Conditions: Colorectal Neoplasms
Keywords: colorectal cancer metastasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
The intensity of tumour response appears to be correlated with the feasibility and the duration of a therapeutic pause or of a reduced maintenance therapy maintained until progression in patients initially controlled by so-called "induction" chemotherapy. Bevacizumab combined with cytotoxic chemotherapy (5-FU, irinotecan and/or oxaliplatin) has shown that it is possible to improve the tumour response rate and patient prognosis in 1st and 2nd lines. With a very favourable safety profile , it is an excellent candidate as induction treatment and also as maintenance treatment. Prospective data from recent trials have actually demonstrated improvement in PFS and/or overall survival with bevacizumab maintenance alone or in combination with 5FU (or capecitabine) after induction chemotherapy (FOLFIRI or FOLFOX + bevacizumab).

At the same time, the maintenance of anti-angiogenic pressure after progression in 1st line metastatic has demonstrated its benefit in terms of PFS and overall survival. Bevacizumab maintenance in 2nd line metastatic, despite progression, thus appears to be a valid strategy.

Detailed description:
Thus, the objective of this work is to combine continuous blocking of angiogenesis by bevacizumab given on the first 3 metastatic lines in a randomised phase II trial evaluating a "descending" strategy of immediate optimisation by 4 cycles of FOLFOXIRI-bevacizumab and 4 cycles of FOLFIRI-bevacizumab, followed by maintenance treatment with 5FU-bevacizumab until progression (re-introduction of induction in case of progression) and evaluate an "ascending" strategy with 5FU-bevacizumab immediately followed, at progression, by the introduction of irinotecan, then oxaliplatin, with maintenance of blocking of angiogenesis by bevacizumab.

Arms:
arm 1: LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin. arm 2: (4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine

Interventions: intervention 1: 5 FLUOROURACYL intervention 2: acide folinique intervention 3: irinotecan intervention 4: Oxaliplatin intervention 5: capécitabine intervention 6: bevacizumab
Intervention descriptions: intervention 1: Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion.

The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2).

The cycles will last 14 days. For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days. intervention 2: 200 mg/m² if Elvorine intervention 3: Irinotecan is administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan.

The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2).

The cycles will last 14 days. intervention 4: Oxaliplatin is administered IV at a dose of 85 mg/m² over 120 minutes. Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with oxaliplatin.

The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2).

The cycles will last 14 days. intervention 5: For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days. intervention 6: Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
PRODIGE 45 - HIGH-LIGHT  
Version 2.1 of 06.06.2016 
 
Page 1 on 36 
 
PRODIGE 45 - FFCD 1408 - HIGH-LIGHT  
RANDOMIZED PHASE II EVALUATION OF EFFICACY AND TOLERANCE OF 2 THERAPEUTIC 
STRATEGIES COMBINING BEVACIZUMAB WITH CHEMOTHERAPY: DE-ESCALATION VERSUS 
ESCALATION IN PATIENTS WITH UNRESECTABLE, NON-PRE-TREATED METASTATIC COLORECTAL 
CANCER 
EudraCT n°: 2016-001225-13  
 
 
COORDINATOR (FFCD representative)
Prof. Jean-Marc PHELIP 
Saint Etienne University Hospital - Hôpital Nord 
HGE Department 
108 rue Albert Raimond - BP 60008 
42277 SAINT PRIEST EN JAREZ 
Tel: 04 77 82 83 20; Fax: 04 77 82 84 52 
E-mail: j.marc.phelip@chu-st-etienne.fr 
 
 
 
 
 
 
 
 
 
SCIENTIFIC CO-RESPONSIBLES (representing UNICANCER GI) 
Dr Valérie BOIGE Digestive Oncology Department  
Department of Oncology Medicine 
Gustave Roussy 
Tel: 01 42 11 43 11 
E-mail: valerie.boige@gustaveroussy.fr 
 
 
 
PROTOCOL DRAFTING COMMITTEE  
JM Phélip, J Bennouna, K Le Malicot, M Schneider 
 
 
TRANSLATIONAL RESEARCH COMMITTEE 
D Tougeron, T Lecomte, P Laurent-Puig 
 
 
 
 
PROMOTER AND CENTER FOR RANDOMIZATION - MANAGEMENT - ANALYSIS (CRGA)   
Fédération Francophone de Cancérologie Digestive (FFCD): Faculté de Médecine, 7 Boulevard Jeanne 
d'Arc, BP 87900, 21079 Dijon Cedex, France 
 
 
Administrative Manager : 
 
Cécile GIRAULT 
 
 
 
 
Tel: + 33 (0)3 80 66 80 13 - Fax: + 33 (0)3 80 38 18 41 
 
 
 
 
E-mail: cgirault@u-bourgogne.fr 
Statistician:  
 
 
Karine LE MALICOT 
 
 
 
 
Tel: + 33 (0)3 80 39 34 71 - Fax: + 33 (0)3 80 38 18 41 
 
 
 
 
E-mail: karine.le-malicot@u-bourgogne.fr 
Project manager:  
 
 
Lila GABA-BERKOUK 
 
 
 
 
Tel: + 33 (0)3 80 39 34 04 - Fax: + 33 (0)3 80 38 18 41 
 
 
 
 
E-mail: lila.gaba@u-bourgogne.fr 
Subscribe to DeepL Pro to edit this document. 
Visit www.DeepL.com/pro for more information. 


 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ............................................................................................................... 4 
PROTOCOL AGREEMENT AND BPC .............................................................................................. 5 
CONTACTS FFCD ............................................................................................................................. 6 
SUMMARY ......................................................................................................................................... 7 
STUDY SCHEDULE ......................................................................................................................... 11 
1 
INTRODUCTION - RATIONALE FOR THE STUDY ................................................................. 12 
1.1 
TREATMENT OF METASTATIC COLORECTAL CANCER ................................................................ 12 
1.2 
RATIONAL FOR DE-ESCALATION STRATEGY ............................................................................. 12 
2 
RESEARCH OBJECTIVES ....................................................................................................... 13 
2.1 
MAIN CRITERION .................................................................................................................... 13 
2.2 
EXPLORATORY RESEARCH OBJECTIVES .................................................................................. 14 
3 
SELECTION CRITERIA ............................................................................................................. 15 
3.1 
INCLUSION CRITERIA .............................................................................................................. 15 
3.2 
NON-INCLUSION CRITERIA ...................................................................................................... 15 
4 
INITIAL BALANCE SHEET ....................................................................................................... 16 
5 
HIKING ....................................................................................................................................... 18 
5.1 
RANDOMIZATION ................................................................................................................... 18 
5.2 
STRATIFICATION .................................................................................................................... 18 
6 
TREATMENT ............................................................................................................................. 18 
6.1 
IN THE 48 HOURS PRECEDING EACH CYCLE ............................................................................. 18 
6.2 
ADMINISTRATION SCHEMES .................................................................................................... 19 
6.2.1 
Arm A standard strategy .............................................................................................................. 19 
6.2.2 
Arm B experimental strategy ....................................................................................................... 20 
6.3 
ASSOCIATED TREATMENTS .................................................................................................... 21 
6.4 
ASSOCIATED TREATMENTS STRICTLY CONTRAINDICATED ........................................................ 21 
7 
TREATMENT TIME ................................................................................................................... 22 
8 
TREATMENT DOSE ADJUSTMENTS ...................................................................................... 23 
8.1 
DOSE ADJUSTMENTS FOR 5FU, OXALIPLATIN AND IRINOTECAN ................................................ 24 
8.2 
CAPECITABINE ....................................................................................................................... 25 
8.3 
BEVACIZUMAB ....................................................................................................................... 25 
9 
PATIENT MONITORING ........................................................................................................... 27 
9.1 
DURING TREATMENT .............................................................................................................. 27 
9.2 
AFTER DISCONTINUATION OF PROTOCOL TREATMENT ............................................................. 28 
10 
ORGANIC LOGISTICS........................................................................................................... 28 
11 
MANAGEMENT OF SERIOUS ADVERSE EVENTS (EIG) ................................................... 28 
11.1 
DEFINITIONS ...................................................................................................................... 28 
11.2 
EVENTS NOT TO BE CONSIDERED SERIOUS .......................................................................... 30 
11.3 
WHAT TO DO ...................................................................................................................... 30 
12 
STATISTICAL ANALYSIS ..................................................................................................... 31 


 
 
 
 
 
 
 
 
 
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12.1 
JUDGING CRITERIA ............................................................................................................. 31 
12.2 
CALCULATING THE NUMBER OF SUBJECTS REQUIRED ........................................................... 32 
12.3 
STATISTICAL ANALYSIS PLAN ............................................................................................... 32 
12.3.1 
Analysis populations ..................................................................................................................... 32 
12.3.2 
Criteria evaluation ........................................................................................................................ 32 
12.4 
STUDY COMMITTEES........................................................................................................... 33 
12.4.1 
Independent Committee ............................................................................................................... 33 
12.4.2 
Board of Directors ........................................................................................................................ 33 
12.4.3 
Biological Committee ................................................................................................................... 33 
13 
LEGAL AND ETHICAL ASPECTS ........................................................................................ 34 
14 
PUBLICATION ....................................................................................................................... 35 
15 
REFERENCES ....................................................................................................................... 36 
 


 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
 
 
ACE 
Carcinoembryonic antigen 
AF 
Folinic acid (leucovorin) 
ALAT  
Alanine aminotransferase (or SGPT: serum glutamic pyruvic transaminase) 
ASAT 
Aspartate aminotransferase (or SGOT: serum glutamic oxaloacetic transaminase) 
BPC 
Good Clinical Practice 
JRC 
Colorectal carcinoma 
CCRm 
Metastatic colorectal carcinoma 
CIRD 
Independent data review committee 
CO 
Observation notebook 
CT 
chemotherapy 
DPD 
dihydropyrimidine 
ECG 
Electrocardiogram  
EI 
Undesirable event 
EIG 
Serious adverse event 
5-FU 
5-fluorouracil 
FFCD 
French-speaking Federation of Digestive Oncology 
FOLFIRI 
5-fluorouracil, leucovorin and rinotecan 
FOLFOX-4 
5-fluorouracil, leucovorin and oxaliplatin 
MODIFIED 
FOLFOXIRI 
5-fluorouracil, leucovorin, irinotecan and oxaliplatin 
HR 
Hazard ratio 
IC 
Confidence interval 
BMI 
Body mass index 
MRI 
Magnetic resonance imaging 
iv 
Intravenous 
j 
Day 
NCI-
CTCAE 
National Cancer Institute - Common toxicity criteria for adverse events 
p.o.  
Per os 
PAL 
Alkaline phosphatases 
PAD 
Diastolic blood pressure 
NOT 
Systolic blood pressure 
QDV 
Quality of life 
RECIST 
Criteria for evaluating tumor response in solid tumors 
SG 
Overall survival 
SSP 
Progression-free survival 
TAP 
Thoracoabdomino-pelvic 
CT SCAN 
Computed tomography 
vs. 
Versus  


 
 
 
 
 
 
 
 
 
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PROTOCOL AGREEMENT AND BPC 
 
 
PRODIGE 45 - FFCD 1408 - HIGH-LIGHT  
RANDOMIZED PHASE II EVALUATION OF EFFICACY AND TOLERANCE OF 2 THERAPEUTIC 
STRATEGIES COMBINING BEVACIZUMAB WITH CHEMOTHERAPY: DE-ESCALATION VERSUS 
ESCALATION IN PATIENTS WITH UNRESECTABLE, NON-PRE-TREATED METASTATIC COLORECTAL 
CANCER 
EudraCT n°: 2016-001225-13 
 
This version of the protocol is approved by :  
 
                                                                                                    
Developer:  
 
Ms Cécile GIRAULT  
Date: 06/17/2016Signature
 
: 
 
 
The Coordinator:  
Pr Jean-Marc PHELIPDate : 17/06/2016Signature:  
 
I, the undersigned, Doctor  
 
 
 
 
 
 
Having read the requirements for this research, the protocol and its appendices, I hereby certify that I will 
conduct this trial in compliance with the regulations in force.   
In particular, I undertake to :  
- respect the protocol and any modifications notified to me by the Promoter  
- agree to supervise research in the center and to train my collaborators in the conduct of research and to 
provide a list of their names  
- have each patient sign a written consent form, after having read the patient information leaflet, before any 
research is carried out  
- report serious adverse events or new facts to the promoter within 24 hours of becoming aware of them  
- respect inclusion and non-inclusion criteria, as well as study start and end dates  
- participate in the biological part of the study, subject to the patient's signing a specific consent form and 
sending samples as recommended  
- complete all items in the observation book, ensure quality data collection and proper product management  
- keep research data and documents for 15 years after the end of the study  
- inform the Promoter of any conflict of interest that may affect my scientific independence in the context of the 
research.  
- inform the Promoter without delay of any action, whether amicable or contentious, brought by a person taking 
part in the research or his successors or assigns, likely to call into question the Promoter's liability  
- accept periodic visits from the ARC FFCD and make available to them all source documents and materials 
relating to the research, so that they can check the data recorded in the observation book.  
- accept an audit by the Promoter and/or an inspection by the health authorities  
- respond to requests for corrections or clarifications to the observation booklet  
- give the ARC FFCD the time it needs to sign the forms, answer any questions and take action.  
 
Date :  
 
 
 
           Signature : 
 
 
CENTER STAMP : 
 
 
Send original to CRGA de la FFCD - 7 bd Jeanne d'Arc - BP 87900 - 21079 Dijon Cedex - France 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
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CONTACTS FFCD 
 
 
NAME 
FUNCTION 
TELEPHONE 
TELECOPIE 
 
EMAIL 
RANDOMIZATION CENTER - MANAGEMENT - ANALYSIS 
Lila GABA-BERKOUK  
Project Manager 
03 80 39 34 83 
03 80 38 18 41 
lila.gaba@u-bourgogne.fr 
Coralie DEVORSINE 
Assistant Project Manager 
03 80 39 34 86 
03 80 38 18 41 
coralie.devorsine@u-
bourgogne.fr 
Karine LE MALICOT 
Statistics Manager 
03 80 39 34 71 
03 80 38 18 41 
karine.le-malicot@u-bourgogne.fr 
Paolo CARNI 
Data Manager 
03 80 39 34 53 
03 80 38 18 41 
paolo.carni@u-bourgogne.fr 
Mickaël VOYE 
Assistant Data Manager 
03 80 39 34 53 
03 80 38 18 41 
mickael.voye@u-bourgogne.fr 
Caroline CHOINE-POURRET 
ARC Coordinator 
04 69 18 19 02 
09 74 44 22 47 
carolinechoine.ffcd@sfr.fr 
 
For contact details of the FFCD ARC responsible for your center : 
- please contact Caroline CHOINE or  
- visit the FFCD website: http://www.ffcd.fr/index.php/organisation-pro/cartographie/arcnew 
 
 
 
 
 
 
 
 
You can also contact the FFCD's CRGA on: 03 80 66 80 13  
(Monday to Friday from 9H00 to 18H00) 
 


 
 
 
 
 
 
 
 
 
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SUMMARY 
 
Title 
PRODIGE 45 - FFCD 1408 - HIGH-LIGHT  
RANDOMIZED PHASE II EVALUATION OF EFFICACY AND TOLERANCE OF 2 
THERAPEUTIC STRATEGIES COMBINING BEVACIZUMAB WITH CHEMOTHERAPY: DE-
ESCALATION VERSUS ESCALATION IN PATIENTS WITH UNRESECTABLE, NON-PRE-
TREATED METASTATIC COLORECTAL CANCER 
Developer 
FFCD 
Type 
 
Phase II randomized non-comparative multicenter study 
Objectives 
 
 
Main objective  
The primary objective is to evaluate the rate of patients without strategy failure 16 months after 
randomization.  
Strategy failure is defined by:  
• 
Progression (defined in each arm)* using RECIST v1.1 criteria or 
• 
Deaths (all causes) or 
• 
Toxicity leading to permanent discontinuation of one of the chemotherapy products 
(oxaliplatin and irinotecan) or 
• 
Patient's refusal to continue the strategy or 
• 
Investigator's decision to discontinue strategy 
 
 
*Progression is defined differently depending on the treatment arm because the two 
strategies are different:  
- 
In the standard (climbing) arm, progression is considered a failure:  
• 
If it occurs during 1ère chemotherapy with LV5FU2 + bevacizumab and 2ème 
chemotherapy with FOLFIRI + bevacizumab cannot be administered 
• 
if it occurs during 2ème chemotherapy with FOLFIRI + bevacizumab and if 3ème 
chemotherapy with FOLFOX + bevacizumab) cannot be administered e or 
• 
if it occurs during 3 ème chemotherapy 
- 
In the experimental strategy (de-escalation), progression is considered a failure: 
• 
if it occurs during chemotherapy with modified FOLFOXIRI + bevacizumab or FOLFIRI 
+ bevacizumab. Progression during treatment with capecitabine + bevacizumab does not 
constitute failure of the strategy. 
 
Secondary objectives  
The secondary objectives are:  
• 
Best response according to RECIST version 1.1 at 16 months 
• 
Time to best response during the strategy 
• 
Time to strategy failure 
• 
Progression-free survival (PFS) at 2 and 3 years over the course of the strategy 
• 
Overall survival (OS) at 2 years and 3 years  
• 
Tolerance of both strategies  
• 
The dose intensity for each treatment and the duration of the strategy 
• 
Quality of life (EORTC QLQ-C30) 
• 
The relationship between progression-free survival and BMI 
Population 
 
 
Inclusion criteria: 
- 
Histologically proven metastatic colorectal cancer (on primary tumor and/or 
metastases) 
- 
Non-resectable and non-pretreated metastases  
- 
Unmutated BRAF 
- 
Patient considered suitable for treatment strategies  
- 
At least one measurable target lesion > 1 cm according to RECIST 1.1  
- 
Tumor evaluation according to RECIST, performed no more than 21 days before 
randomization 
- 
Age ≥ 18 years  
- 
WHO performance index ≤ 2  
- 
Life expectancy over 3 months 
- 
Biological profile: PNN≥1,500/mm3 , platelets≥100,000/mm3 , hemoglobin>9 g / dL 
- 
Creatinine 
clearance 
(Cockcroft 
and 
Gault 
formula)>30mL/min, 
serum 
creatinine<1.5LSN  
- 
Liver workup: total bilirubinemia <1.5xLSN, ASAT/ALAT≤5LSN , alkaline phosphatases 
≤ 2.5 x LSN (or ≤ 5 x LSN in case of liver invasion), if urine dipstick proteinuria ≥ 2+ 
then 24 h proteinuria < 1 g 
- 
Women of childbearing age and men (who have sexual relations with women of 
childbearing age) must undertake to use effective contraception without interruption for 
the duration of treatment and for 6 months following the last administration  
- 
Signed clinical informed consent 
- 
Patient affiliated to a social security scheme 


 
 
 
 
 
 
 
 
 
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Non-inclusion criteria: 
- 
Any patient with potentially resectable colorectal cancer, i.e. for whom the aim of 
chemotherapy is to render all metastases resectable. 
- 
Peripheral sensory neuropathies Grade >1 
- 
Patients with symptomatic metastases 
- 
Symptomatic tumor in place (occlusion, hemorrhage)   
- 
Active peptic ulcer, wound or bone fracture 
- 
Inflammatory bowel disease, extensive small bowel resection 
- 
Clinically significant active heart disease or myocardial infarction within the last 6 
months. 
- 
Hypertension not adequately controlled 
- 
QT/QTc interval > 450 msec for men and QT/QTc interval > 470 msec for women on 
ECG at inclusion 
- 
K+ < LIN, Mg2+ < LIN, Ca2+ < LIN 
- 
Known DPD (Dihydropyrimidine dehydrogenase) deficiency 
- 
Major abdominal or extra-abdominal surgery (except diagnostic biopsy) or irradiation 
within 4 weeks prior to the start of randomization. 
- 
Adjuvant chemotherapy within 4 months of randomization 
- 
Previous treatment with an anti-angiogenic agent or irinotecan  
- 
Metastases or suspected metastases in the central nervous system  
- 
History of malignant pathologies in the last five years, with the exception of properly 
treated basal cell skin carcinoma or carcinoma in situ of the uterine cervix 
- 
Macronodular peritoneal carcinosis 
- 
History of hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL of bright red blood per episode) 
in the month prior to inclusion 
- 
Known hypersensitivity to any component of bevacizumab or to any of the study 
treatments 
- 
Active infection requiring intravenous antibiotics at the start of treatment  
- 
History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or 
active gastrointestinal bleeding in the 6 months preceding the start of the strategy.  
- 
Pregnant or breast-feeding women 
- 
Concurrent participation in another clinical drug study during the treatment phase and 
30 days before starting the study strategy 
- 
Patient unable to undergo medical follow-up for geographical, social, psychological or 
legal reasons. 
 
Diagram 
and stratification 
Phase II, open-label, multicenter, randomized, non-comparative study evaluating the efficacy 
and safety of two treatment strategies combining bevacizumab with chemotherapy in patients 
with untreated, unresectable, non-mutated BRAF mRCC.  
 
Patients will be randomized in:  
 
Standard strategy (A-arm climbing strategy):  
Patients will start the strategy with 1ère chemotherapy based on LV5FU2 (or capecitabine) + 
bevacizumab. After progression, they will receive 2ème chemotherapy with FOLFIRI + 
bevacizumab. After progression, they will receive 3ème chemotherapy with FOLFOX4 + 
bevacizumab.  
When progression occurs during 3ème chemotherapy or if 3ème chemotherapy cannot be 
administered, patients will be treated according to the investigator's choice.  
The duration of a chemotherapy cycle is 14 days, or 21 days if the patient is receiving 
capecitabine.  
 
Experimental strategy (de-escalation strategy - arm B):  
Patients will receive 4 cycles of modified FOLFOXIRI + bevacizumab followed by 4 cycles of 
FOLFIRI + bevacizumab and then maintenance treatment with capecitabine and bevacizumab 
until progression.  
After progression during maintenance treatment, the patient will resume treatment with 4 cycles 
of modified FOLFOXIRI + bevacizumab, then 4 cycles of FOLFIRI + bevacizumab, followed by 
maintenance treatment with capecitabine and bevacizumab until progression etc.  
The duration of a chemotherapy cycle is 21 days for maintenance cycles with capecitabine. 
If progression occurs during treatment with modified FOLFOXIRI + bevacizumab or FOLFIRI + 
bevacizumab, patients have failed the strategy and will be treated according to the investigator's 
choice.  
 
Tumor response and disease progression will be assessed in both arms at the same rate: at 
most 21 days before randomization, then every 8 weeks according to RECIST version 1.1 
criteria. 
 


 
 
 
 
 
 
 
 
 
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Randomization will be carried out on a 1:1 basis using the minimization technique with the 
following stratification factors: 
- Center  
- WHO performance index 0/1 vs 2 
Treatment 
and 
follow-up 
Processing : 
Patients will be treated until : 
Unacceptable toxicity  
Strategy failure as defined in primary endpoint  
Patient refusal or investigator's decision 
 
Follow-up:  
Patients will be followed until : 
Strategy failure or at the latest up to 3 years after last patient included 
Withdrawal of consent 
 
Number of 
patients and 
statistical 
analysis 
The study's primary endpoint is the failure rate of the strategy 16 months after randomization. 
 
The clinical hypotheses for the study design are as follows:  
H0 : A rate of 40% of patients alive and without strategy failure at 16 months is not interesting.  
H1 : A live patient rate without strategy failure at 16 months of 55% is expected. 
 
With an α (one-sided) risk of 5% for a power of 80.85%, using an exact binomial method, 75 
patients will be randomized to each strategy.  
Taking into account that 10% of patients in the ITTm population cannot be evaluated, 84 
patients per strategy will be randomized in a 1:1 ratio (168 patients in total).  
 
(ITTm population: patient having received at least one dose of chemotherapy and having an 
imaging evaluation during the strategy). 
 
 
The conclusion of the study will be based solely on the experimental arm according to the rule 
defined below on the first 75 evaluable patients:  
• 
If 38 or more patients are alive and have not failed the strategy at 16 months, then the 
strategy is considered effective. 
 
The characteristics of the population at inclusion (on the ITT population) will be described using 
descriptive statistics in the form of percentages for qualitative variables, and the mean (standard 
deviation), median (with inter-quartile range, minimum and maximum) for continuous variables. 
Results are presented by treatment strategy and for the overall population.  
For the primary endpoint (mITT and ITT populations), a one-sided 95% confidence interval will 
be calculated. 
For efficacy criteria (mITT and ITT populations), survival data (OS and PFS) will be estimated 
from the date of randomization, using the Kaplan-Meier method. Results will be presented by 
strategy.  
All toxicities (Population Tolerance) will be described by strategy. 


 
 
 
 
 
 
 
 
 
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A statistical analysis plan (SAP) will be drawn up before the database is frozen. 
Ancillary studies  
Organic : 
• 
Demonstrate the impact of RAS mutations on response to bevacizumab in mRCC 
• 
Demonstrating the impact of thymidilate synthase (TS) polymorphism 
• 
Prospectively determine the frequency of tumor patients with low levels of mutated RAS 
alleles. 
• 
Evaluate the use of a new, highly sensitive technique for determining RAS status in 
blood. 
• 
Analyze the correlation between the level of mutated RAS alleles in the primary tumor 
and peripheral blood. 
• 
Analyze changes in the rate of mutated RAS alleles over time.  
• 
Assess circulating VEGF (at time of diagnosis and every 2 cures) 
Imaging : 
• 
Assessing the relationship between PFS and tumor size at diagnosis 
• 
Evaluate the relationship between PFS and visceral fat (measured by CT scan at 
inclusion) 
Estimated study 
duration 
The study will last approximately 6 years from the inclusion of the first patient (3 years of 
recruitment, 2 years of treatment and 3 years of follow-up). 
Inclusion rates are estimated at between 10 and 11 patients per month.  
First theoretical inclusion: 2ème quarter 201 6 
 


 
 
 
 
  
 
 
 
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STUDY SCHEDULE 
 
1If KRAS status is not available at inclusion, it will be reported in the case report when available. 
2Baseline imaging to be performed within 21 days of inclusion: thoraco-abdomino-pelvic CT scan (TAP), without and with contrast injection. Send a copy of the baseline CT scan to the CRGA for centralized 
review, as well as the 2-month CT scan in arm B. 
If injection of iodinated contrast is contraindicated, a liver or abdominal MRI with injection and a thoracic CT scan without injection can be performed.  
3For women of childbearing age 
4Complete biological workup: CBC/platelets, blood ionogram (Na, K, Ca), creatinine, protid, albumin, liver workup including ASAT, ALAT, PAL, GGT, total and conjugated bilirubin, PT, TCK, urine dipstick with 
24-hour proteinuria if ≥ 2+, creatinine clearance. If dipstick ≥ 2+: 24-hour proteinuria result must be ≤ 1 g protein to be eligible 
5 Pre-cure workup: CBC/platelets, creatinine, AST, ALT, bilirubinemia, proteinuria by dipstick supplemented by 24-hour proteinuria if > 2 +. 
6 Monitoring: - if the protocol strategy is discontinued due to progression, clinical monitoring is maintained every 3 months for 2 years, then every 6 months for 1 year. - if treatment is stopped before tumor 
progression (toxicities or patient refusal), clinical and biological monitoring, tumor evaluation by imaging and quality of life are continued every 8 weeks. After progression, patients will be seen in consultation 
every 3 months for 2 years, then every 6 months for 1 year.  
7 : ECG before and at the end of each intravenous oxaliplatin infusion  
 
Pre-inclusion  
(≤ 7 days) 
Before each 
cycle 
Every 8 
weeks 
End of treatment 
After 
discontinuation 
of protocol 
treatment 6 
Signed consent 
x 
 
 
 
 
Medical history 
x 
 
 
 
 
Clinical examination with vital signs (blood pressure, pulse), WHO, weight, height 
x 
x 
x 
x 
x 
RAS status 1 
x 
 
 
 
 
ECG 
x 
x7 
x7 
x 
 
Abdominal and pelvic CT or thoracic CT + abdominal and pelvic MRI2 
x 
 
x 
 
x 
Bone scan/skeletal X-ray for suspected bone metastases 
x 
 
 
 
 
Cerebral CT in cases of suspected brain metastases 
x 
 
 
 
 
Pregnancy test3 
x 
 
 
 
 
Biological check-up 
x4 
x5 
x4 
x4 
x4 
Tumor markers: ACE, LDH 
x 
 
x 
 
x 
Toxicity assessment 
 
x 
 
x 
 
Quality of life (QLQ-C30) 
x 
 
x 
 
x 
Translational research: tumor and blood samples (before C1, C2, C5 and C8)  
x 
 
 
 
 


 
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1 
INTRODUCTION - RATIONALE FOR THE STUDY 
 
1.1 
Treatment of metastatic colorectal cancer  
The multiplicity of therapeutic weapons and their very different modes of action mean that we can now envisage 
innovative strategies for the management of metastatic colorectal cancer.  
Optimization of tumor response (by bi- or tri-chemotherapy + biotherapy) has shown its value not only in terms of 
secondary resectability of metastases, but also in improving prognosis in patients with unresectable metastases.  
The intensity of tumor response also seems to correlate with the feasibility and duration of a therapeutic pause or 
light maintenance treatment (1,2) maintained until progression in patients initially controlled by "induction" 
chemotherapy. Bevacizumab combined with cytotoxic chemotherapy (5FU, irinotecan and/or oxaliplatin) has been 
shown to improve tumor response rates (60% partial responses) and prognosis in patients with 1ère and 2ème 
metastatic lines (overall survival of around 25 months). Its highly favorable safety profile makes it an excellent 
candidate for both induction (3, 4, 5, 6) and maintenance treatment. Prospective data from recent phase II and III 
trials have demonstrated an improvement in PFS and/or overall survival by maintaining bevacizumab alone or in 
combination with 5FU (or capecitabine) after disease control with 2 to 3 months of induction chemotherapy 
(FOLFIRI or FOLFOX + bevacizumab) (1, 7, 8). These treatments are listed in the TNCD (http://www.tncd.org/). 
At the same time, the maintenance of antiangiogenic pressure after progression in 1ère  metastatic line (with switch 
of cytotoxic chemotherapy) has demonstrated its benefit in terms of PFS and overall survival (9, 10, 11). Maintaining 
bevacizumab in 2ème metastatic lines, despite progression, therefore appears to be a valid strategy. The molecule's 
action on "healthy" vascular endothelium means that "primary" resistance phenomena cannot be envisaged. This 
concept of continuous blockade of angiogenesis is therefore conceivable for subsequent lines of treatment, but 
there is no current data to validate it. 
 
 
1.2 
Rational for the de-escalation strategy 
Three phase III trials have compared a "top-down" strategy of induction with bi-chemotherapy (5FU + irinotecan or 
oxaliplatin), followed at progression by a switch to irinotecan and oxaliplatin, with a "bottom-up" strategy in which 
5FU is started alone, followed at progression by the introduction of oxaliplatin or irinotecan. The results of these 
trials are consistent, showing no difference in prognosis and overtoxicity in patients starting with bi-chemotherapy 
(12, 13, 14). However, biotherapy was not included in these trials, and response rates were low, with overall survival 
of around 16 months. There is therefore currently a conflicting debate about the value of an ascending vs. 
descending strategy in patients with unresectable metastases. To date, no trial has evaluated these two strategies 
in combination with biotherapies, i.e. with optimized chemotherapy capable of producing high response rates and 
prolonged survival, and allowing maintenance treatment. 
Thus, the aim of this work is to combine continuous blockade of angiogenesis by bevacizumab delivered to the first 
3 metastatic lines in a strategic randomized phase II trial evaluating a "top-down" strategy of upfront optimization 
with 4 courses of modified FOLFOXIRI-bevacizumab and 4 courses of FOLFIRI-bevacizumab followed by 
maintenance 
treatment 
with 
5FU-bevacizumab 
until 
progression 
(retreatment 
with 
5FU-
bevacizumab).bevacizumab and 4 courses of FOLFIRI-bevacizumab followed by maintenance treatment with 5FU-
bevacizumab until progression (reintroduction of induction in the event of progression) versus a "bottom-up" 
strategy with 5FU-bevacizumab followed from the outset, upon progression, introduction of irinotecan followed by 
oxaliplatin, with continued angiogenesis blockade by bevacizumab. The chosen endpoint was the failure rate of the 
strategy at 16 months for phase II. 
 


 
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2 
RESEARCH OBJECTIVES 
 
2.1 
Main criterion  
The main objective is to evaluate the rate of patients without strategy failure 16 months after randomization.  
Strategy failure is defined by (Figure 1):  
• Progression (defined below according to treatment strategy)* using RECIST criteria version 1.1 or 
• Death (all causes) or 
• Toxicity leading to permanent discontinuation of one of the chemotherapy products (oxaliplatin and/or irinotecan) 
or 
• Patient's refusal to continue the strategy or 
• Investigator's decision to discontinue strategy 
 
*Definition of progression according to treatment strategy (two different strategies):  
- 
Standard strategy (escalation), progression will be considered a failure:  
• 
If it occurs during 1ère chemotherapy with capecitabine/LV5FU2 + bevacizumab and if 2ème  chemotherapy 
with FOLFIRI + bevacizumab cannot be administered, or 
• 
if it occurs during 2ème chemotherapy with FOLFIRI + bevacizumab if 3ème chemotherapy with FOLFOX + 
bevacizumab cannot be administered, or 
• 
if it occurs during 3ème chemotherapy with FOLFOX + bevacizumab 
- 
Experimental strategy (de-escalation), progression will be considered a failure: 
• 
if it occurs during the first 2 chemotherapies: modified FOLFOXIRI + bevacizumab or FOLFIRI + 
bevacizumab. 
 
Figure 1 
 
 


 
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Secondary criteria  
The secondary objectives are as follows:  
- Best response according to RECIST version 1.1 at 16 months 
- Time to best response during strategy 
- Time to strategy failure 
- Progression-free survival at 2 years and 3 years during the 
- Overall survival at 2 and 3 years  
- Tolerance of both strategies  
- The dose intensity of each treatment and the duration of the strategy 
- Quality of life (EORTC QLQ-C30) 
The relationship between progression-free survival and BMI 
 
2.2 
Research objectives   
This clinical study comprises 2 types of exploratory research 
A biological collection is planned as part of the protocol cf page 28 "biological logistics". 
Biological: a prospective study of the level of mutated RAS alleles in tissue (tumor) and blood (circulating 
DNA): 
- Demonstrate the impact of RAS mutations on response to bevacizumab in mRCC. 
- Prospectively determine the frequency of tumor patients with low levels of mutated RAS alleles. 
- Evaluate the use of a new, highly sensitive technique for determining RAS status in blood. 


 
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- Analyze the correlation between the level of mutated RAS alleles in the primary tumor and peripheral blood. 
- Analyze changes in the rate of mutated RAS alleles over time.  
- Evaluate circulating VEGF (at diagnosis and every 2 cures)  
Imaging : 
- Assessing the relationship between PFS and tumor size at diagnosis 
- Evaluate the relationship between PFS and visceral fat (measured by CT scan at inclusion) 
 
3 
SELECTION CRITERIA 
 
3.1 
Inclusion criteria 
- Histologically proven metastatic colorectal cancer (on primary tumor and/or metastases) 
- Non-resectable, non-pre-treated metastases  
- Unmutated BRAF 
- Patient considered suitable for treatment strategies  
- At least one measurable target lesion > 1cm according to RECIST 1.1 (Appendix 4) 
- Tumor evaluation according to RECIST, performed no more than 21 days before randomization 
- Age ≥ 18 years  
- WHO performance index ≤ 2 (Appendix 5) 
- Life expectancy over 3 months 
- Biological work-up: neutrophils ≥ 1,500 /mm3 , platelets ≥ 100,000 /mm3 , hemoglobin > 9 g / dL creatinine 
clearance > 30 mL / min (Cockcroft and Gault formula) (dosage modification for capecitabine if creatinine 
clearance < 30-50 mL / min), serum creatinine <1.5 x ULN, if dipstick proetinuria ≥ 2+, then 24h proteinuria 
< 1 g  
- Liver workup: total bilirubin <1.5 x ULN, AST/ALT < 5 x ULN, PAL ≤ 2.5 ULN (or ≤ 5 xLNS in case of hepatic 
invasion) 
- Women of childbearing age and men (who have sexual relations with women of childbearing age) must 
undertake to use effective contraception without interruption for the duration of treatment and for 6 months 
following the last administration.  
- Signed clinical informed consent 
- Patient affiliated to a social security scheme 
 
3.2 
Non-inclusion criteria 
 
- Potentially resectable colorectal cancer, i.e. where the aim of chemotherapy is to render all metastases 
resectable. 
- Peripheral sensory neuropathies grade >1 
- Symptomatic metastases 
- Symptomatic tumor in place (occulsion, hemorrhage)  
- Active peptic ulcer, wound or bone fracture 
- Inflammatory bowel disease, extensive small bowel resection 
- Clinically significant active heart disease or myocardial infarction within the last 6 months. 


 
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- Hypertension not adequately controlled 
- QT/QTc interval > 450 msec for men and QT/QTc interval > 470 msec for women 
- K2+ < LIN, Mg2+ < LIN, Ca2+ < LIN 
- Known DPD (Dihydropyrimidine dehydrogenase) deficiency 
- Major abdominal or extra-abdominal surgery (except diagnostic biopsy) or irradiation within 4 weeks prior to 
the start of randomization 
- Previous treatment with an anti-angiogenic agent or irinotecan  
- Metastases or suspected metastases in the central nervous system  
- History of malignant pathologies in the last five years, with the exception of properly treated basal cell skin 
carcinoma or carcinoma in situ of the uterine cervix 
- Macronodular peritoneal carcinosis 
- History of hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL of bright red blood per episode) in the month preceding 
inclusion 
- Known hypersensitivity to any component of bevacizumab or any of the study treatments 
- Active infection requiring intravenous antibiotics at the start of treatment  
- History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal 
bleeding in the 6 months preceding the start of treatment.  
- Pregnant or breast-feeding women 
- Concurrent participation in another clinical drug study during the treatment phase and 30 days before starting 
study treatment 
- Patient unable to undergo medical follow-up for geographical, social, psychological or legal reasons. 
 
4 
INITIAL BALANCE SHEET  
 
After signing the consents (clinical and biological if applicable), all biological and radiological tests will be carried 
out at local facilities before initiating the strategy.  
Patients must be informed of the possibility of preserving their germ cells. The investigator will ask the patient 
whether he or she wishes to preserve gametes prior to chemotherapy.  
In the 21 days preceding the patient's randomization: 
Morphological assessment of the tumour, with location and measurement of tumour targets according to RECIST 
1.1 criteria (Appendix 4):  
- 
Thoraco-abdomino-pelvic CT scan (TAP-CT), with and without contrast medium injection.  
- 
If injection of iodinated contrast is contraindicated, a liver or abdominal MRI with injection and a thoracic 
CT scan without injection can be performed.  
If bone metastases are suspected, a bone scan or X-ray will be performed; if brain metastases are suspected, a 
brain CT scan will be performed. 
Morphological examinations should be the same throughout the patient's follow-up.  
Don't forget to make an anonymized copy of this 2-month evaluation imaging in arm B (experimental) for 
centralized review; send to the FFCD CRGA (CD Roms or ARC FFCD).  
 
In the 14 days preceding the patient's randomization : 
Full clinical examination:  


 
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- 
Description of clinical signs associated with tumor disease 
- 
Weight, height, body surface area 
- 
Blood pressure (PAS and PAD) 
- 
OMS general condition (appendix 5) 
- 
ECG, or cardiology consultation if necessary  
 
Biological check-up including :  
- 
CBC-platelets 
- 
Blood ionogram (Na, K, Ca), creatininemia, protidemia, albuminemia  
- 
Liver panel including AST, ALT, PAL, GGT, total and conjugated bilirubin 
- 
ACE, LDH 
- 
TP and TCK 
- 
Urine dipstick proteinuria with 24-hour proteinuria if > 2+. 
- 
Measurement 
of 
creatinine 
clearance 
using 
Cockcroft 
& 
Gault 
formula 
 (Appendix 5) 


 
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RAS statutes: 
The results will be recorded in the observation notebook. 
Quality of life questionnaire (Appendix 6) :  
QLQ-C30 questionnaire  
 
Translational research (Appendix 3):  
If the patient wishes to take part in this research and has signed the specific consent form (Appendix 2): 2 x 10 mL 
STRECK tubes (supplied) will be collected before administration of the 1er  cycle of the 1ère chemotherapy strategy 
and sent at room temperature by DHL to the PRODIGE - EPIGENETEC Biological Resource Center (45 rue des 
Saints Pères, 75006 Paris).  
- 
A tumor sample (tumor blocks if available, and any tumor biopsies used for diagnosis) will also be sent to 
the EPIGENETEC BRC.  
Within 72 hours of the first chemotherapy cycle in the strategy: 
- 
For women of childbearing age, perform a blood pregnancy test. 
- 
Provide permanent venous access. 
 
5 
HIKING  
 
5.1 
Randomization 
Randomization will be carried out by the FFCD's CRGA after the eligibility check-up and signature of the informed 
consent form, and after receipt of the randomization fax (Form 1 in the observation booklet), by calling 03 80 38 18 
41. The CRGA is open Monday to Friday, 9am to 6pm.  
For further information, please call 03 80 66 80 13. 
The randomization number and strategy will be communicated to the investigator and pharmacist by return fax. 
If possible, the strategy should be started within 72 hours of inclusion, and within 2 weeks at most. 
An observation booklet will be sent when the center opens. An observation book will be sent after each 
randomization. 
 
5.2 
Stratification  
Patients will be randomized (1:1) using the minimization technique (Pocock and Simon (Biometrics, 1975)) 
according to the following stratification factors:  
• 
Center  
• 
WHO performance index 0/1 vs 2 
 
6 
TREATMENT 
In this academic research, all drugs used in the treatment of modified FOLFOXIRI, FOLFIRI, FOLFOX, LV5FU2, 
capecitabine and bevacizumab (drugs with AMM used in their indication) will be taken from hospital stock in 
accordance with article L1121-16-1 of the French Public Health Code. 
Please note that it is essential for investigators to refer to the AMM SPCs of the drugs used in this trial, attached in 
appendix 7 of the protocol, for patient management; in particular, the indications in section 4.4 "Special warnings 
and precautions for use", as well as the indications relating to concomitant drugs to be used with caution. 
6.1 
In the 48 hours preceding each cycle 
Full clinical examination:  


 
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- 
Weight, body surface area 
- 
Blood pressure (PAS and PAD) 
- 
General condition WHO  
Pre-chemotherapy biochemistry : 
- 
CBC-platelets 
- 
Creatininemia, AST and ALT  
- 
Bilirubinemia  
- 
Dipstick proteinuria supplemented by 24-hour proteinuria if ≥ 2+. 
- 
Toxicity assessment according to NCI-CT version 4.0 of the previous cycle 
 
 
6.2 
Sch emas of administration  
 
6.2.1 Arm A standard strategy 
In the standard arm or escalation strategy, patients will receive 1ère chemotherapy based on LV5FU2 or 
capecitabine + bevacizumab. After progression, they will receive 2ème chemotherapy with FOLFIRI + bevacizumab. 
After progression, they will receive 3ème chemotherapy with FOLFOX4 + bevacizumab.  
When progression occurs during 3ème chemotherapy, or 3ème CT cannot be administered, patients will be treated 
according to the investigator's choice.  
 
Simplified LV5FU2 (or capecitabine) + Bevacizumab:  
Bevacizumab is administered IV before chemotherapy, at a dose of 5 mg/kg over 90 min in cycle 1, then if well 
tolerated, over 60 min in cycle 2 and 30 min in subsequent cycles. 
Folinic acid is administered as a 2-hour IV infusion at a dose of 400 mg/m² (or 200 mg/m² if Elvorine). 
Bolus 5FU is administered in less than 10 minutes at 400 mg/m² (at D1). 
Continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hours (D1 and D2). 
Cycles last 14 days. 
For this 1ère line of chemotherapy, the investigator has the option of using capecitabine instead of LV5FU2, in which 
case the cycle lasts 21 days. Capecitabine is prescribed at 2000 mg/m2 per day, in 2 doses per os, over two weeks, 
followed by a one-week rest period. 
 
FOLFIRI + Bevacizumab:  
Bevacizumab is administered IV before chemotherapy, at a dose of 5 mg/kg over 90 min in cycle 1, then if well 
tolerated, over 60 min in cycle 2 and 30 min in subsequent cycles. 
Irinotecan is administered IV at a dose of 180 mg/m² over 90 min.  
Folinic acid is administered as a 2-hour IV infusion at a dose of 400 mg/m² (or 200 mg/m² if Elvorine), to be 
transferred to the Y at the same time as irinotecan. 
Bolus 5FU is administered in less than 10 minutes at 400 mg/m² (at D1). 
Continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hours (D1 and D2).   
Cycles last 14 days. 


 
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FOLFOX + Bevacizumab:  
Bevacizumab is administered IV before chemotherapy, at a dose of 5 mg/kg over 90 min in cycle 1, then if well 
tolerated, over 60 min in cycle 2 and 30 min in subsequent cycles. 
Oxaliplatin is administered IV at a dose of 85 mg/m² over 120 min.  
Folinic acid is administered as a 2-hour IV infusion at a dose of 400 mg/m² (or 200 mg/m² if Elvorine), to be 
transferred to the Y at the same time as oxaliplatin. 
Bolus 5FU is administered in less than 10 minutes at 400 mg/m² (at D1). 
Continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hours (D1 and D2).   
Cycles last 14 days. 
 
6.2.2 Arm B experimental strategy 
In the experimental arm or de-escalation strategy, induction treatment (4 cycles of FOLFOXIRI + bevacizumab 
followed by 4 cycles of FOLFIRI + bevacizumab) is followed by maintenance treatment with capecitabine and 
bevacizumab until progression. After 1ère progression during maintenance treatment, the patient will be treated 
again with induction treatment (4 cycles of FOLFOXIRI + bevacizumab followed by 4 cycles of FOLFIRI + 
bevacizumab) followed by maintenance with capecitabine and bevacizumab until progression and so on.  
If progression occurs during induction therapy (FOLFOXIRI + bevacizumab or FOLFIRI + bevacizumab), patients 
will be treated according to the investigator's choice.  
 
Modified FOLFOXIRI + bevacizumab (4 cycles):  
Bevacizumab is administered IV prior to chemotherapy, at a dose of 5 mg/kg over 90 min in cycle 1, then if well 
tolerated, over 60 min in cycle 2, then over 30 min in subsequent cycles. 
Irinotecan is administered IV at a dose of 165 mg/m² over 90 min. 
Oxaliplatin is administered IV at a dose of 85 mg/m² over 120 min.  
Continuous 5FU is administered IV at a dose of 3200 mg/m² over 46 hours (D1 and D2).   
Cycles last 14 days. 
GCSF is given systematically from D2 to D5 of each cycle. 
Note that in this modified FOLFOXIRI regimen, irinotecan is at a dose of 165 mg/m², continuous 5-FU is at 
a dose of 3200 mg/m2 and bolus 5-FU is omitted. 
Cycles last 14 days. 
 
FOLFIRI + bevacizumab (4 cycles):  
Bevacizumab is administered IV before chemotherapy, at a dose of 5 mg/kg over 90 min in cycle 1, then if well 
tolerated, over 60 min in cycle 2 and 30 min in subsequent cycles. 
Irinotecan is administered IV at a dose of 180 mg/m² over 90 min.  
Folinic acid is administered as a 2-hour IV infusion at a dose of 400 mg/m² (or 200 mg/m² if Elvorine), to be 
transferred to the Y at the same time as irinotecan. 
Bolus 5FU is administered in less than 10 minutes at 400 mg/m² (at D1). 
Continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hours (D1 and D2).   
Cycles last 14 days. 
Capecitabine + bevacizumab (maintenance treatment) 


 
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CAUTION: Bevacizumab should be administered IV at a dose of 7.5 mg/kg over 90 min every 3 weeks, when 
used in maintenance therapy with capecitabine.  
Capecitabine is prescribed at 2000 mg/m2 per day, in 2 doses per os, over two weeks, followed by a week's rest. 
The cycle lasts 21 days. 
 
6.3 
Associated treatments  
 
With 5FU 
No systematic anti-emetic treatment 
If chest pain: stop 5 FU; check ECG and cardiac enzymes 
If hand-foot syndrome: moisturizing lotion, oily creams 
For severe mucositis: mouthwash with bicarbonate 14 0/00, fungizone oral suspension, viscous Xylocaine® if pain 
and aciclovir if history of herpes. 
 
With irinotecan 
In the event of cholinergic syndrome, prescribe a subcutaneous injection of atropine (0.25 mg) immediately for 
curative purposes, then prophylactically 15 minutes before subsequent administrations of irinotecan®, if there are 
no contraindications (risk of angle-closure glaucoma, risk of urinary retention due to urethro-prostatic obstruction, 
paralytic ileus, achalasia, esophageal spasm, gastroesophageal reflux, toxic megacolon, pyloric stenosis, ulcerative 
colitis). 
The patient should be discharged with a prescription for loperamide: in the event of diarrhoea, from the first liquid 
stool, take loperamide 2 capsules at 2 mg, then 1 capsule every 2 hours (at night, 2 capsules every 4 hours), to be 
continued for 12 hours after the last liquid stool, without exceeding a total of 48 hours of treatment. If diarrhea 
persists after 48 hours, or in the event of concomitant vomiting, fever or neutropenia, prompt hospitalization is 
required. 
 
With bevacizumab 
No recommended treatment; refer to treatment of side-effects for anti-hypertensive treatments or to TNCD 
recommendations (www.tncd.org). 
 
For all treatments 
All anti-emetic, analgesic and anti-diarrheal treatments are authorized. Loperamide is the anti-diarrheal of choice. 
The use of GCSF is permitted in cases of grade 4 neutropenia, febrile neutropenia ≥ grade 3, infection with 
concomitant grade 3-4 neutropenia or persistent neutropenia < 1500/mm3 after one week's deferral. If secondary 
prophylaxis is initiated, it will be maintained for subsequent courses. 
The use of recombinant erythropoietin is authorized according to the usual recommendations. 
Corticosteroids are authorized on an occasional basis, for anti-emetic purposes, but are not recommended for long-
term use. 
All other anti-cancer treatments are prohibited. 
Preliminary radiotherapy is possible on lesions not taken as targets. 
The use of a cooling helmet is permitted. 
6.4 
Associated treatments strictly contraindicated 
With irinotecan 


 
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o 
St. John's wort (Irinotecan): decreased plasma levels of SN-38 
o 
Yellow fever vaccine: risk of widespread vaccine disease 
With capecitabine 
o 
Sorivudine or related drugs (such as brivudine): risk of increased potentially fatal toxicity 
With oxaliplatin : 
o 
Drugs known to prolong the QTc interval (referenced at https://www.crediblemeds.org/) should be 
used with caution. 
 
Please note that it is essential for investigators to refer to the AMM SPCs for 
 
7 
PROCESSING TIME 
 
To correctly evaluate the 2 therapeutic strategies, it is important to respect the alternating treatment 
sequences of each strategy as described in the administration schedule.  
The strategy assigned at randomization will be maintained until therapeutic escape, which differs from one 
strategy to another:  
 
In the standard strategy (escalation strategy), treatment failure is defined as  
- death,  
- progression during 3rd-line chemotherapy (FOLFOX + bevacizumab)  
- the occurrence of a toxicity requiring the definitive discontinuation of one of the chemotherapy products 
(redhibitory toxicity despite dose adjustment, or allergy)  
- the patient's refusal to pursue the strategy 
- the investigator's decision to discontinue the strategy 
 
In the experimental strategy (de-escalation strategy), therapeutic escape is defined as : 
- 
death,  
- 
progression during chemotherapy with modified FOLFOXIRI + bevacizumab or FOLFIRI + bevacizumab.   
- 
the occurrence of a toxicity requiring the definitive discontinuation of one of the chemotherapy products 
(redhibitory toxicity despite dose adjustment, or allergy) 
- the patient's refusal to pursue the strategy 
- the investigator's decision to discontinue the strategy 
Permanent discontinuation of oxaliplatin and irinotecan in modified FOLFOXIRI regimens is considered therapeutic 
escape. It is therefore important to prevent toxicities requiring permanent discontinuation of oxaliplatin and 
irinotecan through dose adjustments. 
However, dose adjustment of oxaliplatin or irinotecan is not considered therapeutic failure. 
Permanent discontinuation of bevacizumab is not considered therapeutic failure. 
If the strategy fails, patients will be treated according to the investigator's choice.  
 
 


 
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8 
DOSE ADJUSTMENTS TREATMENTS 
 
 
Toxicities will be assessed before each cycle by questioning, clinical examination and biology, and graded 
according to NCI-CTC AE version 4.0 criteria (Appendix 8 and leaflet supplied by the FFCD).  
Dose adjustments are made on the basis of maximum toxicity, and if the patient presents several toxicities, 
adjustments are made on the basis of the highest-grade toxicity. 
The decision to reduce the dose is based both on the toxicity present on the day of treatment and during the 
intercourse. 
In the event of persistent toxicity > grade 1 on the theoretical day of treatment, treatment should be postponed for 
1 or 2 weeks until recovery, before resuming treatment at the appropriate dose. Doses reduced for toxicity should 
not be increased again. 
 
 
Oxaliplatin-specific toxicity :  
 
• 
Neurotoxicity (see table 8.1) 
 
• 
Cardiotoxicity 
 
Oxaliplatin cardiotoxicity must be monitored. 
 
In the event of QT/QTc prolongation > 500 msec: discontinue oxaliplatin therapy, with close, continuous, appropriate 
ECG monitoring in hospital, until a cardiologist has been consulted. 
 
• 
Hypersensitivity reactions 
 
Patients with a history of allergic reactions to other platinum-containing products should be carefully monitored. In 
the event of anaphylaxis, the infusion should be stopped immediately and appropriate symptomatic treatment 
initiated. Re-administration of oxaliplatin to patients is contraindicated. Cross-reactions, sometimes fatal, have been 
reported with all platinum-containing porducts. 
 


 
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8.1 
Dose adjustments for 5FU, oxaliplatin and irinotecan 
 
Toxicity Grade 
(NCI-CTC version 4.0) 
5- Fluorouracil 
Irinotecan 
or 
oxaliplatin 
(FOLFIRI or FOLFOX) 
Irinotecan 
and 
oxaliplatin 
(modified FOLFOXIRI) 
Neutropenia, thrombocytopenia  
 
 
2 a 
50% bolus reduction  
No change 
 
3 a 
Elimination of the bolus,  
25% reduction in continuous 5-FU 
No change 
 
4 
Elimination of the bolus,  
25% reduction in continuous 5-FU 
25% discount 
Febrile neutropenia b 
Elimination of the bolus,  
25% reduction in continuous 5-FU 
25% discount 
Diarrhea despite maximum 
treatment 
 
 
 
2 
50% bolus reduction 
25% discount 
 
3 
50% reduction in bolus, 25% reduction in 
continuous 5-FU 
25% discount 
 
4 
Stopping chemotherapy 
Stopping chemotherapy 
Mucite 
 
 
 
2 
50% bolus reduction 
No change 
 
3 
Elimination of the bolus,  
25% reduction in continuous 5-FU 
No change 
 
4 
Stopping chemotherapy 
Stopping chemotherapy 
Vomiting 
 
 
 
3 
No change 
25% discount 
 
4 
Stopping chemotherapy 
Stopping chemotherapy 
Hand-foot syndrome 
 
 
 
2 
25% reduction in continuous 5-FU  
No change 
 
3 
50% bolus reduction,  
50% reduction in continuous 5-FU 
No change 
Peripheral sensory neuropathy   
 
 
2 
No change 
25% reduction in oxaliplatin 
 
3 
No change 
Discontinuation of oxaliplatin 
Non-hematological 
toxicity 
other than alopecia 
 
 
 
3 
25% reduction in bolus and continuous 5-FU  25% discount 
 
4 
Stopping chemotherapy 
Stopping chemotherapy 
a Discuss prescription of G-CSF if neutropenia < 1500 persists after 1 week of postponement 
b PNN<1000 and fever >38.5°C 


 
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8.2 
Capecitabine 
 
In the event of toxicity during the capecitabine cycle, treatment should be stopped and the patient should contact a 
healthcare professional. 
 
Toxicity Grade 
(NCI-CTC version 4.0) 
Dose modification during a treatment cycle Dosage adjustment for next 
cycle/dose (% of initial dosage) 
Grade 1 
Maintain dosage 
Maintain dosage 
Grade 2 
 
 
- 1st appearance 
Interrupt treatment until grade 0-1 returns 
100 % 
- 2nd appearance 
75 % 
- 3rd appearance 
50 % 
- 4th appearance 
Stop treatment permanently 
Not applicable 
Grade 3 
 
 
- 1st appearance 
Interrupt treatment until grade 0-1 returns 
75 % 
- 2nd appearance 
 
50 % 
- 3rd appearance 
Stop treatment permanently 
Not applicable 
Grade 4 
 
 
- 1st appearance 
Stop treatment permanently 
or 
If the physician deems that it is in the patient's 
best interest to continue, discontinue treatment 
until grade 0-1 is restored.  
50 % 
- 2nd appearance 
Stop treatment permanently 
Not applicable 
a Discuss prescription of G-CSF if neutropenia < 1500 persists after 1 week of postponement 
b PNN<1000 and fever>38.5°C 
 
8.3 
Bevacizumab 
Definitive discontinuation of bevacizumab due to toxicity is not a failure of the strategy. Chemotherapy will continue 
to be administered without bevacizumab.  
 
ARTERIAL HYPERTENSION 
• 
take BP after at least 5 minutes' rest 
• 
if Systolic BP > 140 mmHg and/or Diastolic BP > 90 mmHg resume after a further 5 minutes' rest 
 
Treatment of hypertension :  
Grade 1 hypertension: asymptomatic, transient (< 24h) up to 150/100 mmHg  
➔ No treatment and continuation of bevacizumab 
 
Grade 2 hypertension: recurrent or persistent (> 24h) or symptomatic with diastolic BP increased by 20 mmHg or 
PAS/PAD > 150/100 mmHg  
➔ Continuation of bevacizumab, antihypertensive monotherapy without suspension of anti-angiogenic therapy  


 
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Grade 3 hypertension: not controlled by monotherapy (or by dual therapy for patients already treated for 
hypertension prior to bevacizumab therapy)  
➔ Discontinue bevacizumab until balanced BP is achieved  
(PAS/D < 150/100 mmHg) 
 
Grade 4: life-threatening hypertension (hypertensive crisis)  
➔ Permanent discontinuation of bevacizumab  
 
THROMBO-EMBOLIC EVENT 
Permanent discontinuation of bevacizumab in the event of an arterial thromboembolic event  
In the event of venous thromboembolism: suspension of bevacizumab for 2 weeks, to be resumed once effective 
anticoagulant therapy has been established. Permanent discontinuation of bevacizumab if life-threatening 
pulmonary embolism occurs.  
 
PROTEINURY 
If proteinuria ++ or +++ on pretreatment urine dipstick : 
Administer bevacizumab without dose adjustment 
Perform a 24-hour proteinuria test before the next cycle: 
 
- if proteinuria ≤ 2 g/24h: administer bevacizumab without dose adjustment 
 
- if proteinuria > 2 g/24h :  
 
 
- do not administer bevacizumab 
- repeat a 24-hour proteinuria test before the next cycle and apply the same adaptation 
rules 
- perform 24-hour proteinuria tests every cycle as long as proteinuria > 1g/24h 
Permanent discontinuation of bevacizumab if nephrotic syndrome 
 
INTESTINAL PERFORATION  
➔ Permanent discontinuation of bevacizumab  
 
HEMORRAGY 
Grade 3 or 4 
➔ Permanent discontinuation of bevacizumab 
 
REVERSIBLE POSTERIOR ENCEPHALOPATHY SYNDROME (SEPR)  
There have been rare reports of Avastin-treated patients developing signs and symptoms consistent with Reversible 
Posterior Encephalopathy Syndrome (RPEGS), a rare neurological disorder that can manifest itself as, among other 
things, seizures, headache, altered mental status, visual disturbances, cortical blindness, with or without associated 
hypertension. The diagnosis of RRMS requires confirmation by brain imaging, preferably magnetic resonance 
imaging (MRI). In patients who develop RRMS, specific treatment of symptoms, including control of hypertension, 
is recommended, as well as discontinuation of Avastin. The tolerability consequences of resuming Avastin 
treatment in patients who have developed RRMS are not known. 


 
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OSTEONECROSIS OF THE JAW 
Cases of osteonecrosis of the jaw have been reported in cancer patients treated with Avastin, the majority of whom 
had received prior or concomitant treatment with intravenous bisphosphonates, which have a known risk of 
osteonecrosis of the jaw. Particular caution is advised in the case of prior or concomitant administration of Avastin 
with intravenous bisphosphonates. Invasive dental procedures are known to be a risk factor. A dental examination 
and appropriate preventive dental care should be considered before starting Avastin treatment. For patients who 
have previously received or are receiving intravenous bisphosphonate therapy, invasive dental procedures should 
be avoided if possible. 
 
9 
PATIENT MONITORING 
9.1 
During treatment  
- Before each chemotherapy cycle:  
• 
Complete clinical examination: weight, body surface area, general condition WHO, blood pressure  
• 
Biological workup: CBC, platelets, ionogram (Na, K, Ca), creatinine, creatinine clearance, AST, ALT, total, 
free and conjugated bilirubin, proteinuria with urine dipstick and 24h proteinuria if dipstick > 2+.  
• 
Toxicity evaluation according to NCI-CTC Version 4.0 of the previous cycle 
• 
ECG before and at the end of each intravenous oxaliplatin infusion  
• 
If the patient has signed the specific consent form for biological research (Appendix 2): 2 x 10 mL STRECK 
tubes (supplied) will be collected prior to administration of the 2ème , 5ème  and 8ème cycle and sent at 
room temperature by DHL to the PRODIGE - EPIGENETEC Biological Resource Center (45 rue des Saints 
Pères, 75006 Paris). 
 
- Every 8 weeks: 
• 
Clinical examination: weight, body surface area, general condition WHO, blood pressure 
• 
Quality of Life Questionnaire QLQ-C30  
• 
Biological tests :  
- 
CBC-platelets 
- 
Blood ionogram (Na, K, Ca), creatininemia, protidemia, albuminemia  
- 
Liver panel including AST, ALT, PAL, GGT, total and conjugated bilirubin 
- 
ACE, LDH 
- 
TP and TCK 
- 
Urine dipstick with 24-hour proteinuria if ≥ 2+. 
- 
Measurement 
of 
creatinine 
clearance 
using 
Cockcroft 
and 
Gault 
formula  
(in men: (140-age) x weight (kg)/0.814 x creatinine (µmol/L); in women: [(140-age) x weight (kg)/0.814 x 
creatinine (µmol/L)] x 0.85), 
- 
Morphological evaluation of the disease :  
Do not postpone the evaluation schedule, even if cycles are postponed. 
- 
Thoracoabdomino-pelvic CT scan, without and with contrast injection 
- 
In case of contraindication to iodinated contrast injection, hepatic or abdominal MRI with 
gadolinium injection and thoracic CT scan without injection. 
Use the same technique as for the initial assessment.  
 


 
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Don't forget to make an anonymized copy of the 2-month CT scan in arm B (experimental) for centralized 
review; to be sent to the FFCD CRGA (CD Roms or ARC FFCD). 
 
9.2 
After discontinuation of protocol treatment  
- 
If the protocol strategy is discontinued due to progression, clinical monitoring is maintained every 3 months 
for 2 years, then every 6 months for 1 year. The patient's condition and subsequent treatments are recorded 
in the OC. 
- 
If treatment is stopped before tumor progression (due to toxicities or patient refusal), clinical and biological 
monitoring, tumor evaluation by imaging and quality of life are continued every 8 weeks. After progression, 
patients will be seen in consultation every 3 months for 2 years, then every 6 months for 1 year. The patient's 
condition and subsequent treatments will be recorded in the OC. 
 
10 
ORGANIC LOGISTICS 
 
All patients randomized in the PRODIGE 45 - HIGH-LIGHT study and having signed the specific consent form for 
this translational research (prospective study of the rate of mutated RAS alleles at tissue level (tumor) and at blood 
level (circulating DNA) in metastatic colorectal cancer as part of the high-light study) are eligible for inclusion. 
Determining tumor mutation status 
There will be a standard RAS status determination in each hospital. 
Subsequent confirmation of RAS (KRAS and NRAS) status will be carried out centrally (pyrosequencing, Poitiers 
University Hospital) from the collection of tumor blocks. 
The tumour blocks (tumour blocks if available, and any tumour biopsies used for diagnosis) will be sent to the 
EPIGENETEC BRC: 
EPIGENETEC - INSERM Unit U775 
45 rue des Sts Pères 
75006 PARIS 
Determining mutation status in blood 
For centralized analysis of circulating KRAS and mutant NRAS DNA, blood samples will be taken prior to 
chemotherapy infusion in cycles 1, 2, 5 and 8, i.e. a total of 4 samples for each patient. These samples should be 
taken on STRECK tubes supplied, in 2 x 10 mL tubes.  
The tubes will be transported to the EPIGENETEC BRC via a courier immediately after sampling.  
 
11 
MANAGEMENT OF SERIOUS ADVERSE EVENTS (EIG)  
 
Safety will be assessed by evaluating patients' general and clinical condition, and by recording events occurring 
between visits during consultations, and by regular blood tests. Toxicities will be assessed using the NCI-CTC-AE 
version 4.0 toxicity scale, and collected in the observation notebook (see Appendix 8). 
In the event of an emergency, the patient, the patient's family or the patient's doctor should call the investigator to 
inform him of the event. 
11.1 
Definitions 
Adverse Event (AE) 
An adverse event is a noxious occurrence in a person undergoing biomedical research, whether or not it is related 
to the research or to the research product. 
Serious adverse event (SAE) 
A serious adverse event is any event that meets at least one of the following criteria:  


 
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- Resulting in death, 
- Life-threatening, 
- Resulting in hospitalization or prolongation of hospitalization, 
- Causing permanent disability or severe temporary incapacity, 
- Causing birth defects, fetal malformation or abortion, 
- Medically significant  
The terms disability and incapacity refer to any temporary or permanent, clinically significant physical or mental 
handicap affecting the patient's physical activity and/or quality of life. 
Any clinical event or laboratory result considered serious by the investigator and not corresponding to the severity 
criteria defined above is considered medically significant. They may place the patient at risk and require medical 
intervention to prevent an outcome corresponding to one of the above-mentioned severity criteria (e.g. overdoses, 
second cancers, pregnancies and new events may be considered medically significant). 
Pregnancy is a criterion for non-inclusion in this trial, and contraceptive measures must be taken throughout 
treatment and up to 6 months after discontinuation. However, if pregnancy is discovered in an enrolled patient after 
inclusion, she must be excluded from the trial, and the sponsor must be informed without delay via the serious 
adverse event notification form (no severity criteria will be ticked). The patient must be followed until the end of the 
pregnancy, and this outcome, whatever it may be, must be reported to the sponsor.  
Similarly, if a pregnancy occurs in the partner of a patient included in the trial, the sponsor must be informed in the 
same way and will try, as far as possible, to follow the pregnancy to term.  
 
Undesirable effect  
Any noxious and undesired response to an investigational drug at any dose, or to any investigational component. 
An adverse reaction is considered serious if it meets a severity criterion. 
Unexpected Serious Adverse Effect 
An unexpected serious adverse reaction is an event that is not mentioned, or that differs in nature, intensity or 
evolution from the product's reference document (or RCPs). 
Intensity (or severity) 
The intensity criterion should not be confused with the severity criterion, which serves as a guide for defining 
reporting obligations. 
The intensity of events will be estimated according to the CTC-AE version 4.0 classification extract (appendix 8). 
The intensity of adverse events not listed in this classification will be assessed according to the following qualifiers: 
- Mild (grade 1): does not affect the patient's usual daily activity 
- Moderate (grade 2): disrupts the patient's usual daily activity 
- Severe (grade 3): prevents the patient's usual daily activities 
- Very severe (grade 4): requires resuscitative measures / life-threatening 
- Death (grade 5). 
Causal relationship 
Related: an event is said to be related when a causal relationship between the event and the product under study 
can reasonably be suspected.  
Unrelated: an event is said to be unrelated when a causal relationship between the event and the product under 
study cannot reasonably be suspected. 
Doubtful: causality is said to be "doubtful" when there is doubt about the causal relationship between the event and 
the product under study (the relationship can then be neither formally excluded nor formally affirmed). 
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On receipt of the investigator's report of a serious adverse event, the sponsor must issue an opinion on the causal 
relationship between the serious adverse event and the study product(s).  
If the serious adverse event is linked by the investigator and/or sponsor to one of the products under study (i.e. a 
serious adverse event), the investigator and/or sponsor must establish whether the event was expected or 
unexpected. 
In the case of an unexpected serious adverse event, or a new development, the sponsor draws up an initial report 
which is sent to the ANSM, the CPP and the EMA (via EudraVigilance) within 7 days in the case of death or life-
threatening event, otherwise within 15 days. 
If it is an expected serious adverse event, it will be collated for the purposes of the half-yearly and annual safety 
reports. 
 
11.2 
Events not to be considered serious  
Disease progression should not be considered as a SAE. On the other hand, events potentially linked to the 
progression of the disease but which may be secondary to treatment should be reported (e.g. thromboembolic 
events, haemorrhagic phenomena, perforations, etc.). 
Due to the severity of the disease in this study, certain conditions defined as SAEs will be excluded from the SAE 
reporting procedure, i.e. :  
- Hospitalization or surgery specifically related to the treatment of the disease 
- Hospitalization to simplify study treatments or procedures 
 
In this test, the reference documents will be : 
- 
For 5FU, the Summary of Product Characteristics for Fluorouracil Ebewe® 50 mg/mL (Appendix 7)  
- 
For folinic acid, the Summary of Product Characteristics for Elvorine® (Appendix 7)  
- 
For oxaliplatin, the Summary of Product Characteristics for Eloxatine® (Appendix 7) 
- 
For irinotecan, the Summary of Product Characteristics for Campto® (Appendix 7) 
- 
For capecitabine, the Summary of Product Characteristics for Xeloda® (Appendix 7) 
- 
For bevacizumab, the Avastin® Summary of Product Characteristics (Appendix 7) 
The PCR versions used to define whether a product is expected or unexpected are those in force at the time of 
analysis. 
 
NB: for 5-fluorouracil, venous thromboembolic events are considered as expected, although not listed in the RCP. 
11.3 
Procedure  
The investigator informs the sponsor of all Serious Adverse Events (expected and unexpected), whether attributable 
to the research or not, which occur during the study or 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 must be reported without time limit. 
The report is made by faxing the "notification of a serious adverse event" form, documented as accurately as 
possible, dated and signed, within 24 working hours of the SAE's detection, to the FFCD's Centre de Randomisation 
Gestion Analyse (CRGA) by fax (03 80 38 18 41). 
The investigator is responsible for the appropriate medical follow-up of patients until resolution or stabilization of 
the effect, or until the patient's death. This may sometimes involve extending follow-up beyond the trial patient's 
protocol monitoring period. 
He/she transmits the additional information to the sponsor using an SAE reporting form (ticking the Follow-up n° X 
box to specify that this is a follow-up report and not an initial report) within 24 hours of obtaining it. It also transmits 
the last follow-up to the resolution or stabilization of the SAE.  


 
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It responds to requests for additional information to document the initial observation. 
 
12 
STATISTICAL ANALYSIS 
 
12.1 
Judging criteria 
Primary endpoint 
The primary endpoint is the rate of patients without strategy failure 16 months after randomization.  
Strategy failure is defined by (see figure 1):  
• 
Progression (under certain conditions) using  
RECIST criteria  
version 1.1 or 
• 
Deaths (all causes) or  
• 
Toxicity leading to permanent discontinuation of one of the chemotherapy products (oxaliplatin and/or 
irinotecan) or 
• 
Patient's refusal to continue the strategy or 
• 
Investigator's decision to discontinue strategy 
 
Progression has a different definition depending on the strategy, because the two strategies are different:  
In the standard strategy (escalation), progression is considered a failure:  
• 
If it occurs during 1ère chemotherapy (LV5FU2 + bevacizumab) and if 2ème  chemotherapy (FOLFIRI + 
bevacizumab) cannot be administered, or 
• 
if it occurs during 2ème chemotherapy (FOLFIRI + bevacizumab) and if 
bevacizumab) and if 3ème 
chemotherapy (FOLFOX + bevacizumab) cannot be administered e or 
• 
if it occurs during 3ème chemotherapy.  
In the experimental strategy (de-escalation), a progression is considered a failure: 
• 
if it occurs during intensive chemotherapy (modified FOLFOXIRI + bevacizumab) or if it occurs during 
chemotherapy with FOLFIRI + bevacizumab  
 
 
Secondary endpoints 
The best response according to RECIST version 1.1 at 16 months will be assessed on scans performed during the 
strategy.  
The time to best response will be the time between the date of randomization and the date of the first best response 
scan to the strategy.  
Time to strategy failure will be the time between the date of randomization and the date of strategy failure (according 
to the definition of the primary endpoint).  
For progression-free survival, the time between the date of randomization and the date of the first radiological 
progression or death (from any cause) will be calculated. Patients alive without progression will be censored at the 
date of their last news.  
For overall survival, the time between the date of randomization and the date of death (from all causes) will be 
calculated. Living patients will be censored at the date of their last news.  
The tolerability of both strategies will be evaluated according to reported toxicities (NCI-CTC version 4.0) and their 
grade. The following events of particular interest will also be described: hypertension, proteinuria, gastrointestinal 
perforation, abscesses and fistulas, wound healing complications, hemorrhages, arterial and venous 


 
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thromboembolic events, posterior reversible encephalopathy syndrome, congestive heart failure, non-
gastrointestinal fistulas and abscesses. 
The dose intensity of each treatment and the duration of the strategy will be described.  The duration of the strategy 
will be calculated as the time between the date of the first course of treatment and Day 1 of the last course (+14 
days if the patient is receiving 5FU IV or +21 days if the patient is receiving capecitabine). 
Quality of life (QLQ-C30 EORTC v3.0 questionnaire) will be studied descriptively. Time to deterioration in quality of 
life will be studied.  
 
12.2 
Calculating the number of subjects required 
The clinical hypotheses for the study design are as follows:  
H0 : A rate of 40% of patients alive and without strategy failure at 16 months is not interesting.  
H1 : A live patient rate without strategy failure at 16 months of 55% is expected. 
With an α risk (one-sided) of 5% for a power of 80.85%, using the exact binomial method (15) (R software), 75 
patients will be randomized to each strategy.  
Taking into account that 10% of patients will not be evaluable for the mITT population, 84 patients per strategy will 
be randomized according to the 1:1 ratio.  
The conclusion of the study will be based solely on the experimental strategy as defined below and on the first 75 
evaluable patients:  
If 38 or more patients do not fail the strategy at 16 months, the strategy is considered effective. 
 
12.3 
Statistical analysis plan 
12.3.1 Analysis populations  
 
ITT population (ITT): All patients included in the study, regardless of inclusion or non-inclusion criteria, and 
analyzed according to the strategy assigned by randomization.  
 
Modified ITT population (mITT): All patients in the ITT population who received at least one dose of treatment 
(regardless of dose and treatment) and who underwent imaging assessment during the strategy.  
 
Per-protocol population (PP): All patients in the ITT population who have had at least one dose of treatment 
(regardless of dose and treatment) and who have had an imaging evaluation during the strategy and have no major 
protocol deviations. 
 
Population Tolerance (PT): All patients included in the study who received at least one dose of treatment 
(whatever the dose and treatment). The analysis will be performed according to the strategy actually used.  
 
Analysis of the primary and secondary efficacy endpoints will be performed in ITTm and ITT population.  
The primary endpoint and efficacy criteria will also be assessed in the per-protocol (PP) population.  
Tolerance criteria will be analyzed in the tolerance population (TP).  
 
12.3.2 Evaluation of criteria  
 
General considerations  


 
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All analyses will be performed using SAS software version 9.4 or higher or STATA V10 or higher. A statistical 
analysis plan will be drawn up before the database is frozen. Any subsequent changes to this analysis plan must 
be detailed, justified and commented on in an updated version. Such modifications may concern additional 
exploratory analyses not initially envisaged.  
Continuous variables are described using mean, standard deviation, median, inter-quartile range, minimum and 
maximum. Categorical variables are described using frequencies and percentages.  
Demographic and clinical characteristics at inclusion will be described for the ITT population. 
 
Evaluation of efficacy criteria (mITT and ITT):  
The rate of patients without strategy failure at 16 months will be calculated on the basis of the investigator's 
assessment at 16 months +/- 30 days. It will be described using a percentage and a one-sided 95% confidence 
interval.  
Survival and time will be estimated using the Kaplan-Meier method. They will be described by medians and rates 
at different temporalities with their 95% confidence intervals.  
The median follow-up time will be calculated using the "reverse Kaplan-Meier" method.  
The best response to treatment will be described by strategy, as will the time to best response and the time to 
strategy failure. 
QLQ-C30 scores will be described by strategy at inclusion and during follow-up. Based on the overall score, the 
time to definitive deterioration, defined as the time between randomization and the date of a decrease of more than 
5 points (compared with inclusion) without improvement, will also be analyzed by the Kaplan-Meier method. 
 
Evaluation of tolerance criteria (PT) :  
The duration of treatment for each chemotherapy and the total duration of the strategy will be described using 
descriptive statistics. The dose intensity of each treatment will be described. 
Toxicities will be described, by strategy, and by grade. In addition, the following events of particular interest will also 
be described: hypertension, proteinuria, gastrointestinal perforation, abscesses and fistulas, wound healing 
complications, bleeding, arterial thromboembolic events, venous thromboembolic events, posterior reversible 
encephalopathy syndrome, congestive heart failure, fistulas and non-gastrointestinal abscesses. 
12.4 
Study committees 
12.4.1 Independent Committee 
An independent monitoring committee will be set up, including at least 2 gastroenterologists/oncologists, a 
statistician and a pharmacovigilance expert. The independent committee will assess safety data (toxicities and 
SAEs) on a regular basis. It may also be called upon at any time during the study, should the FFCD deem it 
necessary. Their functions will be described in the independent monitoring committee charter.  
The Chairman of the Independent Committee will forward his recommendations to the Chairman of the Steering 
Committee. 
12.4.2 Board of Directors 
A steering committee will be set up, chaired by the main coordinator. This committee will include a UNICANCER 
representative, a representative of the sponsor, the FFCD project manager, the FFCD statistician and the chairman 
of the Biological Research Committee. Its mission will be, among other things, to make decisions relating to the 
management of the research (amendment, premature closure if necessary, etc.). This committee will meet as often 
as necessary throughout the study. 
 
12.4.3 Biological Committee 
A Biological Research Committee will be set up to manage and bank blood and tumor samples. It will identify 
relevant biological prognostic and predictive factors, as well as relevant polymorphisms to be tested. It will organize 
analyses with selected laboratories. This committee will include the members of the study's steering committee; its 


 
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chairman will be the head of the EPIGENETEC CRB, Prof. Pierre Laurent-Puig. 
This committee will meet regularly and report on its biological research projects to the steering committee and the 
sponsor. 
 
13 
LEGAL AND ETHICAL ASPECTS 
 
 
STUDY SPONSOR 
The study sponsor is the Fédération Francophone de Cancérologie Digestive (FFCD). The study has been 
registered under EudraCT number 2016-001225-13. 
 
 CURRENT LEGISLATION 
This test will be carried out in accordance with the new European Directive 2001/20/EC.  
 
LIABILITY INSURANCE 
Insurance was taken out by the promoter on 17/03/2016 under number 137681, in accordance with article L 1121-
10 of the public health code (Appendix 10).  
 
REQUEST FOR AUTHORIZATION FROM CPP AND ANSM 
This protocol received the favorable opinion of the CPP (Comité de protection des personnes) Sud Est I on 
11/05/2016 (Appendix 11). 
This protocol received authorization from the ANSM (Agence Nationale de Sécurité du médicament et des produits 
de santé) on 18/05/2016 (Appendix 12). 
 
 
OBTAINING THE PATIENT'S CONSENT 
The investigator undertakes to obtain the patient's written clinical and biological consent (information sheets and 
consent forms in Appendices 1 and 2) before the patient is enrolled in the study. The investigator must keep a copy 
of these consents for 15 years, for presentation to the regulatory authorities in the event of inspection. The original 
must be given to the patient. 
In accordance with the recommendations of the Cancer Plan (Measure 5.4), this document has been submitted to 
the Patients' Committee for Clinical Research (CPRC) of the Ligue Nationale Contre le Cancer. 
 
HOSPITAL MANAGEMENT INFORMATION AND RESEARCH AGREEMENT 
Prior to setting up the study, hospital management will be informed by the promoter of the investigator's interest in 
participating in the trial. 
A research agreement will be drawn up between the administrator of the investigating center and the sponsor.  
 
DATA ARCHIVING 
Records will remain confidential and may only be consulted under the responsibility of the doctors in charge of the 
patients. The promoter and, in the event of an inspection, the health authorities 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. 


 
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IT SUPPORT 
In accordance with the French Data Protection Act no. 78-17 of January 6, 1978, as amended by the Act of August 
9, 2004, trial data will be stored in a computer database at the FFCD's Randomization and Analysis Management 
Center, with the exception of information relating to patient identity. 
 
DATA PROCESSING 
The FFCD's Center for Randomization, Management and Analysis (CRGA) will be responsible for data 
management and analysis.  
 
MONITORING, QUALITY ASSURANCE AND INSPECTIONS BY THE AUTHORITIES 
The investigator accepts in advance that the files of included patients may be consulted by a person mandated by 
the FFCD and/or the health authorities to carry out an audit. On-site file visits, scheduled with the investigator's 
agreement, may take place during or after the trial inclusion period. 
This protocol will be monitored by the FFCD's mobile ARCs.  
 
 
14 
PUBLICATION 
PRODIGE publication rules will be applied (Appendix 9). Publications follow ICMJE recommendations (16). 
 


 
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15 
 REFERENCES 
 
 
1- Koopman M, Simkens LH, Ten Tije AJ et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction 
treatment with chemotherapy and bevacizumab in metastatic colorectal cancer: The phase III CAIRO3 study of the Dutch Colorectal Cancer 
Group. J Clin Oncol;31 (suppl, A 3502)  
2- Chibaudel B, Maindrault-Goebel F, Lledo G et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The 
GERCOR OPTIMOX2 Study. J Clin Oncol 2009;27:5727-33 
3- Falcone A, Cremolini C, Masi G, et al. Modified FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable 
metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group. J Clin Oncol 31, 2013 (suppl; abstr 
3505) 
4- Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N 
Engl J Med 2004;350:2335-42 
5- Lenz H, Niedzwiecki D, Innocenti F et al. CALGB/SWOG 80405: PHASE III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-
FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab. Annals of Oncology (2014) 25 (5): 1-41 
6- Saunders MP et al. Efficacy and safety according to age subgroups in AVEX, a randomized phase III trial of bevacizumab in combination 
with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer. J Clin Oncol 2013 (suppl, A 3521) 
7- Hegewisch-Becker S, Graeven U, Lerchenmüller C et al. Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (Bev), Bev 
alone or no treatment, following a 24-week first-line induction with FP, oxaliplatin (Ox) and Bev for patients with metastatic colorectal cancer: 
Mature data and subgroup analysis of the AIO KRK 0207 phase III study. Annals of Oncology (2014) 25 (suppl_4) 
8- Aparicio T, Bennouna J, Le Malicot et al. Interim analysis of PRODIGE 9, a randomized phase III trial comparing no treatment to bevacizumab 
maintenance during chemotherapy-free intervals in metastatic colorectal cancer. Annals of Oncology (2014) 25 (suppl_4) 
9- Bennouna J, Sastre J, Arnold D et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a 
randomised phase 3 trial. Lancet Oncol 2013 ;14 :29-37 
10- Masi G, Loupakis F, Salvatore L et al. Second-line chemotherapy (CT) with or without bevacizumab (BV) in metastatic colorectal cancer 
(mCRC) patients (pts) who progressed to a first-line treatment containing BV: Updated results of the phase III "BEBYP" trial by the Gruppo 
Oncologico Nord Ovest (GONO). J Clin Oncol 2013 ;31, (Suppl15, A3615) 
11- Van Cutsem E, Tabernero J, Lakomy R et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase 
III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30:3499-
3506 
12- Ducreux M, Castaing M, Etienne PL et al. Strategic trial of chemotherapy for metastatic colorectal cancer (FFCD 2000-05 study). Preliminary 
results. Gastroenterol Clin Biol 2008 ;32 :A25 
13- Koopman M, Antonini NF, Douma J et al. Sequential versus combination chemotherapy with Capecitabine, Irinotecan and Oxaliplatin in 
advanced colorectal cancer (CAIRO): a phase III randomized controlled trial. Lancet 2007 ;370 :135-42 
14- Seymour MT, Maughan TS, Ledermann JA et al. Different strategies of sequential and combination chemotherapy for patients with poor 
prognosis advanced colorectal cancer (MRC FOCUS): a phase III randomized controlled trial. Lancet 2007;370:143-52 
15- A'Hern R. P., Sample size tables for exact single-stage phase II designs. Statistics in medicine 2001; 20:859 - 866 
16- Recommendations for the Conduct, Reporting, Editing, and 
Publication of Scholarly Work in Medical Journals. ICMJE recommendations December 2014 
 

SAP_001.pdf: 
 
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RANDOMIZED PHASE II EVALUATION OF EFFICACY AND TOLERANCE 
OF 2 THERAPEUTIC STRATEGIES COMBINING BEVACIZUMAB WITH 
CHEMOTHERAPY: DE-ESCALATION VERSUS ESCALATION IN 
PATIENTS WITH UNRESECTABLE, NON-PRE-TREATED METASTATIC 
COLORECTAL CANCER 
 
PRODIGE 45 - HIGHLIGHT 
 
 
 
Statistical analysis plan 
Final analysis  
Version 2.0 of 25/11/2020 
 
 
 
 
 
Editor: Karine Le Malicot 
Review committee: Pr Jean-Marc Phelip, Lila Gaba, Francis Diedhiou, Emilie Barbier  
 
 
Subscribe 
to 
DeepL 
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Visit www.DeepL.com/pro for more information. 


 
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Signature page  
 
By signing this sheet, I agree to the statistical analysis plan: 
 
Prof. Jean-Marc Phelip 
Date 
Signature 
Coordinator 
 
 
 
  
 
Karine Le Malicot  
Date 
Signature 
FFCD 
 
 
Biostatistician 
 
 
Emilie Barbier 
Date 
Signature 
FFCD 
 
 
Independent statistician  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table of contents 
1 
Introduction ..................................................................................................................................................................................................................6 
1.1 
Test objectives ..................................................................................................................................................................................................6 
1.1.1 
Main objective .............................................................................................................................................................................................6 
1.1.2 
Secondary objectives ................................................................................................................................................................................6 
1.1.3 
Objectives Biological ancillaries ..........................................................................................................................................................7 
2 
Experimental design ..................................................................................................................................................................................................7 
2.1 
Study diagram ...................................................................................................................................................................................................7 
2.2 
Treatment arms ...............................................................................................................................................................................................7 
2.3 
Randomization .................................................................................................................................................................................................8 
2.4 
Study diagram ...................................................................................................................................................................................................8 
2.5 
Number of subjects required .....................................................................................................................................................................8 
2.6 
Test planning/analysis history .................................................................................................................................................................9 
3 
Study populations for analysis ..............................................................................................................................................................................9 
3.1 
Intent-to-treat (ITT) population ...............................................................................................................................................................9 
3.2 
Modified intention-to-treat population (mITT) ................................................................................................................................9 
3.3 
Per-Protocol (PP) population ....................................................................................................................................................................9 
3.4 
Population for safety analysis (SP) .........................................................................................................................................................9 
4 
General information on statistical analysis methods .................................................................................................................................9 
4.1 
Software ..............................................................................................................................................................................................................9 
4.2 
Agreements concerning dates and durations .....................................................................................................................................9 
4.3 
Conventions concerning missing data ................................................................................................................................................ 10 
4.4 
Baseline definition ....................................................................................................................................................................................... 10 
4.5 
Definition of analysis subgroups ........................................................................................................................................................... 10 
5 
General information on statistical analysis .................................................................................................................................................. 10 
6 
Statistical analysis ................................................................................................................................................................................................... 11 
6.1 
Patient characteristics at randomization .......................................................................................................................................... 12 
6.1.1 
Inclusion and non-inclusion criteria at inclusion ..................................................................................................................... 12 
6.1.2 
Demographics .......................................................................................................................................................................................... 12 
6.1.3 
Clinical and disease-related features ............................................................................................................................................. 12 
6.1.4 
Biological characteristics .................................................................................................................................................................... 13 
6.2 
Efficiency assessment................................................................................................................................................................................. 13 
6.2.1 
Monitoring features ............................................................................................................................................................................... 13 
6.2.2 
Main criterion ........................................................................................................................................................................................... 13 
6.2.3 
Secondary efficacy criteria ................................................................................................................................................................. 14 
6.3 
Tolerance assessment ................................................................................................................................................................................ 16 
6.3.1 
Treatment administration .................................................................................................................................................................. 16 
6.3.2 
Toxicities .................................................................................................................................................................................................... 16 
6.3.3 
Serious adverse events ......................................................................................................................................................................... 16 


 
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6.4 
Quality of life analyses ............................................................................................................................................................................... 16 
6.4.1 
Descriptive analysis ............................................................................................................................................................................... 16 
6.4.2 
Analysis of scores and time to final deterioration ................................................................................................................... 17 
6.5 
Additional analyses ..................................................................................................................................................................................... 17 
6.1 
Ancillary analyses ........................................................................................................................................................................................ 17 
7 
Third-party validation of analyses ................................................................................................................................................................... 17 
 
 
 


 
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Abbreviations :  
 
RECIST 
ResponseEvaluation Criteria In Solid Tumours 
SSP 
Survival without progression 
SG 
Overall Survival 
TS 
Thymidilate Synthase 
ITT 
Intent to treat 
ITTm 
Modified intention to treat 
PP 
Per protocol 
SP 
Safety Population 
BMI 
Body Mass Index 
NOT 
Systolic blood pressure 
PAD 
Diastolic blood pressure 
SOC 
System Organ Class 
PT 
Preferred Term 
 
 
 


 
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1 Introduction 
 
1.1 Objectives of the trial 
 
1.1.1 
Main objective 
 
The primary objective is to evaluate the rate of patients without strategy failure 16 months after randomization.  
 
Strategy failure is defined by :  
• 
Progression (defined in each arm)* using RECIST v1.1 criteria or 
• 
Deaths (all causes) or 
• 
Toxicity leading to permanent discontinuation of one of the chemotherapy products (oxaliplatin and irinotecan) 
or 
• 
Patient's refusal to continue the strategy or 
• 
Investigator's decision to discontinue strategy 
 
*Progression is defined differently depending on the treatment arm because the two strategies are different:  
• 
In the standard (climbing) arm, progression is considered a failure:  
If it occurs during 1st chemotherapy with LV5FU2 + bevacizumab and 2nd chemotherapy with FOLFIRI + 
bevacizumab cannot be administered 
if it occurs during 2nd chemotherapy with FOLFIRI + bevacizumab and if 3rd chemotherapy with FOLFOX + 
bevacizumab) cannot be administered e or if it occurs during 3rd chemotherapy 
 
• 
In the experimental strategy (de-escalation), progression is considered a failure: 
if it occurs during chemotherapy with modified FOLFOXIRI + bevacizumab or FOLFIRI + bevacizumab. 
Progression during treatment with capecitabine/LV5FU2 + bevacizumab does not constitute failure of the 
strategy. 
 
1.1.2 
Secondary objectives 
The secondary objectives are:  
• 
Best response according to RECIST version 1.1 at 16 months 
• 
Time to best response during the strategy 
• 
Time to strategy failure 
• 
Progression-free survival (PFS) at 2 and 3 years over the course of the strategy 
• 
Overall survival (OS) at 2 years and 3 years  
• 
Tolerance of both strategies  
• 
The dose intensity for each treatment and the duration of the strategy 
• 
Quality of life (EORTC QLQ-C30) 
 


 
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1.1.3 
Objectives Biological ancillaries 
 
 Organic : 
• 
Demonstrate the impact of RAS mutations on response to bevacizumab in mRCC 
• 
Demonstrating the impact of thymidilate synthase (TS) polymorphism 
• 
Prospectively determine the frequency of tumor patients with low levels of mutated RAS alleles. 
• 
Evaluate the use of a new, highly sensitive technique for determining RAS status in blood. 
• 
Analyze the correlation between the level of mutated RAS alleles in the primary tumor and peripheral blood. 
• 
Analyze changes in the rate of mutated RAS alleles over time.  
• 
Assess circulating VEGF (at time of diagnosis and every 2 cures) 
Imaging : 
• 
Evaluate the relationship between PFS and tumor size at diagnosis 
• 
Evaluate the relationship between PFS and visceral fat (measured by CT scan at inclusion) 
 
2 Experimental design 
2.1 Study diagram 
 This study is a phase II randomized non-comparative trial. 
 
2.2 Treatment arms 
 
In the standard arm or escalation strategy, patients will receive 1ère chemotherapy based on LV5FU2 or capecitabine 
+ bevacizumab. After progression, they will receive 2ème chemotherapy with FOLFIRI + bevacizumab. After progression, 
they will receive 3ème chemotherapy with FOLFOX4 + bevacizumab.  
When progression occurs during 3ème chemotherapy, or 3ème CT cannot be administered, patients will be treated 
according to the investigator's choice.  
 
In the experimental arm or de-escalation strategy, induction treatment (4 cycles of FOLFOXIRI + bevacizumab 
followed by 4 cycles of FOLFIRI + bevacizumab) is followed by maintenance with (LV5FU2 or capecitabine) and 
bevacizumab until progression. After 1ère progression during maintenance treatment, the patient will be treated again 
with induction treatment (4 cycles of FOLFOXIRI + bevacizumab followed by 4 cycles of FOLFIRI + bevacizumab) followed 
by maintenance with capecitabine and bevacizumab until progression and so on.  
If progression occurs during induction therapy (FOLFOXIRI + bevacizumab or FOLFIRI + bevacizumab), patients will be 
treated according to the investigator's choice. 
 
 


 
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2.3 Randomization  
 Patients were randomized (1:1) using the minimization technique (Pocock and Simon (Biometrics, 1975)) according to 
the following stratification factors:  
• 
Center  
• 
WHO performance index 0/1 vs 2 
 
2.4 Study diagram 
 The following diagram illustrates the patient follow-up process: 
 
 
 
 
2.5 Number of subjects required 
The clinical hypotheses for the study design were :  
 
H0 : A rate of 40% of patients alive and without strategy failure at 16 months is not interesting.  
H1 : A live patient rate without strategy failure at 16 months of 55% is expected. 
 
With an α risk (one-sided) of 5% for a power of 80.85%, using the exact binomial method (R software), 75 patients were 
to be randomized to each strategy.  


 
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Taking into account that 10% of patients will not be evaluable for the mITT population, 84 patients per strategy will be 
randomized according to the 1:1 ratio.  
The conclusion of the study was to be based solely on the experimental strategy according to the rule defined below and 
on the first 75 evaluable patients:  
• 
If 38 or more patients do not fail the strategy at 16 months, the strategy is considered effective. 
 
2.6 Trial planning/analysis history 
 
 The trial was stopped at 21 randomized patients because patient recruitment was slow and difficult.  The last patient 
was randomized on April 10, 2018. 
 
Follow-up of randomized patients has continued, and a final analysis will be carried out when all patients are off 
treatment. 
 
3 Study populations for analysis 
 
3.1 Intention-to-treat (ITT) population 
All patients included in the study, regardless of inclusion or non-inclusion criteria, and analyzed according to the strategy 
assigned by randomization. 
 
3.2 Modified intention-to-treat population (mITT) 
All patients in the ITT population who received at least one dose of treatment (regardless of dose and treatment). 
 
 
3.3 Per-Protocol (PP) population 
Not applicable 
3.4 Population for safety analysis (SP) 
 Not applicable. Safety analysis will be performed on the ITTm population. 
 
4 General information on statistical analysis methods 
4.1 Software 
Statistical analyses will be carried out using SAS software version 9.4 or later and R.  
 
4.2 Agreements concerning dates and durations 
Time since randomization will be defined as the time elapsed since the day of randomization, with the day of 
randomization taken as day 1. 


 
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Time since start of treatment will be defined as the time elapsed since the day of first treatment administration, this day 
being considered as day 1. 
As a result, durations are calculated using the following rule, for example for the time elapsed between death and 
inclusion: day of death - day of inclusion + 1. 
The day preceding the day of inclusion (resp. the day preceding the day of treatment) will be considered as day -1 (day 0 
does not exist). 
 
The date of last news will be the date of the last examination performed or the last treatment taken in the last follow-
up/consultation. 
 
The following conversion rules will be used to convert numbers of days into numbers of months or years: 1 month = 
30.4375 days; 1 year = 365.25 days. 
 
4.3 Missing data conventions 
Except in the cases specified, missing data will not be replaced. 
 
In the event of partially missing date data, the following rules will apply  
For a start date : 
                - if the day is missing (UK/01/2012), the day will be set to "01". 
                - if the month is missing (UK/UK/2012), the date will be set to "01/01/2012". 
For an end date : 
                - if the day is missing (UK/01/2012), the day will be set to "30" (although beware of February). 
               - if the month is missing (UK/UK/2012), the date will be set to "30/12/2012". 
For all other dates: 
                - if the day is missing (UK/01/2012), the day will be set to "15". 
                - if the month is missing (UK/UK/2012), the date will be set to "15/06/2012". 
 
4.4 Baseline definition 
Randomization measurements are the last measurements taken before randomization. In the event of missing data, the 
first measurement taken before the first treatment is used. 
 
4.5 Definition of analysis subgroups 
Not applicable 
 
5 General information on statistical analysis 
 
Quantitative data will be described for each group and for the population as a whole, using the following descriptive 
statistics: headcount, mean, standard deviation, median, first and third quartile, minimum and maximum. These statistics 


 
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will be considered as 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 for each group and for the population as a whole, using the following 
descriptive statistics: frequencies and percentages for each level of the variable. These statistics will be considered as the 
usual statistics for the analysis of categorical variables. Where necessary, confidence intervals for the proportions will be 
calculated.   
 
For the primary endpoint, a two-sided 90% confidence interval will be calculated.   
 
Survival is estimated for censored variables using the Kaplan Meier method (Kaplan and Meier, 1958). This will be 
described by the median and rates calculated at different times. 95% confidence intervals will be provided. Confidence 
intervals for rates will be constructed from the Greenwood variance calculated using the log-log transformation. For the 
median confidence interval, the upper bound will be defined as the smallest time for which the upper bound of the 
associated survival rate confidence interval, calculated using Greenwood's method, is less than or equal to 50%. Similarly, 
the lower bound will be the smallest time for which the lower bound of the confidence interval of the associated survival 
rate is less than or equal to 50%.  
   
The median follow-up time is calculated using the reverse Kaplan-Meier method (Shemper, 1996). 
 
Unless otherwise stated, results will be described separately for each treatment arm; thus, where "total number of 
patients" is specified, the total number of patients in the arm in question should be considered. 
 
6 Statistical analysis 
 
 
 
ITT 
ITTm 
Eligibility 
X 
  
Characteristics of the population at randomization 
X 
  
Main criterion 
Failure-free rate at 16M 
X 
X 
Secondary criteria 
Overall survival 
X 
X 
Progression-free survival 
X 
X 
Best answer 
X 
X 
Time to best response 
X 
X 
Time to strategy failure 
X 
X 


 
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Treatment administration 
 
X 
NCI-CTC toxicities 
 
X 
Quality of Life 
X 
 
 
6.1 Patient characteristics at randomization 
 
Patient characteristics at inclusion will be described by treatment arm and in total for the ITT population. 
 
6.1.1 
Inclusion and non-inclusion criteria at inclusion  
 
A description of the stratification factors (described on the randomization sheet) and of the inclusion and non-inclusion 
criteria for each treatment arm will be carried out to ensure that the stratification factors are correctly distributed, but 
no statistical tests will be performed. 
 
6.1.2 
Demographic characteristics 
  
The following characteristics at inclusion will be described using descriptive statistics: 
• 
Age 
• 
sex, 
 
6.1.3 
Clinical and disease-related features 
The following characteristics at inclusion will be described using descriptive statistics: 
• 
BMI (Kg/m²) 
• 
PAS (mmHg) 
• 
PAD (mmHg) 
• 
kRAS status 
• 
nRAS status 
• 
Delay between randomization and diagnosis 
• 
Histological type 
• 
Tumor size (mm) 
• 
Location 
• 
Resection of the primary tumor 
• 
Adjuvant chemotherapy 
• 
Length of illness 
• 
Metastatic location 
• 
The number of metastatic sites 
 


 
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6.1.4 
Biological characteristics 
The following characteristics at inclusion will be described using descriptive statistics: 
• 
PNN (/mm )3 
• 
Inserts (*10 /mm )33 
• 
HB (g/dL) 
• 
Leukocytes (/mm )3 
• 
Lymphocytes (/mm )3 
• 
TP (%) 
• 
TCK (seconds) or TCA (ratio) 
• 
PAL (IU/L) 
• 
AST (UI/L) 
• 
ALAT (UI/L) 
• 
GGT (UI/L) 
• 
LDH (UI/L) 
• 
Albuminemia (g/L) 
• 
Protidemia (g/L) 
• 
Total bilirubin (µmol/L) 
• 
Conjugated bilirubin (µmol/L) 
• 
Calcium (mmol/L) 
• 
Potassium (mmol/L) 
• 
Magnesium (mmol/L) 
• 
Sodium (mmol/L) 
• 
Creatinine clearance (mL/min) 
• 
Creatininemia (µmol/L) 
 
 
6.2 Efficiency assessment 
 
6.2.1 
Follow-up features 
  
The median follow-up time and its 95% confidence interval will be calculated in months using the inverted Kaplan-Meier 
method. 
 
6.2.2 
Main criterion 
 
6.2.2.1 
Definition of primary endpoint 
The rate of patients without strategy failure at 16 months after randomization will be calculated on the basis of the 
investigator's assessment at 16 months +/- 30 days.  
Strategy failure is defined by :  


 
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• 
Progression (defined in each arm) using RECIST v1.1 or 
• 
Death (all causes) or 
• 
Toxicity leading to permanent discontinuation of one of the chemotherapy products (oxaliplatin and irinotecan) 
or 
• 
Patient's refusal to continue the strategy or 
• 
Investigator's decision to discontinue strategy 
 
Progression is defined differently depending on the treatment arm because the two strategies are different:  
• 
In the standard arm (climbing), progression will be considered a failure:  
If it occurs during 1st chemotherapy with LV5FU2 + bevacizumab and 2nd chemotherapy with FOLFIRI + 
bevacizumab cannot be administered 
if it occurs during 2nd chemotherapy with FOLFIRI + bevacizumab and if 3rd chemotherapy with FOLFOX + 
bevacizumab) cannot be administered or if it occurs during 3rd chemotherapy 
 
• 
In the experimental strategy (de-escalation), progression is considered a failure: 
if it occurs during chemotherapy with modified FOLFOXIRI + bevacizumab or FOLFIRI + bevacizumab. 
Progression during treatment with capecitabine/LV5FU2 + bevacizumab does not constitute failure of the 
strategy. 
 
 
6.2.2.2 
Evaluation of primary endpoint 
It will be described using a percentage and a one-sided 95% confidence interval per arm. 
 
No conclusion on the primary endpoint can be drawn because the number of evaluable patients has not been reached. 
 
6.2.3 
Secondary efficacy criteria 
 
6.2.3.1 
Best RECIST response 
6.2.3.1.1 
Definition   
The best response to treatment is defined according to RECIST v1.1 criteria. 
Imagery taken up to 1 month after stopping treatment and before starting another treatment will be taken into account. 
 
6.2.3.1.2 
Evaluation   
Descriptive statistics will be presented by treatment arm according to the different categories: complete response, partial 
response, stability, progression or non-evaluable.   
 


 
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6.2.3.2 
Time to best answer 
6.2.3.2.1 
Definition   
Time to best response is the time between the date of randomization and the date of the first best response scan to the 
strategy.  
6.2.3.2.2 
Evaluation   
Descriptive statistics will be presented for each treatment arm.   
 
6.2.3.3 
Time to strategy failure  
6.2.3.3.1 
Definition   
Time to strategy failure is the time between the date of randomization and the date of strategy failure.  
6.2.3.3.2 
Evaluation   
Descriptive statistics will be presented for each treatment arm.   
 
6.2.3.4 
Overall Survival (OS) 
6.2.3.4.1 
Definition  
Overall Survival (OS) is defined as the time between the date of randomization and the date of death (whatever the cause). 
For living patients, the time will be calculated between the date of randomization and the date of last news. 
6.2.3.4.2 
Criterion evaluation  
The time scale considered is the year.  
Overall survival will be plotted using the Kaplan Meier estimator, and live patient rates will be given at different time 
points, along with their 95% confidence intervals, and presented by treatment arm. 
 
6.2.3.5 
Progression-free survival  
6.2.3.5.1 
Definition   
Progression is defined as radiological progression according to RECIST v1.1 criteria and/or clinical progression or death. 
Time is defined as the time between the first progression or death and the date of randomization. For patients alive and 
progression-free, time is calculated from the date of randomization to the date of last news. 
6.2.3.5.2 
Evaluation   
The time scale considered is the year.  
Progression-free survival will be plotted using the Kaplan Meier estimator, and rates of live patients will be given at 
different time points, along with their 95% confidence intervals, and presented by treatment arm. 
 
 


 
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6.3 Tolerance assessment 
 
6.3.1 
Treatment administration  
The duration of treatment for each chemotherapy and the total duration of the strategy will be described using 
descriptive statistics. The dose intensity of each treatment will be described. 
 
The dose intensity of each treatment and the duration of the strategy will be described.  The duration of the strategy will 
be calculated as the time between the date of the first treatment course and Day 1 of the last course (+ 14 days if the 
patient is receiving 5FU IV or + 21 days if the patient is receiving capecitabine). 
 
6.3.2 
Toxicities 
 Toxicities will be described by treatment arm and treatment causality (related/doubtful versus unrelated) according to 
NCI-CTC version 4.0 criteria by : 
• 
toxicities over all cycles will be summarized according to maximum grade per soc/ preferred term for each 
patient. 
• 
the number (%) of patients with at least one maximum grade 1-2 and 3-4-5 toxicity by type (SOC and PT); 
• 
number (%) of patients with maximum grade 1-2 and 3-4-5 toxicity, all types combined 
 
In addition, the following events of particular interest will also be described: hypertension, proteinuria, gastrointestinal 
perforation, abscesses and fistulas, wound healing complications, hemorrhages, arterial thromboembolic events, venous, 
posterior reversible encephalopathy syndrome, congestive heart failure, fistulas and non-gastrointestinal abscesses. 
 
A list of grade 5 toxicities will be provided.  
 
6.3.3 
Serious adverse events 
 
The FFCD's pharmacovigilance department will provide a summary of all SAEs. 
 
6.4 Quality of life analyses 
Quality of life will be assessed using the QLQ-C30 questionnaire. Questionnaires are completed before inclusion and 
during the study.  
The QLQ-C30 questionnaire comprises 30 items, with 15 dimensions and 15 scores to calculate: 5 functional ability scores 
(physical ability, ability to work or perform any household task, cognitive ability, emotional state, social state), a global 
quality of life score, a financial problems score and 8 symptom scores (fatigue, nausea/vomiting, pain, dyspnea, sleep 
disturbance, loss of appetite, constipation, diarrhea). 
 
6.4.1 
Descriptive analysis 
 
A description of the number of patients in the following categories by treatment arm will be provided: 


 
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• 
Having a baseline questionnaire 
• 
With at least one follow-up questionnaire 
• 
Having a baseline questionnaire and at least one follow-up questionnaire 
For follow-up questionnaires, a table showing the number of questionnaires per treatment arm will be presented, in 
particular to validate whether the score analyses described below make sense. 
 
6.4.2 
Analysis of scores and time to final deterioration  
 
 
For the QLQ-C30 scores of overall health, physical ability, cognitive ability and fatigue, longitudinal evolution will be 
studied, along with the percentage of symptomatic progression, defined as the percentage of patients with a score 
reduction of at least 5 points compared with inclusion, with no subsequent improvement. 
For the global health score, time to definitive deterioration will also be studied, defined as the time interval between the 
date of randomization and the date of a score decrease of more than 5 points (compared with the score at inclusion) 
without subsequent improvement of more than 5 points, or death, or the date of last news. Living patients without a score 
decrease of more than 5 points will be censored at last news. 
 
6.4.2.1 
Evaluation 
Survival to definitive deterioration of overall health score will be estimated using the Kaplan-Meier method. 
 
6.5 Additional analyses 
Not applicable  
 
6.1 Ancillary analyses 
The ancillary analyses provided for in the protocol will be the subject of one or more statistical analysis plans. 
 
7 Third-party validation of analyses 
 
No analysis validation is planned, since the analyses will be descriptive only.