mucositis or hand-foot syndrome ................................................................................. 24 
9.3.6 
Adjustments for cardiac toxicity ....................................................................................................................... 24 
9.3.7 
Adjustments for Docetaxel hypersensitivity reaction ....................................................................................... 24 

 
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9.3.8 
Adjustments for other toxicities ....................................................................................................................... 24 
9.4 
ADJUSTMENT FOR SPARTALIZUMAB .................................................................................................................... 25 
9.4.1 
Management of infusion-reactions related to Spartalizumab ......................................................................... 25 
9.4.2 
Toxicity management guidelines for immune-related AEs associated with Spartalizumab ............................. 26 
10 
BIOLOGICAL BANKING FOR FURTHER ANCILLARY STUDIES .................................................................................... 29 
10.1 
TUMOR SAMPLES.................................................................................................................................................. 29 
10.2 
BLOOD SAMPLES ................................................................................................................................................... 29 
10.3 
SAMPLING SCHEDULE FOR BIOLOGICAL SAMPLES................................................................................................ 29 
11 
EFFICACY AND SAFETY CRITERIA ............................................................................................................................ 30 
11.1 
EFFICACY CRITERIA................................................................................................................................................ 30 
11.2 
SAFETY CRITERIA ................................................................................................................................................... 30 
12 
SAFETY ................................................................................................................................................................... 30 
12.1 
GENERAL RULES - INSTRUCTIONS ......................................................................................................................... 30 
12.2 
DEFINITIONS ......................................................................................................................................................... 30 
12.2.1 
Adverse Event (AE) ....................................................................................................................................... 30 
12.2.2 
Adverse Reaction ......................................................................................................................................... 31 
12.2.3 
Serious Adverse event .................................................................................................................................. 31 
12.2.4 
Suspected Unexpected Adverse Reaction .................................................................................................... 31 
12.3 
INVESTIGATOR’S RESPONSABILITIES..................................................................................................................... 31 
12.3.1 
Detection and registration of adverse events .............................................................................................. 31 
12.3.2 
All AEs have to be searched, reported and recorded, processed and evaluated. ........................................ 31 
12.3.3 
SAE reporting process .................................................................................................................................. 32 
12.3.4 
Special cases ................................................................................................................................................ 33 
13 
STATISTICAL CONSIDERATIONS .............................................................................................................................. 34 
13.1 
NUMBER OF SUBJECTS .......................................................................................................................................... 34 
13.2 
STATISTICAL ANALYSIS .......................................................................................................................................... 34 
14 
QUALITY CONTROL ................................................................................................................................................ 35 
14.1 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ..................................................................................... 35 
14.2 
QUALITY ASSURANCE ............................................................................................................................................ 36 
15 
ETHICS AND REGULATORY CONSIDERATIONS ........................................................................................................ 36 
15.1 
CLINICAL TRIAL AUTHORISATION .......................................................................................................................... 36 
15.2 
INFORMATION OF PATIENTS INVOLVED IN THE RESEARCH .................................................................................. 37 
15.3 
INVESTIGATOR RESPONSIBILITIES ......................................................................................................................... 37 
15.4 
DATA CONFIDENTIALITY ....................................................................................................................................... 38 
16 
DATA AND DOCUMENTS KEEPING ......................................................................................................................... 38 
16.1 
DATA EBTRY AND HANDLING ................................................................................................................................ 38 
16.2 
ARCHIVING ............................................................................................................................................................ 38 
16.3 
PUBLICATION POLICY ............................................................................................................................................ 38 
17 
FUNDING AND INSURANCE .................................................................................................................................... 39 
17.1 
FUNDING .............................................................................................................................................................. 39 
17.2 
INSURANCE ........................................................................................................................................................... 39 
18 
REFERENCES ........................................................................................................................................................... 39 
 
 

 
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1 LIST OF ABBREVIATIONS  
AE 
adverse event 
AESI 
adverse even of special interest 
ANC 
absolute neutrophil count 
ALT 
alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
CPS 
combined positive score 
DFS 
disease-free survival 
CA 19.9 
carbohydrate antigen 19.9 
CBC 
complete blood cells count 
CEA 
carcinoembryonic antigen 
CI 
confidence intervals 
CPS 
combined positif score 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
D 
Day  
DNA 
deoxyribonucleic acid 
DFS 
Disease-progression Free Survival 
EBV 
epstein–barr virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDTA 
ethylene diamine tetra-acetic acid 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
G-CSF 
granulocyte colony stimulating factor 
GEJ 
gastroesophageal junction  
GGT 
gamma glutamyltransferase 
GOJ  
gastroesophageal junction 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IHC 
immunohistochemistry 
MASCC 
multinational Association of Supportive Care in Cancer 
MRI 
magnetic resonance imaging 
MSI 
microsatellits instability 
NSAID 
nonsteroidal anti-inflammatory drugs 
NYHA 
New York Heart Association 
NCI 
national cancer institute 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
pCR 
pathological complete regression 
PCR 
polymerase chain reaction 
PD-1 
programmed death-1 
PD-L1 
programmed death-ligand 1 
PD-L2 
programmed death-ligand 2 
QTc 
corrected QT interval 
RECIST 
response evaluation criteria in solid tumors 
SAE 
serious adverse event 
T4 
serum thyroxine 
TAP 
thorax, abdomen and pelvis 
TMB 
tumor mutational burden 
TSH 
thyroid stimulating hormone 
ULP 
upper limit of normal 
WBC 
white blood cell count 

 
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2 SYNOPSIS  
TITLE 
Perioperative Treatment in Resectable Gastric Cancer with Spartalizumab (PDR001) in 
Combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT): A phase II 
study (GASPAR) 
Coordinator 
Dr Mélanie DOS SANTOS 
Indication 
Resectable gastric or gastroesophageal junction adenocarcinoma 
Design 
Multicenter, open-label, nonrandomized, phase 2 trial 
Objectives 
Main objective 
To evaluate the pathologic response after pre-operative treatment 
Secondary objectives 
- To evaluate the impact of perioperative treatment on survival outcomes (disease-
free and overall survival) 
- To evaluate the histological R0 resection margin  
- To establish the association between pCR and survival outcomes outcomes 
(disease-free and overall survival) 
- To determine the safety profile of the combination Spartalizumab + FLOT regimen 
- To evaluate the post-operative morbidity and mortality 
Exploratory end point: 
To constitute biological collections (blood, tumoral tissue) for further biological 
explorations such as: 
- Evaluation of the impact of biomarkers (ctDNA and tissue) in terms of oncological 
outcomes and response to treatment 
 
These biomarkers may include: 
❖ ctDNA levels over time 
❖ PD-L1 expression measured as the CPS 
❖ MSI status 
❖ EBV status 
❖ TMB 
- Exploration of tumor organoid cultures 
Judgement 
criteria 
 
Main criterion 
The primary endpoint is the proportion of patients with pCR in the primary tumour 
defined as: no tumour residue found in the tissue collected during the surgery evaluated 
by the pathologist 
Secondary criteria 
The secondary endpoint are: 
- 
Disease-free survival (DFS) defined as time between inclusion and first progression 
according to RECIST v1.1 criteria or death whatever cause (in the absence of 
progression); patients without disease progression or death at the time of analysis 
will be censored at the time of the latest date of assessment 
- 
Overall survival (OS) defined as the time between inclusion and death whatever 
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 aliv. 
- 
Proportion of patients with margin-free resection (R0), defined as a microscopically 
margin-negative resection, in which no gross or microscopic tumor remains in the 
primary tumor bed 
- 
Correlation between pCR and DFS  

 
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- 
Correlation between pCR and OS 
- 
Toxicities of the combination Spartalizumab + FLOT regimen according to NCI 
CTCAE criteria v5.0 
- 
Post-operative morbidity, defined post-operative complications grades II-V according 
to Clavien-Dindo classification during surgery, within 30 days after surgery or during 
the hospital stay 
- 
Post-operative mortality, defined as the rate of patients died due to any cause during 
the 30 days post-surgery 
Inclusion 
criteria 
- 
Age ≥ 18 years 
- 
Untreated localized gastric or GEJ adenocarcinoma considered resectable (clinical 
stage ≥cT2 and/or cN+ and no metastasis) 
- 
Histologically confirmed adenocarcinoma 
- 
ECOG performance status score of 0 or 1 
- 
Tumor tissue must be provided for biomarker analyses (fresh or archival with an 
FFPE tissue block) 
- 
All subjects must consent to allow the acquisition of blood samples for performance 
of correlative studies 
- 
Screening laboratory values must meet the following criteria: 
o WBC ≥ 2000/ mm³ 
o Neutrophils ≥ 1500/ mm³ 
o Platelets ≥ 100 000/ mm³ 
o Hemoglobin ≥ 9.0 g/dL 
o Bilirubin ≤ 1.5 x ULN, AST and ALT ≤ 3 x ULN 
o Measured or calculated creatinine ≥ 50 ml/min clearance (CrCl) (using the 
Cockcroft-Gault formula)  
o Potassium ≥ LLN 
o Magnesium ≥ LLN 
o Calcium ≥ LLN 
- 
Female subject of childbearing potential must have a negative urine or serum 
pregnancy test within 72h before study start 
- 
Subject in reproductive age must be willing to use adequate contraception during the 
study and at least 9 months in men and 12 months in women after the last dose of 
investigational drug. In addition, given the toxicities observed on the male 
reproductive system, a conservation of gametes will be proposed for men, as usually 
in routine practice 
- 
Subject affiliated to a social security regimen 
- 
Patient has signed informed consents obtained before any trial related activities and 
according to local guidelines 
Non inclusion 
criteria 
- 
Subject with any distant metastasis 
- 
Subject with no recovering from the effects of major surgery or significant traumatic 
injury within 14 days before inclusion 
- 
Documented significant cardiovascular disease within the past 6 months before the 
first dose of study treatment, including: history of congestive heart failure (defined as 
NYHA III or IV), myocardial infarction, unstable angina, coronary angioplasty, 
coronary stenting, coronary artery bypass graft, cerebrovascular accident or 
hypertensive crisis 
- 
History of anterior organ transplant, including stem cell allograft 
- 
Pneumonitis or interstitial lung disease 
- 
History of other malignancy within the previous 3 years (except for appropriately 
treated in-situ cervix carcinoma and non-melanoma skin carcinoma) 
- 
Subject with active, known, or suspected autoimmune disease 
- 
Subject with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 
days of start of study treatment 

 
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- 
Known history of HIV or HBV infection 
- 
Known active HCV infection 
- 
Known history of active tuberculosis 
- 
Vaccination with live vaccine within 30 days before the first dose of study treatment 
- 
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or 
drug specifically targeting T-cell co-stimulation or checkpoint pathways 
- 
Recent or concomitant treatment with brivudine (herpes virostatic) 
- 
Prior anticancer therapy for the current malignancy 
- 
Known hypersensitivity to any of the study drugs or their excipients 
- 
Chronic inflammable gastro-intestinal disease 
- 
Uracilemia ≥ 16 ng/ml 
- 
QT/QTc > 450 msec for men and > 470 msec for women 
- 
Peripheral neuropathy ≥ Grade II 
- 
Uncontrolled diabetes 
- 
Active infection requiring systemic therapy 
- 
Participation in another therapeutic clinical study 
- 
Patient deprived of liberty or placed under the authority of a tutor 
- 
Patient assessed by the investigator to be unable or unwilling to comply with the 
requirements of the protocol 
Experimental 
Plan  
 
Patients should initiate the combination treatment by FLOT regimen plus Spartalizumab 
within 7 days after inclusion. 
Systemic treatment will include: 
• 
a pre-operative neoadjuvant 8-week phase of treatment  
• 
a post-operative 8-week phase of treatment 
The administered treatment will be as follows: 
❖ Standard FLOT regimen 
▪ Docetaxel 50 mg/m² IV infusion on D1 
▪ Oxaliplatine 85 mg/m² IV infusion on D1 
▪ Leucovorin 200 mg/m² IV infusion on D1 
▪ Fluorouracile 2600 mg/m² 24 h IV infusion on D1 
This regimen will be administered every two weeks (q2w) for 4 pre-operative cycles (8 
weeks) and 4 post-operative cycles (8 weeks)  
❖ Spartalizumab PDR001 
Patients will received the fixed dose of 400 mg per IV infusion on D1 every four weeks 
(q4w) for 2 pre-operative cycles (8 weeks) and 2 post-operative cycles (8 weeks) 
 
 
 

 
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Surgery 
For patients with confirmed resectability of the tumor by an imaging assessment (thoraco-
abdominopelvic CT-scan and optional MRI and endoscopy), surgery will be realized 
within 4-6 weeks after the last dose of preoperative chemotherapy. 
• For gastric tumors: surgery will consist on a total or subtotal distal (for antropyloric 
tumors) gastrectomy with D2 lymphadenectomy 
• For type 1 GEJ tumors: transthoracic esophagectomy (Ivor-Lewis procedure) with 
resection of the proximal stomach and 2-field (mediastinal and abdominal) 
lymphadenectomy 
• For type 2 or 3 GEJ tumors: gastrectomy with transhiatal distal oesophagectomy and  
D2 lymphadenectomy 
Post-operative systemic treatment will be initiated within 4-10 weeks after surgery. 
Statistical 
considerations 
We used an optimal Simon’s two stage phase II design to estimate the sample size. 
According to Al-Batran S-E et al outcomes1, 16% [95%CI: 10-23] of complete responses 
have been observed in the study (n=128). Assuming a histological complete response of 
10% as unacceptable (lower CI limit), and ≥23% as acceptable (upper CI limit), with 
=5% and 1-=80%, 58 assessable patients are required (including 20 in the first stage). 
Taking into account that 15% of patients will be lost or unevaluable, we plan to include a 
total of 67 patients in the present trial (23+44). 
A safety analysis has been planned and performedone month’s follow-up after the 
surgery of 10th patient. Enrolment has been halted during this safety analysis after 
inclusion of 10 patients.  
Safety analysis of FLOT plus immunotherapy in neoadjuvant treatment on 10 patients 
showed tolerance observations consistent with the safety profile of similar association in 
this setting. No safety signal that may have compromised the pursuit of the trial was 
noticed.  
Similarly, the type and frequency of toxicities observed during the peri-operative period (up 
to one month post-surgery) were in line with events usually observed in this setting and 
compatible with the pursuit of the trial. No death was observed. 
Overall, the IDMC recommends the Sponsor to pursue the study without modification but 
to plan a second formal safety analysis after the inclusion of the 30th patient. 
To be noticed, data concerning surgical pathologic response were available for 9 patients 
included in the first safety analysis, and reported in the file presented to the IDMC. The 
results fulfilled the futility criterion of the Simon design. In this context, the IDMC indicated 
the planned interim analysis will have no more decisional impact on the pursuit of the 
study. It therefore recommended not to realise the planned interim analysis but to include 
available efficacy data in the second safety report, to assess the benefit/risk ratio of the 
combination as approved by authorities. 
Participating 
centres 
Around 16 centres  
Ancillary 
studies 
Tumor Tissue Collection and Correlative Studies Blood Sampling will be done:   
• Mandatory tumor tissue (fresh or archival with an FFPE tissue block) at inclusion, 
before treatment 
• Mandatory blood samples at inclusion before chemotherapy initiation, after pre-
operative treatment, after surgery, after post-operative treatment and 3 months from 
the end of treatment 
• Optional fresh tumor biopsies and Peripheral Blood Mononuclear Cell (PBMC) at 
inclusion, before treatment (only at Centre François Baclesse site) 
Study duration 
Study duration : 72  months approximately 
Enrollment period : 30 months 
Treatment period : 8 months 
Follow-up period : Up to disease progression 
 

 
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3 STUDY FLOW CHART 
 
Before 
inclusion 
(within 28  
days prior 
inclusion) 
DURING TREATMENT  
End of 
treatment 
30 days after 
the end of 
treatment  
(+/- 7 days) 
Follow-up  
every 3 
months  
up to 
progression  
(+/- 15 days) 
 
Overall 
survival  
after disease 
progression  
Pre-operative treatment 4 
+/- 3 days 
Before 
SURGERY 
Post-operative treatment 5 
+/- 3 days 
D1 
D15 
D29 
D43 Within 3 weeks 
before surgery D1 
D15 
D29 
D43 
FLOT (q2w) 
Spartalizumab PDR001 (q4w)  
 
◆ 
◆ 
◆ 
 
◆ 
◆ 
◆ 
 
 
◆ 
◆ 
◆ 
 
◆ 
◆ 
◆ 
 
 
 
 
 
 
 
 
 
 
 
 
No study 
visit is 
required. 
The 
following 
treatment/ex
amns are at 
the 
discretion of 
physician  
 
Signed Informed Consent before any study 
procedures 
✓ 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment 
Physical examination including weight, ECOG, vital signs 
Adverse Events collection and concomitant treatments 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
✓ 
Biological assessment 
Hematology and biochemistry1 
 
✓ 
✓2,3 
✓3 
✓3 
✓3 
✓ 
✓3 
✓3 
✓3 
✓3 
✓ 
 
Uracilemia 
✓ 
 
 
 
 
 
 
 
 
 
 
 
Urine or serum pregnancy test 
 
✓3 
 
✓3 
 
 
✓3 
 
✓3 
 
 
 
Thyroid-function: TSH, free T4 
✓ 
✓2 
 
✓3 
 
✓ 
✓3 
 
✓3 
 
✓ 
 
Tumor markers: CEA, CA 19.9 
✓ 
✓2 
 
 
 
✓ 
✓3 
 
 
 
✓ 
 
ECG 
✓ 
✓7 
✓7 
✓7 
✓7 
 
✓7 
✓7 
✓7 
✓7 
 
 
CT-scan (thoracic and abdomino-pelvic) 
MRI optional 
✓ 
✓ 
 
 
 
 
✓ 
✓ 
 
 
 
 
✓ 
✓ 
✓8 
✓ 
Endoscopy 
✓9 
 
 
 
 
✓ 
optional 
 
 
 
 
 
 
Blood samples for translational research10 
✓ 
 
 
 
 
✓  
✓  
 
 
 
✓  
✓6 
 
1 
CBC-platelets, Creatininemia, kaliema, magnesemia, calcemia, albumin, glycemia, lipase, bilirubin, ALT, AST, GGT 
2 
Only if realized more 3 days before D1 
3 
Within 3 days before treatment administration 
4 
The initial combination treatment by FLOT regimen plus Spartalizumab should be initiated within 7 days after inclusion 
5 
The combination treatment by FLOT regimen plus Spartalizumab should be initiated within 4-10 weeks after surgery 
6 
Blood sample only for follow-up at 3 months  
7 
To be realized before and after oxaliplatin intravenous infusion 
8 
Every 3 months (+/- 15 days) for the first 2 years and every 6 months (+/- 1 month) for the next 3 years  
9 
Within 6 weeks prior to inclusion with available archival tumor (otherwise, fresh tumor) 
And optional fresh tumor biopsies only at François Baclesse site for organoids research (additional specific consent form) 
10 
Mandatory blood samples for ctDNA 
   
And optional PBMC at baseline only at François Baclesse site for organoids research (additional specific consent form). 

 
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4 SCIENTIFIC RATIONALE OF THE STUDY 
4.1 DISEASE EPIDEMIOLOGY 
Gastric cancer is one of the most common and deadly cancers worldwide. It represents the fifth 
most common cancer and the third leading cause of cancer deaths in the world.2 Perioperative 
chemotherapy and surgery is a standard of care for patients with resectable gastric or GEJ 
adenocarcinoma. Despite this combination of treatment, the prognosis remains poor for this 
population.  
4.2 CURRENT TREATMENTS 
Perioperative treatment was considered as the standard compared to surgery alone according to 
the MAGIC Trial, evaluating ECF (epirubicin, cisplatin and fluorouracile), 3 pre- and 3 post-
operative cycles, compared to surgery alone.3 This large randomized trial was conducted among 
503 patients with resectable locally advanced gastric or GEJ adenocarcinoma, and showed an 
improved OS with a 5-year survival rate of 36% versus 23% for surgery alone. However, in a 
controlled open-label phase 2/3 trial, conducted among 716 patients, the FLOT regimen 
(fluorouracil, leucovorin, oxaliplatin, and docetaxel), 4 pre- and 4 post-operative cycles, was 
associated with better results compared to ECF as perioperative chemotherapy.4 OS was 
increased in the FLOT group compared with the ECF group with a median overall survival of 50 
months versus 35 months. Moreover, there was a higher proportion of pCR: 16% [95% CI: 10–23] 
versus 6% [95% CI: 3–11].1 Furthermore, a recent meta-analysis investigated the impact of pCR on 
survival outcomes among 1143 patients with resectable gastric or GEJ cancer, after neoadjuvant 
chemotherapy and radical surgery.5 pCR was clearly associated with lower risk of death and 
recurrence compared with patients with any residual disease. 
The FLOT regimen is now considered as the new standard chemotherapy regimen for 
perioperative strategy of resectable gastric or GEJ adenocarcinoma. However, the 5-year OS rate 
remains only at 45% following radical surgery.4 New approaches are needed to improve these 
outcomes. 
4.3 MECHANISM OF ACTION OF PRODUCT 
PD-1 is a critical immune checkpoint receptor. Engagement of PD-1 by its ligands, PD-L1 and PD-
L2, transduces a signal that inhibits T-cell proliferation, cytokine production, and cytolytic function, 
attenuating tumor immunity and facilitating tumor progression.6 PD-1 and its ligand PD-L1 are 
expressed on up to 50% of gastric or GEJ tumors, with a controversial impact on survival.7,8  
Immunotherapy with antibodies that inhibit PD-1/ PD-L1 interaction has recently emerged as a new 
treatment option with promising and encouraging early trial results for patients with advanced or 
metastatic gastric or GEJ adenocarcinoma.9 Muro et al, conducted a phase 1b trial (KEYNOTE-
012) with 39 patients with PD-L1-positive advanced gastric or GEJ adenocarcinoma to investigated 
the safety and activity of the anti-PD-1 antibody pembrolizumab.10 Pembrolizumab demonstrated a 
22% objective response rate with a manageable toxicity profile. Fuchs et al, conducted a phase II 
trial (KEYNOTE-059) with pembrolizumab monotherapy in 259 patients with previously treated 
advanced gastric and GEJ cancer (at least 2 lines of treatment).11 They showed durable 
responses, with great response rate, especially for PD-L1–positive tumors. Results from these 
studies allowed approval of pembrolizumab by the US FDA as third line treatment for patients with 
advanced or metastatic gastric or GEJ cancer PD-L1–positive. Moreover, an update of the 
KEYNOTE-059 trial demonstrated a manageable safety and promising efficacy of first-line 
immunotherapy combined with chemotherapy (cisplatin and fluorouracil).12 In a first-line study 
(KEYNOTE-062), Shitara et al showed encouraging benefit with pembrolizumab versus 
chemotherapy among patients with untreated advanced gastric and GEJ cancer with higher levels 

 
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of PD-L1 and microsatellite instability–high (MSI-H) tumours.13 The CheckMate 649 trial recently 
showed that nivolumab and chemotherapy versus chemotherapy alone improved OS and PFS as 
first-line treatment in patients with non-HER-2-positive advanced gastric, GEJ or oesophageal 
cancer.14 
Currently, no trials have investigated the impact of neoadjuvant immunotherapy in combination with 
chemotherapy for resectable gastric or GEJ adenocarcinoma. Nevertheless, some studies suggest 
a change in the tumor immune micro-environment following neoadjuvant chemotherapy in locally 
advanced gastric cancer, with an increased expression of immune markers.15 Tumor samples, 
before and after neoadjuvant chemotherapy, of 60 patients with locally advanced gastric cancer 
were retrospectively identified and analyzed by multiplex immunohistochemistry, with a panel 
including PD-1 and PD-L1. Following neoadjuvant chemotherapy, the overall median expression 
levels of PD1 and PD-L1 were significantly increased. Moreover, high upregulation levels of these 
checkpoint molecules were correlated with survival benefits.  
4.4 STUDY RATIONALE AND PURPOSE 
All these data are encouraging in the use of immunotherapy in combination with perioperative 
chemotherapy, with the aim of improving treatment efficacy and survival outcomes.  
PDR001 (Spartalizumab) is a high-affinity, ligand-blocking, humanized Immunoglobulin G4 
antibody directed against PD-1 that blocks the binding of PD-L1 and PD-L2. Spartalizumab has 
demonstrated pharmacodynamic activity and a favorable toxicology profile in preclinical studies. 
The available safety data from clinical studies indicate that PDR001 is generally well tolerated. 
As of the safety cut-off date of 26-Mar-2020, 1702 patients across the 17 Novartis-sponsored 
clinical studies described have been treated with PDR001. In the open label multicenter phase I/II 
study of the safety and efficacy of PDR001 administered to patients with advanced malignancies, 
the results of phase I dose escalation among 58 patients have been published.16 The maximum 
tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W 
or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those 
typical of other PD-1 antibodies. In this phase I trial 16, the most common treatment-related adverse 
events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), 
and nausea (10%). 
In this study, we aim to evaluate the efficacy and safety of Spartalizumab in combination with the 
FLOT regimen as perioperative treatment for resectable gastric or GEJ adenocarcinoma. 
4.5 ANCILLARY STUDIES 
The Cancer Genome Atlas studies have identified four molecular subgroups of gastric cancer: 
tumors positive for EBV, MSI tumors, genomically stable tumors, and tumors with chromosomal 
instability.17 Immune-checkpoint blockade seems to have durable antitumor activity and improved 
survival in a subset of patients with PD-L1-expressing, MSI, and EBV-positive tumors.18  
Moreover, a recent study, showed that TMB high was independent predictor of prolonged PFS for 
patients with advanced gastric cancer treated with immune checkpoint blockade.19 ctDNA has 
shown potential in some studies as a biomarker with predictive and prognostic implications. 
Correlation of ctDNA with treatment response has been noted, implicating a possible role in 
monitoring treatment response.20 
However there is a need to confirm this data and for additional predictive biomarkers to improve 
patient selection, especially in the neoadjuvant setting.  
Organoids (and cancer-derived organoids), are three-dimensional tissue-resembling cellular 
clusters derived from tissue or tumor specific stem cells that mimic the in vivo characteristics, as 
well as cell heterogeneity.21 They are very similar morphologically and genetically to the tumor from 
which they are derived.22,23 The emergence of tumor organoid cultures has recently opened up new 

 
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opportunities in preclinical personalised therapy testing. These organoids are obtained after 
inclusion of the cells derived from the tumor in the Matrigel and placed in culture in the presence of 
growth factors essential for stem cells. Advantages of the organoid cultures are a rapid 
amplification, a high rate of establishment success and unlimited potential proliferation. Moreover, 
they can be transfected and cryopreserved. Tumor organoid panels were thus established and 
characterized from tumor samples from the colon, liver, breast, prostate, bladder, ovary, 
glioblastoma, squamous cell carcinoma of the head and neck, and also gastric and esophageal 
cancer.23–28 Tumor organoid cultures have shown interesting results to predict individual therapy 
response and patient outcome. A study evaluated the benefit of using organoids derived from 
metastatic colorectal and esogastric tumors to predict the response of patients to anticancer 
treatments (100% sensitivity, 93% specificity, 88% positive predictive value and 100% negative 
predictive value).29 Other studies have shown a correlation between the organoid response and the 
clinical response for patients with colorectal cancer treated with irinotecan-based therapies and for 
patients with for rectal cancer treated with radiochemotherapy.30–32 Several clinical trials are 
underway to determine whether tumor organoids can predict patient response and help treatment 
decisions. In particular, two of them involve the use of tumor organoids in immunotherapy 
(NCT03778814, NCT02718235). In fact, some works are currently underway to make organoid 
culture systems more complex by incorporating immune cells and to test treatments based on 
immunotherapy. A study was able to demonstrate the maintenance of the stromal and 
immunological environment around tumor organoids within an air-liquid interface system.33 In 
addition, organoids from colorectal and lung tumors of patients have been cultured with autologous 
peripheral blood, allowing specific activation and expansion of T-cells for some patients.34 Finally, 
the proof of the feasibility of a functional test predictive of the response to immunotherapies was 
recently carried out on co-cultures of organotypic tumor spheroids and their autologous immune 
cells derived from murine syngeneic models.35 The response of spheroids to an anti-PD-1 strategy 
has been correlated with the response of the mouse model in vivo, suggesting that such predictive 
functional tests based on tumor organoids could eventually be implemented from samples of 
human origin. 
 
In this study, the main objective of ancillary biological exploration is therefore to identify subgroups 
of responder patients. Cancer immunotherapies represent an important and novel class of 
antitumor agents. However, the mechanism of action of these exciting new therapies is not 
completely understood and much remains to be learned regarding how best to leverage these new 
drugs in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered. These 
efforts may identify predictive biomarkers and generate information that could help in patient 
selection with personalized medicine programs. 
 
 
 
 
 
 
 
 
 
 

 
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5 STUDY OBJECTIVES 
5.1 PRIMARY OBJECTIVE 
The primary objective is to assess the pathologic response after pre-operative treatment. 
5.2 SECONDARY OBJECTIVES 
The secondary objectives are: 
- 
To evaluate the impact of perioperative treatment on survival outcomes (outcomes 
(disease-free and overall survival) 
- 
To evaluate the histological R0 resection margin  
- 
To establish the association between pCR and survival outcomes (outcomes (disease-free 
and overall survival) 
- 
To determine the safety profile of the combination Spartalizumab + FLOT regimen 
- 
To evaluate the post-operative morbidity and mortality 
5.3 FURTHER ANCILLARY STUDIES 
Tumoral and blood samples will be collected for further biological explorations such as: 
- 
Evaluation of the impact of biomarkers (ctDNA and tissue) in terms of oncological outcomes 
and response to treatment,  
 
These biomarkers may include: 
❖ ctDNA levels over time 
❖ PD-L1 expression measured as the CPS 
❖ MSI status 
❖ EBV status 
❖ TMB 
- 
Exploration of tumor organoid culture 
6 ENDPOINTS 
6.1 PRIMARY ENDPOINT 
The primary endpoint is the proportion of patients with pCR in the primary tumor, defined as no 
tumor residue found in the tissue collected during the surgery evaluated by the pathologist. 
6.2 SECONDARY ENDPOINTS 
The secondary endpoints are: 
- 
Disease-free survival (DFS) defined as time between inclusion and first progression 
according to RECIST v1.1 criteria or death whatever cause (in the absence of progression); 
patients without disease progression or death at the time of analysis will be censored at the 
time of the latest date of assessment. 
- 
Overall survival (OS) defined as the time between inclusion and death whatever 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. 
- 
Proportion of patients with margin-free resection (R0), defined as a microscopically margin-
negative resection, in which no gross or microscopic tumor remains in the primary tumor 
bed 
- 
Correlation between pCR and DFS  
- 
Correlation between pCR and OS 
- 
Toxicities of the combination Spartalizumab + FLOT regimen according to NCI CTCAE 
criteria v5.0 

 
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- 
Post-operative morbidity, defined post-operative complications grades II-V according to 
Clavien-Dindo classification during surgery, within 30 days after surgery or during the 
hospital stay 
- Post-operative mortality, defined as the rate of patients died due to any cause during the 30 
days post-surgery 
7 STUDY DESIGN 
7.1 METHODOLOGY 
We propose to implement a multicenter, open-label, non-randomized phase II trial to evaluate the 
efficacy and safety of Spartalizumab in combination with the FLOT regimen as perioperative 
treatment for resectable gastric or GEJ adenocarcinoma in patients. 
7.2 STUDY DURATION 
Overall study duration: 72 months approximatively 
Enrollment period:  30 months 
Treatment period: 8 months 
Follow-up period: Up to disease progression 
7.3 SUBJECTS SELECTION 
7.3.1 Inclusion criteria 
- 
Age ≥ 18 years 
- 
Untreated localized gastric or GEJ adenocarcinoma considered resectable (clinical stage 
≥cT2 and/or cN+ and no metastasis) 
- 
Histologically confirmed adenocarcinoma 
- 
ECOG performance status score of 0 or 1 
- 
Tumor tissue must be provided for biomarker analyses (fresh or archival with an FFPE 
tissue block) 
- 
All subjects must consent to allow the acquisition of blood samples for performance of 
correlative studies 
- 
Screening laboratory values must meet the following criteria: 
- 
WBC ≥ 2000/ mm³ 
- 
Neutrophils ≥ 1500/ mm³ 
- 
Platelets ≥ 100 000/ mm³ 
- 
Hemoglobin ≥ 9.0 g/dL 
- 
Bilirubin ≤ 1.5 x ULN, AST and ALT ≤ 3 x ULN 
- 
measured or calculated creatinine ≥ 50 ml/min clearance (CrCl) (using the Cockcroft-Gault 
formula)  
- 
Potassium ≥ LLN 
- 
Magnesium ≥ LLN 
- 
Calcium ≥ LLN 
- 
Female subject of childbearing potential must have a negative urine or serum pregnancy 
test within 72h before study start 
- 
Subject in reproductive age must be willing to use adequate contraception during the study 
and at least 9 months in men and 12 months in women after the last dose of investigational 
drug. In addition, given the toxicities observed on the male reproductive system, a 
conservation of gametes will be proposed for men, as usually in routine practice 
- 
Subject affiliated to a social security regimen 
- 
Patient has signed informed consents obtained before any trial related activities and 
according to local guidelines 

 
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7.3.2 Non-inclusion criteria 
- 
Subject with any distant metastasis 
- 
Subject with no recovering from the effects of major surgery or significant traumatic injury 
within 14 days before inclusion 
- 
Documented significant cardiovascular disease within the past 6 months before the first 
dose of study treatment, including: history of congestive heart failure (defined as NYHA III 
or IV), myocardial infarction, unstable angina, coronary angioplasty, coronary stenting, 
coronary artery bypass graft, cerebrovascular accident or hypertensive crisis 
- 
History of anterior organ transplant, including stem cell allograft 
- 
Pneumonitis or interstitial lung disease 
- 
History of other malignancy within the previous 3 years (except for appropriately treated in-
situ cervix carcinoma and non-melanoma skin carcinoma) 
- 
Subject with active, known, or suspected autoimmune disease 
- 
Subject with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
start of study treatment 
- 
Known history of HIV or HBV infection 
- 
Known active HCV infection 
- 
Known history of active tuberculosis 
- 
Vaccination with live vaccine within 30 days before the first dose of study treatment 
- 
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways 
- 
Recent or concomitant treatment with brivudine (herpes virostatic) 
- 
Prior anticancer therapy for the current malignancy 
- 
Known hypersensitivity to any of the study drugs or their excipients 
- 
Chronic inflammable gastro-intestinal disease 
- 
Uracilemia ≥ 16 ng/ml 
- 
QT/QTc > 450 msec for men and > 470 msec for women 
- 
Peripheral neuropathy ≥ Grade II 
- 
Uncontrolled diabetes 
- 
Active infection requiring systemic therapy 
- 
Participation in another therapeutic clinical study 
- 
Patient deprived of liberty or placed under the authority of a tutor 
- 
Patient assessed by the investigator to be unable or unwilling to comply with the 
requirements of the protocol 
7.4 STUDY PLAN 
7.4.1 Consent sign 
The study will be proposed by oncologists, gastroenterologists or digestive surgeons to patients 
meeting all the eligibility criteria. Patients will be given study information (explanation on the study, 
reading and giving of the information notice). Patients will have a reflection period of the duration of 
their choice. 
The specific exams/procedure requested in the study before inclusion (baseline visit) will be 
realized after signed consent and before inclusion. 
7.4.2 Inclusion procedure 
After collection of the signed informed consent and checking of all eligibility criteria, inclusion will 
be performed before initiation of treatment. 
The inclusion will be recorded on the software dedicated to the study via an internet portal. 
An inclusion number will be assigned to the patient and will be used during the whole study. 

 
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7.4.3 Drug administration 
Patients should initiate the combination treatment by FLOT regimen plus Spartalizumab within 7 
days after inclusion. 
Systemic treatment will include: 
• 
a pre-operative neoadjuvant 8-week phase of treatment  
• 
a post-operative 8-week phase of treatment. 
 
The administered treatment will be FLOT associated to spartalizumab as follows: 
❖ Standard FLOT regimen 
Docétaxel 50 mg/m² IV infusion on D1   
Oxaliplatine 85 mg/m² IV infusion on D1 
Leucovorin 200 mg/m² IV infusion on D1 
Fluorouracile 2600 mg/m² 24 h IV infusion on D1 
Chemotherapy will be administered every two weeks (q2w) for 4 pre-operative cycles (8 weeks) 
and 4 post-operative cycles (8 weeks). 
 
❖ Spartalizumab PDR001 
Patients will receive the fixed dose of 400 mg per IV infusion over 30 minutes on D1 every four 
weeks (q4w) for 2 pre-operative cycles (8 weeks) and 2 post-operative cycles (8 weeks). 
 
 
7.4.4 Surgery 
For patients with confirmed resectability of the tumor by an imaging assessment (TAP CT-scan and 
optional MRI and endoscopy), surgery will be realized within 4-6 weeks after the last dose of 
preoperative chemotherapy. 
• 
For gastric tumors: surgery will consist on a total or subtotal distal (for  antropyloric 
tumors) gastrectomy with D2 lymphadenectomy 
• 
For type 1 GEJ tumors: transthoracic esophagectomy (Ivor-Lewis procedure) with 
resection 
of 
the 
proximal 
stomach 
and 
2-field 
(mediastinal 
and 
abdominal) 
lymphadenectomy 
• 
For type 2 or 3 GEJ tumors: gastrectomy with transhiatal distal oesophagectomy and  D2 
lymphadenectomy 
 
Local pathologists from expert centers selected will perform standardized evaluation of pathological 
response in surgically resected specimens.  
Tumour regression grade will be assessed according to the Becker regression criteria.36 
Post-operative systemic treatment will be initiated within 4-10 weeks after surgery. 

 
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7.4.5 Premedication  
• 
For FLOT regimen: 
It is recommended to use antiemetic treatment according to the ASCO/MASCC recommendation 
guideline (moderate risk of nausea / vomiting) with aprepitant and setron. 
Corticoid as premedication to doxetaxel should be avoided. However, if usually used as standards-
of-care, a single dose of 60 mg on the day of administration of Taxotere will be allowed, but must 
be documented in the eCRF. 
• 
For Spartalizumab 
Premedication is not recommended for Spartalizumab. 
7.5 SCHEDULE OF ASSESSMENT 
7.5.1 Inclusion Assessments 
For the patients will be given their written informed consent, an inclusion assessment will be 
performed within 28 days prior inclusion and will include: 
• 
Clinical assessment (medical history) with complete physical examination (including 
weight, height, ECOG, vital signs) 
• 
Laboratory Assessments  
- CBC-platelets 
- Creatininemia, kaliema, magnesemia, calcemia, albumin, glycemia, lipase, bilirubin, 
ALT, AST, GGT 
- Uracilemia 
- TSH, free T4 
- CEA, CA19.9 
• 
Cardiac assessment with ECG. The Fridericia correction method for calculating QTc will 
be used. 
• 
Tumor Assessments 
- Endoscopy (within 6 weeks prior to inclusion) 
- CT-scan (thoracic and abdomino-pelvic)  
- MRI in optional 
For translational research: 
• 
Blood sample for ctDNA (mandatory) 
• 
Optional fresh tumor biopsies and blood sample PBMC for organoids research only at 
François Baclesse site (additional specific consent form) 
7.5.2 Assessments during treatment 
❖ PRE-OPERATIVE TREATMENT 
✓ Day 1 (D1) 
• 
Complete physical examination (including weight, ECOG, vital signs, concomitant 
treatments) 
• 
Laboratory Assessments (only if realized more 3 days before D1) 
- CBC-platelets 
- Creatininemia, kaliema, magnesemia, calcemia, albumin, glycemia, lipase, bilirubin, 
ALT, AST, GGT 
- TSH, free T4 
- CEA, CA19.9 
- Negative urine or serum pregnancy test within 72h before study start 
• 
Cardiac assessment with electrocardiogram : ECG to be realized before and after 
oxaliplatin intravenous infusion 

 
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✓ D15, D29 and D43 (+/- 3 days) 
• 
Complete physical examination (including weight, ECOG, vital signs, concomitant 
treatments) 
• 
Laboratory Assessments (within 3 days before drugs administration) 
- CBC-platelets 
- Creatininemia, kaliema, magnesemia, calcemia, albumin, glycemia, lipase, bilirubin, 
ALT, AST, GGT 
- TSH, free T4 only on D29 
- Negative urine or serum pregnancy test within 72h before study start only on D29 
• 
Cardiac assessment with electrocardiogram : ECG to be realized before and after 
oxaliplatin intravenous infusion 
 
❖ BEFORE SURGERY 
The assessment will be performed within 3 weeks before surgery and will include: 
• 
Complete physical examination (including weight, ECOG, vital signs, concomitant 
treatments) 
• 
Laboratory Assessments  
- CBC-platelets 
- Creatininemia, kaliema, magnesemia, calcemia, albumin, glycemia, lipase, bilirubin, 
ALT, AST, GGT 
- TSH, free T4 
- CEA, CA19.9 
• 
Tumor Assessment 
- 
CT-scan (thoracic and abdomino-pelvic)  
- 
MRI in optional 
- 
Endoscopy in optional 
For translational research: 
• 
Blood sample for ctDNA 
 
❖ POST-OPERATIVE TREATMENT 
Post-operative systemic treatment will be initiated within 4-10 weeks after surgery. 
✓ D1, D15, D29 and D43 (+/- 3 days) 
• 
Complete physical examination (including weight, ECOG, vital signs, concomitant 
treatments) 
• 
Laboratory Assessments (within 3 days before drugs administration) 
- CBC-platelets 
- Creatininemia, kaliema, magnesemia, calcemia, albumin, glycemia, lipase, bilirubin, 
ALT, AST, GGT 
- TSH, free T4 only on D1 and D29 
- CEA, CA19.9 only on D1 
- Negative urine or serum pregnancy test within 72h before study start only on D1 and 
D29 
• 
Cardiac assessment with electrocardiogram: ECG to be realized before and after 
oxaliplatin intravenous infusion 
For translational research, only at D1: 
• 
Blood sample for ctDNA 

 
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7.5.3 End of treatment assessments  
Patients who discontinue the treatment for another reason than disease progression will be 
followed-up 30 days (+/- 7 days) after the last dose of study treatment: 
• 
Complete physical examination (including weight, ECOG, vital signs, concomitant 
treatments) 
• 
Laboratory Assessments  
- CBC-platelets 
- Creatininemia, kaliema, magnesemia, calcemia, albumin, glycemia, lipase, bilirubin, 
ALT, AST, GGT 
- TSH, free T4 
- CEA, CA19.9 
• 
Tumor Assessments 
- CT-scan (thoracic and abdomino-pelvic)  
- MRI in optional 
For translational research: 
• 
Blood sample for ctDNA 
7.5.4 Follow-up assessments  
Patients who discontinue the treatment for another reason than disease progression will be 
followed-up every 3 months (+/- 15 days) up to progressive disease with: 
• 
Complete physical examination (including weight, ECOG, vital signs, concomitant 
treatments) 
• 
Tumor Assessments (every 3 months for the first 2 years and every 6 months for the next 
3 years) 
- CT-scan (thoracic and abdomino-pelvic)  
- MRI in optional 
For translational research: 
• 
Blood sample for ctDNA at 3 months from the end of treatment 
 
For patients withdrawn from treatment due to progression, a follow-up for survival will be performed 
about every 6 months (+/- 1 month). The following anti-cancer treatment is at the discretion of 
physician and will be collected in the e-CRF. 
7.6 CRITERIA FOR PREMATURE WITHDRAWAL 
The treatment will be interrupted at any time under the following circumstances: 
- 
Disease progression  
- 
Need to initiate another anti-tumor treatment such as radiotherapy. Antalgic radiotherapy is 
also a criterion for stopping treatment of the study 
- 
Unacceptable toxicity, not compatible with study treatment 
- 
Patient's decision (the data already collected during the search can be kept and exploited 
unless the patient opposes it) 
- 
Intercurrent illness or other reason that necessitates stopping treatment of the study 
- 
Patient lost to view 
- 
Investigator's decision 
 
Any patient who prematurely withdraws from the study treatment only will continue to be followed, 
unless he/she withdraws from the study. 

 
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7.7 CONCOMITANT MEDICATION 
All concomitant medications received within 28 days prior to the first dose of study intervention and 
up to 30 days after the last dose of study intervention should be recorded. 
 
The following treatments/procedures are permitted: 
• 
G-CSF is recommended as a secondary prophylaxis of severe neutropenia or febrile 
neutropenia. A systemic primary G-CSF prophylaxis from the first cycle of treatment is 
allowed and at the discretion of the investigator. 
• 
Erythropoietin and/or transfusions at the discretion of the Investigator. 
• 
The systematic administration of antiemetic by aprepitant and setron is recommended. 
• 
Anti-diarrheal medications (e.g. loperamide) for patients who develop diarrhea. 
• 
Pain medication to allow the patient to be as comfortable as possible. 
• 
Nutritional support. 
• 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications. 
 
The following treatments are not permitted: 
• 
Treatment with other systemic anticancer agents (e.g., chemotherapy, hormonal therapy 
other than megestrol acetate, immunotherapy) or other treatments not part of protocol-
specified anticancer therapy 
• 
Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. 
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE that 
is suspected to have an immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
Notes: 
o A short course of steroids may be used as concomitant medication for either 
treatment of an AE or medical condition with Sponsor approval. 
o Use of prophylactic corticosteroids to avoid allergic reactions (eg, IV contrast dye or 
transfusions) is permitted. 
o 
The use of intermittent inhaled steroids or intranasal or local injection of 
corticosteroids is permitted. 
o 
Use of steroids for premedication is not recommended. However, a single dose of 
60 mg on the day of administration of Taxotere is permitted but must be 
documented. 
 
Other Restrictions and Precautions: 
• 
Drugs known to prolong the QTc interval should be used with caution. The list of those 
drugs can be found on https://www.crediblemeds.org/. 
 
 

 
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8 PHARMACEUTICAL FORM OF STUDY MEDICATION: 
SPARTALIZUMAB 
SPARTALIZUMAB (PDR001) is the Investigational Medicinal Product (IMP) in this study. It will be 
supplied by Novartis firm. 
8.1 PRESENTATION OF THE PRODUCT 
The chemical name of the study treatment is spartalizumab (PDR001). 
8.2 PACKAGING AND LABELLING 
Spartalizumab (PDR001) will be provided as concentrate for solution for infusion (100 mg / 4 mL). 
8.3 STORAGE CONDITIONS 
PDR001 drug product should be stored at 2 to 8 °C, protected from light. Do not freeze. 
The Investigator, or an approved representative (e.g., pharmacist), will ensure that all IMP and any 
other study related material is stored in a secured area, under recommended temperature 
monitored storage conditions, in accordance with applicable regulatory requirements. Screening 
will be required for staff members authorized to handle controlled substances who are not medical 
practitioners.  
8.4 METHOD OF ADMINISTRATION 
Spartalizumab (PDR001) will be administered intravenously as a 30-minute infusion (up to 2 hours, 
if clinically indicated). 
8.5 LABEL 
The product will be labeled according to current legal requirements. 
9 DOSE ADJUSTMENTS OF ANTICANCER PRODUCTS 
9.1 GENERAL RULES 
 No dose reduction will be applied for Spartalizumab  
 2 dose reductions is possible for FLOT regimen 
 Once doses are reduced, no dose increase will be possible. 
 The maximum interruption allowed is 28 successive days for the study treatments, 
starting from the day of onset of toxicity. Beyond this time, the patient will be withdrawn 
from the study treatment. 
 For FLOT regimen, participants must have ANC ≥1500/mm³ AND platelets ≥100 000/mm³ 
on day of infusion or within 72 hours prior to receiving treatment. Participants who do not 
meet these values will have their cycle start delayed and Spartalizumab will also be 
delayed.  
 In case of Spartalizumab delay for reasons of toxicity, chemotherapy could be either 
delayed or administered according to investigator opinion (depending on the severity of the 
toxicity and the estimated delay: < or ≥ 2 weeks) and after contact with the sponsor. 
 The decision to reduce the doses will be based on the maximum toxicity observed during 
the intercourse. The dose adjustments should be based on the most significant toxicity 
grades. If a patient has several types of toxicity, the dose administered will be the one with 
the least risk to the patient. 
 
 

 
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9.2 DOSE LEVELS 
Agent 
Starting Dose 
Dose Level - 1 
Dose Level - 2 
Docetaxel 
50 mg/m² 
40 mg/m² 
30 mg/m² 
Oxaliplatin 
85 mg/m² 
65 mg/m² 
50 mg/m² 
Leucovorin 
200 mg/m² 
Not applicable 
Not applicable 
Fluorouracil 
2600 mg/m² 
2000 mg/m² 
1600 mg/m² 
Spartalizumab 
400 mg 
Not applicable 
Not applicable 
 
Any subjects 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. 
9.3 ADJUSTEMENT FOR FLOT REGIMEN 
The chemotherapy doses must be adapted in case of severe hematological or non-hematological 
toxicities.  
Subjects who discontinue one of the study drugs on the FLOT regimen may, at the investigator 
discretion, continue administration of the other study drugs. For example, if Oxaliplatin is 
discontinued, Docetaxel and Fluorouracil may be continued at the intended dose and schedule. 
 
For the management of patients, especially concerning contraindications, duration of 
contraception, special warnings and precautions, posology adaptation (only is not referencing in 
the protocol), monitoring, as well as medications that are contraindicated or must be used with 
caution, please refer to the SmPC of the products on the website : http://base-donnees-
publique.medicaments.gouv.fr 
9.3.1 Dose Modifications for hematologic toxicity 
Before any chemotherapy administration, the following laboratory parameters should be checked: 
- 
ANC ≥ 1 500/mm³ 
- 
platelets ≥ 100 000/mm³ 
 
G-CSF is recommended as a secondary prophylaxis of neutropenia. 
 
 
NEUTROPENIA 
If ANC < 1.5 on Day 1: hold treatment. 
If ANC ≥ 1.5 within 2 weeks (G0/G1), start treatment at the dose level noted across from the 
lowest ANC result of the delayed week(s). 
If delayed 2 weeks consider discontinuing. 
Dose after toxicity: 
Grade 
ANC (x109/L) 
Docetaxel 
Oxaliplatin 
Fluorouracil 
I 
≥ 1.5 
no dose reduction 
II 
1 to 1.5 
no dose reduction 
III 
0.5 to 1 
-1 dose level 
-1 dose level 
no dose 
reduction 
IV 
Or febrile 
neutropenia 
< 0.5 
-1 dose level 
-2 dose levels 
-1 dose level 

 
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THROMBOPENIA 
If Platelets < 100 on Day 1: hold treatment. 
If  Platelets ≥ 100 within 2 weeks, start treatment at the dose level noted across from the lowest 
result of the delayed week(s). 
If delayed 2 weeks consider discontinuing. 
Dose after toxicity: 
Grade 
Platelets 
(x109/L) 
Docetaxel 
Oxaliplatin 
Fluorouracil 
I 
≥ 75 
no dose reduction 
II 
50 to 75 
no dose reduction 
III 
25 to 50 
-1 dose level 
-1 dose level 
no dose 
reduction 
IV 
< 25 
-1 dose level 
-2 dose levels 
-1 dose level 
9.3.2 Dose Modifications for oxaliplatin neurologic toxicity 
If oxaliplatin is stopped because of neurotoxicity, 5-FU should be continued. 
Docetaxel may also cause neurologic toxicity. Docetaxel dose reductions in addition to oxaliplatin reductions 
will be determined by clinician at their discretion. 
9.3.3 Dose modifications for diarrhea 
NB: rare case of enterocolitis. If suspected, the patient will be referred urgently to a specialist 
(gastroenterologist). 
We recommend a permanent discontinuation of docetaxel in case of enterocolitis. 
 
Grade 
Duration 
1-7 days 
7-14 days 
Persisting 
between cycles 
I: Paresthesias/dysesthesias of short 
duration that resolve; do not interfere 
with function 
no dose reduction 
II: Paresthesias / dysesthesias 
interfering with function, but not 
activities of daily living  
no dose reduction 
-1 dose level 
-1 dose level 
III: Paresthesias / dysesthesias with 
pain or with functional impairment 
which interfere with activities of daily 
living 
Interrupt until 
resolved to Grade 2 
And restart at -1 
dose level 
Interrupt until 
resolved to Grade 2 
And restart at -1 
dose level 
Discontinue 
therapy 
IV: Persistent paresthesias / 
dysesthesias that are disabling or 
life-threatening 
Discontinue therapy 
Discontinue therapy 
Discontinue 
therapy 
Acute laryngopharyngeal 
dysesthesia 
 
If during Oxaliplatin infusion: premedication + increase 
duration to 6 hours 
If during Docetaxel infusion: treat as per anaphylactic reaction 
Grade 
Docetaxel 
Oxaliplatin 
Fluorouracil 
I or II 1st episode 
no dose reduction, start supportive treatment 
II 2nd episode 
no dose reduction 
-1 dose level 
III 
Interrupt until resolved to Grade 
2 
And restart at -1 dose level 
Interrupt until resolved to 
Grade 2,  and restart at: 
1st episode: -1 dose level 
2nd episode: -2 dose levels 
IV 
Discontinue therapy 

 
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9.3.4  Dose modification for liver toxicity 
9.3.5 Dose modification for mucositis or hand-foot syndrome 
These toxicities are caused by Fluorouracil. If grade 3-4 toxicity occurs, stop chemotherapy until 
recovery (≤ grade 2) and Fluorouracil infusion will be reduced by 1 dose level for the remaining 
courses. 
9.3.6 Adjustments for cardiac toxicity 
• 
In case of prolongation of the QT/QTc interval to > 500 msec, oxaliplatin treatment should 
be discontinued. In the event of QT/QTc interval prolongation greater than 500 ms (grade 3 
toxicity):initiation of close and appropriate ECG monitoring (continuously) in hospital until a 
cardiologist’s opinion is issued. 
• 
In case of suspicion of cardiac toxicity related to Fluorouracil (chest pain, arrhythmia, acute 
coronary syndrome), Fluorouracil must be suspended until confirmation or exclusion of its 
causality by a cardiologist. Fluorouracil can be restart if any relationship was eliminated. 
The others agents can be continued without modification at the discretion of the 
Investigator. 
9.3.7 Adjustments for Docetaxel hypersensitivity reaction 
9.3.8 Adjustments for other toxicities 
• 
Other toxicities ≥ grade 3, except anemia and alopecia, may justify an interruption of 
chemotherapy until recovery (≤ grade 2) and a dose reduction of 1 dose level of the drug(s) 
involved according to the investigator. 
• 
Any oxaliplatin-related decrease in creatinine clearance to < 30 mL/min requires 
discontinuation of oxaliplatin. 
• 
Any grade ≥ 3 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) felt to be causing the reaction. The drug not felt to be related 
to the hypersensitivity reaction or infusion reaction may be continued. 
• 
In the event of infection, fever, digestive disorders suggestive of enterocolitis, a blood count 
(NFS) will be performed. 
Grade 
AST/ALT 
 
Bilirubin 
Docetaxel 
Oxaliplatin 
Fluorouracil 
I 
< 3 x ULN 
and 
≤ 1.5 ULN 
no dose reduction 
no dose reduction 
II 
3 - 5 x ULN 
or 
1.5 - 3 ULN 
-1 dose level 
no dose reduction 
III 
5 -20 ULN 
or 
3 -10 ULN 
Interrupt until resolved 
to Grade 2 
-1 dose level 
Interrupt until resolved to Grade 
2 
no dose reduction 
IV 
> 20 x ULN 
or 
>10 ULN 
Discontinue therapy 
Grade 
Docetaxel 
I 
As per institutional guidelines or at the discretion of the Investigator 
II 
STOP docetaxel temporarily. 
Administration of an anti H1 (Polaramine 5mg IV or equivalent), an anti H2 (Ranitidine 50mg IV) 
and corticoid (Solumedrol 1mg/kg IV or equivalent). 
Restart docetaxel perfusion if complete resolution. 
For subsequent cycles, systematic use of the same premedication protocol. 
III / IV 
STOP docetaxel definitively. 
Administration of an anti H1 (Polaramine 5mg IV or equivalent), an anti H2 (Ranitidine 50mg   IV) 
and corticoid (Solumedrol 1mg/kg IV or equivalent). 
Administration of atropine or epinephrine if necessary. 
IV 
Discontinue therapy 

 
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9.4 ADJUSTMENT FOR SPARTALIZUMAB 
There is no dose adaptation for Spartalizumab. Dose escalation or reduction is not recommended. 
Dosing delay or discontinuation may be required based on individual safety and tolerability. 
Investigators must be vigilant and carefully identify AEs that may be suggestive of potential 
immune-mediated AEs, as their appearance may be sub-clinical (for example an asymptomatic 
laboratory abnormality) and early diagnosis is critical for appropriate management.  
Some symptoms, that potentially may involve every organ system, may evocate immune-mediated 
mechanisms. In such cases, a particular attention may be paid by investigators. For example, 
these symptoms may include:  
• 
Fatigue 
• 
Decreased appetite 
• 
Anaemia 
• 
Dyspnea 
• 
Nausea 
• 
Pyrexia 
• 
Cough 
• 
Constipation and diarrhea 
• 
Vomiting  
• 
Back pain and abdominal  
• 
Pruritus and rash  
The Investigator Brochure of Spartalizumab should be consulted in case of Adverse Event. 
9.4.1 Management of infusion-reactions related to Spartalizumab 
Patients should be monitored for signs and symptoms of infusion-related reactions including 
pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. 
Toxicity grade (CTCAE 
v 5.0) 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
Investigator. 
Consider slowing infusion rate until recovery of 
symptoms 
None 
Grade 2 
Requires infusion 
interruption but 
responds promptly to 
symptomatic treatment 
Prophylactic 
medications indicated 
for ≤ 24 hrs 
Stop Infusion and keep line open.  
Additional appropriate medical therapy (eg, IV 
fluids, antihistamines, NSAIDs, paracetamol, 
oxygen, corticostreroids, bronchodilators...). 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable. 
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate. 
 Premedication prior to 
Spartalizumab infusion with: 
Antihistamine 
Paracetamol (500 to 1000 
mg)  
 
Permanently discontinued in 
case of recurring infusion 
reaction despite adequate 
premedication and prolonged 
infusion/slow infusion rate. 
Grade 3  
Prolonged; recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae 
 
or Grade 4 
Life-threatening; 
pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy (eg, 
epinephrine, IV fluids, antihistamines, NSAIDs, 
paracetamol, narcotics, oxygen, bronchodilators, 
corticosteroids…). 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable. 
Hospitalization as indicated. 
In cases of anaphylaxis, epinephrine should be 
used immediately. 
Permanently discontinue Spartalizumab. 
No subsequent dosing 

 
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9.4.2 Toxicity management guidelines for immune-related AEs associated with Spartalizumab 
AEs 
Toxicity grade  
(CTCAE v 5.0) 
Action with  
Spartalizumab 
Corticosteroid  
and/or other therapies 
Monitoring and follow-up 
Nephritis  
Grade 2 
1.5-3 x baseline;1.5-3 x ULN 
Withhold until 
resolved to Grade ≤ 1 
• Corticosteroids (0.5-1 mg/kg prednisone or 
equivalent) followed by taper. 
Monitor creatinine. 
Rule-out other causes (e.g. fluids, 
medications, IV contrast). 
Promote hydration and cessation of 
nephrotoxic drugs. 
Consult with nephrologist and consider 
renal biopsy. 
Persistent Grade 2 despite management 
Or  
Grade 3 or 4 
>3 baseline or ULN 
Permanently 
discontinue 
• Corticosteroids (1-2 mg/kg) followed by taper. 
Skin events 
Grade 1 
(e.g. rash, pruritus) 
Continue 
• Consider treatment with topical corticosteroids 
and/or other symptomatic therapy (eg, 
antihistamines). 
 
Grade 2 
(e.g. rash, pruritus) 
Consider dose 
interruption until 
resolved to Grade ≤ 1 
• Topical corticosteroids. 
• Consider adding low dose systemic 
corticosteroid as needed (0.5-1 mg/kg/day). 
Consider patient referral to dermatologist. 
 
Grade 3 
(e.g. rash, pruritus) Other severe 
cutaneous adverse reactions, Bullous 
dermatitis 
Withhold until 
resolved to Grade ≤ 1 
• High-potency topical steroids 
• Corticosteroids 1mg/kg/day followed by taper. 
Refer patient to dermatologist and consider 
skin biopsy. 
Persistent Grade 2 or 3 despite 
management 
Or  
Grade 4 
Life-threatening 
Permanently 
discontinue 
• Corticosteroids (1-2 mg/kg prednisone or 
equivalent) followed by taper. 
Refer patient to dermatologist and obtain a 
skin biopsy. 
Stevens-Johnson syndrome, toxic 
epidermal necrolysis 
Permanently 
discontinue 
• Hospitalization and urgent dermatology 
consultation 
• Supportive care immediately as per institutional 
guidelines. 
 
Hyperthyroidism 
Grade 2 
Symptomatic; thyroid  
suppression therapy  
indicated; limiting  
instrumental ADL 
Withhold until 
resolved to Grade ≤ 1 
· Initiate treatment with   anti-thyroid drug 
(eg,methimazole or carbimazole) as needed. 
· Monitor for signs and symptoms of thyroid 
disorders. 
· Monitor TSH and free T4 levels. 
· Consider patient referral to endocrinologist. 
Grade 3  
Severe symptoms; limiting self-care ADL; 
hospitalization indicated 
Withhold until 
resolved to Grade ≤ 1 
 
· Initiate treatment with   anti-thyroid drug as 
needed. 
· Consider beta-blocker. 
· Monitor for signs and symptoms of thyroid 
disorders. 
· Monitor TSH and free T4 levels. 
· Refer to endocrinologist. 
Persistent Grade 2 or 3 despite 
management 
Or  
Grade 4 
Life-threatening 
Permanently 
discontinue 
 
 
 

 
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AEs 
Toxicity grade  
(CTCAE v 5.0) 
Action with  
Spartalizumab 
Corticosteroid  
and/or other therapies 
Monitoring and follow-up 
Hypothyroidism 
 
 
Grade 2 
Symptomatic; thyroid  
replacement indicated;  
limiting instrumental 
ADL 
Continue 
· Initiate thyroid replacement hormones (eg, 
levothyroxine) per standard of care. 
· Monitor for signs and symptoms of thyroid disorders. 
· Monitor TSH and free T4 levels. 
· Consider patient referral to endocrinologist. 
 
Grade 3  
Severe symptoms; 
limiting self-care ADL; 
hospitalization indicated 
Withhold until 
resolved to 
Grade ≤ 2 
Persistent Grade 2 or 
3 despite management 
Or  
Grade 4 
Life-threatening 
Permanently 
discontinue 
Hypophysitis 
Grade 3  
Severe or medically 
significant; 
hospitalization 
indicated; limiting self-
care ADL 
Withhold until 
resolved to 
Grade ≤ 2 
 
 
· Corticosteroids (1-2 mg/kg prednisone or 
equivalent) followed by taper and initiate 
hormonal replacements as clinically 
indicated. 
· Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency) 
Persistent Grade 2 or 
3 despite management 
Or  
Grade 4 
Life-threatening 
Permanently 
discontinue 
Type 1 diabetes 
mellitus (T1DM)  
or 
Hyperglycemia 
New onset T1DM  
or hyperglycemia 
Grade 3  
Insulin therapy initiated; 
hospitalization indicated 
Withhold until 
resolved to 
Grade ≤ 2 
 
· Initiate insulin replacement therapy. 
 
· Monitor participants for signs and symptoms of diabetes. 
· Monitor glucose levels. 
· Refer to endocrinologist. 
Persistent Grade 2 or 
3 despite management 
Or  
Grade 4 
Life-threatening 
Permanently 
discontinue 
Guillain-Barré, 
encephalitis, 
Grade 2 
Moderate 
Consider 
interruption until 
resolved to 
Grade ≤ 1 
· Initiate symptomatic treatment. 
· Consider corticosteroids. 
 Ensure adequate evaluation to confirm etiology or 
exclude other causes. 
 Refer to a specialist. 

 
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Grade 3 or 4 
Permanently 
discontinue 
· Corticosteroids based on severity of AE 
(1-2 mg/kg prednisone or equivalent) 
followed by taper. 
Myasthenic 
syndrome/myast
henia gravis 
All grade 
Permanently 
discontinue 
 
 Ensure adequate evaluation to confirm etiology or 
exclude other causes. 
 Refer to a specialist. 
Other immune-
related AEs 
(including 
myositis, 
myocarditis, 
hypopituitarism, 
uveitis, 
etc.) 
Grade 2 
Moderate 
Consider 
interruption until 
resolved to 
Grade ≤ 1 
· Initiate symptomatic treatment. 
· Consider corticosteroids. 
 Ensure adequate evaluation to confirm etiology or 
exclude other causes. 
 Refer to a specialist. 
Grade 3 
Severe 
Withhold until 
resolved to 
Grade ≤ 1 
 
Except for 
myocarditis : 
Permanently 
discontinue 
· Corticosteroids based on severity of AE 
(1-2 mg/kg prednisone or equivalent) 
followed by taper. 
Recurrent grade 3 
immune-related adverse 
reactions 
Permanently 
discontinue 
 
Grade 4 
Life-threatening 
Permanently 
discontinue 
· Hospitalization. 
· Corticosteroids based on severity of AE 
(1-2 mg/kg prednisone or equivalent) 
followed by taper. 
 

 
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10 BIOLOGICAL BANKING FOR FURTHER ANCILLARY STUDIES 
10.1 TUMOR SAMPLES 
Possible approaches will be developed with additional grants. 
Tumour samples will be collected for further explorations in baseline tumor tissue. 
These analyses may include for example:  
• 
PD-L1 expression by IHC  
• 
Tumor mutational burden 
• 
Analyze of deficient MisMatch Repair (dMMR) DNA by IHC 
• 
EBV status 
For each included patient, a mandatory analysis of the primary tumor will be performed.  
These analyzes will be carried out centrally. 
 
Optional additional fresh primary tumor samples before treatment will be proposed (additional specific 
consent form), only at François Baclesse site (Caen) for tumor organoid cultures. The tissue samples 
will be sent directly to BioTICLA laboratory of INSERM unit U1086 (Caen), who will have been 
informed before of the patient's inclusion. 
10.2 BLOOD SAMPLES 
Blood samples will be collected at 5 times: inclusion before chemotherapy initiation, after pre-
operative treatment, after surgery, after post-operative treatment and 3 months from the end of 
treatment. The samples will be frozen on site and will be repatriated at the end of the inclusions at the 
request of the promoter. 
Translational further researches may be used to identify and monitor ctDNA during treatment. 
 
Optional whole blood samples will be proposed only at François Baclesse site (additional specific 
consent form) before treatment, for preparation of PBMCs and storage for possible tumor organoid 
cultures. 
10.3 SAMPLING SCHEDULE FOR BIOLOGICAL SAMPLES 
 
Type of  
sample 
Baseline 
After pre-
operative 
treatment 
After 
surgery 
After post-
operative 
treatement 
3 months 
from the end 
of treatment 
Tumor 
samples 
Fresh or 
archival  
1 FFPE 
tissue block 
 
 
 
 
Fresh 
optional* 
3-4 cores 
 
 
 
 
Blood 
samples 
Plasma 
blood 
✓ 
✓ 
✓ 
✓ 
✓ 
PBMC* 
✓ 
 
 
 
 
* Optional samples only at François Baclesse site (Caen) for organoids research (additional specific 
consent form) 
 

 
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11 EFFICACY AND SAFETY CRITERIA 
11.1 EFFICACY CRITERIA 
Response to treatment will be evaluated according to pathologic response after pre-operative 
treatment and DFS and OS after post-operative treatment. 
For the primary objective, the pathologic response after pre-operative treatment will be assessed by 
the local experienced pathologists. Tumour regression grade will be quantified using the Becker 
regression criteria 36, which are based on the estimation of the percentage of vital tumour cells in 
relation to the macroscopically identifiable tumour bed and include the following categories:  
• 
TRG1a (equivalent to pathological complete regression; no residual tumour cells);  
• 
TRG1b (subtotal regression; <10% residual tumour cells);  
• 
TRG2 (partial regression; 10–50% residual tumour cells); and  
• 
TRG3 (minor or no regression; >50% residual tumour cells). 
11.2 SAFETY CRITERIA 
The safety assessment will be done by evaluating the general condition (ECOG, weight) and clinical 
status of the patients, and by collecting the events during the trial (from the inform consent signature 
to 30 days after treatment discontinuation) will be listed on the eCRF. The intensity of the events will 
be estimated according to the NCI-CTCAE version 5.0 classification (grade 1 to 5 toxicity).  
The intensity of adverse events not listed in this classification will be graded as follows: 
• Grade 1: mild Discomfort noticed but no disruption of normal daily activity 
• Grade 2: moderate Discomfort sufficient to reduce or affect daily activity; no treatment or 
medical intervention is indicated although this could improve the overall well-being or 
symptoms of the patient 
• Grade 3: severe Inability to work or perform normal daily activity; treatment or medical 
intervention is indicated in order to improve the overall well-being or symptoms; 
delaying the onset of treatment is not putting the survival of the patient at direct risk 
• Grade 4:  Life-threatening/disabling 
 
 
An immediate threat to life or leading to a permanent mental or physical conditions 
that prevents work or performing normal daily activities; treatment or medical 
intervention is required in order to maintain survival 
• Grade 5:  
Death AE resulting in death 
12 SAFETY 
12.1 GENERAL RULES - INSTRUCTIONS 
Safety management will be conducted according to the French regulatory requirements (Law No. 
2012-300 of 05/03/2012 as amended by Ordinance No. 2016-800 of 16 June 20161) 
12.2 DEFINITIONS 
12.2.1 Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to it. 

 
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12.2.2 Adverse Reaction 
All untoward medical occurrences in a patient or clinical investigation subject which participate to 
research involving the human person related to the study procedure or to the experimental 
product. 
All untoward responses to an investigational medicinal product related to any dose administered. 
12.2.3 Serious Adverse event  
A serious adverse event (SAE) is an AE that fulfils one or more of the following criteria: 
- 
Results in death 
- 
Is immediately life-threatening 
- 
Requires in-patient hospitalization or prolongation of existing hospitalization  
- 
Results in persistent or significant disability or incapacity  
- 
Is a congenital abnormality or birth defect 
- 
Is an important medical event*. 
* Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as 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. These should also 
usually be considered serious. 
 
Some “hospitalization/prolonged hospitalization” are not considered to be reported as SAE:  
- 
Admission for administrative or social reasons  
- 
Hospitalization predefined by the protocol 
- 
Hospitalization for medical or surgical treatment  planned before the beginning of the trial  
- 
Passage to day hospital 
- 
Hospitalizations for pre-existing signs and symptoms that have not been aggravated 
12.2.4 Suspected Unexpected Adverse Reaction 
Any serious adverse reaction for which the nature, severity, frequency or outcome is not consistent 
with the applicable product information (e.g investigator’s brochure for an unauthorized 
investigational product or summary of product characteristics for an authorised product). 
Any serious adverse reaction for which the nature, severity, frequency or outcome is not consistent 
with the applicable product information, diagnostic or therapeutic study mandated procedure (non-
invasive and/or invasive) evaluated in the protocol. 
12.3 INVESTIGATOR’S RESPONSABILITIES 
12.3.1 Detection and registration of adverse events  
12.3.2 All AEs have to be searched, reported and recorded, processed and evaluated. 
With the exception of serious adverse events (see section 12.3.3), all adverse events occurring, once 
the informed consent form has been signed, during treatment and 45 days after the last study 
drug administration must be recorded by the investigator. 
 
The intensity of the events will be estimated according to the NCI-CTCAE version 5.0 classification 
(grade 1 to 5 toxicity). The intensity of adverse events not listed in this classification will be graded as 
follows: 
 

 
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• Grade 1: mild : Discomfort noticed but no disruption of normal daily activity 
• Grade 2: moderate : Discomfort sufficient to reduce or affect daily activity; no treatment or 
medical intervention is indicated although this could improve the overall well-being or 
symptoms of the patient 
• Grade 3: severe : Inability to work or perform normal daily activity; treatment or medical 
intervention is indicated in order to improve the overall well-being or symptoms; 
delaying the onset of treatment is not putting the survival of the patient at direct risk 
• Grade 4:  Life-threatening/disabling : An immediate threat to life or leading to a permanent 
mental or physical conditions that prevents work or performing normal daily activities; 
treatment or medical intervention is required in order to maintain survival 
• Grade 5:  Death AE or resulting in death 
 
The investigator will specify for each event: 
✓ The seriousness 
✓ The date of start +/- the date of end of the event 
✓ The duration 
✓ The intensity 
✓ The causality assessment 
✓ The outcome  
If a SAE occurs, the sponsor should be notified of the event awareness by the investigator without 
any delay. This will be done by mailing sponsor’s Serious Adverse Event Report Form. 
12.3.3 SAE reporting process 
The investigator has to report the Sponsor of all serious adverse events occurring, once the informed 
consent form has been signed, during treatment and 150 days after the last study drug 
administration,  
All late Serious Adverse Events and considered as reasonably related to the study treatment(s) or to 
the study procedure must be reported without delay limitation. 
The investigator has to immediately report to the sponsor all serious adverse events with the 
exception of those that are identified as not requiring immediate reporting in the protocol or the 
investigator’s brochure. 
This will be done by mailing sponsor’s Serious Adverse Event Report Form, and it will be 
following by some report, as needed, containing all available information concerning the SAE.  
The investigator will specify for each event: 
✓ The description as clear as possible according to the medical terminology, 
✓ The intensity, 
✓ The date of start and the date of end of the event, 
✓ Measures taken and the necessity or not for a corrective treatment, 
✓ If the treatment of the study was discontinued or if dose was modified 
✓ The outcome: For a non-fatal event, the event should be followed until resolution or return to 
the initial status or to stabilization of potential sequels, 
✓ The causality assessment: he has to assign a causality of “related to study treatment”, if 
there is a “reasonable possibility” that the study treatment caused the event, or "not related to 
study treatment" if there is “no reasonable possibility” that the study treatment caused the 
event. The investigator must also assess whether the serious adverse event is “possibly 
related” to any study mandated procedure or activity, or others concomitants treatments, or 
under study or any others disease. 
 

 
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The investigator should also, when possible, attach to the serious adverse event report: 
✓ A copy of the hospital report/hospitalization prolongation, 
✓ A copy of the autopsy report, 
✓ A copy of the results of all additional exams performed, including relevant negative results 
together with the range of normal laboratory values, 
✓ Any other document judged useful and pertinent (including imaging) 
All these documents should be anonymized. 
Additional information may be requested by the sponsor. 
 
The investigator should document the event as best as possible, provide medical diagnosis where 
possible and establish a causal link between the serious adverse event and the research, the study 
treatment, the associated drugs, an underlying pathology, progression of the disease or other cause. 
The investigator shall promptly provide the sponsor with additional information regarding serious 
adverse events as he becomes aware of them. 
The investigator should follow the patient who has had a serious adverse event until resolution, 
stabilization at a level acceptable to the investigator or return to the previous status, even if the 
patient withdraws from study and inform the sponsor of the serious adverse event outcome. 
12.3.4 Special cases 
ADVERSE EVENT OF SPECIAL INTEREST 
An adverse event of special interest (AESI) is a serious or non-serious adverse event that requires 
special attention and will be specifically searched. AESIs should be notified and followed as serious 
adverse events.  
As part of this research, the following events are considered as AESI:  
• 
Immune related diseases:  
• 
Endocrine disorders (i.e. hypothyroidism, hyperthyroidism, diabetes, hypophysitis, 
hypopituitarism, adrenal insufficiency) 
• 
Pneumonitis 
• 
Colitis  
• 
Immune mediated liver injury 
• 
Nephritis 
• 
Other immune-mediated events 
Others:  
• 
Infusion reactions to spartalizumab 
• 
Skin reactions: grade 3/4 , Stevens-Johnson syndrome and toxic epidermal necrolysis 
 
REPORTING EXCEPTIONS 
Serious adverse event not to be notified immediately 
Any event that is part of the natural history of the disease (progression of the disease or 
hospitalization for progression of the disease) should not be notified to pharmacovigilance on the 
SAE form but has to be reported into the e-CRF. 
Warning: disease progression resulting in death has to be notified  
Some "hospitalization/prolongation of hospitalization" are not considered as serious adverse events 
and do not require notification to pharmacovigilance (see last paragraph "Serious adverse event "). 
 
PREGNANCY 
If a woman starts a pregnancy as part of the study or in some cases if her partner participates in the 
study (drug that can reach the seminal line of the man), the investigator has to report pregnancy to 
the sponsor. 

 
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The investigator informs the sponsor who will send him a "PREGNANCY NOTIFICATION FORM". 
The investigator has to follow the patient until the end of the pregnancy or its interruption and notify 
the outcome to the sponsor. If the outcome of pregnancy falls within the definition of serious adverse 
events (spontaneous abortion with hospitalization, fetal death, congenital anomaly, ...) the 
investigator has to complete a SAE form and has to follow the complete SAE reporting process. 
If it’s a paternal exposure, the investigator has to obtain the parturient consent to report pregnancy 
data. 
13 STATISTICAL CONSIDERATIONS 
13.1 NUMBER OF SUBJECTS 
We used an optimal Simon’s two stage phase II design to estimate the sample size.  
According to Al-Batran S-E et al outcomes, patients rate achieving pathological complete regression 
with FLOT regimen was 16% [95%CI: 10-23] (n=128). To assess efficacy of FLOT regimen combined 
with spartalizumab, we assume a histological complete response rate p<10% as unacceptable 
(corresponding to the lower CI limit of response rate in Al-Batran), and a response rate p>23% as 
demonstrating efficacy of the treatment combination (corresponding to the upper CI limit). With an 
alpha level of 5% and statistical power of 80%, 58 assessable patients are required, including 20 in 
the first stage.  
Taking into account that 15% of patients will be lost or non assessable, we plan to include a total of 
67 patients in the trial (23 in the first stage and 44 in the second). 
13.2 STATISTICAL ANALYSIS 
All enrolled patients who receive at least one dose of study medication will be evaluable for the 
efficacy analysis as well as included in the safety analysis. 
Safety analysis 
A safety analysis was planned one month’s follow-up after the surgery of 10th patient. Enrolment was 
halted during this safety analysis. 
This analysis included analyses of safety data, of the delays in performing surgery and of the 
perioperative complications. 
A substantial amendment was submitted to the ANSM for authorization with: 
- 
A summary of data from this analysis of the safety data of the first 10 patients 
- 
The opinion of the IDMC concerning these safety data, with an analysis of the impact of 
neoadjuvant treatment on the time frame for the surgery, the reasons for postponing the 
surgery, and the consequences for the continuation of the clinical trial. 
Safety analysis of FLOT plus immunotherapy in neoadjuvant treatment on 10 patients, 
including toxicities and dose reductions, showed tolerance observations consistent with the 
safety profile of similar association in this setting. No safety signal that may have 
compromised the pursuit of the trial was noticed. In particular, the grade 3 immune-mediated 
encephalitis that occurred in one patient was rapidly reversible after the prompt 
implementation of a specific and adapted management. 
Similarly, the type and frequency of toxicities observed during the peri-operative period (up to 
one month post-surgery) were in line with events usually observed in this setting and 
compatible with the pursuit of the trial. No death was observed. 
Overall, the IDMC recommends the Sponsor to pursue the study without modification but to 
plan a second formal safety analysis after the inclusion of the 30th patient : this safety analysis 

 
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will notably focus on grade 3 and 4 toxicities, spartalizumab-related toxicities, as well as all 
SAE (severe adverse events) and AESI (adverse events of special interest) notified to 
pharmacovigilance. 
- 
The inclusions must only be restarted after authorization from the ANSM. 
Interim analysis: 
According to the optimal Simon’s two stage phase II design used in this trial, an interim analysis after 
the 23th inclusion was planned, without halting inclusions. A minimum of 3 complete responses out of 
20 assessable patients in the first stage will allow pursuing the study in the second stage. Otherwise, 
the study will stop for insufficient efficacy. 
To be noticed, data concerning surgical pathologic response were available for 9 patients included in 
the first safety analysis, and reported in the file presented to the IDMC. The number of complete 
pathological responses observed among of these 9 assessable patients fulfilled the futility criterion of 
the Simon design. In this context, the IDMC indicated the planned interim analysis will have no more 
decisional impact on the pursuit of the study. It therefore recommended not to realise the planned 
interim analysis but to include available efficacy data in the second safety report, to assess the 
benefit/risk ratio of the combination. 
Final analysis:  
On the 58 assessable patients considered for the final analysis, the study will conclude to efficacy if 
at least 10 complete responses are observed. Besides this such obtained efficacy criterion, the 
response rate will be estimated with a 95%CI confidence interval. 
 
General considerations: 
The number of patients who were not evaluable, who died or withdrew before treatment began will be 
specified. Categorical variables will be summarized using numbers and proportions. Quantitative 
variables will be summarized using quartiles and range (mean and standard error for Gaussian-like 
variables). Chi-squared test and T-Student test will be used to measure association of, respectively, 
qualitative and quantitative variables with pCR response. 
Time-to-event variables will be summarized by the Kaplan-Meier estimator. Association of time-to-
event variables with factors of interest will be measured by a Cox model and the log-rank test.  
Adverse events of the Spartalizumab + FLOT regimen combination will be described according to 
NCI CTCAE criteria v5.0 and tabulated by grade and frequence, based on time of occurrence and 
relationship to treatment.  Will be excluded events unrelated or not likely related to treatment, but 
included events for which the relationship with treatment is not assessable. Tolerability will be 
summarized by duration of treatment, reasons of discontinuation, dose reduction rates and reasons 
for dose reductions. 
14 QUALITY CONTROL 
14.1 INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 
An IDMC will be set-up to ensure the protection of patients, to ensure the ethical conduct of the 
study, to evaluate the benefit/risk ratio of the study and to insure an independent review of the 
scientific outcomes during and at completion of the study. 
The Independent Committee exercises a consultative role for the promoter who takes the final 
decision for implementing the recommendations proposed by the committee. 
The committee will include a statistician, a pharmacologist and a clinical physician.  
 
 

 
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This committee will be consulted:  
 Before the trial initiation 
 At safety analysis (after the surgery of 10th patient)  
 At safety analysis (after the inclusion of the 30th patient) 
 At the final analysis  
 
Dealing with safety, the committee will be informed of regular reviewing of safety data and advice. 
The Sponsor will sent the annual safety reports and eventually SAEs and / or SUSARS according to 
the conditions provided for during the first meeting, The committee should propose to stop inclusions 
in case of unacceptable toxicities (in terms of severity and/or frequency). 
For this purpose, regular teleconferences will be planned and will contain two parts: the first one with 
the Sponsor introducing the teleconference with a safety review, and the second one with only IDMC 
members who will independently deliberate. A tracking form for Grade ≥ 3 AEs and the relationship to 
the study treatments will be distributed ahead of time and jointly reviewed at each teleconferences. 
The statistician of the Sponsor will be in charge of reporting all safety concerns to the IDMC, in terms 
of grade and timing along with treatment protocol adherence. 
All the decisions will be documented in writing and communicated to all the investigators.  
If needed, ad hoc teleconferences may be organized for any safety alert.  
 
 
14.2  QUALITY ASSURANCE 
In order to ensure the authenticity and credibility data in accordance to Good Clinical Practices 
(GCP), the sponsor will implement a quality assurance system that includes: 
- 
the management of the test according to the procedures of the Clinical Research Unit 
- 
the quality control of the data of the investigator site by the monitor whose role is to check 
the concordance and the coherence of the data of case report form of observation compared 
to the documents-source 
- 
the provision if the funding provides for dedicated staff in the service to assist the 
investigator in the logistics of the study and the collection of data in the case report form. 
15 ETHICS AND REGULATORY CONSIDERATIONS 
The study will be conduct in accordance with the French Public Health Law, specially relating to 
research involving the biomedical human person of the Public Health Code, articles L1121-1 and 
following (Law No. 2012-300 of 05/03/2012 as amended by Ordinance No. 2016-800 of 16 June 
2016), the Bioethics Law, the law related to the protection of physical persons for the treatments of 
personal data and related to information technology, database and liberties, the Helsinki declaration 
and the Good Clinical Practices. 
15.1 CLINICAL TRIAL AUTHORISATION 
An authorization request will be sent by the sponsor to the French regulatory authorities before the 
study initiation:  
• 
Ethics Committee (Committee for the Protection of Persons, CPP)  
• 
Competent Health Authority (ANSM) 
Information will be given to the Competent Authority (ANSM), with transmission of the synopsis of the 
study and the favorable opinion of the CPP. 

 
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This study is under of the "Reference Methodology" (MR-001) in application of the provisions of 
article 54 paragraph 5 of the law of 6 January 1978 as amended relating to data processing, files and 
freedoms. This change was approved by decision of 5 January 2006. 
The François Baclesse Center respects the regulations in force, in particular the rights of the persons 
being treated according to the EU regulation 2016/679 on the protection of data ("RGPD"). 
Any substantial modification in the protocol about objectives, design, population, evaluation, 
significant administrative modifications will need the coordinator approval, the sponsor approval, CPP 
approval and the competent authority authorization. 
15.2 INFORMATION OF PATIENTS INVOLVED IN THE RESEARCH 
Patients will be completely and faithfully informed with understandable words on the objectives and 
constraints of the research, potential risks, required measures for monitoring and safety, of their right 
to decline the participation in the study or the possibility to withdraw from the study at any time. 
All these information are included in the informed consents form given to the patient: one for the main 
study, other for ancillary studies. The investigator, or the physician who represents him, will collect 
the signed written informed consent(s) before the definitive inclusion in the study. A copy of the 
information and consent form signed by the two parties will be given to the patient; the investigator 
will keep the second copy.  
For any significant modification of the protocol related to the objectives of the research, its design, the 
population, the exams or significant administrative aspects, a new consent from each person 
participating to the research will be collected if needed. 
15.3 INVESTIGATOR RESPONSIBILITIES 
The Principal Investigator of each participating center is committed to conduct the clinical trial in 
accordance with the trial protocol and with the regulations in force, notably the decision of 24 
November 2006 related to Good Clinical Practices. 
The Principal Investigator is responsible for: 
✓ Giving to Sponsor his/her curriculum vitae and that of co-investigators 
✓ Identifying persons involved in the research in his/her team and defining their responsibilities 
✓ Initiating the inclusion of patients after Sponsor authorization 
✓ Making the maximum effort to include the required number of patients within the established 
recruitment period. 
 
Each Investigator is responsible for: 
✓ Obtaining the signed and dated informed consent and personally signing this consent for each 
participating patient before any procedure specific to the trial 
✓ Regularly completing the CRF for each patient included in the trial and to allow to CRAs 
mandated by the Sponsor a direct access to source data in order to validate the data entered 
in the CRF 
✓ Dating, correcting and signing any correction in the CRFs and data clarification forms (DCF) 
✓ Accepting the regular monitoring visits of the monitor and eventual auditors mandated by the 
Sponsor or inspectors of supervisory authorities 
Source documents, defined as any document or original item that allow to prove the existence or 
accuracy of a data or a fact recorded during the study, will be kept during 15 years by the investigator 
or the hospital if the source is a hospital medical record. 
The archiving of the data will be the responsibility of the investigator and according to the legislation. 
The patient should keep the data and a patient identification list for a minimum of 15 years after the 
end of the study. 

 
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15.4 DATA CONFIDENTIALITY 
The investigator will ensure the confidentiality of all information concerning the project for himself and 
for all persons involved in the conduct of the trial until the publication of the test results. This 
confidentiality obligation will not apply to information that the investigator will be required to provide to 
patients in the context of their participation in the trial or to information already published. The 
investigator will ensure not to publish, disclose or use, in any way, directly or indirectly, scientific or 
technical informations of the trial. 
The study may not be the subject of any written or oral commentary without the agreement of the 
sponsor; all the information communicated or obtained during the realization of the test belonging in 
full right to the sponsor who can freely dispose of it. 
16 DATA AND DOCUMENTS KEEPING 
16.1 DATA EBTRY AND HANDLING 
Data management will be performed by the Data Processing Center (CTD) of the North West 
Cancéropôle (Centre de Traitement des Données du Cancéropôle Nord-Ouest). The CTD provides a 
database management software dedicated to clinical research: Ennov Clinical (version 7.5.10, 
ENNOV / CLINSIGHT, 33155 Cenon, France). 
This software package, which is based on an Oracle database architecture, is designed for the 
overall management of clinical and epidemiological studies, meets the regulatory requirements 
related to this type of study. The CTD Ennov Clinical instance is validated in its computing 
environment. A data validation plan will be developed jointly by the Clinical Research Unit and the 
Data Processing Center and will describe in detail the controls to be performed for each variable. 
A database specific to the study will be created, tested and validated before the start of the study. All 
information required by the protocol must be recorded on the paper observation books - or on the 
electronic observation booklet - under the responsibility of the principal investigator and an 
explanation must be provided for each missing data item. The data will have to be entered in these 
notebooks as they are obtained, and the sponsor will take over the monitoring. 
The data will then be checked by the CTD in accordance with the data validation plan. 
The database will be frozen after final quality control and then exported to the adequate format for 
statistical analysis according to an automated and validated procedure. 
16.2 ARCHIVING 
The sponsor must ensure the archiving of essential documents on the conduct of the study in 
conditions ensuring their safety, for the minimum duration provided by BPC, 15 years after the end of 
the research. 
These documents are the protocol and annexes, including any amendments, original signed 
information forms and consents, questionnaires, case report forms, follow-up documents, statistical 
analyzes, the final report of the study. 
16.3 PUBLICATION POLICY 
The results of this study, property of the Sponsor (Centre François Baclesse), will be published under 
scientific articles. Publications relating to or resulting from this research will be communicated and 
submitted for review by the study coordinators to all investigators. 
The authors include investigators that have included most patients, the biostatistician who has 
performed the data analysis, the clinical researcher monitor and the participants who provided 
substantial contribution to the development of the study, the analysis and interpretation of results and 
/ or the writing of the manuscript. 

 
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Acknowledgement to IDMC members will be indicated in final publication. 
No publication or presentation of the results will be allowed without the agreement of all the parties. 
Each investigator will be author in the order determined by the number of eligible patients included. 
No publication or communication will be performed without the agreement of the coordinating 
investigator and the Sponsor with the obligation to mention the name of the Sponsor, the organism 
which financially supported the conduct of the trial and thanking to Laboratories Novartis that provided 
Spartalizumab. Each publication will indicate the following sentence: “This study was supported by a 
grant from the French Cancer Institute INCa and the ARC French Foundation for Cancer Research 
(reference CLIPPNo 19-022, INCa_14824)”. 
Some dedicated publications for ancillary studies will be also performed. 
This work will be the property of all authors and will be at their disposal for transversal 
communications and publications. 
Publications related to the results of potential ancillary studies need prior approval of the coordinating 
investigator and methodologist and will be done after the publication of the main study, which should 
be cited as reference. 
17 FUNDING AND INSURANCE 
17.1 FUNDING 
Any additional costs referred to the Code of Public Health are being negotiated between the CFB and 
the representative of the institution, taking into account the financial resources available to the CFB in 
the frame of its public promotion activities. 
However, the CFB will ensure the study implementation and supply of the following material 
(protocol, CRF, investigator file) needed to the conduct of the study. 
In the case of equipment or treatments are provided by other partners, the conditions must be 
specified in the study agreement. 
17.2 INSURANCE 
The sponsor has subscribed for the duration of the study an insurance covering his own liability and 
that of any physician involved in the realization of the study. It will also ensure full compensation for 
the harmful consequences to search for the person undergoing it and assigns, unless evidence 
against him that the damage is not attributable to its fault or that of any intervener, without that can be 
opposite the act of a third party or the voluntary withdrawal of the person who had originally agreed to 
participating to research. (Article L 1121-10) 
 
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