Clinical trial NCT02827201
Conditions: Metastatic Pancreatic Cancer
Keywords: pancreatic cancer
Sponsor: Federation Francophone de Cancerologie Digestive
Start date: 2015-11-01; Completion date: 2021-03-01
Enrollment: 127 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this trial is to evaluate every 2 months alternating nab-paclitaxel/gemcitabine and FOLFIRI.3 versus nab-paclitaxel + gemcitabine, regarding the progression of disease at 6 months.

Detailed description:

Arms: arm 1: Alternance of :

* 2 months with nab-paclitaxel (125 g/m² - 30 min in IV) + gemcitabine (1000 mg/m², 30 min in IV, 3 injections follow by 1 week free)
* follow by 2 months with FOLFIRI.3 (irinotecan: 90 mg/m² at D1, acid folinic 400 mg/m², 5Fu continus: 2000 mg/m² IV 46 hours, and irinotecan at D3, 90 mg/m²) This alternance continus until progression arm 2: nab-paclitaxel (125 g/m² - 30 min in IV) + gemcitabine (1000 mg/m² - 30 min in IV) 3 injections follow by 1 week free, until progression
Interventions: intervention 1: FOLFIRI.3 intervention 2: nab-paclitaxel+ gemcitabine
Intervention descriptions: intervention 1: For each cycle : 1 week out of 2 - injection at Day1, J15 Irinotécan 90 mg/m² at day1 in perfusion over 60 min in Y of folinic acid Folinic Acid 400 mg/m² (or 200 mg/m² Elvorine) at Day 1 in perfusion over 2 hours 5FU continu 2000 mg/m² during 46 hours Irinotécan at 90 mg/m² in perfusion over 60 mn at Day 3 (when 5FU perfusion is over) intervention 2: For each cycle : 3 weeks out of 4 - injection at Day 1, 8 and 15 Nab-paclitaxel : 125 mg/m² of nab-paclitaxel in perfusion over 30 mn. Gemcitabine 1000 mg/m² in perfusion over 30 mn immediately after Nab paclitaxel administration is over.

Protocol documents:
Prot_000.pdf: 
PRODIGE 37 - FIRGEMAX 
Version 1.1 – 08.12.2014 
 
Page 1 of 26 
 
PRODIGE 37 (FFCD 1406) FIRGEMAX  
MULTICENTER RANDOMISED PHASE II TRIAL ASSESSING NAB-PACLITAXEL + 
GEMCITABINE/FOLFIRI.3 VERSUS NAB-PACLITAXEL + GEMCITABINE AS A 
SEQUENTIAL FIRST-LINE TREATMENT OF METASTATIC PANCREATIC CANCER  
Phase II randomised - multicenter 
EudraCT n° 2014-004449-28 
 
FFCD – UNICANCER GI - GERCOR Intergroup Trial 
 
 
COORDINATOR (FFCD): 
Pr Julien TAIEB  
HÔPITAL EUROPEEN G. POMPIDOU 
Service d'Hépato-gastro-entérologie 
20 Rue Leblanc 
75015 PARIS  
Tel.: 01 56 09 50 42 - Fax: 01 56 09 35 29 
Email: julien.taieb@egp.aphp.fr 
 
CO-COORDINATOR (UNICANCER-GI):  
Dr David MALKA 
Institut Gustave Roussy 
Service d'HGE 
114 rue Edouard Vaillant 
94805 VILLEJUIF CEDEX 
Tel.: 01 42 11 42 11 – Fax : 01 42 11 52 29 
Email: malka@igr.fr 
CO-COORDINATOR (GERCOR):  
Dr Jean Baptiste BACHET 
Groupe Hospitalier Pitié-Salpétrière  
Service d'Hépato-gastro-entérologie 
47- 83 Boulevard de l'Hôpital 
75651 PARIS CEDEX 13 
Tel.: 01 42 16 10 41 – Fax : 01 42 16 12 38 
Email: jean-baptiste.bachet@apr.aphp.fr 
 
EDITORIAL BOARD 
J.B. BACHET (Paris), K. LE MALICOT (Dijon), E. MAILLARD (Dijon), D. MALKA (Villejuif), M. 
MOREAU (Dijon), A.L. POINTET (Paris), J. TAIEB (Paris), I. TROUILLOUD (Paris)  
 
SPONSOR AND RANDOMISATION-MANAGEMENT-ANALYSIS CENTRE (CRGA): 
French Federation of Digestive Oncology (FFCD), Faculté de Médecine, 7, Boulevard Jeanne d’Arc, BP 87900, 
21079 Dijon Cedex 
 
Administrative Director: 
Cécile GIRAULT 
 
Tel: 03 80 66 80 13 – Fax: 03 80 38 18 41 
 
Email: cecile.girault@u-bourgogne.fr 
 
 
Statistician: 
Emilie MAILLARD 
 
Tel: +33 (0) 3 80 39 34 81– Fax: +33 (0) 3 80 38 18 41 
 
Email: emilie.maillard@u-bourgogne.fr 
 
Project leader: 
Marie MOREAU 
 
Tel: 03 80 39 34 04 – Fax: 03 80 38 18 41 
 
Email: marie.moreau@u-bourgogne.fr 
 
 
Confidential 
This document is the property of the French Federation of Digestive Oncology and cannot - in whole or in part - be transmitted, reproduced, published or 
used without the express permission of the French Federation of Digestive Oncology 
 
 


PRODIGE 37 - FIRGEMAX 
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Page 2 of 26 
TABLE OF CONTENTS 
 
• 
Chest-abdomen-pelvis CT-Scan or MRI ........................................................................................ 9 
1. 
STUDY OBJECTIVES ............................................................................................................... 10 
1.1 
Main objective .................................................................................................................................. 10 
1.2 
Secondary objectives ......................................................................................................................... 10 
2. 
SELECTION OF PATIENTS AT REGISTRATION ............................................................... 10 
2.1 
Inclusion criteria ............................................................................................................................... 10 
2.2 
Non-inclusion criteria ........................................................................................................................ 11 
3. 
INCLUSION RESULTS ............................................................................................................. 11 
4. 
RANDOMISATION .................................................................................................................... 12 
5. 
STUDY DESIGN ......................................................................................................................... 12 
6. 
TREATMENT ............................................................................................................................. 12 
6.1 
ALTERNATING NAB-PACLITAXEL/GEMCITABINE AND FOLFIRI.3 (Arm A) ....................... 12 
6.2 
NAB-PACLITAXEL + GEMCITABINE (Arm B) ............................................................................ 13 
7. 
DOSE ADAPTATION ACCORDING TO THE TOXICITIES ................................................ 13 
7.1 
Criteria required before completion of any new course of treatment ................................................... 13 
7.2 
Dosage adjustment based on toxicities observed during the intercure period ...................................... 14 
7.3 
Dose adaptation related to the occurrence of febrile neutropenia ........................................................ 15 
7.4 
Dose adaptation related to the onset of peripheral neuropathy ............................................................ 15 
7.5 
Dose adjustment in case of occurrence of pulmonary embolism ......................................................... 15 
Premedication, concomitant treatment and contraindicated treatment.............................................................. 15 
8. 
BIOLOGICAL STUDY LOGISTICS ........................................................................................ 16 
9. 
PATIENT MONITORING ......................................................................................................... 16 
9.1 
Before each treatment administration ................................................................................................ 16 
9.2 
Quality of life questionnaire .............................................................................................................. 16 
9.3 
Assessment every 8 weeks ................................................................................................................ 16 
9.4 
Follow-up after stopping treatment .................................................................................................... 17 
10. SUBSEQUENT TREATEMENT ............................................................................................... 17 
11. MANAGEMENT OF SERIOUS ADVERSE EVENTS (SAE) .................................................. 18 
12. STATISTICAL ANALYSIS ....................................................................................................... 20 
12.1 
Provisional study timetable ............................................................................................................... 20 
12.2 
Endpoints ........................................................................................................................................ 20 
12.2.1 
Primary efficacy endpoint ......................................................................................................... 20 
12.2.2 
Secondary endpoints ................................................................................................................. 20 
12.3 
Calculation of the number of required subjects, statistical hypotheses ......................................... 21 
12.4 
Statistical analysis plan ................................................................................................................... 21 
13. STUDY COMMITTEES ............................................................................................................. 22 
13.1 
Independent committee ..................................................................................................................... 22 
13.2 
Steering committee ........................................................................................................................... 22 
13.3 
Medical review ................................................................................................................................. 22 


PRODIGE 37 - FIRGEMAX 
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Page 3 of 26 
13.4 
Biological Research Committee ........................................................................................................ 22 
14. BASIC INFORMATION AND STUDY JUSTIFICATION ...................................................... 22 
14.1 
Pancreatic cancer, a prognosis with a modest improvement ............................................................... 22 
14.2 
The development of multi-drug chemotherapy................................................................................... 23 
14.3 
The FIRGEM study, the first sequential strategy in metastatic pancreatic cancer................................ 23 
14.4 
FIRGEMAX, the optimisation of 4 alternating chemotherapies.......................................................... 23 
15. BIBLIOGRAPHIC REFERENCES ........................................................................................... 24 
16. ADMINISTRATIVE CONSIDERATIONS ............................................................................... 25 
17. RULES FOR PUBLICATION .................................................................................................... 26 
 
 
 


PRODIGE 37 - FIRGEMAX 
Version 1.1 –8.12.2014 
 
Page 4 of 26 
LIST OF ABBREVIATIONS 
 
 
 
AE 
Adverse event 
ALAT 
Alanine aminotransferase (or SGPT:  Serum Glutamic-Pyruvic Transaminase) 
ANC 
Absolute Neutrophil count 
ANSM 
French National Agency for Medicines and Health Products Safety 
ASAT 
Aspartate-aminotransferase (or SGOT: serum glutamic oxaloacetic transaminase) 
CEA 
Carcinoembryonic antigen 
CI 
Contraindication 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CT 
Chemotherapy 
CT-scan 
X-ray computed tomography 
CTC  
Common Toxicity Criteria 
EC 
Ethics committee 
EDTA 
Ethylenediaminetetraacetic acid 
EGF  
Epidermal Growth Factor  
EGFR 
Epidermal Growth Factor Receptor  
5FU 
5-fluorouracile 
FBC 
Full Blood Count 
FFCD 
French Federation of Digestive Oncology 
FOLFIRI 
Folinic acid - Fluorouracile – Irinotecan 
GGT 
Gamma glutamyl transpeptidase 
Hb 
Haemoglobin 
HBP 
High blood pressure  
HR 
Hazard ratio  
INR 
International Normalised Ratio 
IRM 
Magnetic resonance imaging 
ITT 
Intention to treat 
IV 
Intravenous 
D 
Day 
KM 
Kaplan Meier 
LDH 
Lactate dehydrogenase 
LLN 
Lower Limit of Normal 
MDRD 
Modification of the Diet in Renal Disease 
mTNS 
Modified Total Neuropathy Score 
N 
Normal  
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse Events 
OS 
Overall Survival 
OR 
Objective Response  
PAL 
Alkaline phosphatase 
PFS 
Progression-free survival 
PR 
Partial Response 
PT 
Prothrombin Time 
Q1-Q3 
Quartiles 
RECIST 
Response Evaluation Criteria In Solid Tumours 
SAE 
Serious adverse event 
SD 
Stability (stable disease) 
CAP 
Chest-abdomen-pelvis  
UICC 
Union for International Cancer Control 
WHO 
World Health Organisation 


PRODIGE 37 - FIRGEMAX 
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Page 5 of 26 
FFCD CONTACTS FOR THE STUDY 
 
NAME 
FUNCTION 
TELEPHONE 
FAX 
E-MAIL 
FFCD ADMINISTRATIVE DIRECTOR CONTACTS 
Cécile GIRAULT 
Administrative 
Director 
03 80 39 33 87 
03 80 38 18 41 
cecile.girault@u-bourgogne.fr 
RANDOMISATION - MANAGEMENT – ANALYSIS CENTRE 
Marie MOREAU 
Project leader 
03 80 39 34 04 
03 80 38 18 41 
marie.moreau@u-bourgogne.fr 
Emilie MAILLARD 
Biostatistician 
03 80 66 34 81 
03 80 38 18 41 
emilie.maillard@u-bourgogne.fr 
Fadil MASSKOURI 
Data Manager 
03 80 39 34 05 
03 80 38 18 41 
fadil.masskouri@u-bourgogne.fr  
Mickaël VOYE 
Assistant Data 
Manager 
03 80 39 34 05 
03 80 38 18 41 
mickael.voye@u-bourgogne.fr 
Géraldine VAUDRIT 
Assistant Project 
Leader 
03 80 39 33 86 
03 80 38 18 41 
Geraldine.Vaudrit@u-bourgogne.fr 
FFCD CRA team 
Caroline CHOINE-
POURRET 
CRA coordinator 
04 69 18 19 02 
09 74 44 22 47 
carolinechoine.ffcd@sfr.fr 
Florence GUILIANI-
KPODOH 
CRA 
06 16 15 04 58 
09 74 44 20 40 
ffcd.guilianiflorence@sfr.fr 
Hicham FATTOUH 
CRA 
06 29 59 06 92 
03 80 38 18 41 
Fcham30@hotmail.com 
Nouredine LASMI 
CRA 
06 24 08 10 05 
03 80 38 18 41 
nouredine.lasmi@hotmail.fr 
Nicolas LE 
PROVOST 
CRA 
07 77 99 31 25 
05 56 05 03 59 
nicolasleprovost@gmail.com 
Guillaume 
ARNOULD 
CRA 
06 23 46 52 98 
03 80 38 18 41 
garnould@outlook.fr 
Morgane MAURY-
NEGRE 
CRA 
06 26 62 40 17 
03 80 38 18 41 
morgane.maury-negre@hotmail.fr 
Alexandra 
GUERRIER 
CRA 
06 34 50 26 71 
03 80 38 18 41 
alexandra.guerrier.ffcd@gmail.com 
 


PRODIGE 37 - FIRGEMAX 
Version 1.1 –8.12.2014 
 
Page 6 of 26 
PROTOCOL ACCEPTANCE FORM 
 
ETUDE PRODIGE 37- FFCD 1406 – FIRGEMAX  
Multicenter randomised phase II trial assessing nab-paclitaxel + gemcitabine/folfiri.3 versus nab-
paclitaxel + gemcitabine as a sequential first-line treatment of metastatic pancreatic cancer  
EudraCT n° 2014-004449-28 
Version 1.1 –8.12.2014 
 This version of the protocol is approved by: 
For the sponsor:  Mme Cécile GIRAULT 
Date: 08.12.2014       
Signature:    
 For the Coordinator: Pr Julien TAIEB 
Date: 08.12.2014  
Signature:   
I the undersigned, Doctor: 
 ............................................................................................................................  
 
Having reviewed the prerequisites of this research, the Protocol and its Appendices, certify that I conduct this 
trial in accordance with Good Clinical Practice and in accordance with the applicable provisions of the Code of 
Public Health.  
I undertake in particular: 
- 
to respect the protocol as well as any changes notified by the Sponsor, 
- 
to agree to supervise research in the centre and to train my colleagues in conducting research and to 
supply a nominative list of my colleagues,  
- 
in the case of patients lost to follow-up, to request information on the patients condition from their 
home town mairies at the time of analysis or when the Sponsor requests it, 
- 
to have each patient sign a written consent after making them aware of the information sheet 
intended for them and this before any research act, 
- 
to report serious adverse events or developments within 24 hours after having become aware of 
them, in accordance with protocol indications,  
- 
to respect the criteria for inclusion and non-inclusion, as well as the start and end dates of the study, 
- 
to participate in the biological part of the study and to dispatch the samples as recommended, 
- 
to complete all items of the CRF (case report form), monitor the quality of data collection, and good 
product management, 
- 
to archive and keep documents related to the trial for a period of 15 years after the end of the study,  
- 
to inform the Sponsor of all conflict of interest situations likely to impair my scientific 
independence in relation to the research, 
- 
to immediately inform the Sponsor of any cordial or contentious action exerted by a person 
undergoing the research or their dependents which may invoke the responsibility of the Sponsor, 
- 
to accept the periodic visits of the Sponsor's representatives, provide them with all research-related 
source documents and material, to ensure quality control of the data recorded in the case report 
form. Accept a form of audit control from the Sponsor and/or inspection by the health authorities, 
- 
to respond by telephone or email to requests for corrections or clarifications on the case report form, 
- 
to allocate adequate time to the FFCD CRA for the signing of forms, response to questions and 
actions to be taken. 
Date: 
Signature: 
 
 
SEAL: 
 
 
 
Address the original to the CRGA of the FFCD – 7 bd Jeanne d’Arc – BP 87900 – 21079 Dijon Cedex 


PRODIGE 37 - FIRGEMAX 
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SYNOPSIS 
Title  
PRODIGE 37 - FIRGEMAX 
Multicenter randomised phase II trial assessing nab-paclitaxel + 
gemcitabine/folfiri.3 versus nab-paclitaxel + gemcitabine as a sequential first-
line treatment of metastatic pancreatic cancer  
 
Sponsor  
French Federation of Digestive Oncology (FFCD) 
Design 
Multicenter Randomised Open Phase II Study 
Study objectives 
Main objective: 
The main objective of Phase II is to assess the rate of patients alive with no radiographic 
(RECIST V1.1) and/or clinical progression at 6 months in each arm 
Secondary objectives: 
- 
Overall survival 
- 
Objective response rate 
- 
Progression-free survival 
- 
Time to treatment discontinuation 
- 
Toxicities according to the NCI CTC v4.0 
- 
Peripheral neuropathic toxicities according to the mTNS simplified scale (Modified 
Total Neuropathy Score of GOG-Taxane scores)  
- 
Quality of life (EORTC QLQ-C30 questionnaire)  
Inclusion Criteria 
 
- 
Histological or cytological confirmation of pancreatic adenocarcinoma (in primary 
tumour or metastatic lesion) 
- 
Distant metastatic disease 
- 
Scan (or MRI if scanner contraindicated) completed within 3 weeks of the start of 
treatment 
- 
At least one lesion measurable by RECIST v1.1 
- 
Life expectancy> 3 months  
- 
No previous chemotherapy (adjuvant chemotherapy with gemcitabine authorised if 
administered more than 6 months prior to enrolment) 
- 
No previous radiotherapy (unless at least one measurable target lesion outside of the 
irradiation zone) 
- 
Pain must be monitored before inclusion  
- 
18 years < age < 75 years 
- 
Performance status: WHO < 2 
- 
ANC ≥ 1500/mm3, platelets ≥ 100 000/mm3, haemoglobin ≥ 9 g/dL 
- 
ASAT (SGOT), ALAT (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases found  
- 
Bilirubin ≤ 1.5 x ULN (patients drained using the retrograde technique are 
includable), creatinine < 120 μmol/L, or MDRD creatinine clearance > 60 mL/min 
- 
Women of childbearing age must have a negative pregnancy test (β HCG) before 
starting treatment  
- 
Women of childbearing age as well as men (who have sexual relations with women 
of childbearing age) must agree to use effective contraception without interruption 
for the duration of treatment and 6 months after administration of the last treatment 
dose   
- 
Patient affiliated to the social security scheme 
- 
Patient information and signature of informed consent 
Exclusion Criteria 
 
- 
Other types of pancreatic tumours, especially endocrine or acinar cell tumours 
- 
Ampulloma 
- 
Presence of meningeal or cerebral metastases, bone metastases 
- 
Gilbert's syndrome  
- 
Presence of neuropathy> grade 1 according to NCIC-CTC 4.0 
- 
Contraindications specific to the studied treatments 
- 
History of chronic diarrhoea or inflammatory disease of the colon or rectum, or of 
unresolved occlusion or sub-occlusion for which symptomatic treatment is being 
administered 
- 
Other concomitant cancer or history of cancer during the 5 years, with the exception 
of carcinoma in situ of the cervix or basal cell or squamous cell carcinoma, 
considered cured  
- 
Significant history of heart or respiratory disease, including any history of interstitial 
pneumonia  
- 
Patient already included in another clinical trial with an experimental molecule 


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- 
Women who are breast-feeding 
- 
Persons deprived of liberty or under guardianship  
- 
Unable to submit to medical monitoring during the trial due to geographical, social 
or psychological reasons 
Treatment plan 
Arm A (experimental arm): Alternating 2 months of nab-Paclitaxel + gemcitabine with 
2 months of FOLFIRI.3  
Nab-Paclitaxel + gemcitabine (3 wks/4 for 2 months) 
• 
Nab-Paclitaxel = 125 mg/m² 
• 
Gemcitabine = 1000 mg/m² in IV 30 minutes 
On D1, D8, D15 and D29, D36, D43 
Then 
• 
FOLFIRI.3 (a course every 14 days for 2 months) 
Irinotecan 90 mg/m² on D1 in 60 min Y port infusion of folinic acid,  
Folinic acid 400 mg/m² (or 200 mg/m² Elvorine) on D1 as a 2 hour infusion, continuous 
5FU 2000 mg/m² for 46 hours, 
Back to irinotecan 90 mg/m² (1hr) from D3 to the end of the 5FU infusion 
On D1, D15, D29 and D43 
The sequence will be repeated until disease progression or unacceptable toxicity. 
 
Arm B  (reference arm): nab-Paclitaxel + gemcitabine 
Nab-Paclitaxel + gemcitabine (3 wks/4) 
Nab-Paclitaxel • = 125 mg/m 
• Gemcitabine = 1000 mg/m² IV 30 minutes 
On D1, D8, D15 and D29, D36, D43 
 
- 
The treatment will be repeated until disease progression or unacceptable toxicity. 
Randomisation 
Randomisation (1:1) of patients will be carried out according to the minimisation technique 
and will be stratified according to the following stratification factors:  
- 
Centre 
- 
WHO: 0 vs. 1 vs. 2 
- 
Metastatic site: 1 vs. > 1 
Calculation of the 
sample size 
Binomial Method 
The hypotheses for the calculation of the required number of subjects are: 
H0: rate of patients alive without a progression of 40 % at 6 months is insufficient. 
H1: rate of patients alive without progression of over 40% at 6 months is hoped for.  
A rate of 60% is expected 
By using the exact binomial method, an alpha one-sided risk of error of 5% and a power of 
90%, it is necessary to include 56 patients per arm. The decision rules only apply to the 
experimental arm. 
At the end of recruitment, during the analysis: 
- 
If 27 patients or less are alive without progression the treatment is judged 
ineffective. 
- 
If 28 patients or more are alive without progression we reject H0 and conclude that 
the treatment is effective. 
Assuming a rate of patients lost to follow-up or not evaluable at 10%, it is necessary to 
include 62 patients per arm or 124 patients in all. 
Statistical Analysis  
 
Analysis of the primary endpoint will be by intention to treat (ITT) modified with all 
evaluable patients included in the study regardless of eligibility criteria and the treatment 
received.  
The descriptive analysis will be carried out in strict ITT. 
The tolerance analysis will be performed on all patients who received at least one treatment 
dose during the study. 
A statistical analysis plan (SAP) will be drafted before the base gel. 
Ancillary study 
A biological study will assess: 
- The constitutional genetic polymorphisms that may influence the efficacy and tolerance of 
chemotherapy molecules (UGT1A1, ERCC1, MTHFR, DPD, TS...). 
- A study of sections in paraffin in search of immunohistochemical biomarkers predictive of 
treatment response 
Number of patients  
124 patients 
Duration of inclusion 
and participation of 
each patient 
Rhythm of theoretical inclusions: 5 patients per month 
Number of centres: 20 centres 
Start of inclusions: April 2015 
End of inclusions: 24 months after the start of the inclusions or April 2017. 
First analyses: October 2017 


 
 
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TREATMENT MONITORING AND EXAMINATION SCHEDULE 
 
 
*: 
FBC, platelets, PT, sodium, potassium, calcium, bilirubin (total, free and conjugated), ALAT, ASAT, Alkaline phosphatase, LDH, serum Creatinine, creatine 
clearance de la (MDRD), albuminemia 
**:  
In the 3 weeks preceding inclusion  
***:    FBC, platelets, bilirubin (total, free and conjugated), serum creatinine, sodium, potassium  
 
 
 
 
BEFORE TREATMENT 
DURING TREATMENT 
 and in case of stopping treatment without progression (e.g. toxicity or 
patient refusal) 
AFTER STOPPING 
TREATMENT  
 for progression (failed 
strategies) 
In the 7 days preceding 
the start of 
treatment  (excluding 
CT-scan)  
Before each administration of 
treatment 
Every 8 weeks and 30 days after the 
date of last administration of CT 
regardless of the arms 
 
Every 2-3 months until death 
Signed Informed clinical and biological Consent  
X 
 
 
 
CLINICAL EXAMINATION 
Weight, body surface  
X 
X 
X 
X 
Height 
X 
 
 
 
WHO performance status 
X 
X  
X 
X 
Evaluation of toxicities NCI-CTCAE version 4.0 
 
X 
X 
X (tox. persistent) 
Evaluation of peripheral sensory neuropathies (v4.0) 
X 
X 
X 
X 
Evaluation of neurotoxicity's simplified mTNS scale 
X 
 
X 
X (2 months after stopping 
ttt) 
QLQ-C30 
X 
X  (every month for the first 4 
months)  
X (every month for the first 4 
months) 
X 
Morphine treatment and pain assessment (VAS) 
X 
X 
X 
 
BIOLOGICAL TESTS 
Biological test 
X* 
X*** 
X* 
 
Pregnancy test 
X 
 
X and within 30 days after stopping 
treatment 
 
CA19 -9 and CEA Markers 
X 
 
X 
 
PARACLINICAL EXAMS 
Chest-abdomen-pelvis CT-Scan or MRI  
X** 
 
X 
X 
ECG 
X** 
 
 
 
ANCILLARY BIOLOGICAL STUDY 
2 EDTA tubes 5 or 7 mL of blood 
X  
 
 
 
Biopsies or tumour block, fixed in paraffin 
X 
 
 
 


 
 
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1. 
Study objectives  
1.1 
Main objective  
The main objective is to evaluate the rate of patients alive and with no radiographic (RECIST V1.1) and/or clinical 
progression at 6 months in each arm. 
Clinical progression is defined as a worsening of the general condition not related to treatment, tumour mass 
palpable on clinical examination (lymphadenopathies, tumour hepatomegaly, peritoneal carcinomatosis), pleural 
effusion or ascites 
1.2 
Secondary objectives  
- 
Overall survival 
- 
Objective response rate by RECIST v1.1 
- 
Progression-free survival 
- 
Time to treatment discontinuation 
- 
Toxicities according to NCI CTC v4.0 
- 
Peripheral neuropathic toxicities according to the mTNS simplified scale (Modified Total Neuropathy 
Score)  
- 
Quality of life (EORTC QLQ-C30) questionnaire 
 
A biological study will assess: 
- The constitutional genetic polymorphisms may influence the efficacy and tolerance of chemotherapy molecules 
(UGT1A1, ERCC1, MTHFR, DPD, TS...). 
- A study in paraffin sections in search of immunohistochemical biomarkers predictive of treatment response 
2. 
Selection of patients at registration 
2.1 
Inclusion criteria 
- 
Histological or cytological confirmation of pancreatic adenocarcinoma  
- 
Distant metastatic disease 
- 
Scan (or MRI if scanner contraindicated) completed within 3 weeks of the start of treatment 
- 
At least one lesion measurable by RECIST v1.1 criteria 
- 
Life expectancy> 3 months  
- 
No previous chemotherapy (adjuvant chemotherapy with gemcitabine authorised if administered more than 
6 months prior to inclusion) 
- 
No previous radiotherapy (unless at least one measurable target lesion outside the irradiation zone) 
- 
Pain must be monitored before inclusion  
- 
18 years < age < 75 
- 
Performance status: WHO < 2 
- 
ANC ≥ 1500/mm3, platelets ≥ 100 000/mm3, haemoglobin ≥ 9 g/dL 
- 
ASAT (SGOT), ALAT (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases found  
- 
Bilirubin ≤ 1.5 x ULN (patients drained by retrograde technique are includable), creatinine < 120 μmol/L, 
or MDRD creatinine clearance > 60 mL/min 
- 
Women of childbearing age must have a negative pregnancy test (β HCG) before starting treatment  
- 
Women of childbearing age as well as men (who have sexual intercourse with women of childbearing age) 
must agree to use effective contraception without interruption for the duration of treatment and 6 months 
after the administration of the last treatment dose   
- 
Patient affiliated to the social security scheme 
- 
Patient information and signature of informed consent 
 
 


 
 
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2.2 
Non-inclusion criteria 
- 
Other types of pancreatic tumours, especially endocrine or acinar cell tumours 
- 
Ampulloma 
- 
Presence of meningeal or cerebral metastases, bone metastases 
- 
Gilbert's syndrome  
- 
Presence of neuropathy> grade 1 according to NCIC-CTC 4.0 
- 
Contraindications specific to the studied treatments 
- 
History of chronic diarrhoea or inflammatory disease of the colon or rectum, or of unresolved occlusion or 
sub-occlusion for which symptomatic treatment is being administered 
- 
Other concomitant cancer or history of cancer during the 5 years, with the exception of a carcinoma in situ 
of the cervix or basal cell or squamous cell carcinoma, considered cured  
- 
Significant history of heart or respiratory disease, including any history of interstitial pneumonia  
- 
Patient already included in another clinical trial with an experimental molecule 
- 
Women who are breast-feeding 
- 
Persons deprived of liberty or under guardianship  
- 
Unable to submit to medical monitoring during the trial due to geographical, social or psychological 
reasons 
3. 
INCLUSION RESULTS 
 
Inclusion results should be carried out in the 8 days prior to starting treatment, except for the paraclinical tests that 
can be carried out within 3 weeks prior to randomisation. 
 
Clinical tests:  
- 
Measurement of weight, height and body surface  
- 
General condition according to the WHO scale  
- 
Evaluation of the peripheral neurological symptoms according to the mTNS simplified scale and NCI 
CTC v4.0 
- 
Pain assessment by VAS (patient expresses the degree of pain they feel on a scale of 0 to10 (0 being 
"no pain" and 10 being "worst imaginable pain") 
- 
Morphine treatment: dose, type 
 
Biological tests dated less than 7 days: 
- 
FBC, platelets, PT, sodium, potassium, calcium 
- 
Total bilirubin, free and conjugated, ALAT, ASAT, alkaline phosphatases, LDH 
- 
Serum creatinine, creatinine clearance (MDRD – Appendix 4) 
- 
Serum albumin 
- 
Markers: CA 19-9, CEA 
-     Pregnancy test for women of childbearing age 
  
Quality of life questionnaire: 
- 
QLQ-C30 to be completed by the patient before randomisation (same day or within 15 days before 
randomisation but before the first treatment) 
 
Morphological and paraclinical examinations in the three weeks prior to inclusion: 
- 
Chest-abdomen-pelvis CT (CAP CT-scan or MRI scan if contraindicated) ECG  
 
Ancillary biological study (Appendix 3 and chapter 8): 
- 
Sampling of 2 EDTA tubes of 5 or 7 ml of blood before the first treatment. The justification and 
logistics of this study are described jointly in Appendix 3 and Chapter 8.  
 
 


 
 
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4. 
RANDOMISATION 
Following signing of the consent form and validation of the results of the initial inclusion review, eligible patients 
will be randomised by the Center for Randomisation - Management - Analysis (CRGA) of the FFCD. 
  
The investigator must fax the completed and signed randomisation sheet to the CRGA of the FFCD:  
Monday to Friday from 9am to 6pm 
Fax: + 33 (0) 3 80 38 18 41 / Tel: + 33 (0) 3 80 66 80 13 
 
A registration confirmation will be faxed back to the investigator and pharmacist with the patient's registration 
number and the arm assigned by randomisation.  
After randomisation of the patient in the study, treatment should begin as soon as possible and within a maximum 
period of 14 days. 
A case report will be sent at the opening of the centre. A new case report will then be sent after each randomised 
patient 
 
Stratification 
 
The randomisation (1:1) of patients will be conducted by minimisation and will be carried out according to the 
following stratification factors: 
- Centre 
- WHO: 0 vs. 1 vs. 2 
- Metastatic site: 1 vs. > 1 
 
5. 
STUDY DESIGN 
 
 
 
 
 
 
 
 
 
* If progressive, limiting toxicity with one of the 2 treatments, continuation of the other treatment until progression, unacceptable toxicity or 
patient refusal  
 
6. 
TREATMENT  
6.1 
ALTERNATING NAB-PACLITAXEL/GEMCITABINE AND FOLFIRI.3 (Arm A) 
 
Every 2 months alternating nab-paclitaxel/gemcitabine and FOLFIRI.3 
 
NAB-PACLITAXEL + GEMCITABINE   
3 weeks out of 4, an injection on D1, D8, D15 and D29, D36 and D43 (2 month treatment).  
 
• 
Nab-paclitaxel: 125 mg/m² of nab-paclitaxel by 30 min infusion  
R 
Arm A (experimental arm)  
Every 2 months alternating nab-paclitaxel + gemcitabine (2 months: 6 
injections 3 wks/4) and FOLFIRI.3 (2 months, 4 treatments 1wk/2) until 
progression, unacceptable toxicity or patient refusal* 
Arm B  (reference arm)  
Nab-paclitaxel + gemcitabine (3 wks/4)  until progression, unacceptable 
toxicity or patient refusal  


 
 
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• 
Gemcitabine 1000 mg/m² infusion over 30 min immediately after the end of the nab-paclitaxel infusion 
 
FOLFIRI.3:  
1 week out of 2, or an injection on D1, D15, D29, D43 - or 2 months of treatment. 
 
• 
Irinotecan 90 mg/m² on day 1 60 min Y infusion of folinic acid 
• 
Folinic acid 400 mg/m² (or 200 mg/m² Elvorine) on D1 as a 2 hour infusion 
• 
5FU continuous 2000 mg/m² for 46 hours 
• 
Then back to irinotecan - 90 mg/m² in 60 min infusion on day 3, at the end of the 5FU infusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In case of progression, limiting toxicity with one of the two treatments it is recommended (except against-
indication or rejection) to continue the other treatment until progression, unacceptable toxicity or patient refusal. 
 
 
6.2 
NAB-PACLITAXEL + GEMCITABINE (Arm B) 
 
3 weeks out of 4, or an injection on D1, D8, D15 and resumption on D29 (for each treatment, D1 = D29).  
 
• 
Nab-paclitaxel: 125 mg/m² by infusion of nab-paclitaxel over 30 min 
• 
Gemcitabine 1000 mg/m² by infusion over 30 min immediately after the end of the nab-paclitaxel infusion 
 
 
7. 
DOSE ADAPTATION ACCORDING TO THE TOXICITIES 
Toxicities requiring dosage adjustment will be evaluated according to the NCI-CTCAE v4.0 scale (Appendix 7). 
 
7.1 
Criteria required before completion of any new course of treatment 
Criteria required before completion of any new course of treatment: 
- 
ANC > 1500/mm3 
- 
Platelets > 100 000/mm3 
- 
Gastrointestinal toxicities < grade 1 
 
As long as these criteria have not been met, symptomatic treatment should be optimised and an FBC will be 
conducted every 7 days until obtaining the required figures. The treatment can then be carried out.  
In addition to these criteria: 
- 
treatment by FOLFIRI.3 may only be administered if serum bilirubin< 1.5 times the normal. 
- 
gemcitabine may be administered if the transaminases are< 5 times the normal. 
Otherwise, a biological control shall be performed every 7 days until obtaining the required figure; administration 
of FOLFIRI.3 can then be conducted. 
Folinic acid 
400 mg/m² (or 200 mg/m² if 
Elvorine) 
5 FU continous 
2000 mg/m² 
Irinotecan 
90 mg/m² 
1hr 
2hr 
46hr (D1 and D2) 
Irinotecan  
90 mg/m² 
1hr (D3) 


 
 
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As long as these criteria are not met, the treatment should be postponed for a week. 
If over 21 days of treatment deferral after the last administration, the patient will stop the treatment under study and 
will continue to be monitored as part of the protocol. 
7.2 
Dosage adjustment based on toxicities observed during the intercure period 
Depending on the maximum grade of toxicity observed during the intercure period, dosage adjustments will be 
required according to the below table.  
 
Treatment will only begin when the criteria required before completion of any new treatment is obtained (see 
section 7.1). 
 
The occurrence of a grade 4 toxicity (excluding haematological toxicities or other manageable toxicity) will impose 
the permanent cessation of the study treatment. Secondary treatments will be at the discretion of the investigator. In 
all cases, the patient will continue to be monitored as part of the protocol and according to the protocol rythym. 
 
The occurrence of febrile neutropenia, peripheral neuropathy or pulmonary embolism is the subject of a separate 
paragraph (see paragraphs 7.3, 7.4 and7.5). 
       Table n°1: Haematological toxicity or not: dose adaptation of the various treatments 
 
1. In case of non-recovery of toxicities at D14: gastrointestinal (grade > 2 diarrhoea persistence) or haematological (persistence of grade>  2 
for ANC or grade> 1 at D21 for platelets), we will carry out reductions in doses recommended for grade 3.  
2. Except: alopecia, cholinergic syndrome and nausea/vomiting in the absence of adequate treatment 
3. In case of persistent grade 3 neutropenia despite dosage adjustment and administration of G-CSF, Nab-Paclitaxel will be reduced to 75 
mg/m².  
If, despite these dose adaptations, at D14 there is a persistence of grade> 2 for ANC or grade> 1 for platelets, the patient will exit the study. 
4. G-CSF: WBC growth factors 
 
Toxicity/Grade 
CTCAE v4.0 
1 
2 
3-4 
FOLFIRI.3 
Gemcitabine 
+ Nab-Paclitaxel 
Anaemia  
 
No 
modification  
No modification, 
transfusion 
support to be 
discussed 
No modification,  
transfusion support mandatory  
Neutropenia,  
 
Thrombopenia 
No 
modification 
No modification 
if administration 
within a period 
of 14D1 
Administration 
of G-CSF4 to be 
discussed 
 - 5FU 1600 mg/m² (46h) 
 - Irinotecan 80 mg/m² 
(J1-J3) 
- Gemcitabine 800 g/m² 
- Nab-Paclitaxel3 100 mg/m² 
If neutropenia, administration of G-CSF4 required. 
Toxicity/Grade 
CTCAE v4.0 
1 
2 
3 
Diarrhoea 
 
No 
modification  
No modification 
if administration 
within a period 
of 14 D 1 
 -5FU: no modification 
 - Irinotecan 80 mg/m² 
(J1-J3) 
- Gemcitabine 800 mg/m² 
- Nab-Paclitaxel 100 mg/m² 
Other2 
No 
modification  
No modification 
 - 5FU 1600 mg/m² (46h) 
 - Irinotecan 80 mg/m² 
(J1-J3) 
- Gemcitabine 800 mg/m² 
- Nab-Paclitaxel 100 mg/m² 


 
 
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7.3 
Dose adaptation related to the occurrence of febrile neutropenia 
The treatment should be discontinued until resolution of fever and recovery of an ANC rate of > 1500/mm3.   The 
treatment will be resumed according to the recommended dosage reductions for grade 3, on condition of 
administration of G-CSF.  
If febrile neutropenia occurs during treatment with gemcitabine + Nab-Paclitaxel, while doses have already been 
reduced, Nab-Paclitaxel will be reduced to 75 mg/m².  
7.4 
Dose adaptation related to the onset of peripheral neuropathy 
Dose adjustment will depend on the scale of peripheral neurological toxicities CTCAE v4 (Appendix 6). 
Gemcitabine or FOLFIRI.3 will be continued with no dose modification. 
In the event of grade 1 or 2 peripheral neuropathy, dose adjustment is not recommended. 
In the event of ≥ grade 3 peripheral neuropathy, Nab-Paclitaxel must be suspended until recovery from ≤ grade 1 
and then continued at 100 mg/m².  
If grade 3 neuropathy occurs when Nab-Paclitaxel doses are already reduced, it should be suspended until recovery 
of grade ≤ 1 and then continued at 75 mg/m². 
7.5 
Dose adjustment in case of occurrence of pulmonary embolism 
Clinically asymptomatic or mild pulmonary embolism can be treated with low molecular weight heparin without 
suspension of treatment. 
In patients with moderate to severe pulmonary embolism (grade 3-4), treatment should be permanently 
discontinued and the patient should stop the protocol treatment. 
 
Premedication, concomitant treatment and contraindicated treatment 
 
The treatment considered necessary for patient well-being can be administered at the discretion of the investigator. 
The subcutaneous administration of growth factor is permissible: 
According to EORTC 2010 [38] recommendations, the risk of febrile neutropenia should be assessed before each 
chemotherapy cycle. The validated risk factors are: age> 65 years, a history of febrile neutropenia and advanced 
disease. 
 
In the event of severe neutropenia, i.e. grade 3-4, patients are at high risk of febrile neutropenia and infection 
notably in the event of concomitant diarrhoea. If these symptoms occur, dosage adjustments are planned for the 
next treatment and the prescription of hematopoietic growth factors should be considered. 
 
The administration of hematopoietic growth factors is not routinely recommended at the 1st NAB paclitaxel / 
GEMCITABINE or FOLFIRI.3 treatment, however they may be specified in each case depending on the patient's 
clinical condition. Treatment with lenograstim (GRANOCYTE®), filgrastim (Neupogen®, ZARZIO®) or 
pegfilgrastim (Neulasta®) is advisable. 
 
The concomitant opioid treatment as well as pain assessment (VAS) should be reported in the case report. Data 
should be collected from the inclusions visit and throughout the treatment. 
For pain assessment, the patient expresses their degree of pain on a scale of 0-10 (0 being "no pain" and 10 being 
"worst pain imaginable" 
 
Contraindicated treatments  
5FU: Yellow fever vaccine, live attenuated vaccines, and phenytoin for prophylactic purposes. 
Irinotecan: association with St. John's wort, yellow fever vaccine. 
Nab-paclitaxel:  No interaction study has been performed, caution is required when using inhibitors or enzyme 
inducing drugs. 


 
 
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8. 
BIOLOGICAL STUDY LOGISTICS  
For patients who have signed the biological informed consent form, details of the biological sub-study are located 
in Appendix 3 of this protocol. 
 
Necessary samples  
- A blood sample of 2 EDTA tubes of 5 (or 7) ml prior to starting treatment (during inclusion review or before the 
1st treatment). 
 
The tubes are sent, via DHL box provided at opening of the centre to:  
Centre de Ressource Biologique EPIGENETEC 
Unité UMR-S 1147 
45 rue des Sts Pères, 75006 PARIS 
Diriected by Pr Pierre LAURENT-PUIG 
 
Only use the DHL box containing the INSERM Unit U775 DHL paking slip. 
 
After sending this box, the box required for the inclusion of the next patient will be sent by EPIGENETEC. 
 
- Paraffin embedded tumour block.   
 
Dispatch blocks or slides via maxi letter provided to the centre at opening:  
Centre de Ressource Biologique EPIGENETEC 
Unité UMR-S 1147 
45 rue des Sts Pères, 75006 PARIS 
Directed by Pr Pierre LAURENT-PUIG 
 
In case of logistics questions or problems, contact Claire MULOT at +33(0) 1 42 86 38 61, 
claire.mulot@parisdescartes.fr. 
9. 
PATIENT MONITORING  
9.1 
Before each treatment administration 
 
o Clinical exam: weight, WHO 
o Evaluation of tolerance (toxicity according to NCI-CT v4.0) including systematic evaluation of the 
peripheral neuropathy according to the NCI-CT v4.0 scale (Appendix 6) 
o Concomitant morphine treatment and pain assessment by VAS 
o FBC, platelets, total bilirubin, free and conjugated, serum creatinine, sodium, potassium 
 
If necessary provide for the administration of growth factors in subsequent treatment. 
 
9.2 
Quality of life questionnaire 
 
QLQ-C30 version 3.0 every month during the first 4 months and then every 2 months 
 
9.3 
Assessment every 8 weeks  
 
Patients will be evaluated every 8 weeks by:  
 
o Clinical tests: weight, WHO, evaluation of the peripheral neuropathy according to the NCI-CT v4.0 
scale and the mTNS simplified scale (Appendix 6) 
o Evaluation of toxicities from the preceding cycle 
o Concomitant morphine treatment and pain assessment by VAS 


 
 
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o Quality of Life Questionnaire QLQ-C30 Version 3.0 (every month during the first 4 months and 
then every 2 months) 
o Biological tests: FBC, platelets, bilirubin (total and conjugated), PT, PAL, ASAT, ALAT, sodium, 
potassium, calcium, serum creatinine, creatinine clearance (MDRD), albuminemia, LDH. 
o Pregnancy test for women of childbearing age  
o Markers: CA 19-9, CEA 
Morphological Rating: CAP CT-scan or MRI if contraindication to injected CT scan 
A CAP CT-scan at 6 months after initiation of treatment is MANDATORY (whatever the 
number of treatments carried out, in order to assess the primary endpoint unless the patient 
is subject to prior progression) 
 
 
9.4 
Follow-up after stopping treatment  
 
a/ Within 30 days for evaluating the toxicity of the last treatment:  
o Biological tests: FBC, platelets, bilirubin (total and conjugated), PT, PAL, ASAT, ALAT, sodium, 
potassium, calcium, serum creatinine, MDRD creatinine clearance, albuminemia, LDH 
o Evaluation of toxicities from the preceding cycle 
Pregnancy test 
 
b/ After radiological or clinical progression (as defined in 1.1), patients will be monitored every 2 to 3 
months up to death: 
o Clinical exam: weight, WHO 
o Evaluation of persistant toxicities  
o Evaluation of the peripheral neuropathy 2 months after stopping the study treatment by mTNS 
simplified scale (Appendix 6) 
CAP-CT scan (or MRI) 
o Quality of life questionnaire QLQ-C30 version 3.0  
 
c/ After premature discontinuation of treatment other than for progression*, patients will be 
monitored in the same way every 8 weeks until progression: 
 
o Clinical exam: weight, WHO 
o Evaluation of persistant toxicities 
o Evaluation of peripheral neuropathy 2 months after stopping the study treatment by mTNS 
simplified scale (Appendix 6) 
o TAP-CT scan (or MRI) 
o Quality of life questionnaire QLQ-C30 version 3.0  
o Tumoral markers 
 
* Toxicity, disease progression, withdrawal of consent, lost to follow-up, patient refusal, pregnancy or suspected 
pregnancy  
10. 
SUBSEQUENT TREATEMENT 
Recommended treatment in the event of progression or toxicity 
- 
In sequential arm A (alternating nab-paclitaxel/gemcitabine and FOLFIRI.3): 
If the patient must prematurely stop one of the two treatments due to limiting toxicity or progression in a sequence 
(for example nab-paclitaxel/gemcitabine), the investigator must absolutely pursue the other sequence (in this case 
FOLFIRI. 3) until progression. 
 
In case of further progression, the investigator will assess the use of further treatment. 
 


 
 
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- 
In the reference arm B (nab-paclitaxel/gemcitabine), 
In case of premature discontinuation of treatment, the investigator will assess the use of further treatment. 
11. 
MANAGEMENT OF SERIOUS ADVERSE EVENTS (SAE) 
Safety endpoints 
The safety assessment will be carried out by assessing the general and clinical condition of patients and by the 
collection of events occurring between visits during consultations, by regular blood tests. The toxicities shall be 
evaluated by the NCI-CTCAE toxicity scale version 4.0 (Appendix 6). 
In an emergency, the patient, family members or physician should call the investigator to inform them of an event. 
Definitions 
a. 
Adverse event (AE) 
An adverse event is a harmful event occurring in a person volunteering for biomedical research, whether this 
event is related or not to the research or product of this research. 
All adverse events will be recorded in the case report form in the pages provided for this purpose. 
b. 
Serious Adverse Event (SAE) 
Considered a serious adverse event, is any event 
• 
causing death, 
• 
life threatening, 
• 
causing hospitalisation or extension of hospitalisation, 
• 
causing permanent disability or serious temporary incapacity  
• 
causing a congenital abnormality, foetal malformation or abortion, 
• 
medically significant (e.g.: overdosage, secondary cancer and new issue that may be considered medically 
significant) 
The terms disability and incapacity correspond to any temporary or permanent physical or psychological 
disability, clinically significant and devastating to physical activity and/or the quality of life of the patient.    
Considered medically significant are all clinical events or laboratory results assessed as serious by the 
investigator and not corresponding to the above-defined severity criteria. They may pose a risk to the patient 
and require medical intervention to prevent an outcome corresponding to one of the severity criteria mentioned 
above e.g.: overdosage, secondary cancer, pregnancy and new issue that may be considered medically 
significant). 
 
Pregnancy is an exclusion criterion in this trial. However, if a pregnancy is discovered after inclusion, the 
patient should be excluded from the trial. The sponsor should be informed immediately via the serious adverse 
event report card (no severity criterion shall be checked). The patient should be monitored until the end of 
pregnancy and the outcome whatsoever, must be reported to the sponsor. This declaration and follow-up shall 
also apply in the context of a pregnancy in a patient's partner. 
 
If the pregnancy outcome falls within the scope of the definition of serious adverse events (spontaneous or 
therapeutic abortion requiring hospitalisation, foetal death, congenital anomaly...) the investigator must follow 
the SAE reporting procedure. 
 
All neonatal deaths occurring within 28 days following the birth should be reported, regardless of the causality 
as an SAE. In addition, any infant deaths occurring after these 28 days and suspected by the investigator to be 
related to in utero exposure to drug testing must also be reported to the sponsor within 24 hours of the 
Investigator becoming aware of the event by following the procedure for reporting SAEs. 
c. 
Adverse Event 
Any harmful and unintended response to an experimental drug whatever administered dose or any 
experimental element. The AE is severe if it presents a serious criterion. 
d. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A Suspected Unexpected Serious Adverse Reaction is an event not consistent or different by its nature, 
intensity or evolution in relation to the product reference document (or pCRs). 


 
 
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e. 
New development 
A new development may be: an unexpected frequency of an expected SAR, a SAR related to the trial 
procedure, insufficient efficacy in life-threatening diseases, clinical data. 
f. 
Intensity (or severity) 
The intensity criteria should not be confounded with the severity criteria that are used to define the declaration 
procedure. 
The event intensity is graded according to the CTCAE version 4.0 classification (Appendix 4). The intensity of 
adverse events not listed in this classification shall be evaluated according to the following scale: 
- 
Mild (grade 1): not affecting the patient's usual activity. 
- 
Moderate (grade 2): disrupts the patient's usual activity. 
- 
Severe (grade 3): prevents the patient's usual activity. 
- 
Very severe (grade 4): Life-threatening consequences/urgent intervention indicated. 
- 
Death (grade 5) 
g. 
Causality 
- 
Related: an event is related when there is suspected reasonable possibility of causality between the 
product undergoing study and the event 
- 
Non-related: an event is said to be non-related when a causality between the event and the trial product 
cannot reasonably be suspected 
- 
Unlikely: causality is "questionable" when there is doubt as to the causality between the event and the 
product under study (then the relationship can neither be formally excluded nor formally affirmed) 
h. 
Sponsor's responsibility 
On receiving the serious adverse event declaration determined by the investigator, the sponsor must advise on 
the causal link between the serious adverse event and the products undergoing study. 
If the serious adverse event is connected by the investigator and/or sponsor to the product being studied (it is 
therefore a serious adverse event), they must demonstrate the expected or unexpected character of this effect. 
If it is an unexpected serious adverse event, or a new event, the sponsor drafts an initial report to be 
transmitted to the ANSM, the EC and the EMA (via EudraVigilance) within 7 days in case of death or if life-
threatening otherwise within 15 days. 
Events not considered serious 
The progression of the disease should not be treated as an SAE. 
Events potentially related to the progression but that can also be secondary to the treatment shall continue to be 
reported (e.g. thromboembolic events, haemorrhagic phenomena, perforations…) 
Due to the severity of the disease in this study, certain conditions defined as SAEs shall be excluded from the SAE 
declaration procedure, i.e.: 
Hospitalisation or surgery related to treatment of the disease. However, hospitalisation or extension of 
hospitalisation for a complication of these treatments should be reported as an SAE. 
Hospitalisation in order to simplify study treatment or procedures.  
In this trial reference documents will be: 
• 
For nab-paclitaxel, Abraxane® summary of product characteristics (Appendix 7) 
• 
For gemcitabine, Gemzar® summary of product characteristics (Appendix 7) 
• 
For 5-fluorouracile, Fluorouracile Ebewe® 50 mg summary of product characteristics (Appendix 7) 
• 
For folinic acid, Elvorine® summary of product characteristics (Appendix 7)  
• 
For irinotecan, Campto® summary of product characteristics (Appendix 7) 
Mcm versions used for the expected or unexpected character definition will be those in effect at the time of the 
analysis. 
Course of action 
The investigator informs the sponsor of all (Expected and unexpected) Serious Adverse Events whether or not 
caused by the research and occurring during the study or during the 30 days after the last treatment dose. 
All delayed Serious Adverse Events (occurring after this 30-day period) considered reasonably related to (x) 
protocol or research treatment must be declared without limitation of delay. 


 
 
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The declaration is carried out by faxing the "notification of a serious adverse event" form (Appendix 9) 
documented as precisely as possible, dated and signed, within 24 business hours after initial observation to the 
Centre for Randomisation Management Analysis (CRGA) of the FFCD: by fax to 03 80 38 18 41. 
The investigator is responsible for the appropriate medical follow-up of patients until recovery, stabilisation of the 
event and/or the death of the patient. This can sometimes imply that this monitoring is extended after the patients 
exit from the trial. 
They transmit the additional information to the sponsor with an SAE report form (by ticking the "Follow-up" box 
and incrementing the number, to specify that it is a follow-up report and not an initial report) within 24 hours after 
its receipt. They will also send the last follow-up at resolution or stabilisation of the SAE. 
They shall respond to requests for additional information in order to document the initial observation. 
 
 
12. 
STATISTICAL ANALYSIS 
12.1 
Provisional study timetable  
Rhythm of start of inclusions: 5 patients per month 
Start of inclusions: April 2015 
End of inclusions: 24 months after the beginning of inclusions i.e. April 2017 
First analysis: October 2017 
12.2 
Endpoints  
12.2.1 Primary efficacy endpoint  
The primary endpoint is the rate of patients alive without progression 6 months after inclusion.  
The progression is clinically and/or radiologically assessed by the investigator (as defined in 1.1) according to 
RECIST v1.1 criteria. 
12.2.2 Secondary endpoints 
The secondary endpoints are:  
- 
Overall survival (OS): defined as the time interval between the randomisation date and the date of death 
(all causes). The patients alive will be censored at the end-point or the date of the latest event  
- 
The objective response rate (ORR): defined as complete or partial response rates in imaging by RECIST 
v1.1 over the entire treatment  
- 
The best response to treatment shall be evaluated from imaging throughout the treatment 
- 
Progression-free survival: defined as the time interval between the randomisation date and the date of first 
progression (clinical and/or radiological) or death (whatever the cause). Living patients without 
progression will be censored at the end-point or date of latest event.   
- 
Time to discontinuation of treatment: defined as the time interval between the randomisation date and 
treatment stop date (regardless of cause) or date of latest events for living patients without stopping 
treatment. 
- 
Toxicities are evaluated according to NCI CTC v4.0. 
- 
Peripheral neuropathy toxicities are evaluated according to the Mtns simplified scale (Modified Total 
Neuropathy Score of GOG-Taxane scores) 
- 
The time to first occurrence of grade 3 and 4 toxicity: defined as the time interval between the date of 
randomisation and the first occurrence of a 3.4 grade event. 
- 
Quality of life (assessed according to the EORTC QLQ-C30 questionnaire): This scale comprises 30 items 
with 15 dimensions for calculating 15 scores (5 functional ability scores, 8 symptom scores, an overall 
score, and a financial problems score). These scores will be calculated and described at inclusion. Of an 
exploratory manner, time to deterioration of the overall health score will be calculated: it is defined as the 
time interval between the date of randomisation and the date of reduction of over 5 points compared to the 
baseline (5 points being considered the minimum to define a clinically significant difference) or death. 


 
 
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12.3 
Calculation of the number of required subjects, statistical hypotheses 
The hypotheses for calculating the number of subjects required are: 
H0: rate of patients alive without progression of 40 % at 6 months is insufficient. 
H1: rate of patients alive without progression of over 40 % at 6 months is hoped for.  
       A rate of 60 % is expected 
 
By using the exact binomial method, an alpha one-sided 5% risk error and a power of 90%, it is necessary to 
include 56 patients per arm. The decision rules apply to the experimental arm only. 
 
At the end of recruitment, during the analysis: 
- 
If 27 patients or less are living without progression the treatment is judged ineffective. 
- 
If 28 patients or more are living without progression we then reject H0 and the treatment will be considered 
of interest. 
 
By considering a rate of patients lost to follow-up or not evaluable by 10%, it is necessary to include 62 patients per 
arm or 124 patients in all. 
 
Analysis of the primary endpoint shall be carried out in modified intent to treat in all evaluable patients included in 
the study regardless of the eligibility criteria and the treatment received.  
 
Patients with no evaluation at 6 months will be reviewed using the following rules:  
• 
If the patient has a later evaluation (7 months or more) and is not in progression at that date they shall be 
considered as progression-free at 6 months 
• 
If the patient has documented progression of more than 6 months without imagery at 6 months then the 
patient shall be considered in progression at 6 months. 
If a progression is documented before the 6-month evaluation, the patient is considered as in progression at 6 
months. 
 
12.4 
Statistical analysis plan 
Population analysis: 
Patient description will be conducted with intention to treat (ITT) on all randomised patients regardless of their 
eligibility criteria and treatment received.  
 
Analysis of the primary endpoint will be conducted with modified intent to treat (mITT) among all randomised 
patients evaluable (clinically and/or radiologically) regardless of their eligibility and the treatment received. 
 
The tolerance population is defined as all randomised patients who have received at least one dose of 
chemotherapy (regardless of the product).   
 
Descriptive analyses 
The continuous variables will be described using mean, standard deviation, median, minimum, maximum, and the 
inter-quartile range (Q1-Q3).  
 
Qualitative variables shall be described using frequencies and percentages. The percentages will be calculated 
without taking into account the missing data modality. 
 
Censored data will be estimated and plotted using the Kaplan-Meier method. The median times and rates at 
different temporalities shall be described as well as their confidence intervals at 95%.  
Median follow-up will be determined by the reverse Kaplan-Meier method. 
 
Tolerance analysis  


 
 
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The number of treatments, the dose received and the percentages of actual dose received on theoretical dose will be 
described, as well as the percentage of patients with at least one dose modification or at least an administrative 
report. 
The toxicities will be described by treatment arm, the number of patients and toxicities according to various grades 
and SOC. They will also be described by grouping grades 1-2 versus 3-4-5. 
Every six months a safety report will be provided by pharmacovigilance centres to all the study investigative 
centres. 
13. 
STUDY COMMITTEES 
13.1 
Independent committee 
An Independent Committee will be set up and will include at least two gastro-oncologists, a 
statistician/methodologist and a pharmacovigilance expert. The independent committee will be referred to at any 
point during the protocol when the sponsor deems it necessary. 
13.2 
Steering committee 
A Steering Committee will be set up. The steering committee director shall be the study coordinator. This 
committee will also include the co-coordinators, the FFCD project manager, the FFCD statistician and the 
President of the Biological Research Committee. Its mission among others will be to make decisions related to 
research management (amendment, premature termination if required…). This committee shall meet whenever 
necessary throughout the study. The steering committee will make the necessary decisions concerning substantial 
amendments to the protocol, the closing or extension of the study.  
13.3 
Medical review  
A medical review board shall be set up in order to improve the quality of clinical data collected. In case of 
discrepancy between the data provided by the investigator and those in the medical review, requests for 
clarification will be sent to the investigator by data management. 
13.4 
Biological Research Committee 
A Biological Research Committee will be established; it will manage the problems related to sampling, their 
addition to the biobank and the organisation of their analysis. The committee will meet regularly and report its 
proposals to the Steering Committee. This committee will include among others the study coordinator and a 
biologist; it will be chaired by Pr Pierre LAURENT PUIG. 
 
14. 
BASIC INFORMATION AND STUDY JUSTIFICATION  
14.1 
Pancreatic cancer, a prognosis with a modest improvement  
Due to its very poor prognosis, which puts it in fifth position in cancer deaths, but also due to its steadily increasing 
incidence in Western countries (1), pancreatic adenocarcinoma is a major challenge for therapeutic strategies in 
gastrointestinal oncology. Due to the aggressiveness of this cancer, and its initially insidious mode of development, 
around 85% of patients develop unresectable disease at diagnosis. In the presence of visceral metastases, median 
survival of untreated patients does not exceed three to six months, and among patients who could benefit from 
curative resection, more than 80% relapse within 2 years after surgery (2).  
The chemo/radiation resistance of this cancer, when the patient's general condition authorises systemic treatment, 
explains the multitude of negative clinical trials (3) and the maintenance for years of Gemcitabine as the reference 
treatment in first line metastatic treatment (4). 
Nevertheless, in recent years, 2 positive Phase III trials have given hope to caregivers and patients: 


 
 
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- 
the PRODIGE 4/ACCORD 11 (5) study assessing the multiple drug chemotherapy regimen FOLFIRINOX, 
with 5-fluorouracil, oxaliplatin, irinotecan and folinic acid 
- 
and the MPACT study (6), evaluating the combination of Gemcitabine with Nab-Paclitaxel: a nanoparticle 
albumin molecule enabling the vectorisation of Paclitaxel in tumour cells and the optimisation of its 
pharmacokinetics.  
 
14.2 
The development of multi-drug chemotherapy  
The anti tumour effect of irinotecan in cellular cultures of pancreatic adenocarcinoma appears promising, with an 
inhibition of tumour growth greater than cisplatin, mitomycin-C and fluorouracil (7). However, the observed 
response and survival rate remains disappointing (8-11). Diagrams for enhancing this anti-tumour effect have been 
developed by combining irinotecan to 5-FU in patients with colorectal cancer (12,13). Among these, FOLFIRI.3 
wherein irinotecan is administered before and after a 46-hour continuous infusion of 5-FU, has yielded encouraging 
results (14). We have tested this regimen in a phase II trial in patients with metastatic pancreatic cancer, with an 
objective response of 37.5%, a median OS of 12 months for an acceptable tolerance (15).  
 
14.3 
The FIRGEM study, the first sequential strategy in metastatic pancreatic cancer 
 
Given these results, we have proposed a scheme combining FOLFIRI.3 and Gemcitabine alone, sequentially, with 
the aim to increase the survival of patients while preserving quality of life. This innovative approach was 
underpinned by the results of certain studies, indicating that the administration of different models of sequential 
multidrug regimens was independently associated with overall survival in patients with pancreatic adenocarcinoma 
and metastatic colorectal cancer (16,17). Accordingly, it has been proven that sequential strategies using 
chemotherapy without cross-resistance can increase the anti-tumour effects of these drugs, and limit their 
cumulative and non-cumulative toxicities. 
We conducted a randomised multicenter phase II trial: the FIRGEM trial comparing an experimental sequential 
arm consisting of FOLFIRI.3 alternating with Gemcitabine, to the reference arm: Gemcitabine as monotherapy in 
patients with non-pretreated metastatic pancreatic adenocarcinoma (Trouilloud et al, ASCO 2012). This study has 
helped to establish the FIRGEM strategy as an effective first-line treatment option in patients with metastatic 
pancreatic cancer who are in good general condition. The main criterion has been reached, with a progression-free 
survival rate at 6 months of 45% in the FIRGEM arm, against only 26% in the gemcitabine arm. This encouraging 
progression-free survival rate was also maintained at 12 and 18 months (26.2% and 18% respectively), when the 
median PFS was 5 months. In addition, an impressive objective response rate (40%) was observed in the FIRGEM 
arm compared to gemcitabine alone (11%). These results confirm the initial phase II trial evaluating the FOLFIRI.3 
regimen (objective response rate of 37.5%) (15) in patients with pancreatic cancer, and compares favourably to the 
rates in recent phase III trials (31.6% and 23% in trials evaluating FOLFIRINOX and Gemcitabine + Neb -
Paclitaxel respectively). 
Regarding the median overall survival, it was 11 months with FIRGEM, against 8.2 months with gemcitabine alone 
(HR: 0.710; 95% CI: 0.457 to 1.103). Once again, the sequential experimental design has given promising results, 
in the range of those observed with FOLFIRINOX (11.1 months). The tolerance profile of the FIRGEM strategy 
was acceptable, with a higher hematologic toxicity in the Gemcitabine arm alone. It is worth noting that a limiting 
sensory neuropathy with the sequential design was not observed, and a significant increase in time to deterioration 
of quality of life was objectified compared to the gemcitabine as monotherapy arm.  
 
14.4 
FIRGEMAX, the optimisation of 4 alternating chemotherapies. 
 
Whereas Nab-Paclitaxel significantly improves the survival of patients with metastatic pancreatic cancer when 
combined with Gemcitabine, associating this drug with the FIRGEM strategy could prove particularly interesting. 
Adding this new option would enable anti-tumour action based on four different drugs without any cross-resistance 
described between them, administered in succession in the first four months of treatment. This new concept, 
consisting of three therapies of Gemcitabine + Nab-paclitaxel, followed by two additional non-neurotoxic 
chemotherapy treatments of FOLFIRI.3, would give the patient more than 29 days necessary to recover a potential 
secondary neurotoxicity with Nab-Paclitaxel. This "rest period" without Nab-Paclitaxel could help eliminate or at 
least significantly delay the onset of cumulative sensory neuropathy induced by this molecule. Consequently, the 
sequential administration of the two proposed chemotherapy regimens would act as a "stop and go" strategy. 


 
 
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We therefore propose to start the FIRGEMAX phase II randomised trial, assessing the reference arm Gemcitabine 
+ Nab-Paclitaxel and a sequential arm with two months of Gemcitabine + Nab-paclitaxel, followed by two months 
of FOLFIRI 3 before continuing this alternating sequence. 
 
15. 
BIBLIOGRAPHIC REFERENCES 
1.    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. Oct 2010;60(5):277-300.  
2.  Wray CJ, Ahmad SA, Matthews JB, Lowy AM. Surgery for pancreatic cancer: recent controversies and current 
practice. Gastroenterology. mai 2005;128(6):1626-1641  
  3.     Ahlgren JD. Chemotherapy for pancreatic carcinoma. Cancer 1996; 78(3 Suppl):654-63 
  4.  Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy with 
gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized 
controlled trial. JAMA J Am Med Assoc. 17 janv 2007;297(3):267-277. 
 
5.  
Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients 
with metastatic adenocarcinoma of the pancreas (MPACT). -- Von Hoff et al. 31 (4): LBA148 -- ASCO 
Meeting 
Abstracts 
[Internet]. 
[cité 
9 
févr 
2013]. 
Disponible 
sur: 
http://meeting.ascopubs.org/cgi/content/abstract/31/4_suppl/LBA148?sid=1808b507-ffbc-4ec7-b96e-
98922aceea6b 
6.  
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus 
gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 12 mai 2011;364(19):1817‑1825.  
7.  
Matsuoka H, Yano K, Seo Y, Saito T, Tomoda H, Takiguchi S, et al. Cytotoxicity of CPT-11 for 
gastrointestinal cancer cells cultured on fixed-contact-sensitive plates. Anticancer Drugs. juin 
1995;6(3):413‑418.  
8.  
Wagener DJ, Verdonk HE, Dirix LY, Catimel G, Siegenthaler P, Buitenhuis M, et al. Phase II trial of CPT-11 
in patients with advanced pancreatic cancer, an EORTC early clinical trials group study. Ann. Oncol. févr 
1995;6(2):129‑132.  
9.  
Klapdor R, Fenner C. Irinotecan(Campto R): efficacy as third/forth line therapy in advanced pancreatic 
cancer. Anticancer Res. déc 2000;20(6D):5209‑5212.  
10.  Ulrich-Pur H, Raderer M, Verena Kornek G, Schüll B, Schmid K, Haider K, et al. Irinotecan plus raltitrexed 
vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma. Br. J. 
Cancer. 22 avr 2003;88(8):1180‑1184.  
11.  Zaniboni A, Aitini E, Barni S, Ferrari D, Cascinu S, Catalano V, et al. FOLFIRI as second-line chemotherapy 
for advanced pancreatic cancer: a GISCAD multicenter phase II study. Cancer Chemother. Pharmacol. juin 
2012;69(6):1641‑1645.  
12.  Hebbar M, Ychou M, Ducreux M. Current place of high-dose irinotecan chemotherapy in patients with 
metastatic colorectal cancer. J. Cancer Res. Clin. Oncol. juin 2009;135(6):749‑752.  
13.  Ducreux M, Raoul J-L, Marti P, Merrouche Y, Tigaud J-M, Rebischung C, et al. High-dose irinotecan plus 
LV5FU2 or simplified LV5FU (HD-FOLFIRI) for patients with untreated metastatic colorectal cancer: a new 
way to allow resection of liver metastases? Oncology. 2008;74(1-2):17‑24.  
14.  Mabro M, Artru P, André T, Flesch M, Maindrault-Goebel F, Landi B, et al. A phase II study of FOLFIRI-3 
(double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients. 
Br. J. Cancer. 8 mai 2006;94(9):1287‑1292.  


 
 
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15.  Taïeb J, Lecomte T, Aparicio T, Asnacios A, Mansourbakht T, Artru P, et al. FOLFIRI.3, a new regimen 
combining 5-fluorouracil, folinic acid and irinotecan, for advanced pancreatic cancer: results of an 
Association des Gastro-Enterologues Oncologues (Gastroenterologist Oncologist Association) multicenter 
phase II study. Ann. Oncol. mars 2007;18(3):498‑503.  
16.  Kelly H, Goldberg RM. Systemic therapy for metastatic colorectal cancer: current options, current evidence. 
J. Clin. Oncol. 10 juill 2005;23(20):4553‑4560.  
17.  Klapdor R, Bahlo M, Babinsky A. Further evidence for prolongation of survival of pancreatic cancer patients 
by efficacy orientated sequential polychemotherapy (EOSPC) based on serial tumor marker determinations 
(CA 19-9/CEA). Anticancer Res. juin 2005;25(3A):1687‑1691.  
16. 
ADMINISTRATIVE CONSIDERATIONS 
STUDY SPONSOR  
 
The study sponsor is the French Federation of Digestive Oncology (FFCD). The study was registered under the 
number EudraCT 2014-004449-28. 
 
REMINDER OF TEXTS IN FORCE 
 
This trial will be conducted according to the French law in force in accordance with the ethical principles of the 
Declaration of Helsinki 1964 and its revisions, the International Conference on Harmonization (ICH) on Good 
Clinical Practice (GCP) guidelines (ICH-E6, 7/17/96), with EU directives (2001/20/EC) on the conduct of clinical 
trials, the modified (12.20.98) French law for the Protection of persons involved in biomedical research known as 
"Loi Huriet" and the provisions of the "Information technology and Freedom of the Individual" (law n°78-17 dated 
6/01/78 modified by law n° 94-548 dated 1/07/94. 
 
CIVIL LIABILITY INSURANCE  
 
Insurance has been obtained by the sponsor on 10/11/2014 under the number 137.68, in accordance with article L 
1121-10 of the code of public health (Appendix 9). 
 
REQUEST FOR AUTOHRISATION FROM THE ETHICS COMMITTEE AND THE ANSM 
 
This protocol has received approval from the Ethics Committee IDF VIII on 2/12/2014 (Appendix 12). 
This protocol has received the approval of the ANSM (French National Agency for Medecines and Health Products 
safety on 22.05.2015 (Appendix 13). 
 
COLLECTION OF INFORMED PATIENT CONSENT 
 
After informing the patient the investigator agrees to collect their written clinical and biological consent 
(information and consent forms in Appendix 1) prior to registering the patient in the study. The investigator shall 
retain a copy of this consent for 15 years, to be submitted to the regulatory authorities for inspection. The original 
must be given to the patient. 
 
In accordance with the Cancer plan recommendations (Measure 4.3.). This document has been submitted to the 
Committee of Patients for Clinical Research (CRPC) of the National Cancer League  
 
HOSPITAL ADMINISTRATION INFORMATION AND RESEARCH AGREEMENT 
 
Prior to starting this study, the hospital administrators will be informed by the sponsor of the investigators interest 
in participating in this trial. 
A research agreement will be established between the administrator of the investigating centre and the sponsor. 
 
DATA STORAGE 


 
 
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The files shall remain confidential and may only be consulted under the responsibility of the physicians charged 
with the care of the patients. The sponsor and health authorities in the event of an inspection will have direct access 
to these documents. 
At the end of the trial, the case report forms will be kept for 15 years by the investigator. 
 
IT SUPPORT  
 
According to the text of Law n° 78-17 of January 6, 1978 amended by the Law of August 9, 2004 relating to 
computers, files and liberties, trial data will be stored in a databank of the Centre for Randomisation, Management 
and Analysis of the FFCD, with the exclusion of elements relating to the identity of the patients. 
 
DATA TREATMENT 
 
The Centre for Randomisation, Management and Analysis (CRGA) of the FFCD shall be responsible for the 
management and analysis of the data. 
 
MONITORING, QUALITY ASSURANCE AND INSPECTION BY THE AUTHORITIES 
 
The investigator agrees in advance that the included patient records be consulted by a person authorised by the 
Sponsor and/or the health authorities to carry out an audit. The programmed on-site visits to consult files with 
investigator agreement may take place during or after the period of inclusion in the trial. 
The FFCD mobile CRA will monitor this trial. 
17. 
RULES FOR PUBLICATION 
They shall comply with those established by the PRODIGE Group (Appendix 10). 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRODIGE 37 - FIRGEMAX (FFCD 1406) 
 
Phase II randomized multicenter trial evaluating sequential treatment with 
nab-Paclitaxel + Gemcitabine / FOLFIRI.3 versus nab-Paclitaxel + 
Gemcitabine as 1st line treatment in metastatic pancreatic cancer 
 
 
 
Statistical Analysis Plan 
Final analysis 
 
 
 
 
 
 
 
 
Version: 2.2 
Date: December 8, 2017 
 
 
 
Editor: E.Barbier 
Review committee: J.Taïeb, K. Le Malicot, J.Bez, M.Voye.  


 
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Developer 
FFCD, Faculty of Medicine,  
7 boulevard Jeanne d'Arc, 
BP 87900, 21079, Dijon Cedex 
 
Coordinator (FFCD)   
Pr Julien Taïeb 
HÔPITAL EUROPEEN G. POMPIDOU  
Hepato-gastro-enterology department  
20 Rue Leblanc  
75015 PARIS  
Tel: 01 56 09 50 42 - Fax: 01 56 09 35 29  
Email : julien.taieb@egp.aphp.fr 
 
Co-Coordinator (UNICANCER-GI) 
Dr David Malka 
Gustave Roussy Institute  
HGE Department 
114 rue Edouard Vaillant  
94805 VILLEJUIF CEDEX  
Tel: 01 42 11 42 11 - Fax: 01 42 11 52 29  
Email : malka@igr.fr 
 
Co-Coordinator (GERCOR) 
 
Dr Jean Baptiste Bachet 
Pitié-Salpétrière Hospital Group  
Hepato-gastro-enterology department  
47- 83 Boulevard de l'Hôpital  
75651 PARIS CEDEX 13  
Tel: 01 42 16 10 41 - Fax: 01 42 16 12 38  
Email : jean-baptiste.bachet@apr.aphp.fr 
 
Project manager  
Mr Jérémie Bez 
FFCD, Faculty of Medicine,  
7 boulevard Jeanne d'Arc, 
BP 87900, 21079, Dijon Cedex 
Tel: 03 80 39 34 83 - Fax: 03 80 38 18 41 
Email : jeremie.bez@u-bourgogne.fr 
 
Biostatistics Manager Ms Karine Le Malicot 
FFCD, Faculty of Medicine,  
7 boulevard Jeanne d'Arc, 
BP 87900, 21079, Dijon Cedex 
Tel: 03 80 39 34 71 - Fax: 03 80 38 18 41 
Email : karine.le-malicot@u-bourgogne.fr 


 
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1 Table of contents 
1 
TABLE OF CONTENTS ................................................................................................................3 
2 
ABBREVIATIONS AND DEFINITIONS .........................................................................................5 
3 
INTRODUCTION ........................................................................................................................6 
3.1 
Test objectives ................................................................................................................................................. 6 
3.1.1 Main objective .....................................................................................................................................................................6 
3.1.2 Secondary objectives.........................................................................................................................................................6 
3.1.3 Ancillary analyses ..............................................................................................................................................................6 
4 
EXPERIMENTAL DESIGN ...........................................................................................................6 
4.1 
Study diagram .................................................................................................................................................. 6 
4.2 
Treatment arms............................................................................................................................................... 6 
4.3 
Randomization and blinding ....................................................................................................................... 7 
4.4 
Chronological sequence ................................................................................................................................ 7 
4.5 
Justification of the number of subjects required ................................................................................... 7 
4.6 
Test steps .......................................................................................................................................................... 8 
4.6.1 Final analysis .......................................................................................................................................................................8 
4.6.2 Adjustments .........................................................................................................................................................................8 
5 
STUDY POPULATION FOR ANALYSIS .........................................................................................8 
5.1 
Definition of analysis populations ............................................................................................................. 8 
5.1.1 Intention-to-treat (ITT) population .............................................................................................................................8 
5.1.2 Modified intention-to-treat population (mITT) .......................................................................................................8 
5.1.1 Per-protocol population (PP) .........................................................................................................................................9 
5.1.2 Population for safety analysis (SP)...............................................................................................................................9 
5.2 
Definition of analysis subgroups ................................................................................................................ 9 
6 
GENERAL INFORMATION ON STATISTICAL METHODS ..............................................................9 
6.1 
Software ............................................................................................................................................................. 9 
6.2 
Agreements concerning dates and durations ......................................................................................... 9 
6.3 
Conventions concerning missing data .................................................................................................... 10 
6.4 
Baseline definition........................................................................................................................................ 10 
6.5 
Statistics .......................................................................................................................................................... 10 
7 
STATISTICAL ANALYSIS .......................................................................................................... 11 
7.1 
Patient characteristics at inclusion ......................................................................................................... 11 
7.1.1 Eligibility ............................................................................................................................................................................ 11 
7.1.1 Stratification criteria ...................................................................................................................................................... 11 
7.1.2 Demographics ................................................................................................................................................................... 11 
7.1.3 Clinical features ............................................................................................................................................................... 11 
7.1.4 Biological characteristics .............................................................................................................................................. 11 
7.1.5 Disease-related characteristics................................................................................................................................... 12 
7.2 
Follow-up features ........................................................................................................................................ 12 


 
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7.3 
Primary endpoint.......................................................................................................................................... 12 
7.3.1 Definition of primary endpoint................................................................................................................................... 12 
7.3.1 Assessment of primary endpoint ............................................................................................................................... 13 
7.4 
Secondary efficacy criteria ......................................................................................................................... 13 
7.4.1 Overall survival ................................................................................................................................................................ 13 
7.4.1 Progression-free survival ............................................................................................................................................. 13 
7.4.1 Better response to treatment ...................................................................................................................................... 13 
7.4.2 Survival to WHO >1 ........................................................................................................................................................ 14 
7.5 
Tolerance assessment ................................................................................................................................. 14 
7.5.1 Chemotherapy administration.................................................................................................................................... 14 
7.5.1 Toxicities ............................................................................................................................................................................ 15 
7.5.1 EIG ........................................................................................................................................................................................ 15 
7.6 
Quality of life assessment ........................................................................................................................... 15 
7.6.1 Definition ........................................................................................................................................................................... 15 
7.6.2 Evaluation .......................................................................................................................................................................... 16 


 
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2 Abbreviations and definitions 
 
SEE   
Serious adverse event 
HR  
Hazard ratio 
CI 
Confidence Interval 
ITT 
Intention to  
treat 
ITTm 
Modified intention  
to treat 
mTNS 
modified  Total Neuropathy Score 
NCI-CTC  
National Cancer Institute Common Toxicity Criteria 
WHO 
World Health Organization 
PP 
Per-protocol  
RECIST 
Response evaluation criteria in solid tumors 
SG 
Overall survival 
PFS 
Progression-free survival 
SP  
Tolerance population 
 
 


 
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3 Introduction 
 
3.1 Objectives of the trial 
 
3.1.1 
Objective main 
The primary objective of the study is to evaluate, in each arm, the rate of patients alive and free of 
radiological and/or clinical progression at 6 months. 
 
3.1.2 
Secondary objectives 
The secondary objectives of the study are to evaluate: 
• Overall survival  
• Objective response rate  
• Progression-free survival  
• Time to treatment discontinuation  
• Toxicities according to NCI CTC v4.0  
• Peripheral neuropathic toxicities according to the simplified mTNS scale  
• Quality of life (EORTC QLQ-C30 questionnaire)  
 
3.1.3 
Ancillary analyses 
A biological ancillary analysis is planned to evaluate :  
• Constitutional genetic polymorphisms that can influence the efficacy and tolerability of chemotherapy 
molecules (UGT1A1, ERCC1, MTHFR, DPD, TS ...) 
• Immunohistochemical biomarkers predictive of treatment response thanks to a kerosene section study 
 
4 Experimental design 
 
4.1 Study diagram 
This is a multicenter, randomized, non-comparative Phase II trial.  
 
4.2 Treatment arms 
In this study there are 2 treatment arms: 
• 
Arm A (experimental arm): Alternating 2 months of nab-Paclitaxel + gemcitabine with 2 months 
of FOLFIRI.3  
Nab-Paclitaxel + gemcitabine (3 weeks/4 for 2 months) at D1, D8, D15 and at D29, D36, D43  
Then FOLFIRI.3 (a cure every 14 days for 2 months) at D1, D15, D29 and D43.  
• 
Arm B (reference arm): nab-Paclitaxel + gemcitabine  
Nab-Paclitaxel + gemcitabine (3 weeks/4) at D1, D8, D15 and at D29, D36, D43  
Treatment is continued until progression or unacceptable toxicity.  


 
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4.3 Randomization and blinding  
The trial is open-label. Randomization is centralized and balanced between arms in a 1:1 ratio. The 
minimization technique will be used for treatment allocation by randomization stratifying on : 
- the center  
- WHO: 0 vs 1 vs 2  
- Number of metastatic sites: 1 vs > 1  
 
4.4 Chronological sequence 
Each patient will follow the chronological sequence described below: 
 
 
 
4.5 Justification of the number of subjects required 
The assumptions used to calculate the number of subjects required were :  
H0: A progression-free survival rate of 40% at 6 months is insufficient.  
H1: A progression-free survival rate of over 40% at 6 months is hoped for.  
A rate of 60% is expected  
Using the exact binomial method, a 5% risk of one-sided alpha error and 90% power, it was necessary to 
include 56 patients per arm.  
Assuming a 10% rate of patients lost to follow-up or unable to be assessed, it was necessary to include 62 
patients per arm, for a total of 124 patients.  
 
Randomization 
Morphological monitoring and assessment 
Every 8 weeks until progression 
Then every 2-3 months until death 
Arm A: Alternating nab-Paclitaxel + gemcitabine (3 
weeks/4 for 2 months) then FOLFIRI.3 (one course 
every 14 days for 2 months) 
 
Arm B: Nab-Paclitaxel + gemcitabine (3 weeks/4)   
 
Inclusion report 
- morphological and paraclinical  
In the 3 weeks prior to randomization 
-
clinical and biological 
In the 8 days preceding the start of treatment 


 
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4.6 Test steps 
 
4.6.1 
Analysis Final 
The final analysis will be performed once the information on the last patient included has been retrieved. 
The cut-off date for the analysis is the randomization date of the 124ème patient + 6 months. 
At the end of recruitment, during analysis :  
- If 28 or fewer patients are alive without progression at 6 months, the treatment is deemed ineffective.  
- If 29 or more patients are alive without progression at 6 months, we reject H0 and conclude that the 
treatment is effective.  
These decision rules apply only to the experimental arm, and will be recalculated if necessary, based on the 
number of patients actually evaluable.  
4.6.2 
Adjustments  
Adjustments may be made to this analysis plan in the event of amendments to the protocol, or if phenomena 
not initially foreseen require statistical adaptations. In all cases, these modifications must be made before 
the database is frozen. 
 
5 Study population for analysis 
The study focuses on patients with metastatic pancreatic adenocarcinoma. 
 
5.1 Definition of analysis populations 
 
5.1.1 
Intention-to-treat (ITT) population 
The intention-to-treat population is defined as all patients randomized to the study, irrespective of 
eligibility criteria and treatment received. Patients will be analyzed in the treatment group allocated at 
randomization. 
Analyses on this population will be carried out on an exploratory basis to confirm the results of the main 
ITTm analysis. 
 
5.1.2 
Population modified intention-to-treat (mITT) 
The modified intention-to-treat population is defined as the ITT population of evaluable patients. A patient 
is considered evaluable if he or she has received at least one dose of treatment. Patients will be analyzed in 
the treatment group allocated at randomization. 
A list of patients excluded from the ITTm population will be provided, together with the reasons for their 
exclusion. 
All analyses will be carried out in ITTm, unless otherwise specified for certain criteria). 
 


 
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5.1.1 
Per-protocol population (PP) 
The per-protocol population is defined as all patients who met all the major inclusion criteria of the protocol 
and received at least 2 months (8 weeks) of treatment: 
• 
For Arm A: Nab-Paclitaxel + gemcitabine for 2 months followed by at least one course of FOLFIRI.3 
(i.e. at least until alternation) 
 
• 
Arm B: Nab-Paclitaxel + gemcitabine for 2 months  
 
The main inclusion criteria were : 
- Adenocarcinoma of the pancreas,  
- Metastatic disease 
 
Patients will be analyzed according to the treatment they actually received. 
A list of patients excluded from the PP population will be provided, together with the reasons for their 
exclusion. 
 
5.1.2 
Population for tolerance analysis (SP) 
It is defined as the ITT population having received at least one dose of chemotherapy (whatever the 
product). Patients will be analyzed according to the actual treatment received. 
Tolerance criteria will be assessed for this population. 
A list of patients excluded from the SP population will be provided, together with the reasons for their 
exclusion. 
 
5.2 Definition of analysis subgroups 
For exploratory purposes, the primary endpoint will also be analyzed in the subgroup of WHO 0-1 patients. 
 
6 General information on statistical methods 
Statistical analyses will be carried out by CRGA. 
 
6.1 
Software 
Statistical analyses will be carried out using SAS software version 9.4 or later. Some graphs may be 
produced using R software version 2.11 or later. 
 
6.2 
Agreements concerning dates and durations 
Time since randomization will be defined as the time elapsed since the day of randomization, with the day 
of randomization taken as day 1. 
Time since start of treatment will be defined as the time elapsed since the day of the first treatment course, 
the day of the first treatment course being considered as day 1.  
For this reason, durations are calculated using the following rule, for example for the time elapsed between 
death and randomization: day of death - day of randomization + 1. 
The day preceding the day of randomization (resp. the day preceding the day of treatment) will be 
considered as day -1 (day 0 does not exist).  


 
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The date of last news will default to the date of the last examination/monitoring performed. 
The following conversion rules will be used to convert numbers of days into numbers of months or years: 1 
month = 30.4375 days; 1 year = 365.25 days. 
 
6.3 
Missing data conventions 
Except in the cases specified, missing data will not be replaced. 
 
6.4 
Baseline definition 
Baseline measurements are the last measurements taken at randomization. In the event of missing data, the 
last measurement taken before the first treatment is used. 
 
6.5 
Statistics 
Quantitative variables will be described using headcount, median, mean, standard deviation of the mean, 
minimum, maximum and inter-quartile range (Q1-Q3). Quantitative variables can be categorized using their 
median or a cut-off known from the medical literature. 
Categorical variables will be described using percentages, and if necessary their bilateral 95% confidence 
intervals (calculated using the exact method). 
Missing values are not taken into account when calculating frequencies and percentages. 
The confidence intervals provided will be two-sided 95% confidence intervals, except for the main 
criterion where a one-sided 95% confidence interval will be given. 
Survival data will be estimated and plotted using the Kaplan-Meier method (Kaplan and Meier, 1958).  
This will be described by the median and rates calculated at different times. Two-sided 95% confidence 
intervals will be provided. Confidence intervals for rates will be constructed from the Greenwood variance 
calculated using the log-log transformation. 
The median follow-up time is calculated using the reverse Kaplan-Meier method (Shemper, 1996). 
For uni and multivariate analyses, hazard ratios will be estimated using a Cox model (Cox, 1984). The 
proportionality hypothesis will be tested using the graphical representation and residual-based test of 
Schöenfeld (Grambsch, 1994); the linearity of the effect of continuous variables on risk will be assessed 
using the graphical representation of martingale residuals. Confidence intervals for Cox model coefficient 
estimates will be calculated using Wald's method. 
There are no statistical comparisons planned between the arms of this study, but the HR between 
the arms with their IC95% will be calculated, and statistical comparisons with the calculation of p-
values may be made for exploratory purposes. 
 
 


 
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7 Statistical analysis 
 
 
ITT 
ITTm 
PP 
SP 
Eligibility 
X 
x 
x 
 
Characteristics at randomization 
X 
x 
x 
 
Main criterion 
Progression-free rate at 6M 
X 
X 
X 
 
Secondary criteria 
Overall survival 
X 
x 
x 
 
Progression-free survival 
X 
x 
x 
 
Objective/best response rate 
X 
x 
x 
 
Treatment administration 
 
x 
x 
X 
NCI-CTC toxicities 
 
 
 
X 
Neuro Toxicities mTNS 
 
 
 
X 
Quality of life 
X 
 
 
 
 
7.1 Patient characteristics at inclusion 
 
7.1.1 
Eligibility 
Patient eligibility for randomization will be verified and described by : 
▪ Number and percentage of patients who met all inclusion criteria  
▪ Number and percentage of patients who met all non-inclusion criteria  
▪ Number and percentage of patients who met all criteria (inclusion and non-inclusion)  
 
7.1.1 
Stratification criteria 
▪ WHO general status (0 vs 1 vs 2) 
▪ Number of metastatic sites (1 vs >1)  
 
7.1.2 
Demographic characteristics 
The following randomization characteristics will be described: 
▪ Inclusion center (number of patients included per center - described in total only) 
▪ Age (year) 
▪ Gender (Male vs Female) 
 
7.1.3 
Clinical features 
The following randomization characteristics will be described: 
▪ BMI (kg/m ) 2 
▪ EVA score 
▪ Presence of morphine treatment (Yes vs. No) 
▪ Presence of neurotoxicity at inclusion: described by grade and type of toxicity 
7.1.4 
Biological characteristics 
The following randomization characteristics will be described: 


 
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▪ Hemoglobin (g/dL) 
▪ PNN (/mm )3 
▪ Wafers (x10 /mm )33 
▪ Total bilirubin (≤ N vs ]N-2.5N] vs ]2.5N-5N] vs > 5N) 
▪ Conjugated bilirubin (≤ N vs ]N-2.5N] vs ]2.5N-5N] vs > 5N) 
▪ PAL (≤ N vs ]N-2.5N] vs ]2.5N-5N] vs > 5N) 
▪ LDH (mmol/L) 
▪ Albuminemia (g/dL) 
▪ Lymphocytes (/mm )3 
▪ ALAT (≤ N vs ]N-2.5N] vs ]2.5N-5N] vs > 5N) 
▪ ASAT (≤ N vs ]N-2.5N] vs ]2.5N-5N] vs > 5N) 
▪ Leukocytes (/mm )3 
▪ TP (%) 
▪ Calcium (mmol/L) 
▪ Potassium (mmol/L) 
▪ Sodium (mmol/L) 
 
7.1.5 
Disease-related characteristics 
The following randomization characteristics will be described: 
▪ Location of metastatic sites (liver, peritoneum, lung, bone, other) 
▪ Primary surgery (Yes vs. No) and if yes, type of resection (R0 vs. R1 vs. R2) 
▪ Presence of at least one previous treatment (Yes vs No) and if yes :  
- Neoadjuvant treatment (Yes vs. No) and if yes, listing of treatment types 
- Adjuvant treatment (Yes vs. No) and if yes, listing of treatment types 
 
7.2 Follow-up features 
The median follow-up time and its 95% confidence interval will be calculated in months, by treatment arm 
and in total.  
 
7.3 Primary endpoint 
 
7.3.1 
Definition of primary endpoint 
The primary endpoint was the rate of patients alive and progression-free 6 months after randomization. 
Progression is assessed by the investigator and defined radiologically according to RECIST v1.1 criteria 
and/or clinically as deterioration in general condition unrelated to treatment, tumor masses palpable on 
clinical examination (adenopathies, tumor hepatomegaly, peritoneal carcinosis), pleural effusion, ascites. 
Patients who progressed or died before 6 months will be considered to have failed the primary endpoint at 
6 months. 
The 6-month images will be the images taken at 6 months with a window of +/- 1 month. 
Patients without a 6-month assessment will be reviewed according to the following rules:  


 
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- 
If the patient has a later assessment (7 months or more) and is not progressing at that date, he or 
she will be considered progression-free at 6 months.  
- 
If the patient has documented progression at more than 6 months without imaging at 6 months, 
then this patient should be reviewed.  
 
7.3.1 
Evaluation of primary endpoint 
The rate of patients alive and progression-free at 6M will be calculated by treatment arm with its one-sided 
95% confidence interval. 
 
7.4 Secondary efficacy criteria 
 
7.4.1 
Overall survival 
7.4.1.1 
Defining overall survival 
It is defined as the time between the date of randomization and the date of death (whatever the cause). 
Patients lost to follow-up or alive at the time of analysis will be censored at the date of last news. 
7.4.1.1 
Assessment of overall survival 
The time scale considered will be the month. 
Overall survival will be plotted using the Kaplan Meier estimator for each treatment arm. Median survival 
and survival rates at 4, 8, 12, 18 and 24 months will be calculated, along with their 95% confidence intervals. 
For the various OS tests, HRs (IC95%) between the 2 treatment arms will be calculated, and p values may 
also be calculated for exploratory purposes. 
 
7.4.1 
Progression-free survival 
7.4.1.1 
Defining progression-free survival 
It is defined as the time between the date of randomization and the date of 1ère progression (clinical and/or 
radiological) or death (whatever the cause). Patients alive without progression at the time of analysis will 
be censored at the date of last news. 
7.4.1.1 
Assessment of progression-free survival 
The time scale considered will be the month. 
Progression-free survival will be plotted using the Kaplan Meier estimator. Median survival and rates at 
different time points will be calculated, along with their 95% confidence intervals. 
For the various PFS tests, HRs (IC95%) between the 2 treatment arms will be calculated, and p-values may 
also be calculated for exploratory purposes. 
 
7.4.1 
Better response to treatment 
7.4.1.1 
Defining the best response 
The best response rate is defined by treatment arm over the entire treatment. 


 
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The objective response rate is defined as the complete + partial response rate. 
The disease control rate is defined as the complete + partial + stable response rate. 
7.4.1.1 
Evaluating the best response 
The percentages of complete response, partial response, stable response, progression and non-evaluable 
response will be specified and described using standard statistics. 
The best response rate will also be described in terms of objective response versus no objective response 
and disease control versus no control in each arm. 
 
7.4.2 
Survival to WHO >1 
7.4.2.1 
Definition 
Survival to WHO >1 will be analyzed for each arm. 
It is defined as the time between the date of randomization and the date of clinical evaluation when WHO is 
>1 or the date of death (whatever the cause). Living patients without WHO >1 at the time of analysis will be 
censored at the date of last news.  
7.4.2.2 
Evaluation 
The time scale considered is the month. 
Survival to WHO >1 will be plotted using the Kaplan Meier estimator. Median survival to WHO >1 and rates 
at different time points will be calculated, along with their 95% confidence intervals. 
For the various tests of survival to WHO >1, the HR (IC95%) between the 2 treatment arms will be calculated 
for exploratory purposes. 
 
7.5 Tolerance assessment 
 
7.5.1 
Chemotherapy administration 
7.5.1.1 
Treatment duration 
The duration of treatment (converted into months) is calculated using the formula : 
Start date of last administration - start date of first administration + 1 day 
Temporary stoppages and any deferral days during this period will not be subtracted from this duration. It 
will be described using the usual descriptive statistics for each treatment arm. 
7.5.1.2 
Doses administered 
The average number of cures will be postponed. 
The cumulative average dose administered (over all courses of treatment) will be calculated in mg/m2 for 
each type of treatment: 5FU Continu, irinotecan, Nab-paclitaxel, Gemcitabine. 
The body surface area used will be that supplied by the investigator on the treatment form, otherwise, if it 
is not provided, it will be calculated using the Gehan and Georges formula: 
0.0235 × height(cm)0.42246 × weight(kg)0.51456 


 
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The weight used will be the weight indicated for the treatment in question. If the weight is missing, the non-
missing weight from the previous treatment will be used instead. If no weight information is available, the 
weight at inclusion will be used. 
 
The ratios of treatment doses received to theoretical doses will be described by type of treatment, using the 
usual descriptive statistics for each treatment arm. 
The % of patients who received more than 80 and 90% of the theoretical treatment dose will be reported. 
7.5.1.1 
Dose modification 
The number of patients with at least one dose modification will be described according to the usual 
descriptive statistics by arm and type of treatment. 
7.5.1.2 
Permanent cessation of treatment 
The number and percentage of patients permanently discontinuing protocol treatment, and the reasons for 
discontinuing protocol treatment (% out of the number of patients discontinuing treatment) will be 
described using the usual descriptive statistics for each treatment arm. 
 
7.5.1 
Toxicities 
Toxicities will be described during treatment and during post-treatment follow-up in the same way. 
Toxicities (graded according to NCI-CTC v 4.0) will be described per treatment arm by : 
▪ Total number of patients by maximum grade of toxicity, grouped by grade (grade 1-2 and grade 3-4 and 
grade 5) 
▪ The number of patients and the maximum grade of toxicity achieved by grouping grades (grade 1-2 and 
grade 3-4 and grade 5) by SOC and type of toxicity. 
 
Peripheral neuropathic toxicities (graded according to mTNS) will be described per treatment arm by : 
▪ Total number of patients by maximum grade of toxicity (grade 1-2-3-4) 
▪ Number of patients and maximum toxicity grade reached (grade 1-2-3-4) by toxicity type 
 
7.5.1 
EIG 
A summary of all SAEs will be provided by pharmacovigilance. 
 
 
7.6 Assessment of quality of life 
The number of patients analyzable for QoL (having at least one questionnaire) and the percentage (out of 
the number of patients included) will be described. 
 
7.6.1 
Definition 
It will be assessed using the QLQ-C30 questionnaire (version 3.0). The QLQ-C30 will be completed before 
randomization, then every month for the first 4 months, then every 2-3 months until progression or death. 


 
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This 30-item scale comprises 15 dimensions enabling 15 scores to be calculated: 5 functional ability scores 
(physical ability, ability to work or perform any household task, cognitive ability, emotional state, social 
state), a global quality of life score, a financial problems score and 8 symptom scores (fatigue, 
nausea/vomiting, pain, dyspnea, sleep disturbance, loss of appetite, constipation, diarrhea). 
 
For the overall health score, time to definitive deterioration, defined as the time interval between the date 
of randomization and the date of a score decrease of more than 5 points (compared with the score at 
randomization) without subsequent improvement of more than 5 points, or death, or the date of last news, 
will be studied in an exploratory way. Living patients without a score decrease of more than 5 points will 
be censored at last news. 
 
7.6.2 
Evaluation 
An estimate of the time to definitive deterioration of the global health score will be made using the Kaplan-
Meier method, and compared, in an exploratory way, according to the treatment arm, by a Log Rank test.