Conditions: Colorectal Cancer With Non Resectable Hepatic Metastasis
Keywords: Metastatic colorectal Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 58
Healthy volunteers: no

Brief summary:
Treatment of patients with colorectal cancer having liver metastases is currently based on systemic chemotherapy.

Triple therapy with 5FU, oxaliplatin and irinotecan intravenously was effective in terms of response and secondary resectability, however it is particularly toxic.

Hepatic intra-arterial chemotherapy (HIA) has been the subject of several studies. It has shown good efficacy with oxaliplatin and FUDR. However, the procedure is difficult to set up and reserved for experienced centers.

The objective of this protocol is to use a triple therapy based on 5FU and oxaliplatin associated to irinotecan which is administered by hepatic intra-arterial route, loaded onto microbeads (DEBIRI). Furthermore, the procedure for chemo-embolization DEBIRI is limited to 2 sessions, and therefore could be more easily generalized.

Detailed description:

Arms:
arm 1: Intra-arterial hepatic beads loaded with irinotecan with systemic FOLFOX

Interventions: intervention 1: HIA DEBIRI + systemic FOLFOX
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
DEBIRI Protocol Version 1.2 of 28/07/2015 
1/39 
 
  
FFCD-1201 
INTRA-ARTERIAL TREATMENT WITH IRINOTECAN (DEBIRI) LOADED 
MICROBEADS CONCOMITANTLY WITH FOLFOX SYSTEMIC CHEMOTHERAPY IN 
PATIENTS WITH COLORECTAL CANCER WITH NON-RESECTABLE LIVER 
METASTASES - THE FIRST STUDY OF ITS KIND IN THE WORLD 
PHASE II MULTICENTER NON RANDOMIZED 
 
Eudract number: 2012-004166-18 
 
 
COORDINATOR : 
Pr Julien TAIEB 
 
 
 
 
Georges Pompidou European Hospital 
Department of Gastroenterology 
20 Rue Leblanc 
75908 PARIS CEDEX 15 
Tel: 01 56 09 50 42 - Fax: 01 56 09 35 29 
E-mail : julien.taieb@egp.aphp.fr 
 
 
 
SCIENTIFIC CO-LEADER : 
 
 
 
 
Dr Simon PERNOT  
 
 
 
 
Georges Pompidou European Hospital 
Department of Gastroenterology 
20 Rue Leblanc 
75908 PARIS CEDEX 15 
Tel: 01 56 09 50 42 - Fax: 01 56 09 35 29 
E-mail : simon.pernot@gmail.com 
 
Protocol Writing Committee: 
Thierry Debaere, Boris Guiu, Karine Le Malicot, Come Lepage, Olivier Pellerin, Simon Pernot, Julien Taieb.  
 
 
SPONSOR AND CENTER FOR RANDOMIZATION-MANAGEMENT-ANALYSIS (CRGA) :  
Fédération Francophone de Cancérologie Digestive (FFCD), Faculty of Medicine, 7 Boulevard Jeanne 
d'Arc, BP 87900, 21079 Dijon Cedex, France 
 
 
Francophone Federation 
of Digestive Oncology (FFCD) :  
Cécile GIRAULT- Administrative Director   
 
 
 
 
 
Tel: 03 80 66 80 13 - Fax: 03 80 38 18 41 
 
 
 
 
 
E-mail: cecile.girault@u-bourgogne.fr 
 
 
Statistician :   
 
Karine LE MALICOT 
 
 
 
 
 
Tel: 03 80 39 34 71- Fax: 03 80 38 18 41 
 
 
 
 
 
E-mail: karine.le-malicot@u-bourgogne.fr 
 
Project manager:  
 
 
Martina SCHNEIDER 
 
 
 
 
Tel: 03 80 39 34 83- Fax: 03 80 38 18 41 
 
 
 
 
 
E-mail : jeremie.bez@u-bourgogne.fr 
 
 
Subscribe to DeepL Pro to edit this document. 
Visit www.DeepL.com/profor more information. 


DEBIRI Protocol Version 1.2 of 28/07/2015 
2/39 
SUMMARY 
 
I. 
OBJECTIVES OF THE TRIAL .................................................................................................................................................. 9 
I.1 
Main objective .......................................................................................................................................................................... 9 
I.2 
Secondary objectives ................................................................................................................................................................ 9 
II. 
PATIENT SELECTION ............................................................................................................................................................... 9 
III. 
PRE-INCLUSION ASSESSMENT ............................................................................................................................................ 11 
IV. 
INCLUSION ................................................................................................................................................................................ 11 
I. 
TREATMENT ............................................................................................................................................................................. 13 
I.1 
Treatment scheme  ................................................................................................................................................................. 13 
I.2 
Chemoembolization ................................................................................................................................................................ 15 
I.3 
Treatment with simplified FOLFOX 4 ................................................................................................................................. 18 
I.4 
Precautions to be taken  ......................................................................................................................................................... 20 
II. 
EXPECTED TOXICITIES AND DOSE ADJUSTMENT ....................................................................................................... 20 
II.1 
FOLFOX ................................................................................................................................................................................. 20 
II.2. 
Chemoembolization ................................................................................................................................................................ 22 
III. 
MONITORING OF PATIENTS DURING AND AFTER TREATMENT ............................................................................. 23 
IV. 
DISCONTINUATION OF THE STUDY .................................................................................................................................. 25 
V. 
CENTRALIZED READING OF CT AND MRI SCANS ........................................................................................................ 25 
VI. 
MANAGEMENT OF SERIOUS ADVERSE EVENTS (SIA) ................................................................................................. 26 
VI.1 
Definitions ............................................................................................................................................................................... 26 
VI.2 
Conduct to be followed ........................................................................................................................................................... 27 
VII. 
ANCILLARY STUDIES ....................................................................................................................................................... 29 
VIII. 
STATISTICAL ANALYSIS .................................................................................................................................................. 29 
VIII.1 Provisional schedule of the study .......................................................................................................................................... 30 
VIII.2 Judging criteria ...................................................................................................................................................................... 30 
VIII.3 Calculation of the number of subjects needed ..................................................................................................................... 31 
VIII.4 Statistical analysis plan .......................................................................................................................................................... 31 
VIII.5 Independent Supervisory Committee ................................................................................................................................... 32 
VIII.6 Imaging Review Committee/Radiologist Panel .................................................................................................................... 33 
VIII.7 Steering Committee ................................................................................................................................................................ 33 
VIII.8 Biological Research Committee ............................................................................................................................................. 33 
IX. 
JUSTIFICATION OF THE TEST ............................................................................................................................................ 33 
X. 
REFERENCES ............................................................................................................................................................................ 35 
XI. 
LEGAL AND ETHICAL ASPECTS ADMINISTRATIVE CONSIDERATIONS................................................................ 37 
XII. 
PUBLICATION ..................................................................................................................................................................... 39 
XIII. 
APPENDICES .................................................................................................................. ERREUR ! SIGNET NON DEFINI. 
APPENDIX 1: INFORMATION NOTE AND CLINICAL CONSENT .................................................. Erreur ! Signet non défini. 
APPENDIX 2: INFORMATION AND CONSENT NOTE FOR THE BIO STUDY ............................... Erreur ! Signet non défini. 
APPENDIX 3: RECIST CRITERIA V1.1 .................................................................................................. Erreur ! Signet non défini. 
APPENDIX 4: EASL CRITERIA ............................................................................................................... Erreur ! Signet non défini. 
APPENDIX 5: TOXICITY ASSESSMENT - NCI-CTC SCALE Version 4.0 ......................................... Erreur ! Signet non défini. 
APPENDIX 6: WHO - Calculation of Clearance ....................................................................................... Erreur ! Signet non défini. 
APPENDIX 7: SUMMARY OF FOLFOX PRODUCT CHARACTERISTICS ..................................... Erreur ! Signet non défini. 
APPENDIX 8: SERIOUS ADVERSE EVENT FORM ............................................................................. Erreur ! Signet non défini. 
APPENDIX 9: FFCD PUBLICATION RULES ......................................................................................... Erreur ! Signet non défini. 
APPENDIX 10: CERTIFICATE OF INSURANCE .................................................................................. Erreur ! Signet non défini. 
APPENDIX 11: OPINION OF THE IDF 8 PERSONAL PROTECTION COMMITTEE (CPP) ......... Erreur ! Signet non défini. 
APPENDIX 12: ANSM AUTHORIZATION ............................................................................................. Erreur ! Signet non défini. 
 


FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page3 on39 
 
 
CONTACTS FFCD  
 
Randomization + EIG declaration : Fax : 03 80 38 18 41 - Tel : 03 80 66 80 13  
NAME 
FUNCTION 
PHONE 
TELECOPIE 
ADMINISTRATIVE MANAGEMENT 
Cécile GIRAULT 
Administrative Director 
03 80 39 33 87 
03 80 38 18 41 
Martina SCHNEIDER 
Assistant Administrative 
Director 
03 80 39 34 83 
03 80 38 18 41 
Aurélie DUBREU 
Executive secretary 
03 80 38 13 14 
03 80 38 18 41 
RANDOMIZATION CENTER - MANAGEMENT - ANALYSIS 
Karine LE MALICOT 
Statistician 
03 80 39 34 71 
03 80 38 18 41 
Emilie MAILLARD 
Statistician 
03 80 39 34 81 
03 80 38 18 41 
Marie MOREAU 
Project Manager 
03 80 39 34 04 
03 80 38 18 41 
Géraldine VAUDRIT  
Assistant Project Manager 
03 80 38 33 86 
03 80 38 18 41 
Jérémie BEZ 
Project Manager 
03 80 39 34 83 
03 80 38 18 41 
Jaïque CARIO 
Assistant Project Manager 
03 80 39 34 86 
03 80 38 18 41 
Gaëlle DELIGNETTE 
Assistant Project Manager 
03 80 39 34 86 
03 80 38 18 41 
Caroline CHOINE-
POURRET 
ARC Coordinator 
04 69 18 19 02 
09 74 44 22 47 
Guillaume ARNOULD 
ARC 
06 30 73 42 78 
03 80 38 18 41 
Hicham FATTOUH 
ARC 
04 78 66 13 08 
04 78 66 13 08 
Florence GUILIANI-
KPODOH 
ARC 
04 30 67 80 23 
09 74 44 20 40 
Nouredine LASMI 
ARC 
06 26 36 92 56 
03 80 38 18 41 
Nicolas LE PROVOST 
ARC 
05 33 05 62 21 
05 56 05 03 59 
Fadil MASSKOURI 
Data Manager 
03 80 39 34 05 
03 80 38 18 41 
Charles FUCHEY 
Data Manager 
03 80 39 34 81 
03 80 38 18 41 
Elodie GAUTIER 
Data Manager 
03 80 39 34 84 
03 80 38 18 41 
Carole MONTERYMARD 
Data Manager 
03 80 39 34 84 
03 80 38 18 41 
 
You can also contact the CRGA of the FFCD at: 03 80 66 80 13 (Monday to Friday from 9H00 to 18H00) 
 


FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page4 on39 
 
 
PROTOCOL AGREEMENT AND BPC 
TRIAL 
FFCD-1201: 
INTRA 
ARTERIAL 
IRINOTECAN 
(DEBIRI) 
LOADED 
MICROBALLS IN COMBINATION WITH FOLFOX SYSTEMIC CHEMICAL THERAPY 
IN COLORECTAL CANCER PATIENTS WITH NON-RESCURABLE HEPATIC 
METASTASIS - NON RANDOMIZED MULTICENTRIC PHASE II  
EudraCT No: 2012-004166-18 
Version 1.2 of 28/07/2015 
 
This version of the protocol is approved by : 
 
The Promoter :   
Ms. Cecile GIRAULT  Date:  07/28/2015Signature 
: 
 
The Coordinator:  
Pr Julien TAIEB 
 
Date: 
07/28/2015Signature:  
 
I, the undersigned, Doctor  
 
 
 
 
 
 
After having read the requirements of this research, the protocol and its annexes, I hereby certify that I will 
conduct this trial in accordance with Good Clinical Practice and in compliance with the applicable 
provisions of the Public Health Code. 
 
In particular, I agree to: 
• 
comply with the protocol and any modifications notified to it by the promoter 
• 
agree to supervise research in the center and to train collaborators in the conduct of research and provide 
a list of names 
• 
have each patient sign a written consent after having read the information note intended for him/her, 
before any research is carried out 
• 
Report serious adverse events or developments within 24 hours of learning of them, and as directed  
• 
respect the inclusion and non-inclusion criteria, as well as the start and end dates of the study 
• 
participate in the translational part of the study and send copies of the evaluation reports 
• 
to complete all the items in the observation book, to ensure the quality of data collection, and the proper 
management of the products  
• 
retain research data and documents for 15 years 
• 
inform the sponsor of any conflict of interest situation that may affect its scientific independence in the 
context of the research 
• 
inform the sponsor without delay of any action, whether amicable or contentious, brought by a person 
involved in the research or his or her beneficiaries, which may call into question the sponsor's liability 
• 
accept periodic visits by the sponsor's representatives, and make available to them all source documents 
and materials related to the research in order to ensure quality control of the data recorded in the 
observation book. I accept control in the form of an audit by the sponsor and/or inspection by the health 
authorities 
• 
respond by phone or mail to requests for corrections or clarifications regarding the data collection 
• 
Allow time for the ARC FFCD to sign off on the forms, answer any questions, and take action. 
 
 
Date: 
 
 
 
 
           Signature: 
 
 
STAMP of the CENTER : 
 
 
 
 
 
 
 
 
Send 
the 
original 
to 
CRGA 
de 
la 
FFCD 
- 
7 
bd 
Jeanne 
d'Arc 
- 
BP 
87900 
- 
21079 
Dijon 
Cedex


FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page5 on39 
 
 
SYNOPSIS 
Essay title:  
 
Trial FFCD-1201: INTRA ARTERIAL IRINOTECAN (DEBIRI) 
LOADED MICROBALLS IN COMBINATION WITH FOLFOX 
SYSTEMIC CHEMICAL THERAPY IN COLORECTAL CANCER 
PATIENTS WITH NON-RESCURABLE HEPATIC METASTASIS - 
NON RANDOMIZED MULTICENTRIC PHASE II 
Trial number 
FFCD- 1201 
Developer 
FFCD 
Coordinator(s) 
Pr. Julien Taïeb, Dr Simon Pernot 
Rationale 
for 
the 
study 
The treatment of patients with colorectal cancer with liver metastases is 
currently based on systemic chemotherapy.  
Triple therapy combining 5FU, oxaliplatin and irinotecan by IV route has 
been shown to be effective in terms of response and secondary 
resectability, however it is particularly toxic. 
Intra-arterial hepatic chemotherapy (IHC) has been studied in several 
studies. It has shown good efficacy with oxaliplatin and FUDR. However, 
it is a difficult procedure to implement and is reserved for expert centers.  
The aim of this protocol is to use triple therapy with 5FU, oxaliplatin, and 
irinotecan, the latter delivered intra-arterially to the liver, loaded on 
microbeads (DEBIRI). Moreover, the DEBIRI chemoembolization 
procedure is limited to 2 sessions for each lobe, and could be more easily 
generalized. 
Objectives 
Principal:  
Progression-free survival rate at 9 months according to RECIST 1.1. 
Secondary:  
 
Tolerance to treatment  
Response rate according to RECIST 1.1 criteria at 9 months 
Response rate according to EASL criteria at 9 months 
Hepatic progression-free survival according to RECIST 1.1  
Overall survival 
Progression-free survival  
Secondary resection rate  
Evolution of tumor marker levels 
Inclusion criteria  
- 
Histologically proven colorectal adenocarcinoma,  
- 
Radiologically or histologically proven liver metastases 
- 
At least one measurable liver lesion according to RECIST v1.1 
criteria  
- 
Age ≥ 18 years 


FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page6 on39 
 
 
- 
WHO index 2  
- 
Life expectancy 3 months 
- 
No extra-hepatic disease, except pulmonary nodules if number 
3 and size < 10 mm each 
- 
Hepatic Involvement < 60  
- 
Primary tumor resected or in place 
- 
No prior chemotherapy for metastases (except peri-operative 
chemotherapy, if the last cycle was given at least 12 months 
ago)  
- 
Adjuvant chemotherapy after resection of the primary site 
allowed if the last cycle was administered at least 12 months 
ago 
- 
Normal liver function: total bilirubin ≤ 1.5N, AST≤ 5N, ALT ≤ 
5N and PAL≤ 5N. 
- 
TP ≥ 60% 
- 
Adequate hematologic function: PNN ≥ 1500/mm3 , platelets ≥ 
100,000/mm3 , Hb ≥ 9g/dL 
- 
Good renal function: creatinine clearance ≥ 60 mL/min  
- 
No cardiac dysfunction: no cardiovascular events in the past 6 
months or no NYHA ≥ 2 
Non-inclusion criteria  
 
- 
Patient eligible for curative treatment (resection and/or 
radiofrequency ablation) according to a PCR (including the 
opinion of a liver surgeon) 
- 
Pregnant or breastfeeding women or patients of either sex of 
childbearing age who are not using an adequate method of 
contraception (see section V. 4) 
- 
Previous cancer, except for non-melanoma skin cancers and 
curatively treated cervical in situ cancers. Other curatively 
treated cancers are allowed provided they have not recurred for 
more than 5 years 
- 
Peripheral neuropathy 
- 
Inflammatory bowel diseases  
- 
Intestinal occlusion  
- 
Chronic liver disease (viral, alcoholic or metabolic) 
- 
Immunodeficiency syndromes (history of transplantation, HIV 


FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page7 on39 
 
 
infection) 
- 
Known contraindications to 5FU, oxaliplatin, folinic acid, 
irinotecan or contrast media 
- 
Patient with known contraindication to liver embolization 
procedures:  
 
Presence of bilio-digestive anastomoses or biliary prosthesis 
 
 
Cruciate or tumor thrombosis of the portal vein 
- 
Patient who for psychological, social, family or geographical 
reasons could not be followed regularly 
- 
Legal incapacity (persons deprived of liberty or under 
guardianship) 
- 
Patient not affiliated to a social security system 
- 
Concurrent participation in another study investigating the 
effect of a treatment until 4 weeks after the end of this study.  
Study 
design 
and 
treatment plan  
 
Microbeads (100-300µm), loaded with irinotecan (DEBIRI).  The 
maximum dose per procedure is 100 mg of irinotecan, combined with 
intravenous FOLFOX.  
For patients with unilobar or bilobar liver involvement, DEBIRI will be 
injected at D17 and D45 (after the 2nd and 4th cycle of systemic 
chemotherapy with FOLFOX).  
Patients with bilobar involvement but for whom the investigator decides 
that the treatment will be unilobar and sequential, there will be 4 sessions. 
Thus, the right and left livers will be treated alternately. The DEBIRI 
administrations will then be performed at D17, D31, D45, D59, or in case 
of a shift in chemotherapy treatment, after the 2ème , 3ème , 4ème and 5ème 
cycle of FOLFOX. 
FOLFOX will be administered every 2 weeks until progression or 
unacceptable toxicity.   
Statistical methods 
 
A 1-step Fleming design will be used, with a one-sided α risk of 5% and a 
power (1-β) of 90%. 
 
The assumptions are: 
• H0: A proportion of patients living without progression of 55% 
during the first 9 months is uninteresting; 
• H1: A proportion of patients living without progression of more 
than 55% during the first 9 months would show the interest of the 
treatment; a proportion of 75% is hoped for. 


FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page8 on39 
 
 
 
Total number: 48 evaluable patients 
Taking into account a 20% rate of lost to follow-up or non-evaluable 
patients, 58 patients should be included. 
 
At the end of recruitment: 
 During analysis: 
- if 32 or fewer patients are alive without progression, then the treatment is 
considered ineffective  
- if 33 or more patients are alive without progression, then the treatment is 
considered effective  
The decision rule will be adjusted based on the actual number of evaluable 
patients. 
Number of subjects 
needed 
58 
Associated 
translational studies  
- 
On lipid parameters: 
 The objective of this study will be to evaluate the impact of the different 
parameters of the lipid profile and the metabolism of lipoproteins on the 
response to treatment. 
- 
On Pathology: 
At the end of the study, if a sufficient number of patients have undergone 
secondary resections of liver metastases, a collection of surgical parts will 
be organized. An anatomopathological study of the tumor parenchyma and 
the healthy parenchyma resected after DEBIRI treatment will be 
performed. 
Planned study period 
Expected start date of inclusion: April 2013 
Expected completion date of inclusion: April 2016 
Expected completion date: July 2018 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page9 on39 
  
I. 
OBJECTIVES OF THE TRIAL 
I.1 
Main objective  
Evaluate the investigator-assessed 9-month progression-free survival rate (according to 
RECIST 1.1 criteria).  
 
I.2 
Secondary objectives 
 
Tolerance to treatment 
Response rate according to RECIST 1.1 criteria at 9 months 
Response rate according to EASL criteria, assessed at 9 months, by centralized review 
Hepatic progression-free survival according to RECIST 1.1  
Overall survival 
Progression-free survival 
Secondary resection rate  
Evolution of tumor marker levels  
 
II. 
PATIENT SELECTION 
II.1 
Inclusion criteria 
Inclusion in the study requires that all of the inclusion criteria listed below be met: 
- 
Histologically proven colorectal adenocarcinoma 
- 
Radiologically or histologically proven liver metastases 
- 
At least one measurable liver lesion according to RECIST v1.1 criteria 
- 
Age ≥ 18 years 
- 
WHO Index 2  
- 
Life expectancy 3 months 
- 
No extra-hepatic disease, except pulmonary nodules if number 3 and size < 10 
mm each 
- 
Hepatic invasion < 60%. 
- 
Primary tumor resected or in place 
- 
No prior chemotherapy for metastases (except peri-operative chemotherapy, if the 
last cycle was given at least 12 months ago)  
- 
Adjuvant chemotherapy after resection of the primary site allowed if the last cycle 
was administered at least 12 months ago 
- 
Normal liver function: total bilirubin ≤ 1.5N, AST≤ 5N, ALT ≤ 5N and PAL≤ 5N. 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page10 on39 
  
- 
TP ≥ 60% 
- 
Adequate hematologic function: PNN ≥ 1500/mm3 , platelets ≥ 100,000/mm3 , Hb 
≥ 9g/dL 
- 
Good renal function: creatinine clearance ≥ 60 mL/min 
- 
No cardiac dysfunction: no cardiovascular events in the past 6 months or no 
NYHA ≥ 2.  
 
II.2 
Non-inclusion criteria  
Inclusion in the study requires that none of the non-inclusion criteria listed below are present:  
- 
Patient eligible for curative treatment (resection and/or radiofrequency ablation) as 
determined by the PCR (including the opinion of a liver surgeon) 
- 
Pregnant or breastfeeding women or patients of either sex of childbearing age who 
are not using an adequate method of contraception (see section V. 4) 
- 
Previous cancer, except for non-melanoma skin cancers and curatively treated 
cervical in situ cancers. Other curatively treated cancers are allowed provided they 
have not recurred for more than 5 years 
- 
Peripheral neuropathy 
- 
Inflammatory bowel diseases  
- 
Intestinal occlusion 
- 
Chronic liver disease (viral, alcoholic or metabolic) 
- 
Immunodeficiency syndromes (transplant history, HIV infection) 
- 
Known contraindications to 5FU, oxaliplatin, folinic acid, irinotecan or contrast 
media 
- 
Patient with known contraindication to liver embolization procedures:  
Presence of bilio-digestive anastomoses or biliary prosthesis 
 
 
Cruciate or tumor thrombosis of the portal vein 
- 
Patient who for psychological, social, family or geographical reasons could not be 
followed regularly 
- 
Legal incapacity (persons deprived of liberty or under guardianship) 
- 
Patient not affiliated with a social security plan. 
- 
Concurrent participation in another study investigating the effect of a treatment 
until 4 weeks after the end of this study.  
 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page11 on39 
  
III. 
PRE-INCLUSION ASSESSMENT  
To be performed within 21 days prior to treatment and before inclusion:  
- Thoracoabdomino-pelvic CT scan, documenting at least one measurable liver lesion 
- Hepatic MRI 
- PET scan strongly recommended before inclusion.  
Remember to keep the radiology CDs in the patient's file; the ARC FFCD will make a 
copy of these imaging studies. 
 
To be completed within 14 days prior to inclusion: 
- Complete clinical examination including: weight, height, vital signs, WHO index, 
pain assessment (VAS) 
- Medical history 
- Description of the disease 
- Biological workup consisting of measurements of hematological, nephrological and 
hepatic 
parameters: 
CBC/platelets, 
blood 
ionogram, 
creatinine, 
albumin, 
transaminases (AST, ALT), alkaline phosphatases (ALP), total and conjugated 
bilirubin, PT, APTT, fibrinogen level 
- Determination of lipase  
- ACE and CA 19-9 assay  
- KRAS status will be determined at each center but not routinely at inclusion 
- Fasting sample for patients participating in the 'lipid' translational study; don't forget 
to perform it (according to the corresponding section, p25). 
 
IV. 
INCLUSION 
After the patient has signed the clinical consent form (Appendix 1) and the results of the 
examinations necessary for inclusion in the study have been verified, the patient can be 
included. For centers participating in the associated 'lipid' study, the specific information and 
consent form (Appendix 2) must be proposed. 
The patient's inclusion will be done directly via the eCRF; the inclusion confirmation and the 
inclusion number will be sent to you by email. For any help, the FFCD Randomization - 
Management - Analysis Center in Dijon is open from Monday to Friday from 9:00 am to 6:00 
pm.  
After inclusion in the study, treatment should begin within a maximum of 2 weeks.  
 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
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FFCD 1201 Protocol v 1.2 of 28/07/2015 
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V. 
TREATMENT 
V.1 
Treatment scheme: 
Bilobar treatment in 2 sessions: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Following this initial treatment plan, all patients will receive FOLFOX chemotherapy every 2 weeks according to the usual schedule until 
progression or unacceptable toxicity. 
 
Sequential unilobar treatment in 4 sessions: 
Tumor evaluation 
Evaluation of the 
resectability of metastases 
 CE 
J45 
 CE 
J17 
J42 
J14 
.....
cycle 
cycle 
cycle 
cycle 
cycle 
cycle 17 
cycle 
J1 
J28 
J56 
Inclusion 
J -14 
D63 to D70 
CAT SCAN/ 
MRI 
Evaluation every 
2 months 
CAT SCAN/ MRI 
Sessions of 
chemo-embolization 
D- 21 to be 
CAT SCAN/ MRI 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page14 on39 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The chemoembolization treatment can, at the investigator's choice, be administered in a unilobar and sequential manner, in 4 sessions. Thus, the right and left livers will be 
treated alternately. The administrations of DEBIRI will then be performed at D17, D31, D45, D59 (+/- 2 days), or in case of delayed chemotherapy treatment, 3 days (+/- 2 
days) after C2, C3, C4 and C5 of FOLFOX. After this initial treatment plan, all patients will receive FOLFOX chemotherapy every 2 weeks according to the usual 
schedule until progression or unacceptable toxicity. 
 CE 
J59 
 CE 
J31 
J28 
J56 
Tumor evaluation 
Evaluation of the resectability 
of metastases 
 CE 
J45 
 CE 
J17 
J42 
J14 
......
cycle 
cycle 
cycle 
cycle 
cycle 
cycle 17 
cycle 
J1 
Inclusion 
J -14 
J63 to J70 
CAT SCAN/ 
MRI 
Evaluation every 2 
months 
CAT SCAN/ MRI 
Sessions of 
chemo-embolization 
D- 21 to be 
CAT SCAN/ 
MRI 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
Page15 on39 
  
V.2 
Chemoembolization 
 
V.2.1 
Scheduled irinotecan dose  
Each vial of DC Bead is loaded with 100 mg of irinotecan. It is intended to use the 
contents of one vial per lobe.  For unilobar disease, there will be 1 vial loaded with 100 
mg of irinotecan and for bilobar disease, 2 vials loaded with 200 mg, if the treatment is 
done in one session. 
 
V.2.2 
Microbead size 
Microbeads with a size of 100-300µm will be used in this study and provided by the sponsor. 
 
V.2.3 
Precautions and instructions for loading the medication: 
Instructions for loading the beads will be provided in the investigator's binder and the 
pharmacy bag. 
 
V.2.4 
Dilution of the loaded microbeads with a contrast agent 
Remove the excess supernatant of the irinotecan solution from the vial containing the loaded 
microbeads before mixing with the contrast agent. A non-ionic contrast agent should be used. 
It is recommended that the microbeads be diluted prior to injection with a volume of at least 
5-10 mL of contrast agent per mL of microbeads (i.e., 10-20 mL of contrast per vial of 
microbeads). A good suspension of the microbeads in the contrast must be obtained before 
administration.  
 
V.2.5 
Conservation of loaded microbeads: 
Irinotecan-loaded microbeads can be stored for up to 24 hours in a refrigerator at 2°C to 8°C 
or for up to 4 hours at room temperature, with or without a non-ionic contrast agent. 
 
V.2.6 
Pre-administration assessment: 
Prior to each chemoembolization procedure, the patient should be ensured to have adequate 
liver and hematologic function (total bilirubin ≤ 1.5N, ALT, ASAT, and PAL ≤ 5N, albumin 
≥ 2.5g/dL; PNN ≥ 1500/mm3 , platelets ≥ 100,000/mm3 , INR <1.5) and a patent portal trunk. 
V.2.7 
Procedure  
The DEBIRI procedure will begin with a 4 or 5Fr peripheral arterial approach at the operator's 
convenience. 


 
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The operator will first proceed to a diagnostic phase. Successively, he will catheterize the 
superior mesenteric artery and the celiac trunk. During these angiographies, the operator will 
identify the disposition of the hepatic arterial vascularization, the permeability of the portal 
trunk and the vascular topography of the lesions. The operator may be required to perform 
selective angiography of the phrenic, inferior epigastric, and internal mammary arteries when 
peripheral hepatic tumors have been identified. 
After this diagnostic phase, lobar administration will be used whenever possible. The 
operator will catheterize the right and left hepatic arteries with a maximum 3Fr microcatheter. 
Prior to DEBIRI injection, the operator will place the microcatheter on the right downstream 
of the cystic artery, and on the left downstream of the right gastric artery. The right gastric 
artery may be prophylactically embolized if the operator deems it necessary. 
Each vial of irinotecan-loaded microbeads (DEBIRI) will be mixed with at least 10-20 mL of 
non-ionic iodinated contrast medium (e.g. Imeron 350, Omnipaque 350). 
The goal of the procedure is to deliver the entire dose of irinotecan. It is important to maintain 
anterograde flow in the vessel during the procedure.   
DEBIRI should be injected slowly, at a rate of 1 mL of solution per minute.  
 
When the near stasis point is observed prior to the full dose of irinotecan, the injection of 
DEBIRI is discontinued regardless of the volume of beads delivered at that time. Therefore, 
some patients may not receive the entire contents of the prepared vial and may receive a total 
dose of less than 100 or 200 mg, respectively, in cases of lobar or bilobar involvement. The 
operator will make sure to respect these recommendations to prevent an inappropriate reflux 
of DEBIRI that would cause ischemia or necrosis of non-targeted territories.  
When the planned dose of irinotecan is administered before the near-stasis point is reached, 
no additional embolization should be performed with products such as gelfoam, lipiodol or 
microspheres.  
The operator will take care to avoid sedimentation of the beads in the syringe during the 
procedure by performing gentle rotations or using a three-way valve to keep the beads 
suspended in the solution. 
Extrahepatic vessels may be embolized prophylactically, at the discretion of the interventional 
radiologist, to minimize extrahepatic infusion of irinotecan beads. 
For multifocal or bilobar disease, embolization of each lobe will be performed, at the 
investigator's discretion, either during the same session or in a unilobar and sequential 
manner, in 2 sessions. If the treatment is done in one session, the catheter will be placed in the 


 
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right and then left hepatic artery and a maximum of one vial of DEBIRI will be administered 
in each lobe. 
Catheter removal and hemostasis at the puncture site will be accomplished by manual 
compression or by placement of a percutaneous puncture site closure device (e.g., 
Angioceal™). 
Patients will need to be hospitalized overnight following the procedure. After the 
chemoembolization procedure, vital signs, femoral access point, pain management and 
hydration will be observed in all patients. 
The amount of contrast material delivered to the patient during the procedure, the radiation 
dose, and the fluoroscopy exposure time should be recorded. The embolized vessels and the 
amount of embolic agent will be recorded.  
All treatments used during the procedure, including analgesic treatments, should be recorded.  
Any unused irinotecan-loaded microbeads will be discarded. 
 
V.2.8 
Peri-chemoembolization treatment recommendations/pre-medication for 
chemoembolization: 
 
Primary prophylaxis with G-CSF should be used until all chemoembolization procedures have 
been completed and then left to the discretion of the investigator thereafter. The choice of G-
CSF is left to the discretion of the investigator.  
 
The following prophylactic treatments are recommended: 
 
▪ Prophylactic treatment to prevent renal failure: IV hydration started the day before 
chemoembolization and continued until day 2, with a 2,000-mL bag per day (1,000 
mL of saline + 1,000 mL of 5% glucose). 
 
▪ Prophylactic treatment of gastric toxicities: esomeprazole 80 mg at D0, D1 and D2, 
infusion (oral possible for D1 and 2).  
 
▪ Prophylactic treatment of nausea and vomiting: ondansetron 8 mg or granisetron 3 
mg, before chemoembolization and 8 mg 6h after (at D0) and prednisolone 40 mg 
twice a day at D0, D1; then 40 mg/d at D2, D3, D4, D5 
 
▪ Prophylactic treatment of pain:  
Ideally, self-administration of level 3 analgesics by PCA (Patient Control Analgesia) is 
implemented. The injected preparation is oxycodone 2 mg, injected by a pump with a 


 
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refractory period of 3 min and with a maximum dose of 20 mg per 4h. This PCA will 
be maintained for 12 hours after chemoembolization.  
Otherwise, 5 to 10 mg of morphine, 30 minutes before and 6 hours after 
chemoembolization. This prophylaxis is given as an indication and can be modified at 
the investigator's discretion.  
Intra-arterial infusion of 1-3 mL of 1% lidocaine immediately prior to 
chemoembolization with DEBIRI. 
 
▪ 
Prophylactic treatment of infections: 2000 mg of cefazolin twice a day, at D0, D1 
and D2. 
 
V.3 
Simplified FOLFOX 4 treatment 
 
Simplified FOLFOX 4 administered IV every 2 weeks:  
 
- Oxaliplatin 85 mg/m2  in 2h in 250 mL of G5% (H + 0) 
- Folinic acid 400 mg/m2 in 2h in 250 mL of G5% (H + 0) 
- 5FU 400 mg/m2 in 10 min in 100 mL of G5% (H + 2H) 
- 5FU 2400 mg/m2 as a continuous infusion over 46 hours in G5% in a portable infuser 
(qsp 230 mL, 5mL/h), pump, or portable syringe pump 
 
 
Patients with uni- or bilobar involvement will have chemoembolization and FOLFOX 
administrations at the following visits: 
Or in a bilobar treatment in 2 sessions 
 
Visit n° 
FOLFOX cycle number 
Chemoembolization cycle number 
Time (days) 
1 
1 
 
T=0 
2 
2 
 
T+14 
3 
 
1 
T+17 
4 
3 
 
T+28 
5 
4 
 
T+42 
6 
 
2 
T+45 
7 
5 
 
T+56 
 


 
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Either in a unilobar treatment in 4 sessions 
 
 
Visit n° 
FOLFOX cycle number 
Chemoembolization cycle number 
Time (days) 
1 
1 
 
T=0 
2 
2 
 
T+14 
3 
 
1 
T+17 
4 
3 
 
T+28 
5 
 
2 
T+31 
6 
4 
 
T+42 
7 
 
3 
T+45 
8 
5 
 
T+56 
9 
 
4 
T+59 
 
No targeted therapy is proposed in this protocol for the first line (neither anti-EGFR nor anti-
VEGF). 
 
 
 
Preventive treatments related to FOLFOX 
Prophylaxis for FOLFOX administration is at the discretion of the investigator. However, the 
following prophylactic regimens are recommended: 
 
➢ Prevention of chemo-induced nausea and vomiting (AFSOS recommendations): 
• Before chemotherapy (D1):  
- Anti-5-HT3: Odensetron (Zophren) IV 8 to 16 mg, 30 minutes before, respecting 
cardiac contraindications (congenital long QT syndrome, uncorrected hypokalemia 
or hypomagnesemia) 
- Aprepitant (Emend): per os, 125 mg, 1h before 
- Dexamethasone: IV 8 to 16 mg before 
• After chemotherapy: 
   - Aprepitant per os: 80 mg in the morning of D2 and D3 
 


 
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➢ Prevention of mucositis (based on AFSOS recommendations): 
- Mouthwash prescriptions:  
o Sodium bicarbonate 1.4% pure, no other product added 
o As often as possible, minimum 8-10 times a day 
o In gargle 
o Away from meals 
- Oral hygiene tips (soft toothbrush) 
 
➢ Prevention 
of 
neutropenia: 
G-CSF 
prophylaxis 
should 
be 
used 
until 
all 
chemoembolization procedures have been completed and then left to the discretion of the 
investigator thereafter. 
 
➢ Prevention of neuropathy: 
- calcium gluconate (1g) and magnesium sulfate (1g) in 30 minutes IV before and after 
oxaliplatin at D1 
 
To know all the other authorized and contraindicated treatments, please refer to the different 
RCP (see annex 7).  
 
V.4 
Precautions to take: 
Women and men of childbearing age who participate in this trial must use effective 
contraception throughout their participation in the trial and for 12 months afterwards. 
Effective contraceptives may be hormonal (e.g., birth control pills, injections, or implants) or 
mechanical (e.g., condoms, IUDs, diaphragms, or other devices). For women using 
mechanical contraceptives, it is strongly recommended to combine 2 methods of mechanical 
contraception (such as condom, IUD, diaphragm or other device). Women who use hormonal 
contraceptives are advised to use a mechanical method of contraception at the same time. 
 
 
VI. 
EXPECTED TOXICITIES AND DOSE ADJUSTMENT 
Chemotherapy toxicities will be assessed using the NCI-CTC v4 scale (Appendix 5). 
 
VI.1 
FOLFOX 
The expected toxicities with FOLFOX are mainly: 
For oxaliplatin: 


 
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- allergic reactions 
- cramps, dysesthesias (aggravated by cold) 
- moderately emetogenic 
- laryngeal spasm (reversible) 
- peripheral sensory neuropathies  
 
For 5-FU: 
- mucositis 
- diarrhea 
- hand-foot syndrome 
- weakly emetogenic 
- hematological toxicity 
 
 
 
 
 
 
 
Dose adaptations for guidance only: 
Persistent paresthesias between 2 treatments 
(grade 2) 
Reduce oxaliplatin to 65 mg/m2 
Painful paresthesias or with functional discomfort 
(grade 3) 
Stopping oxaliplatin 
Dermal toxicity grade > 2 
Reduce 
bolus 
5-FU 
to 
300 
mg/m2 
 Reduce continuous 5-FU to 1800 mg/m². 
Neutropenia < 1000/mm³ (> grade 2) or 
thrombocytopenia < 50,000/mm³ (> grade 2) 
Stop bolus 5-FU and reduce oxaliplatin to 
65 mg/m² if thrombocytopenia 
Diarrhea, mucositis or other toxicity grade > 2 
Reduce oxaliplatin to 65 mg/m². 
Reduce 
bolus 
5-FU 
to 
300 
mg/m2 
 Reduce continuous 5-FU to 1800 mg/m². 
Grade 3-4 cardiac, cerebellar or allergy toxicity  
discontinuation of chemotherapy 
 
Wait for resolution of toxicities in case of grade 3 or 4 before resuming the cycle. 
On the day of the resumption of the cycle D1: 1,500 PNN/mm³ and 100,000 platelets/mm³ 
are needed to resume the cycle. 


 
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VI.2 
Chemoembolization 
 
The main adverse effects expected with chemoembolization are: 
- 
Unwanted reflux or passage of microbeads into normal arteries adjacent to the targeted 
lesion or through the lesion to other arteries or arterial beds 
- 
Non-targeted embolization 
- 
Pulmonary embolization 
- 
Capillary bed saturation and tissue damage 
- 
Ischemic stroke or ischemic infarction 
- 
Rupture of a vessel or lesion and hemorrhage 
- 
Neurological deficits including cranial nerve palsy 
- 
Vasospasm 
- 
Repermeabilization 
- 
Foreign body reactions requiring medical intervention 
- 
Infection requiring medical intervention 
- 
Catheter tip clot formation and subsequent mobilization 
- 
Deaths 
 
Expected effects for the embolization procedure (from CNIHM anticancer files November 2008): 
- 
Fever, right upper liver quadrant pain, vomiting 
- 
Transient thrombocytopenia and liver dysfunction 
- 
Increased transaminases (cytolysis) 
- 
Local ischemic and septic manifestations (cholecystitis, hepatic infarction, hepatic 
abscess, digestive hemorrhage) 
- 
Renal insufficiency 
 
Adaptations for chemoembolization: 
• The chemoembolization procedure will be stopped in case of:  
o Inability to catheterize the hepatic artery 
o Dissection of the hepatic artery 
o Anaphylactic shock to contrast medium 
o Per-procedural discovery of portal vein occlusion or arteriovenous shunt 
o near-stasis (stop-flow) observed prior to the full dose of irinotecan 
• If the following grade 3 or 4 toxicities occur as a result of chemoembolization, no 
additional session will be performed (but FOLFOX will be continued). 


 
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o Arteritis  
o Grade 3 or 4 hepatic impairment 
o Local ischemic and septic manifestations (cholecystitis, hepatic infarction, 
hepatic abscess, digestive hemorrhage) of grade 3 or 4 
o Grade 3 or 4 renal insufficiency 
• The interval between chemoembolization sessions may be extended to allow 
for recovery of liver function. 
• No dose adjustment of irinotecan is planned for chemoembolization sessions. 
• In case of hematological toxicity, FOLFOX dose adjustment rules will be applied 
and chemoembolization will be continued. 
 
In case of doubt, do not hesitate to ask for advice from the study's referring radiologist, 
Dr. Olivier Pellerin, through the FFCD. 
 
 
VII. 
PATIENT 
MONITORING 
DURING 
TREATMENT 
AND 
AFTER WITHDRAWAL OF TREATMENT 
 
 
Monitoring during treatment: 
• Before each cycle of FOLFOX: 
- Complete clinical examination including: weight, vital signs, WHO, pain assessment 
(VAS) 
- Biological check-up: CBC/platelets 
- Adverse event evaluations according to NCI CTC version 4.0 
 
• Before each chemoembolization session 
- Complete clinical examination including: weight, vital signs, WHO, pain assessment 
(VAS) 
- Biological workup consisting of measurements of hematological, nephrological and 
hepatic 
parameters: 
CBC/platelets, 
blood 
ionogram, 
creatinine, 
albumin, 
transaminases (AST, ALT), alkaline phosphatases (ALP), total and conjugated 
bilirubin, PT 
- Adverse event evaluations according to NCI CTC version 4.0 
 


 
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CEA and CA 19-9 assays, as well as thoracoabdomino-pelvic CT and liver MRI will be 
performed at an initial evaluation between D63 and D70 and then every 2 months after the 
start of treatment.  
For patients participating in the associated 'lipid' translational study, please remember to 
perform the fasting sample and then technician the sample.  
 
After the chemoembolization treatment period:  
All patients will receive chemotherapy with FOLFOX every 2 weeks according to the usual 
regimen until progression or unacceptable toxicity. 
 
 


 
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VIII. 
STOP PROCESSING THE STUDY  
 
The processing of the study will be stopped in case of: 
- Investigator's decision 
- Major toxicity requiring discontinuation of treatment (despite protocol adaptations) 
- Serious or unexpected event requiring discontinuation of protocol treatment 
- Progression of the disease 
- Patient refusal or withdrawal of consent 
 
In all cases of treatment discontinuation, the patient remains in the analysis for intention-to-
treat and overall survival, and for 30 days after the last study treatment for toxicity. 
There is no exclusion period for a subsequent therapeutic trial.  
 
IX. 
CENTRALIZED READING OF CT SCANS AND MRI 
 
Responses will be evaluated according to RECIST version 1.1 criteria (Appendix 3) and will 
be reviewed by a panel of independent radiologists according to RECIST version 1.1 criteria 
and EASL criteria (Appendix 4).  
Don't forget to keep the CDs and the report of the CT and MRI evaluation in the 
patient's file; the FFCD CRA will make a copy of these imaging assessments to centralize 
them at the CRGA on the 'FFCD Images' platform using a secure transmission via the 
company ETIAM. 
 
 
 


 
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X. 
MANAGEMENT OF SERIOUS ADVERSE EVENTS (SIA)  
 
Safety will be assessed by evaluating the general, clinical and biological status of patients at 
the time of scheduled visits and by collecting events occurring between visits. Toxicities will 
be assessed using the NCI-CTC Toxicity Scale version 4.0 (Appendix 5). 
 
X.1 
Definitions 
Adverse Event (AE) 
An adverse event is a harmful occurrence in a person who is a subject of biomedical research, 
whether or not the occurrence is related to the research or the product being investigated. 
All adverse events will be recorded in the observation book on the pages provided. 
 
Serious Adverse Event (SAE) 
A serious adverse event is any event that meets at least one of the following criteria: 
• Resulting in death, 
• Life-threatening, 
• Leading to hospitalization or prolonged hospitalization, 
• Causing permanent disability or severe temporary incapacity, 
• Causing a birth defect, fetal malformation or abortion, 
• Medically significant (examples: overdoses, second cancers, pregnancies and new 
developments may be considered medically significant) 
Pregnancy is an exclusion criterion in this trial.  
However, if a pregnancy is discovered after inclusion, the patient must be excluded from the 
trial. The sponsor should be informed immediately via the Serious Adverse Event Reporting 
Form (no severity criteria should be checked). The patient should be followed until the 
outcome of the pregnancy and this outcome, whatever it may be, should be reported to the 
sponsor. 
Hospitalizations included in the protocol will not be considered an SAE. 
 
Undesirable Effect  
Any noxious and undesired response to an investigational drug at any dose or to any 
investigational component. The adverse reaction is serious if it meets the severity criteria (see 
above). 


 
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Unexpected Serious Adverse Effect 
An unexpected serious adverse reaction is an event that is not mentioned, or is different in 
nature, intensity, or evolution from the product reference document.  
In this essay the reference documents will be: 
• For irinotecan-loaded beads (DEBIRI): the Investigator's Brochure  
• For FOLFOX: the Summaries of Product Characteristics for oxaliplatin, 5-
fluorouracil, folinic acid (Appendix 7) 
 
The versions of the PCRs used for the definition of expected or unexpected will be the latest 
available on the anniversary date of the start of the trial. 
 
X.2 
Course of action  
The investigator informs the sponsor of all Serious Adverse Events (Expected and 
Unexpected), whether or not attributable to the research, that occur during treatment and 
within 30 days of the last treatment administration.  
 
All Delayed Serious Adverse Events (occurring after this 30-day period) considered 
reasonably related to the protocol treatment(s) or research should be reported without time 
limitation. 
 
The report is made by faxing the "notification of a serious adverse event" form 
(Appendix 8), documented as precisely as possible, dated and signed, within 24 working 
hours of their discovery to the FFCD's Randomization Management Analysis Center 
(CRGA): by fax to 03 80 38 18 41. 
 
Modalities and duration of follow-up of individuals following the occurrence of adverse 
events. 
The investigator is responsible for appropriate medical follow-up of patients until resolution 
or stabilization of the effect or until the patient's death. This may sometimes mean that this 
follow-up extends beyond the patient's discharge from the trial. 
 
He/she transmits the additional information to the sponsor using an SAE reporting form 
(checking the Follow-up No. X box to specify that it is a follow-up report and not an initial 
report) within 24 hours of obtaining it. It also forwards the latest follow-up to the resolution or 
stabilization of the SAE.  


 
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He keeps the documents concerning the suspected adverse reaction in order to allow, if 
necessary, to complete the information previously transmitted. 
 
 
 
 


 
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XI. 
ANCILLARY STUDIES 
o Associated 'lipid' study 
Recent publications show that the plasma lipoprotein profile influences the risk of colorectal 
cancer; a high level of HDL cholesterol is a good prognosis.   
One of the objectives of this study will be to evaluate the relationship between the different 
parameters of the lipid profile and lipoprotein metabolism on the response to treatment. 
A lipid profile (including cholesterol, triglycerides, LDL and HDL profiles, activity of plasma 
lipid transfer proteins, etc.) will be performed before and after the protocol treatment.  
If your center is participating in this study, you will have a specific information note to offer 
to your patients (Appendix 2).  
Two fasting samples (16 hours fasting), on 7 mL EDTA tube will be taken; the first one 
before any administration and the other one at the time of the first evaluation (after the 
chemoembolization sessions, between D63 and D70).  
These samples will be centrifuged on site at 1500 g, for 15 min, at 4°C and this maximum 4 
hours after sampling. The supernatant will be aliquoted in 1 mL tubes; they will be stored at -
80°C until the end of the inclusions. The sponsor will organize a grouped shipment on dry ice. 
 
o Associated anatomopathological study 
At the end of the study, if a sufficient number of patients have undergone secondary 
resections of liver metastases, a collection of surgical parts will be organized. The objective 
will be to evaluate the histological response according to the TRG grade.  Will be analyzed: 
- healthy peri-tumor liver parenchyma 
- liver metastases 
The surgical specimens will be analyzed macroscopically and microscopically by standard 
techniques of morphological cytological and architectural studies, standard staining 
(Hematoxylin Eosin (HES), and Periodic Acid Shiff (PAS)), and immunohistochemistry, to 
determine: the limits of excision, tumor response and tumor necrosis to treatment on 
histological criteria, but also the impact on the healthy parenchyma of the chemoembolization 
procedure, by assessing hepatic fibrosis, hepatic necrosis, steatosis and steatohepatitis, and 
vascular lesions of the healthy parenchyma. 
XII. 
STATISTICAL ANALYSIS 
 
 


 
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XII.1 
Provisional timetable for the study 
Expected start date of inclusion: April 2013 
Expected completion date of inclusion: April 2015 
Expected completion of study: July 2017 
 
XII.2 
Judging criteria 
  
XII.2.1 
Main criterion  
 
The primary endpoint will be the proportion of patients alive without progression (death will 
be considered as progression) at 9 months after the start of treatment according to RECIST 
V1.1 criteria, as assessed by the investigator. 
 
Progression-free survival time will be defined as the time interval between the date of 
inclusion and the date of progression or death (regardless of cause). For patients alive without 
progression, the time interval between the date of inclusion and the date of last morphological 
evaluation will be taken. 
 
XII.2.2 
Secondary Criteria  
 
The secondary endpoints will be:  
- 
Tolerance to the treatment 
- 
Response rate according to RECIST v1.1 criteria at 9 months (according to the 
investigator) 
- 
Response rate according to EASL criteria (assessed by centralized review) at 9 months 
- 
Hepatic progression-free survival according to RECIST v1.1 criteria at 9 months  
- 
Overall survival 
- 
Progression-free survival  
- 
The rate of secondary resections  
- 
Changes in tumor marker levels 
 
Liver progression-free survival will be defined as the time interval between the date of 
inclusion and the date of liver progression as assessed by the investigator's RECIST V1.1 
criteria or death (regardless of cause) or the date of the last morphological assessment for 
patients alive without progression. 
 


 
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Overall survival will be defined as the time interval between the date of inclusion and the date 
of death regardless of the cause of death or the date of last news for living patients. 
 
Tolerance to treatment will be assessed by: 
- 
duration of treatment, doses received, dose reductions and deferrals 
- 
Toxicities collected at each monthly visit, and described according to NCI-CTC 
version 4.0 criteria; Grade 3, Grade 4 and Grade 5 toxicities will be reviewed 
- 
the number and description of SAEs 
 
Changes in tumor marker levels (CEA and CA 19-9) will be assessed throughout the study. 
 
XII.3 
Calculation of the number of subjects needed 
A 1-step Fleming design will be used, with a one-sided α risk of 5% and a power (1-β) of 
90%. 
The assumptions are: 
• H0: A proportion of patients living without progression of 55% during the first 9 
months is uninteresting; 
• H1: A proportion of patients living without progression of more than 55% during the 
first 9 months would show the interest of the treatment; a proportion of 75% is hoped 
for. 
 
Total number: 48 evaluable patients 
Taking into account a rate of 20% of patients lost to follow-up or not evaluable, 58 patients 
should be included. 
 
At the end of recruitment: 
 During analysis: 
• if 32 or fewer patients are alive without progression, then the treatment is considered 
ineffective  
• if 33 or more patients are alive without progression, then the treatment is considered 
effective  
The decision rule will be adjusted based on the actual number of evaluable patients. 
 
XII.4 
Statistical analysis plan 
 
Analysis Populations: 


 
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Patients included in the study will be described on an intention-to-treat (ITT) basis as well as 
patients not evaluable for the primary endpoint.   
A patient is considered evaluable if he or she has had chemoembolization and received at least 
one cycle of chemotherapy and for whom we have at least one evaluation during the 9 months 
of follow-up. 
All efficacy analyses will be performed on a modified intention-to-treat basis (evaluable 
patients) included in the study regardless of eligibility criteria and treatment received. 
Tolerability population: the ITT population that received at least one dose of the treatments. 
In all cases of discontinuation, the patient remains in the intention-to-treat analysis. There is 
no exclusion period for a subsequent therapeutic trial. 
 
Key analyses: 
A statistical analysis plan will be written prior to freezing the database. 
The description of clinical and medical variables will be done using percentages (95% 
confidence interval) for qualitative variables and mean (standard deviation) and median (Min-
Max) as well as inter-quartile range (Q1-Q3) for quantitative analysis. 
Survivals and times will be estimated by the Kaplan Meier (KM) method. They will be 
described by medians and rates at different time points with their 95% confidence intervals. 
Median follow-up time will be calculated using the reverse Kaplan Meir method. 
The time to onset of grade 3/4/5 toxicity will be estimated using the Kaplan Meier method. 
 
Exploratory Analyses: 
- 
research into factors predictive of progression-free survival and/or overall survival 
 
 
 
XII.5 
Independent Committee Supervisory Committee  
An independent committee composed of 1 clinician / 1 methodologist / 1 pharmacovigilant 
expert will be formed before the start of the trial. 
It will have to decide on the continuation of the study in light of the safety data. The sponsor 
may refer to it at any time in the event of significant events concerning the safety of the 
treatment. An analysis of SAEs is planned after the inclusion and intra-arterial treatment of 
the first 10 patients. 
 


 
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XII.6 
Imaging Review Committee/Radiologist Panel 
The anonymized copies of the evaluation reports will be centralized at the CRGA on the 
'FFCD Images' platform using a secure transmission via the company ETIAM. 
The RECIST version 1.1 and EASL responses will be reviewed by this panel of independent 
radiologists at a later date, who will confirm the responses and dates of tumor progression or 
recurrence once all study examinations have been retrieved.  
 
XII.7 
Steering Committee 
A Steering Committee will be set up. It will be chaired by the study coordinator, Prof. Julien 
TAIEB. This committee will also include the president of the FFCD, the statistician of the 
FFCD and the president of the Biological Research Committee (if applicable). Its mission will 
be, among others, to take decisions related to the management of the research (amendment, 
premature closure if necessary, ...).  
 
XII.8 
14.2 Biological Research Committee 
If it is decided to set up the collection of surgical parts relating to secondary hepatic 
resections, a Biological Research Committee will be established. Its mission will be to deal 
with problems related to the collection and banking of specimens and the organization of their 
analysis. The committee shall meet regularly and report its proposals to the Board of 
Directors. This committee will include the study coordinator and a biologist; the chairperson 
of this committee will be designated afterwards. 
 
 
 
 
XIII. 
JUSTIFICATION OF THE TEST  
 
The treatment of metastatic colorectal cancer has become more diverse in recent years. 
Several chemotherapy regimens and targeted therapies are available as first-line treatment. 
The majority of liver metastases are not immediately resectable (in about 85% of patients) and 
studies with different combinations indicate that aggressive first-line chemotherapy in initially 
inoperable patients can achieve complete resection of metastatic disease (1). It is therefore 
important to develop new therapeutic strategies in metastatic colorectal cancer. 
 
Anti-tumor therapy 


 
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Intravenous triple therapy combining 5FU, oxaliplatin, and irinotecan has been evaluated in 
randomized trials (Falcone et al, (2); Souglakos et al, (3)). They showed good response rates 
(43-60% according to RECIST criteria), progression-free survival (about 62% at 9 months), 
secondary resection rates of liver metastases and overall survival. Tolerability was acceptable 
if the WHO performance status at inclusion was <2, bilirubinemia <1.5 times LNS, and 
primary neutropenia prophylaxis (G-CSF) was administered. These trials suggest that the 
combined use of 5FU, oxaliplatin, and irinotecan is an option in the treatment of first-line 
metastatic colorectal cancer. 
 
Intra-arterial chemotherapy  
It has been shown in numerous trials over the past 20 years that intra-arterial chemotherapy 
can improve response rates and overall survival, particularly in patients with liver-limited 
metastatic disease. In patients with liver-limited metastases, locoregional chemotherapy 
exposes liver tumor cells to high concentrations with minimal systemic toxicity. However, 
FUDR and, more recently, oxaliplatin have been the most extensively tested drugs by this 
route, with high response and secondary resection rates of liver metastases (4-7), but no large 
phase III is currently available to validate their use in daily practice. In addition, there is a 
clear lack of standardization of the therapeutic protocol for IA injection and the use of intra-
arterial devices is still limited to very specialized centers. 
 
 
 
 Advantages of the DEBIRI 
An intra-arterial hepatic chemotherapy protocol with irinotecan-loaded microbeads (DEBIRI) 
has recently been developed. Preliminary results are promising. A phase II study of 82 
patients with unresectable liver metastases, after failure of two lines of chemotherapy, treated 
with DEBIRI achieved a 78% response rate and improved quality of life in 90% of patients 
(8). Acute toxicity is common (post-embolism syndrome in 80% of cases) but easily 
manageable.         
 
This treatment was also tested in another second- or higher-line study in 55 patients with 
colorectal cancer with unresectable liver metastases (9). Results showed a 75% response rate 
at 1 year and a median overall survival of 19 months. This treatment also appeared to be well 
tolerated, with 28% grade 1-3 toxicities. It did not appear to be more toxic in combination 
with systemic chemotherapy (continuous IV or oral 5FU, n = 16) than alone. 
 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
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More recently, a randomized phase III study in the same population (colorectal cancer with 
liver metastases after at least 2 lines of treatment) compared FOLFIRI to DEBIRI (10). 
Results were encouraging with response rates of 68.6% in the experimental arm versus 20% 
in the control arm. Quality of life, median overall survival and progression-free survival were 
also improved in the experimental arm. Tolerance showed more acute toxicities (grade 2-3) in 
the experimental arm and more late toxicities (grade 2-3) in the control arm. Finally, 
healthcare costs were reduced in the experimental arm. 
 
Finally, DEBIRI was combined with FOLFOX in a 1ère metastatic line of treatment for 
patients with metastatic colon cancer in a phase I study of 10 patients. Response rates at 9 and 
12 months were 100%, with 40% secondary resection or removal of metastases. The 
combination was well tolerated with only one grade 3 event (hypertension). 
 
 
Objectives 
The objective of this study is to evaluate the feasibility, safety, and efficacy of chemotherapy 
combining conventional systemic FOLFOX with DEBIRI intra-arterially in the liver as first-
line therapy in patients with CRC with predominantly hepatic metastases in a multicenter, 
single-arm phase II trial. 
 
 
XIV. 
REFERENCES 
 
1 Pozzo C, Basso M, Cassano A, et al: Neoadjuvant treatment of unresectable liver disease 
with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 
15:933-939, 2004 
 
2 Falcone A, Ricci S, Brunetti I, et al: Phase III trial of infusional fluorouracil, leucovorin, 
oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, 
and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo 
Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6 
 
3 Souglakos J, Androulakis N, Syrigos K, et al: FOLFOXIRI (folinic acid, 5-fluorouracil, 
oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-
line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
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from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-
805 
 
4 Boige V, Malka D, Elias D, et al: Hepatic arterial infusion of oxaliplatin and intravenous 
LV5FU2 in unresectable liver metastases from colorectal cancer after systemic chemotherapy 
failure. Ann Surg Oncol. 2008 Jan;15(1):219-26 
 
5 Kemeny NE, Melendez FD, Capanu M, et al: Conversion to resectability using hepatic 
artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases 
from colorectal carcinoma J Clin Oncol. 2009 Jul 20;27(21):3465-71 
 
6 Carnaghi C, Santoro A, Rimassa L, et al: The efficacy of hybrid chemotherapy with 
intravenous oxaliplatin and folinic acid and intra-hepatic infusion of 5-fluorouracil in patients 
with colorectal liver metastases: a phase II study. Invest New Drugs. 2007 Oct;25(5):479-85 
 
7 Malka D., Bourredjem A., Caramella C. et al: Intra-arterial hepatic oxaliplatin (IAH), 5-
fluorouracil (FU), leucovorin (LV), and intravenous (IV) cetuximab in 1st-line unresectable 
colorectal liver metastases (UCM): final results from the CHOICE multicenter phase II trial. 
JFHOD 2012. CO.58 
 
8 Martin RC, Joshi J, Robbins K, et al: Hepatic intra-arterial injection of drug-eluting bead, 
irinotecan (DEBIRI) in unresectable colorectal liver metastases refractory to systemic 
chemotherapy: results of multi-institutional study. 
 
9 Aliberti C et al. Transarterial chemoembolization (TACE) of liver metastases (LM) from 
colorectal carcinoma (CRC) adopting drug eluting beads preloaded with irinotecan (DEBIRI): 
Results of a phase II study on 82 patients. J Clin Oncol 27:15s, 2009 (suppl; abstr 4092) 
 
10 Fiorentini G et al. ESMO 2010 Abstract 588 
 
11 Martin RC et al: Toxicity of irinotecan-eluting beads in the treatment of hepatic 
malignancies: results of a multi-institutional registry. Cardiovasc Intervent Radiol. 2010 
Oct;33(5):960-6 
 
12 Martin RC, Scoggins CR, Tomalty D, et al: Irinotecan Drug-Eluting Beads in the 
Treatment of Chemo-Naive Unresectable Colorectal Liver Metastasis with Concomitant 
Systemic Fluorouracil and Oxaliplatin: Results of Pharmacokinetics and Phase I Trial. 
Journal of Gastrointestinal Surgery, Online First™, 24 April 2012 
 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
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XV. 
LEGAL AND ETHICAL ASPECTS ADMINISTRATIVE 
CONSIDERATIONS 
 
XV.1 
STUDY SPONSOR 
The sponsor of the study is the Fédération Francophone de Cancérologie Digestive (FFCD). 
The study was registered under the number EudraCT 2012-004166-18. 
  
XV.2 
REMINDER OF THE TEXTS IN FORCE 
This trial will be conducted according to French law.  
 
XV.3 
PUBLIC LIABILITY INSURANCE 
Insurance was taken out by the sponsor on 11/01/2012 under the number (137.681) with 
SHAM, in accordance with Article L 1121-10 of the Public Health Code (Appendix 10).  
 
XV.4 
APPLICATION FOR AUTHORIZATION TO THE CPP AND AFSSAPS 
This protocol has been authorized by the CPP (Comité de Protection des Personnes) Ile-de-
France 8, on 14/01/2013 (appendix 11). 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
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This protocol received a favorable opinion from the ANSM, Agence Nationale de Sécurité du 
Médicament et des Produits de Santé (formerly AFSSAPS) on 8/01/2013 (Appendix 12). 
 
XV.5 
COLLECTION OF THE PATIENT'S CONSENT 
The investigator undertakes to collect, after information, the clinical and biological consent (if 
applicable) of the patient in writing; the information sheets and consent forms are in appendix 
1 and 2. A copy of these consents must be kept by the investigator for 15 years. The original 
must be given to the patient. 
 
XV.6 
INFORMATION TO HOSPITAL MANAGEMENT AND RESEARCH 
AGREEMENT 
Prior to the implementation of the study, the hospital management will be informed by the 
sponsor of the investigator's interest in participating in this trial. 
A no-cost research agreement will be established between the investigating center 
administrator and the sponsor.  
XV.7 
DATA ARCHIVING 
The files will remain confidential and can only be consulted under the responsibility of the 
doctors in charge of the patients. The sponsor and the health authorities in case of inspection 
will have direct access to these documents. 
At the end of the trial, the observation book will be kept for 15 years by the investigator. 
 
XV.8 
IT SUPPORT 
In accordance with the text of the law n° 78-17 of January 6, 1978 modified by the law of 
August 9, 2004, relating to data processing, files and freedoms, the data of the trial will be 
recorded in a data bank of the Center of Randomization and Management Analysis of the 
FFCD, with the exception of the elements relating to the identity of the patients. 
 
XV.9 
DATA PROCESSING 
The FFCD's Center for Randomization Management and Analysis (CRGA) will be 
responsible for data management and analysis.  
 


 
FFCD 1201 Protocol v 1.2 of 28/07/2015 
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XV.10 
MONITORING, QUALITY ASSURANCE AND INSPECTIONS BY 
AUTHORITIES 
The investigator agrees in advance that the records of the patients included in the trial may be 
consulted by a person mandated by the FFCD and/or by the health authorities to carry out an 
audit. On-site monitoring of records, scheduled after agreement with the investigator, may 
take place during and after the trial inclusion period. 
This protocol will be monitored by the FFCD's mobile ARCs.  
The investigator agrees to sign the observation books at the end of each visit. 
 
XVI. 
PUBLICATION 
 
The current FFCD publication rules will be applied (Appendix 9) 
 

SAP_001.pdf: 
 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 1 on 19 
 
 
 
 
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
 
INTRA-ARTERIAL TREATMENT WITH IRINOTECAN (DEBIRI) LOADED MICROBEADS 
CONCOMITANTLY WITH FOLFOX SYSTEMIC CHEMOTHERAPY IN PATIENTS WITH 
COLORECTAL CANCER WITH NON-RESECTABLE LIVER METASTASES 
 
Phase II non-randomized - multicenter 
FFCD 1201 - DEBIRI 
 
 
Statistical Analysis Plan 
Final analysis 
 
 
 
 
 
 
 
 
Version: 1.0 
Date: February 9, 2017 
 
Editor: Carole Montérymard 
Review committee: Julien Taieb, Simon Pernot, Jérémie Bez, Karine Le Malicot, Fadil Masskouri. 
 
 
Subscribe 
to 
DeepL 
Pro 
to 
edit 
this 
Visit www.DeepL.com/profor more information. 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 2 on 19 
 
Developer 
French-speaking Federation of Digestive Oncology (FFCD),  
Faculty of Medicine,  
7, Boulevard Jeanne d'Arc, BP 87900,  
21079 Dijon Cedex 
 
Coordinato 
r  
Pr Julien TAIEB  
Georges Pompidou European Hospital 
Department of Gastroenterology 
20 Rue Leblanc 
75908 PARIS CEDEX 15 
Tel. 01 56 09 50 42 
Email : julien.taieb@egp.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  
Email : jérémie.bez@u-bourgogne.fr 
  
 
 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 3 on 19 
1 Table of contents 
1 
Table of contents .........................................................................................................................................................................................................3 
2 
Abbreviations and definitions ...............................................................................................................................................................................5 
3 
Introduction ..................................................................................................................................................................................................................6 
3.1 
Objectives of the study ..................................................................................................................................................................................6 
3.1.1 
Main objective .............................................................................................................................................................................................6 
3.1.2 
Secondary objectives ................................................................................................................................................................................6 
3.1.3 
Exploratory studies...................................................................................................................................................................................6 
4 
Experimental design ..................................................................................................................................................................................................6 
4.1 
Study design ......................................................................................................................................................................................................6 
4.2 
Chronological sequence ...............................................................................................................................................................................6 
4.3 
Justification of the number of subjects needed ..................................................................................................................................7 
4.4 
Planning of test analyses ..............................................................................................................................................................................8 
4.5 
Adjustments .......................................................................................................................................................................................................8 
5 
Study Populations for Analysis .............................................................................................................................................................................8 
5.1 
Definition of the analysis populations ...................................................................................................................................................8 
5.1.1 
Intent-to-treat (ITT) population .........................................................................................................................................................8 
5.1.2 
Modified intention-to-treat (mITT) population - evaluable patients .................................................................................8 
5.1.3 
Tolerance population (TP) ....................................................................................................................................................................8 
5.1.4 
Per-protocol population (PP) ...............................................................................................................................................................9 
6 
General information about statistical methods .............................................................................................................................................9 
6.1 
Software ..............................................................................................................................................................................................................9 
6.2 
Agreements concerning dates and durations .....................................................................................................................................9 
6.3 
Missing Data Conventions ...........................................................................................................................................................................9 
6.4 
Definition of the baseline .............................................................................................................................................................................9 
6.5 
Statistics ..............................................................................................................................................................................................................9 
7 
Statistical analysis ................................................................................................................................................................................................... 11 
7.1 
Patient characteristics at inclusion ...................................................................................................................................................... 11 
7.1.1 
Inclusion Characteristics - Eligibility ............................................................................................................................................. 11 
7.1.2 
Demographic characteristics ............................................................................................................................................................. 11 
7.1.3 
Clinical characteristics ......................................................................................................................................................................... 12 
7.1.4 
Biological characteristics .................................................................................................................................................................... 12 
7.1.5 
Disease-related characteristics ........................................................................................................................................................ 12 
7.2 
Monitoring characteristics ....................................................................................................................................................................... 13 
7.2.1 
Definition of median follow-up time .............................................................................................................................................. 13 
7.2.2 
Assessment of median follow-up time .......................................................................................................................................... 13 
7.3 
Assessment of primary efficacy endpoint ......................................................................................................................................... 13 
7.3.1 
Definition of the primary endpoint ................................................................................................................................................. 13 
7.3.2 
Evaluation of the primary endpoint ............................................................................................................................................... 13 
7.4 
Assessment of secondary efficacy endpoints .................................................................................................................................. 14 
7.4.1 
Response rate according to RECIST v1.1 criteria at 9 months (by investigator) ....................................................... 14 
7.4.2 
EASL response rate at 9 months (based on centralized review) ....................................................................................... 14 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 4 on 19 
7.4.3 
Progression-free survival according to RECIST v1.1 criteria at 9 months .................................................................... 14 
7.4.4 
Progression-free survival .................................................................................................................................................................... 15 
7.4.5 
Overall survival ........................................................................................................................................................................................ 15 
7.4.6 
Secondary resection rate ..................................................................................................................................................................... 16 
7.4.7 
Evolution of tumor marker levels ................................................................................................................................................... 16 
7.5 
Evaluation of tolerance .............................................................................................................................................................................. 16 
7.5.1 
Chemoembolization ............................................................................................................................................................................... 16 
7.5.2 
Administration of FOLFOX ................................................................................................................................................................. 17 
7.5.3 
Toxicities .................................................................................................................................................................................................... 18 
7.5.4 
E.I.G ............................................................................................................................................................................................................... 18 
7.6 
Exploratory Analyses ................................................................................................................................................................................. 18 
7.6.1 
Definition .................................................................................................................................................................................................... 18 
7.6.2 
Evaluation .................................................................................................................................................................................................. 19 
 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 5 on 19 
2 Abbreviations and definitions 
 
  
 
 
 
ACE 
embryonic carcino antigen 
EI 
Adverse event 
ISG 
Serious adverse event 
5FU 
5-fluorouracil 
FFCD 
French-speaking Federation of Digestive Oncology 
FOLFIRI 
FOLinic acid - Fluorouracil - IRInotecan 
HR 
Hazard ratio  
ITT 
Intent to treat 
KM 
Kaplan Meier 
LSN 
Upper limit of normal 
N 
Normal  
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events 
WHO 
World Health Organization 
Q1-Q3 
Quartiles 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RC 
Full Answer 
RP 
Partial response 
RO 
Objective answer 
SG 
Overall survival 
SSP 
Progression-free survival 
SD 
Stable disease 
TAP 
Thoracic-Abdomino-Pelvic 
CT 
CT scan 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 6 on 19 
3 Introduction 
 
3.1 Objectives of the study 
 
3.1.1 
Main objective 
 
The primary objective of this study is to evaluate the progression-free survival rate (proportion of patients alive 
without progression) at 9 months after the start of treatment according to the RECIST 1.1 criteria, assessed by the 
investigator. The events to be considered will be progression or death. 
 
3.1.2 
Secondary objectives 
 
The secondary objectives of the study are to evaluate: 
• 
Tolerance to the treatment 
• 
Best response according to RECIST v1.1 criteria (as determined by the investigator) 
• 
Best response according to EASL criteria (evaluated in centralized review)  
• 
Progression-free survival according to RECIST v1.1 criteria 
• 
Progression-free survival 
• 
Overall survival 
• 
The rate of secondary resections 
• 
Changes in tumor marker levels 
• 
The maximum depth of response 
• 
Early response rate (1ère assessment at 8 weeks)  
 
 
3.1.3 
Exploratory studies 
 
The objective is to search for predictive factors of progression-free survival and/or overall survival. 
 
4 Experimental design 
 
4.1 Scheme of the study 
 
This is an open-label, non-randomized, multi-center Phase II trial.  
 
4.2 Chronological sequence 
 
 
 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 7 on 19 
 
 
• 
Bilobar treatment in 2 sessions 
 
• 
Sequential unilobar treatment in 4 sessions 
 
4.3 Justification of the number of subjects needed 
 
A 1-step Fleming design was used, with a one-sided α risk of 5% and a power (1-β) of 90%.  
The clinical assumptions made were:  
H0 : A 55% progression-free live proportion during the first 9 months is unattractive;  
H1 : A proportion of patients alive without progression of more than 55% during the first 9 months would show the 
interest of the treatment; a proportion of 75% is hoped for. 
 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 8 on 19 
48 evaluable patients were required. Taking into account a 20% rate of patients lost to follow-up or not evaluable, 58 
patients were to be included.  
 
 
The decision rules are as follows: of the 48 evaluable patients  
• 
If 32 or fewer patients are alive without progression, then the treatment is considered ineffective 
• 
If 33 or more patients are alive without progression, then the treatment is considered effective 
 
The decision rule will be adjusted based on the actual number of evaluable patients.  
 
4.4 Planning of the trial analyses 
 
Only a final analysis is planned. 
 
4.5 Adjustments 
 
Adjustments may be made to this analysis plan in case 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 populations for analysis 
 
5.1 Definition of analysis populations  
 
5.1.1 
Intent-to-treat (ITT) population 
 
The intention-to-treat population is defined as all patients included in the study, regardless of eligibility criteria. 
 
5.1.2 
Modified intention-to-treat (mITT) population - evaluable patients 
 
The modified intention-to-treat population is defined as all evaluable included patients, regardless of their eligibility 
criteria and treatment received. 
A patient is considered evaluable if:  
▪ 
he had a chemoembolization and 
▪ 
received at least one cycle of chemotherapy and 
▪ 
at least one assessment during the 9 months of follow-up was done 
 
A listing of patients excluded from the ITTm population will be provided with the reasons for exclusion. 
 
5.1.3 
Tolerance population (TP) 
 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 9 on 19 
The tolerance population is defined as all patients included in the study who received at least one dose of FOLFOX 
treatments.  
 
5.1.4 
Per-protocol (PP) population 
The per-protocol population was defined as all patients who received the 2 or 4 planned DEBIRI sessions and met the 
inclusion/exclusion criteria of the study. 
 
6 General information about statistical methods 
 
Statistical analyses will be performed by the CRGA. 
 
6.1 Software 
Statistical analyses will be performed with SAS software version 9.4. Some graphs can be made with R software version 
2.11 or later. 
 
6.2 Agreements concerning dates and durations 
Time since inclusion will be defined as the time since the day of inclusion, with the day of inclusion considered day 1. 
Therefore, the durations will be calculated according to the following rule, for example for the duration between death 
and inclusion: day of death - day of inclusion + 1. 
The day before the day of inclusion (resp. the day before the day of treatment) will be considered as day -1 (day 0 does 
not exist). 
 
The last date of news will be the date of the last examination performed or the last treatment or the last medical 
consultation/visit. 
The following conversion rules will be used to convert the number of days into 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 Definition of the baseline 
 
Baseline measurements will be the last measurement taken prior to inclusion or the last measurement taken prior to 
the first administration of treatment. 
 
6.5 Statistics 
 
The confidence intervals provided will be two-sided 95% confidence intervals except for the primary endpoint where 
the calculated confidence interval will be a one-sided 95% confidence interval. 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 10 on 19 
 
Quantitative data will be described using the following descriptive statistics: number, mean, standard deviation, 
median, first and third quartile, and minimum and maximum. These statistics will be considered the usual statistics for 
the analysis of quantitative variables. Quantitative variables can be categorized using their median or a cut-off known 
from the medical literature. 
 
Categorical variables will be summarized, using the following descriptive statistics: the number, frequencies and 
percentages for each level of the variable. These statistics will be considered as the usual statistics for the analysis of 
categorical variables. 
When necessary, the 95% confidence intervals for the proportions can be calculated from the exact binomial 
distribution.  
 
Survival data will be estimated and plotted using the Kaplan Meier method (Kaplan and Meier., 1958). They will be 
described by the median and rates calculated at different time points with their two-sided 95% confidence intervals. 
The confidence intervals for the rates will be constructed from the Greenwood variance calculated using the log-log 
transformation.   
 
The median follow-up time will be estimated by the reverse Kaplan-Meier method (Shemper, 1996). 
  
As an exploratory measure, for the uni and multivariate analyses, the hazard ratios will be estimated using a Cox model 
(Cox, 1984). The hypothesis of proportionality of the rates will be tested using the graphical representation and the test 
based on Schöenfeld's residuals (Grambsch, 1994); the linearity of the effect of the continuous variables on the risk will 
be evaluated from the graphical representation of the martingale residuals. Confidence intervals for the coefficient 
estimates of the Cox models will be calculated using the Wald method. 
 
 
 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 11 on 19 
7 Statistical analysis 
 
Population 
ITT 
Population 
ITTm 
Tolerance 
population 
Population 
Per protocol 
Description of Baseline 
 
 
 
 
Eligibility criteria for inclusion 
X 
X 
 
X 
Demographic characteristics 
X 
X 
 
X 
Clinical characteristics at inclusion 
X 
X 
 
X 
Biological characteristics at inclusion 
X 
X 
 
X 
Characteristics related to the disease 
X 
X 
 
X 
Median follow-up time 
X 
X 
 
X 
Main criterion 
 
 
 
 
Progression-free survival rate at 9 months 
X 
X 
 
X 
Secondary criteria 
 
 
 
 
Overall survival, progression-free survival 
X 
X 
 
X 
Progression-free survival at 9 months 
X 
X 
 
X 
Response rate (RECIST) at 9 months 
X 
X 
 
X 
Response rate (EASL) at 9 months (centralized 
review) 
X 
X 
 
X 
Secondary resection rate 
X 
X 
 
X 
Evolution of tumor marker levels 
X 
X 
 
X 
Tolerance 
 
 
 
 
Administration of the treatment (duration, 
dose received ...) 
 
 
X 
 
Toxicities 
 
 
X 
 
Exploratory analysis 
X 
X 
 
X 
 
7.1 Patient characteristics at inclusion 
 
7.1.1 
Inclusion Characteristics - Eligibility 
 
Population: ITT 
Patient eligibility at inclusion will be 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 inclusion and non-inclusion criteria 
 
7.1.2 
Demographic characteristics 
 
Population: ITT 
The following characteristics at inclusion will be described: 
▪ Age (years); 
▪ Inclusion center (number of patients included per center); 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 12 on 19 
▪ Gender (Male vs Female). 
 
7.1.3 
Clinical characteristics 
 
Population: ITT 
The following characteristics at inclusion will be described: 
▪ Weight (kg); 
▪ General WHO status (0 vs 1 vs 2); 
▪ Score by Köhne. 
Definition:  
Bottom:  
o 
WHO 0-1 and a single metastatic tumor site 
Intermediate:  
o 
WHO 0-1 and more than one metastatic tumor site and PAL ≤ 300 U/L 
o 
WHO >1 and white blood cells ≤ 10 x 109 /L and a single metastatic tumor site  
High :  
o 
WHO 0-1 and more than one metastatic tumor site and PAL > 300 U/L 
o 
WHO >1 and white blood cells > 10 x 109 /L 
o 
WHO >1 and white blood cells ≤ 10 x 109 /L and more than one tumor site 
 
7.1.4 
Biological characteristics 
 
▪ Leukocytes (/mm3 ) ; 
▪ Albumin (µmol/L); 
▪ PAL (Ul/L); 
▪ ACE (µg/L); 
▪ CA19-9 (Ul/mL). 
 
7.1.5 
Characteristics related to the disease 
 
Population: ITT 
The following characteristics at inclusion will be described: 
▪ Time from cancer diagnosis to inclusion date (months) 
▪ Location of the primary tumor 
▪ Metastatic location (for liver metastases, right lobe/left lobe and number of liver metastases, presence of lung 
metastases) 
▪ History (diabetes, hypertriglyceridemia, hypercholesterolemia, hypertension, other (a list will be provided)) 
▪ Concomitant treatments (statin, fibrate, anti-coagulant, anti-hypertensive, aspirin, other (a list will be provided)) 
▪ KRAS status 
▪ Performance of a PET scan (presence of pulmonary metastases, locoregional lymph nodes, other ...) 
▪ Previous treatment and description of the type of treatment (RCT, CT, surgery, radiofrequency ...) 
 


 
Statistical Analysis Plan - Final Analysis - FFCD 1201 - DEBIRI - v1.0 : February 2017Page 13 on 19 
7.2 Monitoring characteristics 
7.2.1 
Definition of median follow-up time 
Population: ITT 
Median follow-up time is defined as the time interval between the date of inclusion and the date of last news (patients 
alive or lost to follow-up) or for deceased patients, the date of death (regardless of cause). 
  
7.2.2 
Evaluation of the median follow-up time 
The median follow-up time (for living patients) and its 95% confidence interval will be calculated in months. It will be 
estimated by the inverse Kaplan Meier method. 
 
7.3 Evaluation of the primary efficacy endpoint 
 
Population: ITTm 
 
7.3.1 
Definition of the primary endpoint 
 
The primary endpoint is to evaluate the rate of patients alive without progression at 9 months after the start of 
treatment. Progression is defined as radiological progression according to RECIST V1.1 criteria, as assessed by the 
investigator.  
Patients who progressed or died (from any cause) within 9 months of initiation of therapy (Day 1 of Cure 1) will be 
considered to have failed the primary endpoint at 9 months. 
 
The scans selected for analysis will be the scans before and up to 9 months with a +/- 1 month window.  
Patients without a 9-month evaluation will be reviewed according to the following rules:  
▪ 
If the patient has a late assessment (10 months or more) and is not progressing at that time, then they will be 
considered progression-free at 9 months. 
▪ 
If the patient has documented progression at more than 9 months without imaging at 9 months, then that 
patient will be considered to be in progression at 9 months. If progression is documented at more than 11 
months, the patient will not be considered to be in progression at 9 months. 
▪ 
If progression is documented before the 9-month assessment, the patient is considered to be in progression at 
9 months. 
 
 
7.3.2 
Evaluation of the primary endpoint 
 
The primary endpoint will be assessed on the ITTm population. This criterion will be described according to the usual 
descriptive statistics. A one-sided 95% confidence interval will be calculated using the exact method. 
 
The decision rules to be applied on 48 patients evaluable in the analysis (ITTm population) are:  
• 
If 32 or fewer patients are alive without progression, then the treatment is considered ineffective.   
• 
If 33 or more patients are alive without progression, then the treatment is considered effective.   


 
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These may be adjusted based on the actual number of evaluable patients included. 
  
7.4 Evaluation of secondary efficacy criteria 
 
7.4.1 
Best response according to RECIST v1.1 criteria (as determined by investigator) 
Population:  
 
7.4.1.1 
Definition   
The best response is described by the rates of complete, partial, stable, progression, or non-evaluable response over the 
course of treatment. Response is assessed by the investigator according to RECIST V1.1 criteria.  
 
7.4.1.2 
Evaluation   
Rates will be described using standard statistics. 
 
7.4.2 
Best response according to EASL criteria (according to centralized review) 
Population:  
 
7.4.2.1 
Definition   
The best response is described by the rates of complete response, partial response, stability, and progression over the 
course of treatment. Response is assessed at the centralized review according to EASL criteria. 
 
7.4.2.2 
Evaluation   
Rates will be described using standard statistics. 
 
7.4.3 
Depth of response (DpR) 
Population:  
 
7.4.3.1 
Definition  
It is defined as the relative difference between the sum of the largest diameters of RECIST target lesions at NADIR in the 
absence of new lesions or progression of non-target lesions and the sum of the largest diameters of RECIST target 
lesions at inclusion. It will be given according to the investigator and according to the centralized review of the images. 
 
7.4.3.2 
Evaluation 
It will be described using standard statistics. 
 
7.4.4 
Early response rate (ETS: early tumor shrinkage) 
Population:  
 
7.4.4.1 
Definition  
Early (8-week) tumor shrinkage rate is defined as the relative difference between the sum of the largest diameters of 
the RECIST target lesions at 8 weeks and this sum at inclusion. Tumor shrinkage will be observed when the relative 


 
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difference is > 20% and > 30% (2 thresholds). It will be given according to the investigator and according to the 
centralized review of the images. 
 
7.4.4.2 
Evaluation 
Rates will be described using standard statistics. 
 
7.4.5 
Hepatic progression-free survival according to RECIST v1.1 criteria 
 
Population:  
 
7.4.5.1 
Definition   
 
It is defined as the time interval between the date of inclusion and the date of 1ère hepatic (radiological) progression or 
the date of death (from any cause). Patients alive and without progression will be censored at the date of last news. 
 
7.4.5.2 
Evaluation   
The time scale considered will be the month. 
Survival rates will be calculated at different time points using the Kaplan Meier estimator and its 95% confidence 
interval. 
 
7.4.6 
Progression-free survival  
Population: ITT 
 
7.4.6.1 
Definition of progression-free survival 
 
It is defined as the time interval between the date of inclusion and the date of 1ère radiological progression or the date of 
death (from any cause). Patients alive and without progression will be censored at the date of last news. 
 
7.4.6.2 
Assessment of progression-free survival 
 
The time scale considered will be the month. 
Progression-free survival will be plotted using the Kaplan Meier estimator and survival rates at different time points (6, 
9, 12 and 18 months) will be calculated along with their 95% confidence intervals. 
 
7.4.7 
Overall survival  
Population: ITT 
 
7.4.7.1 
Definition of overall survival 
 
It is defined as the time interval between the date of inclusion and the date of death (regardless of cause). 
Patients lost to follow-up or alive at the time of analysis will be censored at the date of last report. 


 
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7.4.7.2 
Evaluation of overall survival 
 
The time scale considered will be the month. 
Overall survival will be plotted using the Kaplan Meier estimator and survival rates at different time points (6, 9, 12 and 
18 months) will be calculated along with their 95% confidence intervals. 
 
7.4.8 
Secondary resection rate 
Population:    
 
7.4.8.1 
Definition   
The secondary resection rate is defined as the percentage of patients who had surgery for liver metastases. 
The calculated secondary resection rate is defined as the percentage of R0 resection, R1 resection and R2 resection.  
 
7.4.8.2 
Evaluation   
Rates will be described using standard descriptive statistics. 
 
7.4.9 
Evolution of tumor marker levels 
 
7.4.9.1 
Definition   
 
The evolution of tumor markers (CEA and CA19-9) will be evaluated throughout the study, from inclusion to 
progression. It will be described at each evaluation.  
 
 
7.4.9.2 
Evaluation   
The delta for CEA and CA19-9 (value at assessment - value at baseline/value at baseline) *100 will be described at each 
assessment and plotted as a boxplot.  
 
 
7.5 Assessment of tolerance 
Population:  
Tolerance to treatment will be assessed by: 
▪ Duration of treatment, doses received, dose decreases, and deferrals; 
▪ Toxicities described according to NCI-CTC version 4.0 criteria; 
▪ Number and description of SAEs 
 
7.5.1 
Chemoembolization 
 
Chemoembolization therapy (CHE) will be described by: 
▪ 
The number of HEC performed per patient and the total number of HEC performed by type of treatment. 
Causes will be described for patients who did not have the total number of HECs as per the protocol.   
▪ 
The number and percentage of patients who had 1 HEC, 2 HEC, 3 HEC or 4 HEC according to the type of 
treatment (uni-lobar or bi-lobar)  


 
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▪ 
The type of treatment, the lobe involved, the dose of irinotecan administered. Causes will be described when 
the dose of irinotecan was not administered completely. 
▪ 
The number of HEC deferrals and the causes of deferrals  
▪ 
The number and percentage of patients treated with G-CSF 
 
The consequences of treatment will also be described:  
▪ 
The length of hospitalization 
▪ 
The number and percentage of patients who experienced side effects during the procedure. A listing of other 
side effects during the procedure will be reported. 
▪ 
Number and percentage of patients with pain >3 (VAS) 
▪ 
The pain assessment (VAS) before HEC and within 24 hours after HEC will be described by grade (frequency of 
VAS for all HEC).   
 
7.5.2 
Administration of FOLFOX 
 
7.5.2.1 
Duration of treatment 
 
The duration of the treatment will be described by: 
▪ 
The number of treatments per patient; 
▪ 
The duration of treatment (converted to months) will be calculated by the formula: 
Start date of last treatment - start date of first treatment + 1 day 
Therapeutic breaks and any deferral days during this period will not be subtracted from this duration. 
 
It will be described according to the usual descriptive statistics. 
 
7.5.2.2 
Doses administered 
 
▪ 
The average number of treatments will be carried over. 
▪ 
Compliance will be calculated according to the formula : 
(Cumulative dose received (in mg) / theoretical protocol dose (in mg)) x 100 
The protocol doses of treatment are : 
Oxaliplatin = 85 mg/m². 
5FU bolus = 400 mg/m2 
Continuous 5FU = 2400 mg/m².  
Folinic acid = 400mg/m². 
 
Compliance will be described by molecule according to the usual descriptive statistics. 
 
7.5.2.3 
Postponement of cures, modification of administration and reason for modification 
 
▪ 
The number and percentage of patients with at least one deferred treatment and the reasons for these 
deferrals      


 
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▪ 
The number of patients with at least one dose change will be described by treatment type. Causes of dose 
changes will be presented. A listing of others will be provided. 
▪ 
The number and percentage of patients who permanently discontinued protocol treatment and the causes of 
discontinuation will be described.    
 
All parameters will be described according to the usual descriptive statistics.  
 
7.5.2.4 
Subsequent line 
  
▪ 
The number of patients who received a subsequent line and subsequent patterns will be described. 
▪ 
The number of patients who received a new HEC and the number of subsequent HECs will be described. A listing of 
the products used to load the beads will be provided.  
  
All parameters will be described according to the usual descriptive statistics.  
 
7.5.3 
Toxicities 
 
Toxicities during treatment will be described according to NCI-CTC version 4.0 criteria by: 
▪ The number of patients and toxicities by maximum grade and type; 
▪ The number and percentage of patients with at least one toxicity across all courses by grade; 
▪ The number and percentage of patients with at least one maximum grade 3-4-5 toxicity over all courses or at least 
one maximum grade 1-2 toxicity; 
 
7.5.4 
E.I.G  
 
A summary of the SAEs will be provided by pharmacovigilance. 
 
7.6 Exploratory Analyses 
 
7.6.1 
Definition 
The exploratory analysis focuses on the search for factors predictive of progression-free survival and/or overall 
survival.  
 
Progression-free survival is defined as the time interval from the date of inclusion to the date of 1ère radiological 
progression or the date of death (from any cause). Patients alive and progression-free will be censored at the date of 
last report. 
 
Overall survival is defined as the time interval between the date of inclusion and the date of death (regardless of cause). 
Patients lost to follow-up or alive at the time of analysis will be censored at the date of last report. 
 
The variables for which the p-value is lower than 0.10 in univariate analysis or judged clinically relevant among the list 
to be defined will be retained for the multivariate analysis. 


 
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7.6.2 
Evaluation  
 
For univariate and multivariate analyses, hazard ratios will be estimated using a Cox model (Cox, 1984). The 
proportionality of the rates will be tested using the graphical representation and the test based on Schöenfeld's 
residuals (Grambsch, 1994); the linearity of the effect of the continuous variables on the risk will be assessed from the 
graphical representation of the martingale residuals. Confidence intervals for the coefficient estimates of the Cox 
models will be calculated using the Wald method.