Safety, Tolerability and Efficacy of Regorafenib in Combination With FOLFIRINOX in Patients With RAS-mutated Metastatic Colorectal Cancer: a Dose-escalation, Phase I/II Trial
Phase: PHASE1
Conditions: Metastatic Colorectal Cancer
Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
 
Safety, tolerability and efficacy of regorafenib in combination with FOLFIRINOX 
in patients with RAS-mutated metastatic colorectal cancer: a dose-escalation, 
phase I/II trial 
 
FOLFIRINOX-R 
 
N°Study Sponsor 
N°EudraCT  
PROICM 2018-08 FOL 
2018-003541-42 
 
CONFIDENTIAL 
 
Study Sponsor 
 Institut régional du Cancer de Montpellier (ICM) 
 208, rue des Apothicaires 
 34298 Montpellier Cedex 5 - France  
 www.icm.unicancer.fr 
 
Contact 
Dr Jean-Pierre BLEUSE 
Head of the clinical and translational research department  
Phone : +33 4 67 61 31 02 
Fax     : +33 4 67 41 30 23 
Email : DRCI-icm105@icm.unicancer.fr 
 
 
Date & Nom du CPP: CPP EST III, le 06/12/2018            Date de l’ANSM : 21/11/2018 
 
Coordinator 
 
Pr Antoine ADENIS 
Department of Medical Oncology  
ICM 
Phone :+33 4-67-61-47-01 
Email : antoine.adenis@icm.unicancer.fr  
Project manager 
 
Patrick CHALBOS 
DRCI 
ICM 
Phone : +33 4  67 61 25 74 
Fax :     +33 4 67 61 23 55 
Email : 
patrick.chalbos@icm.unicancer.fr 
Manager for partnership projects 
 
Stéphanie DELAINE 
DRCI 
ICM 
Phone : +33 4  67 61 47 39 
Email : 
stephanie.delaine@icm.unicancer.fr 
Biostatistician 
Julien FRAISSE  
Biometrics Unit 
ICM 
Phone :+33 4 67 61 30 30 
Fax :     +33 4 67 61 37 18 
Email : julien.fraisse@icm.unicancer.fr  

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
ABBREVIATIONS 
 
 
 
 
List of 
abbreviations 
Explanation 
AE  
Adverse Event 
ALP 
AlkaLine Phosphatase – phosphatase alcaline 
ALT  
Alanine aminotransferase/glutamic pyruvic Transaminase/sGPT 
ANSM 
Agence nationale de sécurité du médicament et des produits de santé 
(French National Agency of Medicines and Health Products Safety) 
Anti-HER1 
Anticorps dirigé contre le récepteur Erb2 du facteur de croissance 
épidermique humain 
AST  
Aspartate aminotransferase/glutamic oxaloacetic Transaminase/sGOT 
AUC 
Area under curve – aire sous la courbe 
β-HCG 
Beta Human Chorionic Gonadotropin 
BICR 
Blinded independent central review 
BSA 
Body Surface Area 
CA 19-9 
Carbohydrate Antigen 19-9 
CBC  
        Complete Blood Count 
CCRm 
Cancer colorectal métastatique 
CEA 
Carcino-Embryogenic Antigen 
cfDNA 
Circulating cell-Free Desoxy-Ribonucleic Acid Complete Blood Count 
CKD-EPI 
Chronic Kindney Disease – Epidemiology Collaboration 
CPP 
Comité de protection des personnes (Ethic Comittee) 
CRA 
Clinical Research Associate 
CR 
Complete response 
2-CT 
Bichimiothérapie 
3-CT 
Trichimiothérapie 
CT Scan 
Computed Tomography Scanner 
DCF  
Data Clarification Form 
DCR 
Disease control rate – Taux de contrôle de la maladie 
DDR1 
Discoidin Domain Receptor tyrosine kinase 1 
DLT 
Dose Limiting Toxicity – Toxicité limitant la dose 
DPD 
DihydroPyrimidine Dehydrogenase 
DPR 
        DeePness of Response – profondeur de la réponse 
DMT 
        Dose maximale tolérée 
ECG 
ElectroCardioGram - électrocardiogramme 
ECOG 
Eastern Cooperative Oncology Group 
e-CRF  
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EI 
Evénement indésirable 
EORTC 
European Organisation for Research and Treatment of Cancer 

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
EUDRACT 
European Union Drug Regulating Authorities Clinical Trials 
5-FU 
5 FluoroUracil 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GGT  
Gamma-Glutamyl Transferase 
Hb 
Hemoglobin 
HR  
Hazard Ratio 
ICM 
Montpellier Cancer Institute 
INCA 
Institut National du CAncer 
INR  
International Normalized Ratio 
ISC 
Independent Scientific Committee 
ITT 
Intention-To-Treat 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit Normal 
LIN 
Limite inférieure à la normale 
LSN 
Limite supérieure à la normale 
mCRC 
Metastatic Colorectal Cancer 
MDRD 
Modification of Diet in Renal Disease 
MRI  
Magnetic Resonance Imaging 
MS 
Maladie stable 
MTD 
Maximum Tolerated Dose 
NCI/ CTCAE 
National Cancer Institute (US) Common terminology criteria for 
adverse events 
NYHA 
New-York Heart Association 
ORR 
Objective response nude 
OS 
Overall survivall 
PFS 
Progression Free Survival 
PR 
Partial Response 
PT 
Prothrombine time – temps de prothrombine 
PTT 
Partial Thromboplastin Time – temps de prothrombine partielle 
R 
Taux de résection 
RAS 
RAt Sarcoma viral oncogene homolog 
RBC 
Red Blood Count 
RC 
Réponse complète 
RECIST  
Response Evaluation Criteria in Solid Tumors 
RP 
Réponse partielle 
RP2D 
Recommended Phase II Dose – dose recommandée pour la phase II 
SAE  
Serious Adverse Event 
SD  
Stable Disease 
SG 
Survie globale 
SmPC 
Summary of Product Characteristics 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
TSH 
Thyroid stimulating hormone 

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
UGT1A1 
Uridine diphosphate Glucuronosyl Transferase 1A1 
ULN 
Upper Limit Normal 
WBC 
White Blood Count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
Table of contents 
1. 
Background and rationale .................................................................................. 24 
2. 
Study objectives and Endpoints ........................................................................ 31 
2.1 Objectives..................................................................................................................... 31 
2.1.1 Primary objectives ............................................................................................... 31 
2.1.2 Secondary objective ............................................................................................ 31 
2.2 Endpoints ..................................................................................................................... 32 
2.2.1 Primary endpoint .................................................................................................. 32 
2.2.2 Secondary endpoints .......................................................................................... 33 
3. 
Experimental plan .............................................................................................. 34 
3.1 Study design ................................................................................................................ 34 
3.2 Study period ................................................................................................................. 37 
3.3 Compensation modalities .......................................................................................... 37 
4. 
Population ......................................................................................................... 38 
4.1 Number of planned patients ...................................................................................... 38 
4.2 Inclusion criteria .......................................................................................................... 38 
4.3 Non-inclusion criteria .................................................................................................. 40 
4.4  Procedure .................................................................................................................... 42 
5. 
Visit Schedule .................................................................................................... 42 
5.1 Tabulated overview..................................................................................................... 42 
5.2 Screening period ......................................................................................................... 45 
5.3 Treatment period ......................................................................................................... 48 
5.4 End of treatment Visit ................................................................................................. 51 
5.5 Follow-up ...................................................................................................................... 52 
5.6 End of study ................................................................................................................. 53 
6. 
Treatments ........................................................................................................ 53 
6.1 Experimental treatment or procedures .................................................................... 53 
6.2 Drug packaging and labelling .................................................................................... 54 
6.3 Shipment, storage conditions and accountability and destruction ...................... 55 
6.4 Treatment duration ..................................................................................................... 57 
6.5 Expected Toxicities ..................................................................................................... 58 
6.6 Dose modification and Dose delay........................................................................... 58 
6.7 Authorized associate procedures and treatment ................................................... 66 
6.7.1 Other treatments/procedures ............................................................................. 66 
6.8  Prohibited treatment .................................................................................................. 67 

        
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6.9  Main medications that can interact with regorafenib ............................................ 68 
6.10  Main medications that can interact with irinotecan ............................................ 70 
6.11  Main medications that can interact with 5 FU ..................................................... 71 
6.12  Main medications that can interact with Oxaliplatin ........................................... 71 
7. 
Blinded independent central review (BICR) ....................................................... 72 
7.1. Shipment procedure and storage ......................................................................... 72 
8. 
Ancillary Studies ................................................................................................ 72 
8.1. Activity of DDR1 as a predictor of efficacy of regorafenib ................................ 72 
8.2. cfDNA monitoring .................................................................................................... 73 
8.2.1. Sample timeline ............................................................................................... 73 
8.2.2. Processing of samples .................................................................................... 73 
8.2.3. Shipment and analysis .................................................................................... 74 
9. 
Subject withdrawal/end of study ........................................................................ 75 
9.1. Discontinuation of treatment ................................................................................. 75 
9.2. Withdrawal from the trial ........................................................................................ 76 
9.3. end of study ............................................................................................................. 76 
9.4. Assessment criteria ................................................................................................ 76 
10. 
Statistical considerations ................................................................................ 77 
10.1. 
Sample size .......................................................................................................... 77 
10.2. 
Study populations ................................................................................................ 77 
10.3. 
Statistical methods .............................................................................................. 78 
11. 
Vigilance and safety control ............................................................................ 78 
11.1. 
Adverse Events .................................................................................................... 78 
11.1.1. 
Definition........................................................................................................ 78 
11.1.2. 
Collection and Reporting ............................................................................ 79 
11.1.3. 
Severity Criteria ............................................................................................ 80 
11.2. 
Serious Adverse Events and New Event ......................................................... 80 
11.2.1. 
Definition........................................................................................................ 80 
11.2.2. 
URGENT SAFETY MEASURE (USM) (ARTICLES L.1123-10 ET R. 
1123-62 CSP)................................................................................................................. 82 
11.2.3. 
Suspected Unexpected Serious Adverse Reaction ............................... 82 
11.2.4. 
Pregnancy ..................................................................................................... 82 
11.2.5. 
SAE, New Event, Urgent safety measure, Pregnancy Notification 
Procedure ....................................................................................................................... 83 
11.2.5.1. 
SAE Notification Procedure .................................................................... 83 
11.2.5.2. 
New Event / Urgent safety measure (USM)/ Notification Procedure 84 

        
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11.2.5.3. 
Pregnancy Notification Procedure ......................................................... 84 
11.2.5.4. 
Summary chart of notification by type of event ................................... 85 
11.2.6. 
Obligation of the sponsor ............................................................................ 85 
11.2.7. 
Independent Safety Committee (ISC) ....................................................... 86 
12. 
Quality assurance and control ........................................................................ 87 
12.1. Data collection .......................................................................................................... 87 
12.2 Trial monitoring ......................................................................................................... 88 
12.3 
Audits and inspection.......................................................................................... 89 
13. 
Administrative, ethical and regulatory aspects ................................................ 89 
13.1. 
Conduct of the study and responsibilities ........................................................ 89 
13.2. 
Subject information and consent ...................................................................... 90 
13.3. 
Regulatory authorizations .................................................................................. 91 
13.4. 
Authorization of the biological resource center .............................................. 91 
13.5. 
Processing of research data .............................................................................. 91 
13.6. 
Amendments of the protocol.............................................................................. 91 
13.7. 
Sponsor discontinuation criteria ........................................................................ 92 
14. 
Financing and Insurance ................................................................................ 92 
14.1. 
Financing of Research........................................................................................ 92 
14.2. 
Insurance .............................................................................................................. 92 
15. Publication policy and communication ................................................................ 93 
15.1. 
Publication policy ................................................................................................. 93 
15.2. 
Data sharing statements .................................................................................... 94 
16. References ......................................................................................................... 94 
17. Appendices ......................................................................................................... 96 
 

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
SYNOPSIS (English) 
TITLE 
Safety, 
tolerability 
and 
efficacy 
of 
regorafenib 
in 
combination with FOLFIRINOX in patients with RAS-mutated 
metastatic colorectal cancer: a dose-escalation, phase I/II 
trial 
SYNOPSIS VERSION 
1 
PATHOLOGY 
Metastatic colorectal cancer 
 
PROTOCOL CODES 
Acronym: FOLFIRINOX-R 
Sponsor Code:  PROICM 2018-08 FOL 
EUDRACT: 2018-003541-42 
SPONSOR 
ICM – Institut régional du cancer de Montpellier 
Clinical and Translational Research Department  
Dr Jean-Pierre Bleuse 
208 rue des Apothicaires 
34298 Montpellier Cedex 05 – France  
Mail: DRCI-icm105@icm.unicancer.fr 
Phone: +33 4 67 61 31 02 
Fax: +33 4 67 41 30 23 
STUDY 
COORDINATOR  
Pr Antoine Adenis 
Institut régional du Cancer de Montpellier (ICM) 
Department of Medical Oncology 
208 rue des Apothicaires 
34298 Montpellier Cedex 05 – France 
Phone: +33 4 67 61 47 01 
E-mail:  antoine.adenis@icm.unicancer.fr  
PROJECT MANAGER 
ICM -   Institut régional du Cancer de Montpellier 
DRCI  
Contact Name: Mr Patrick Chalbos 
Phone: +33 4 67 61 25 74 
E-mail:  patrick.chalbos@icm.unicancer.fr 
METHODOLOGY AND 
DATA MANAGEMENT 
CENTER  
ICM -   Institut régional du Cancer de Montpellier 
Biometric Unit  
Contact Name: Mr Julien Fraisse 
Phone: +33 4 67 61 30 30 
E-mail:  julien.fraisse@icm.unicancer.fr  
CLINICAL RESEARCH 
VIGILANCE UNIT 
ICM -    Institut régional du Cancer de Montpellier 
DRCI – PV Unit 
Contact Name : Nadia BENSMAIL 
Phone: +33 4 67 61 45 68 
E-mail: Pharmacovigilance-icm105@icm.unicancer.fr 
STUDY DESIGN 
Prospective, multicenter, open-label, uncontrolled phase I/II trial 
NUMBER OF 
PLANNING PATIENT 
87 patients out of about 174 screened patients 
 

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
BACKGROUND AND 
RATIONALE  
Colorectal cancer (CRC) is a major cause of morbidity and mortality 
globally. More than 50% of patients can be expected to develop 
metastatic disease, and most of these patients will require palliative 
systemic therapy. The primary goal for patients who present with 
technically resectable liver metastases is definitely cure, with R0 
resection as the primary goal. Consequently, any patient with limited 
liver and/or lung metastases should be considered a candidate for 
potential secondary resection as there are no criteria that allow 
physicians to distinguish between those patients for whom purely 
palliative treatment and those or whom potentially curative treatment is 
appropriate. Although survival times are slightly shorter for patients 
who undergo conversion therapy followed by surgery than for patients 
with initially resectable metastatic disease, they are far better than if 
resection is not carried out at all (1). As per ESMO guidelines, first-line 
therapy commonly involves the doublet (2-CT) regimens of 5-
fluorouracil, folinic acid, and either oxaliplatin (FOLFOX) or irinotecan 
(FOLFIRI). The addition of targeted therapies, such as bevacizumab (a 
pure anti-angiogenic agent which binds circulating VEGF-A), 
cetuximab, and panitumumab, to FOLFOX or FOLFIRI may be helpful 
to some patients in improving tumor response and ultimately overall 
survival. The cytotoxic triplet (3-CT) FOLFOXIRI with or without 
bevacizumab may be an option in selected fit and motivated patients 
when cytoreduction (tumour shrinkage) is needed to undergo 
conversion therapy (1). 
 
RAS mutations are found in about 50% of mCRC tumors. As recently 
rephrased by Modest et al. (2) these mutations exclude affected 
patients from epidermal growth factor receptor (EGFR)-directed 
therapy. Besides their negative predictive value, RAS mutations may 
also carry distinct prognostic information. Modest et al. (2) studied the 
prognosis by RAS status of a total of 1239 mCRC patients from five 
randomized trials studying 2-CT. Actually, PFS and OS were 
significantly 
influenced 
by 
molecular 
subgroups. 
Multivariate 
comparison of PFS and OS in patients with mutant tumors versus 
patients with non-mutated tumors revealed a negative prognostic 
effect of RAS mutations. Interestingly, the negative prognostic role of 
these mutations was consistently observed across different treatment 
regimens (subgroups of irinotecan- and oxaliplatin-treated patients as 
well as in bevacizumab- and non-bevacizumab-treated patients). 
Median PFS and OS were 10.3 vs. 9.5 months and 26.9 vs. 21.1 
months in RAS-wildtype (and BRAF-wildtype) and RAS-mut patients, 
respectively 2).The TRIBE consortium reported that a 3-CT 
(FOLFOXIRI) combined with bevacizumab provided a  significantly 
longer PFS (the primary end-point of the study)  than did the 2-CT 
FOLFIRI plus bevacizumab (3, 4). In the subgroup of RAS- and BRAF-
wild-type patients, those in the FOLFOXIRI plus  bevacizumab group 
reported a median PFS of 13.7 months (95% CI, 10.1-18.1) compared 
with 12.2 months (95%CI, 9.5-14.4) in the FOLFIRI plus bevacizumab 
group (HR 0.85, 95%CI 0.55-1.3) (4).   

        
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Later on, the same group reported that FOLFOXIRI plus bevacizumab 
provided a significantly longer overall survival than the FOLFIRI plus 
bevacizumab group (HR 0.80, 95%CI 0·65–0·98; p=0·03) (4). Looking 
at survival by RAS status, Cremolini et al. (4) reported that median OS 
was 37.1 months (95%CI, 29.7–42.7) in the RAS- and BRAF-wild-type 
subgroup compared with 25.6 months (95%CI, 22.4–28.6) in the RAS-
mut subgroup (HR 1.49, 95%CI, 1.11–1·99). Interestingly, median PFS 
was 13.7 months (95% CI 10.1–18.1) in the RAS-wild-type subgroup 
treated with FOLFOXIRI plus bevacizumab, while PFS data were not 
given for the RAS-mut patients (4). However, for these RAS-mut 
patients, it was possible to estimate the median PFS (i.e. 9.4 months) 
from the Kaplan-Meier curve which was provided (4). 
    
Regorafenib is a small-molecule inhibitor of multiple membrane-
bound and intracellular kinases RET, VEGFR 1, 2, 3, c-Kit, PDGFR-α, 
β, FGFR1, 2, TIE2, DDR1, DDR2, Trk2A, Eph2A, RAF-1, BRAF, 
BRAFV600E, SAPK2, PTK5, and Abl. Beyond its well-known 
antiangiogenic properties, regorafenib has also less-known anti-
proliferative activities in human colon cancer cell lines. Interestingly, 
regorafenib potently inhibits growth of patient-derived CRC xenografts 
alone and in combination with irinotecan (5-7). Regorafenib is 
approved for refractory mCRC patients (8), for locally advanced, 
unresectable or metastatic GIST patients and for HCC patients 
previously treated with sorafenib. The recommended dose is 160 mg 
(40 mg × 4 tablets) orally, once daily for the first 21 days of each 28-
day cycle. Two phase III trials demonstrated a significant overall 
survival benefit for regorafenib over  placebo in patients with mCRC 
who progressed on standard therapies (8, 9). Two phase II trials 
studied the safety and efficacy profile of regorafenib when combined to 
chemotherapy in patients with mCRC (10, 11). In vitro data indicate 
that both regorafenib and its metabolite M-2 inhibit glucuronidation 
mediated by UGT1A1 and UGT1A9 (whereas M-5 only inhibits 
UGT1A1), hence triggering potential pharmacokinetic interactions. The 
study from Schultheis et al. (10) was designed to explore whether 
addition of regorafenib to FOLFOX or FOLFIRI could be feasible as a 
treatment of mCRC, in terms of safety and pharmacokinetic 
interactions of the various drug components of the regimen.  Forty-five 
patients were treated every 2 weeks with 5-fluorouracil 400 mg/m²  
bolus then 2400 mg/m² over 46 h, folinic acid 400 mg/m², and either 
oxaliplatin 85 mg/m² or irinotecan 180 mg/m².  
On days 4–10, patients received regorafenib 160 mg orally once daily. 
Drug-related adverse events resulted in dose modification, dose 
interruption, or permanent discontinuation of study treatment in 31 
(69%) patients overall (18 [72%] FOLFOX and 13 [65%] FOLFIRI). 
Dose reduction or dose interruption of at least one of the 
chemotherapy components was observed in 52% of patients  treated 
with FOLFOX and 65% of patients receiving FOLFIRI. A dose 
reduction of 5-fluorouracil due to AEs was necessary in 18% of 
administered cycles. 5-Fluorouracil administration was omitted   

        
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in 8% of cycles. Oxaliplatin and irinotecan doses were reduced in 11% 
and 12% and interrupted in 11% and 5% of administered cycles, 
respectively. Actually, regorafenib had acceptable tolerability in 
combination with chemotherapy. The most frequent grade 3-4 AEs 
were: neutropenia (45%), Hand-Foot Skin Reaction (15%), diarrhea 
(10%), and hypophosphatemia (12%). Regarding pharmacokinetics, 
area under the curve (AUC) of irinotecan was significantly higher in 
cycle 2 (following regorafenib dosing) than in cycle 1 (before 
regorafenib dosing); the ratio of AUC values (cycle 2:cycle 1) was 1.28 
(90% confidence interval [CI] 1.06 –1.54). Cmax of irinotecan was only 
slightly increased, and t½ was unchanged. For SN–38, AUC was 
significantly higher in cycle 2 than in cycle 1 (ratio 1.44, 90% CI 1.12–
1.85), while Cmax was unchanged. In line with the known elimination 
pathways of platinum and 5-fluorouracil, no pharmacokinetic 
interaction with regorafenib was seen (10). The study from O’Neil  et 
al. (11) was designed to show whether the addition of regorafenib to 
FOLFIRI improves PFS (over a placebo-FOLFIRI arm) when given as 
second-line therapy for patients treated initially with oxaliplatin and 
fluoropyrimidine-based therapy. The regorafenib/FOLFIRI schedule 
that was used was the one proposed by Schultheis et al. (10) (i.e. 
standard FOLFIRI with irinotecan 180 mg/m² plus regorafenib 160 mg 
daily from day 4 to 10). The study met its primary endpoint of 
demonstrating that the addition of regorafenib to FOLFIRI prolongs 
PFS compared to FOLFIRI alone with a HR of 0.72. When looking at 
tumor response, authors found that regorafenib (combined to chemo) 
provided more partial responses than placebo plus chemo (35% vs. 
19%, p= 0.045). The combination was very tolerable, with little 
increase in toxicity compared to the control chemotherapy regimen. Of 
note, regarding the top-3 reported severe (gr. 3-4) AEs, neutropenia, 
diarrhea, and hypophosphatemia were reported in 41%, 15%, and 
14% of the patients, respectively (as compared to 30%, 5%, and 0% in 
the placebo group) (11). 
Actually, there is room to combine regorafenib with  a chemo triplet 
such as FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin) on the 
following conditions: controlling patients on UGT1A polymorphisms (at 
least 
UGT1A1), 
stepwise 
dose-escalation 
of 
irinotecan 
and 
regorafenib, mandatory granulocyte growth-factor injections. 
STUDY OBJECTIVES 
Primary objectives  
 
Phase I: To determine the maximum tolerated dose (MTD) and the  
recommended  phase  II dose (RP2D), based on the Dose Limiting 
Toxicities (DLT) of the combination evaluated during the three  first  
cycles  following  initiation  of  therapy (observational period), 
To evaluate the safety profile of the combination 
 
Phase II : To evaluate the efficacy (48-week disease-control rate) of 
the study combination. 
 

        
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Secondary objectives 
These apply to phase II part of the project. 
 
They include the following evaluations: 
- 
Safety of combination (NCI-CTC v5, neurotoxicity being also 
evaluated with the Levi’s scale), 
- 
Overall response rate and disease control rate according to 
RECIST 1.1, 
- 
Duration of response in patients who were not operated on for 
their metastases, 
- 
8-weeks response rate according to RECIST 1.1, 
- 
Deepness of response, 
- 
Resectability (R0-R1) and unresectability rates (including R2) 
among patients with liver-only metastases, 
- 
Progression-free survival,  
- 
Progression-free survival since maintenance therapy onset with 
regorafenib, 
- 
Overall survival. 
 
As translational studies: 
- 
Impact of DDR1 kinase activity on response, PFS and 
progression-free survival since maintenance therapy onset with 
regorafenib, and study of the variation of DDR1 
activity   in    patients    whom    liver    mets   are   deemed 
      resectable, 
- 
Select a population of mCRC with RAS-mutant cfDNA (already 
done in the PANIRINOX trial) 
- 
Describe the distribution of baseline genotype(s) of RAS-
mutant cfDNA  
- 
Monitor 
the 
RAS 
mutant-allele 
concentration 
along 
FOLFIRINOX-R therapy  
- 
Correlate the baseline RAS mutant-allele concentration and the 
deepness 
of 
decrease 
of 
this 
concentration 
during 
FOLFIRINOX-R with PFS and with the progression-free 
survival since maintenance therapy onset with regorafenib. 
 
 
Primary endpoint:  
Phase I: Adverse events as graded using the common toxicity criteria  
from the NCI-CTCAE v5 and incidence rates of DLT at each dose level 
during the 3 first cycles of combination therapy. 
 
Dose-limiting toxicities (DLT) will be defined as the 
occurrence of one or more of the following drug-related 
toxicities during the three first cycles of treatment: 
 
1. Missing >7 days daily doses of regorafenib due to drug-
related toxicity (scheduled treatment pause of regorafenib 
will not be counted),  

        
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STUDY ENDPOINTS  
 
2. Non-Hematologic DLT:  
 
 Grade ≥ 3 (CTCAE v5) non-hematologic toxicity, except:  
-Grade 3 nausea, vomiting, diarrhea, and Grade 2 
alopecia 
-any untreated HFSR that can be adequately controlled 
with medical intervention,  
-Grade ≥ 3 lipase elevation without signs of pancreatitis,  
 Grade ≥ 2 posterior reversible encephalopathy syndrome 
(PRES),  
 Grade ≥ 2 retinopathy, 
 Liver-specific DLTs are:  
    -Drug-related gr. 3-4 bilirubin increase 
    -Drug-related gr. 3-4 AST and/or ALT increase 
    -Drug-related AST and/or ALT increase > 3 x ULN and  
    associated with concurrent bilirubin increase(> 2 x ULN) 
 
 
3. Hematologic DLT:  
 Grade 4 (NCI-CTCAE v5) neutropenia lasting > 3 days, 
 Grade 3 Febrile neutropenia (ANC < 1,000/mm3 with fever ≥ 
38.5 °C) (NCI-CTCAE v5),  
 Grade 4 Febrile neutropenia (life-threatening consequences; 
urgent intervention indicated),  
 Grade 4 (NCI-CTCAE v5) anemia (i.e. life threatening 
consequences; urgent intervention indicated), 
 Platelets <25,000 /mm3 or platelets < 50,000 /mm3 associated 
with bleeding,  
 INR or PTT elevation of Grade ≥ 3 (NCI-CTCAE v5) with 
associated bleeding,  
 Grade ≥ 3 hemorrhage/bleeding events (NCI-CTCAE v5). 
  
Phase II: 48-week disease-control rate (defined as the rate of non-
progressing patients after central review, at 48-week post-initiation of 
therapy, to all treated patients. 
 
Secondary endpoints:  
Phase II : 
Progression-free survival (PFS), defined as the time from date of 
inclusion 
to 
date 
of 
first 
observed 
disease 
progression 
(investigator’s radiological or clinical assessment) or death due to 
any cause, if death occurs before progression is documented. . A 
central review of CT-scans is planned for patients found 
progression-free at 48 weeks. Patients without tumor progression 
or death at  the time of analysis will be censored at their last date 
of tumor assessment, 

        
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 
Disease control rate (DCR), defined as the rate of patients with 
non progressive disease (i.e., CR, PR or SD), to all included 
patients,  
 
 
Objective response rate (ORR), defined as the rate of patients 
with CR or PR, to all included patients, 
 
 
Deepness of response (DpR) is defined as the relative change 
in the sum of longest diameters of RECIST target 
lesions at the nadir, in the absence of new lesions or 
progression of non-target lesions, as compared to baseline, 
 
 
Time to recurrence under maintenance, defined as the time 
(days) from date of chemotherapy discontinuation (for 
protocolar 
reasons) 
and 
regorafenib 
continuation 
(as 
maintenance treatment) to date of first observed disease 
progression (investigator’s radiological or clinical assessment) 
or death due to any cause, if death occurs before progression 
is documented. Patients without tumor 
progression or death at the time of analysis will be censored at 
their last date of tumor assessment, 
 
 
Overall survival (OS), defined as the time (months) from date of 
inclusion to date of death. Patients lost for follow-up at the time 
of analysis will be censored at their last news, 
 
 
Resection (R) rates: R relates to resection margins. R0/R1 are 
classified by the pathologist and R2 is classified by the 
surgeon. R0 is defined as the absence of cancer cells  
seen microscopically at the resection margin. R1 is defined  
as the presence of cancer cells microscopically at the  
resection margin (microscopic positive margin). R2 is  
defined at gross examination with the presence of tumor  
tissue at the resection margin. 
Resectability   rate   (R0R1)   and    non-resectability    rate 
(including R2)  among   patients  with liver-only metastases 
 
  As translational studies: 
 
Central determination of cfDNA levels at baseline, every 8 
weeks during treatment and at the end of treatment. 
Impact of DDR1 kinase activity on response and PFS, and 
study of the variation of DDR1 activity in patients whom liver 
mets are deemed resectable. 
 
Safety endpoints:  
 
All AEs occurring after the patient has signed the informed 
consent until the end of the safety follow-up period (30 days 
after the end of study therapy) will be documented. This  

        
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 
includes any clinical reactions or  symptoms reported 
by the patient or observed by the investigator at the visits, but 
also any test abnormalities considered clinically relevant by the 
investigator, 
 
This will be done by the means of physical examinations, 
measurements of vital signs, ECG recording, and laboratory 
assessments,            
 
All AE documentation will be event-based (using NCI-CTCAE  
V5 guidelines), 
 
All AEs that will be ongoing at the end of treatment, will be 
reviewed and updated up to at least 30 days after stopping the 
study treatment. They should be followed until resolution or 
stabilization unless, in the investigator’s opinion, the condition 
is unlikely to resolve due to the patient’s underlying disease. 
RISK AND BENEFITS  
 
 
The risk-benefit balance of the study is evaluated continuously by the 
ICM Clinical Research Pharmacovigilance Unit and this risk-benefit 
balance will be discussed in the periodic safety reports. These reports 
will contain all required regulatory aspects and will be submitted to the 
competent authorities and independent scientific committee. 
ELIGIBILITY CRITERIA Eligibility criteria for prescreening 
 
The following criteria must be met at the time of prescreening: 
1. Written informed consent for prescreening 
2. Prescreening of patients will be performed at the investigators’ 
discretion up to a maximum of 21 days prior to full study 
screening. Investigators should ensure all patients will be 
eligible in terms of disease status within this timeframe.  
3. Age ≥ 18 years. 
4. Histological documentation of adenocarcinoma of the colon or 
rectum. 
5. Synchronous or metachronous metastatic colorectal cancer not 
amenable to surgical resection with curative intent. 
6. No prior therapy for metastatic disease. 
7. Eastern Cooperative Oncology Group (ECOG) performance 
status ≤ 1. 
8. Life expectancy of at least 3 months. 
Besides these basic criteria, any criterion as outlined below under 
inclusion eligibility criteria for full study and exclusion criteria,   already 
known to prohibit the patient’s participation in the study should be 

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
 
considered.  No study-related procedures will be performed that are 
not covered by the prescreening informed consent form. 
 
Eligibility criteria for full study 
 
Inclusion criteria 
1. Written informed consent for full study. 
2. Documentation of tumor RAS mutation, wild-type homozygous, 
heterozygous status of UGT1A1 gene. The status of UGT1A1 
gene will be performed by the laboratory chosen by the 
investigator (for information, appendix 1). 
3. Serum uracile < 16 ng/ml 
4. Measurable disease, defined as at least one unidimensional 
measurable lesion on a CT scan, according to RECIST version 
1.1.  
5. ECOG performance status ≤1. 
6. Life expectancy of at least  3 months. 
7. Adequate bone marrow, renal and liver functions  as evidenced 
by the following laboratory requirements within 
7 days prior to study treatment initiation: 
a. Absolute neutrophil count (ANC) ≥ 1,500/ mm3 without 
biologic response modifiers such as granulocyte colony-
stimulating factor (G-CSF),  
            within 21 days before the start of study treatment, 
b. Platelet count ≥ 100 000/mm3 , without platelet 
transfusion within 21 days before the start of study 
treatment,  
c. Hemoglobin (Hb) ≥ 9 g/dL, without blood transfusion or 
erythropoietin, within 21 days before the start of study 
treatment, 
d. Serum creatinine ≤ 1.5 x upper limit of normal(ULN)  
e. Serum calcium ≥ LLN and ≤ 1.2 x UNL ; Serum  
magnesium ≥ LLN and ≤ 1.2 x UNL ; Kalemia ≥ LLN, 
f. Glomerular filtration rate as assessed by the estimated 
glomerular filtration rate (eGFR) ≥ 50  mL/min per 1.73 

        
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m2 calculated by the Modification of Diet in Renal 
Disease (MDRD) abbreviated   formula, 
g. Total bilirubin ≤ 1.5 x ULN, 
h. Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase (AST) ≤ 2.5 x ULN (≤  5 x ULN for 
patients with liver involvement of their cancer),  
i. 
Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN  
for patients with liver involvement for their cancer and/or 
bone metastases). 
8. Lipase ≤ 1.5 x ULN. 
9. Adequate coagulation, as assessed by the following laboratory 
test results: 
a. International 
normalized 
ratio 
(INR) 
≤ 
1.5 
or 
prothrombin time (PT) ≤ 1.5 x ULN, 
b. Partial thromboplastin time (PTT) or activated PTT 
(aPTT) ≤ 1.5 x ULN, 
Note: Patients on stable dose (dose has not been  changed in 
at least 28 days) of anticoagulation therapy will be allowed to 
participate if they have no sign of bleeding or clotting and INR / 
PT and PTT / aPTT test results are compatible with the 
acceptable benefit-risk ratio at the investigator’s discretion. In 
such case, limits as noted would not apply. 
10. For women of reproductive potential, negative serum beta 
human chorionic gonadotropin (β-HCG) pregnancy test 
obtained within 7 days before the start of study treatment. 
Women not of reproductive potential are female patients who 
are postmenopausal or permanently sterilized (e.g., tubal 
occlusion, hysterectomy, bilateral salpingectomy).  
11. For women of childbearing potential and men, agreement to 
use an adequate contraception for the duration of study 
participation and up to 4 months following completion of 
therapy  for women and 6 months for male patients. Females of 
childbearing potential who are sexually active  with  a  non- 

        
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sterilized  male  partner  must  use  2  methods of effective 
contraception. The investigator or a designated associate is 
requested to advise the patient on how to achieve an adequate 
birth control. 
Adequate contraception is defined in the study as any 
medically recommended method (or combination of methods) 
as per standard of care. 
12. Willingness and ability to comply with scheduled visits, 
treatment plan, laboratory tests and other study procedures. 
13. Affiliation to the Social Security System. 
 
Non-inclusion criteria 
 
1. Previous or concurrent cancer that is distinct in primary site or 
histology from colorectal cancer within 5 years prior to study 
inclusion, except for curatively treated cervical cancer in situ, 
non-melanoma skin cancer and superficial bladder tumors [Ta 
(non invasive tumor), Tis (carcinoma in 
situ) and T1 (lamina propria invasion)]. 
2. Discovery of metastases within 6 months after the termination 
of adjuvant chemotherapy. 
3. Previous treatment for metastatic disease. 
Radiotherapy   within   28  days  prior  to  first  dose  of  
treatment. 
4. Active cardiac disease including any of the following: 
a. Congestive heart failure New York Heart 
Association (NYHA) class 2, 
b. Unstable angina (angina symptoms at rest), new-onset 
angina (begun within the last 3 months), 
c. Myocardial infarction less than 6 months before first 
dose of treatment, 
d. Cardiac arrhythmias requiring anti-arrhythmic therapy 
(beta blockers or digoxin are permitted). 
 

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
 
5. ECG with a QT/QTc interval higher than 450 ms for men and 
higher than 470 ms for women Uncontrolled hypertension.  
6. Uncontrolled hypertension. (Systolic blood pressure  > 140 
mmHg or diastolic pressure  > 90 mmHg despite optimal 
medical management). 
7. Arterial or venous thrombotic or embolic events such as 
cerebrovascular accident (including transient ischemic attacks), 
deep vein thrombosis or pulmonary embolism within 6 months 
before start of treatment. 
8. Persistent proteinuria of National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE V5)  
grade 3 (i.e. urinary protein ≥ 3.5 g/24 hrs) 
9. Peripheral neuropathy > grade1 (NCI-CTCAE v5). 
10. Major surgical procedure, open biopsy, or significant traumatic  
injury  within  28  days  prior  to  first  dose  of 
Treatment. 
11. Ongoing infection >grade 2 (NCI-CTCAE v5). 
12. Known history of human immunodeficiency virus (HIV) 
infection. 
13. Chronic hepatitis B or C infection (if hepatitis status cannot be 
obtained from medical records, re-testing is required). 
14. Seizure disorder requiring medication. 
15. Symptomatic metastatic brain or meningeal tumors.  
16. Evidence or history of any grade 3-4. Any hemorrhage or 
bleeding event ≥ grade 3 (NCI-CTCAE v5) within 4 weeks prior 
to the start of study medication. 
17. History of organ allograft. 
18. Non-healing wound, ulcer, or bone fracture. 
19. Dehydration Grade  1 NCI-CTCAE v5). 
20. Substance abuse, medical, psychological, or social conditions 
that may interfere with the patient’s participation in the study or 
evaluation of the study results. 
21. Known hypersensitivity to any of the study drugs, study drug 
classes, or any constituent of the products. 
22. Interstitial lung disease with ongoing signs and symptoms.  

        
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23. Concomitant intake of St. John's wort. 
24. Live attenuated vaccines are prohibited 10 days before the 
treatment, during the treatment and 3 months after the 
termination of treatment 
25. History of gastrointestinal fistula or perforation 
26. Inability to swallow oral medication. 
27. Any malabsorption condition. 
28. Pregnant or breast-feeding subjects.  
29. Any condition that, in the opinion of the investigator, would 
interfere with the evaluation of study treatment or interpretation 
of patient safety or study results. 
30. Participation     in     another     clinical     study     with    an 
investigational product during the last 30 days before inclusion. 
31. Patients who might be interconnected with or dependent on the 
sponsor site or the investigator. 
32. Legal incapacity or limited legal capacity. 
STUDY PRODUCT OR 
MEDICAL DEVICE 
FOLFIRINOX - REGORAFENIB 
ENROLLMENT 
PROCEDURE 
    
 
 
Phase I part 
The phase I part of this study will be designed as a standard 3+3 
design for dose escalation/de-escalation and 3 to 6 patients will be  
enroled in each cohort sequentially, depending on occurrence of dose 
limiting toxicities. 
 

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
TREATMENT 
MODALITIES 
Pre-defined dose levels 
 
Steps 
 
Dose Levels 
Number of patients 
DL-1  
IRI 150/REGO 80 
 
 
0-6 
DL1 
 
IRI 150/REGO 120 
 
 
3-6 
DL2 
 
IRI 180/REGO 120 
 
 
3-6 
DL3 
 
IRI 180/REGO 160 
 
 
3-6 
 
The 6 patients treated at the RP2D in the phase I part will be included 
in the phase II part. 
 
Phase I and II:  
 
FOLFIRINOX will be administered as per standard procedures: 
every 14 days (1 cycle = 14 days): 
Oxaliplatin (Eloxatin® or generic drug): 85mg/m² on day 1, IV infusion 
over 2 hours, immediately followed by 
- Folinic acid 400 mg/m² or Calcium Levofolinate: 200mg/m² given as  
a  2-hour  IV  infusion,  with  the  addition,  after  30 minutes of 
- Irinotecan  (Campto® or generic drug) :  150-180  mg/m²  as  per  
dose-level given as a 90-minute intravenous infusion through a Y-
connector immediately followed by  
5-Fluorouracil: 400mg/m² IV bolus then 2400mg/m² over 46 hours 
continuous infusion.  
Prophylactic    G-CSF   will    be   systematically   given   after 
each  course from Day-7 to Day 12. 
 
REGORAFENIB will be given orally at a dose of 80 to 160 mg, as per 
dose-level, once daily on days 4 to 10 of each cycle 
 
Tumor assessments (computed tomography (CT) or magnetic 
resonance imaging (MRI)) of the chest, abdomen, pelvis (if patient 
allergic to iodine contrast agents) will be performed at the baseline, 
every 8 weeks thereafter.  
ANCILLARY STUDIES 
 
Study n°1 : DDR1 activity as a predictor of efficacy of regorafenib  
Paraffin-embedded human solid tissue blocks will be sent off at room 
temperature at the end of the inclusions. 
Paraffin-embedded human solid tissue blocks will be returned to the 
home institution upon completion of ancillary study. 
We would like to :  

        
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1. assess the baseline activity of DDR1 in colorectal samples,  
2. to compare the baseline DDR1 activity to the one of patients 
(actually those who present some degree of tumor shrinkage) 
who undergo primarily unplanned hepatectomy and let liver 
metastases available to study,  
3. to correlate baseline DDR1 activity to FOLFIRINOX-R efficacy  
(response rate,  PFS,  progression-free  survival since 
maintenance therapy onset with regorafenib),  
4. to correlate DDR1 activity on resected liver metastases to 
the time to recurrence. 
5. To proceed to the following additional in vitro and in vivo 
experiments in order to strengthen the importance of  DDR1 
inhibition provided by regorafenib: 
 Test the capacity of regorafenib (1-10nM) to inhibit 
           invasive properties of colorectal tumor cells induced 
           by DDR1 overexpression in collagen matrix in vitro. 
 Test  in  vivo  the  capacity  of  regorafenib  treatment 
(10mg/kg) to block metastatic development induced by 
DDR1 overexpression in colorectal tumor cells that 
were transplanted in the spleen of nude mice. 
  
Actually, with this translational research, we aim to assess  
DDR1  activity  as  a  predictor  of  efficacy  in mCRC patients 
treated with a regorafenib-based therapy. 
 
Study n°2 :  cfDNA monitoring 
 
Three EDTA tubes will be collected at baseline, every 8 weeks during 
treatment and at the end of treatment. 
 
Because cfDNA analysis has the capacity to reflect tumor load, it 
could  be  used  to  monitor  the  efficacy  of  response  of  mCRC  
patients to treatment. 
We aim to better understand the changes of cfDNA concentration 
along a regorafenib-based therapy. 
STATISTICAL 
CONSIDERATIONS 
 
Phase I  
A minimum of 12 and a maximum of 24 patients will be included. The  
dose  escalation  corresponding  to  a  minimum  of  3 and  a 
maximum of 6 patients per dose level.  
A total of 6 patients will be included at the RP2D. 
 
Phase II  
With a one-stage Fleming design, α = 5%, β = 20%, p0 (the probability 
of inefficiency maximum) = 35% and p1 (the probability 
of minimum efficiency) = 50%, it would be necessary to include 65 
evaluable patients (69 patients/ 5% non-evaluable patients).  
The association can be considered sufficiently effective (reject null 
hypothesis) if there are at least 29 success (48 weeks disease 

        
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STATISTICAL 
CONSIDERATIONS 
 
control rate = CR / PR / SD) out of 65 evaluable patients, the 
success rate is significantly greater than 35%. 
The association can be considered insufficiently effective 
(rejection of the alternative hypothesis) if there are 28 or less 
success out of 65 evaluable patients, the success rate is 
significantly lower than 50%. 
 
In total, a maximum of 87 (=18 patients for phase I + 69 patients 
for phase II including 6 patients treated at the RP2D during the 
phase I) patients will be included. 
 
Analysis population 
 
Intent To Treat (ITT) population = all included patients.  
Per-Protocol (PP) population = all eligible patients (patients with 
no major violations of the inclusion/exclusion criteria) and 
evaluable patients (included treated patients with evaluation at 48 
weeks or without evaluation at 48 weeks if progressive or dead 
patient). 
Safety population = all treated patients who received at least one 
dose of treatment.All statistical analysis will be performed on ITT 
population, on PP population for efficacy analysis and on Safety 
population for safety analysis. 
STUDY PERIOD 
 First inclusion: april 2019 
 Inclusion period:12 months Phase I + 12 months Phase II 
 End of the inclusion period: march 2021 
 Expected end of study: june 2022 
 Report: september-december 2022  
 Poster/public: phase I (2020), phase II (april 2023 and july 
2023) 

        
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1. Background and rationale 
Colorectal cancer 
Colorectal cancer (CRC) is a major cause of morbidity and mortality globally. More than 50% 
of patients can be expected to develop metastatic disease, and most of these patients will 
require palliative systemic therapy. The primary goal for patients who present with technically 
resectable liver metastases is definitely cure, with R0 resection as the primary goal. 
However, any patient with limited liver and/or lung metastases should be considered a 
candidate for potential secondary resection as there are no criteria that allow physicians to 
distinguish between those patients for whom purely palliative treatment and those or whom 
potentially curative treatment is appropriate. Although survival times are slightly shorter for 
patients who undergo conversion therapy followed by surgery than for patients with initially 
resectable metastatic disease, they are far better than if resection is not carried out at all (1). 
As per ESMO guidelines, first-line therapy commonly involves the doublet (2-CT) regimens of 
5-fluorouracil, folinic acid, and either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). The 
addition of targeted therapies, such as bevacizumab (a pure anti-angiogenic agent which 
binds circulating VEGF-A), cetuximab, and panitumumab, to FOLFOX or FOLFIRI may be 
helpful to some patients in improving tumor response and ultimately overall survival. The 
cytotoxic triplet (3-CT) FOLFOXIRI with or without bevacizumab may be an option in selected 
fit and motivated patients when cytoreduction (tumour shrinkage) is needed to undergo 
conversion therapy (1). 
 
RAS-mutated (RAS-mut) mCRC 
RAS mutations are found in about 50% of mCRC tumors. As recently rephrased by Modest 
et al. (2) these mutations exclude affected patients from epidermal growth factor receptor 
(EGFR)-directed therapy. Besides their negative predictive value, RAS mutations may also 
carry distinct prognostic information. Modest et al. (2) studied the prognosis by RAS status of 
a total of 1239 mCRC patients from five randomized trials studying 2-CT. Actually, PFS and 
OS were significantly influenced by molecular subgroups. Multivariate comparison of PFS 
and OS in patients with mutant tumors versus patients with non-mutated tumors revealed a 
negative prognostic effect of RAS mutations. Interestingly, the negative prognostic role of 
these mutations was consistently observed across different treatment regimens (subgroups 
of irinotecan- and oxaliplatin-treated patients as well as in bevacizumab- and non-
bevacizumab-treated patients). Median PFS and OS were 10.3 vs. 9.5 months and 26.9 vs. 
21.1 months in RAS-wildtype (and BRAF-wildtype) and RAS-mut patients, respectively 

        
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(2).The TRIBE consortium reported that a 3-CT (FOLFOXIRI) combined with bevacizumab 
provided a significantly longer PFS (the primary end-point of the study) than did the 2-CT 
FOLFIRI plus bevacizumab (3, 4). In the subgroup of RAS- and BRAF-wild-type patients, 
those in the FOLFOXIRI plus bevacizumab group reported a median PFS of 13.7 months 
(95%CI, 10.1-18.1) compared with 12.2 months (95%CI, 9.5-14.4) in the FOLFIRI plus 
bevacizumab group (HR 0.85, 95%CI 0.55-1.3) (4). Later on, the same group reported that 
FOLFOXIRI plus bevacizumab provided a significantly longer overall survival than the 
FOLFIRI plus bevacizumab group (HR 0.80, 95%CI 0·65–0·98; p=0·03) (4). Looking at 
survival by RAS status, Cremolini et al. (4) reported that median OS was 37.1 months 
(95%CI, 29.7–42.7) in the RAS- and BRAF-wild-type subgroup compared with 25.6 months 
(95%CI, 22.4–28.6) in the RAS-mut subgroup (HR 1.49, 95%CI, 1.11–1·99). Interestingly, 
median PFS was 13.7 months (95% CI 10.1–18.1) in the RAS-wild-type subgroup treated 
with FOLFOXIRI plus bevacizumab, while PFS data were not given for the RAS-mut patients 
(4). However, it was possible to estimate median PFS (i.e. 9.4 months) from the Kaplan-
Meier curve which was provided for these RAS-mut patients (4).   
 
The median PFS to benchmark in RAS-mut mCRC is 9.4 months (with FOLFOXIRI plus 
bevacizumab) 
 
Regorafenib 
Regorafenib is a small-molecule inhibitor of multiple membrane-bound and intracellular 
kinases RET, VEGFR 1, 2, 3, c-Kit, PDGFR-α, β, FGFR1, 2, TIE2, DDR1, DDR2, Trk2A, 
Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl. Beyond its well-known 
antiangiogenic properties, regorafenib has also less-known anti-proliferative activities in 
human colon cancer cell lines. Interestingly, regorafenib potently inhibits growth of patient-
derived CRC xenografts alone and in combination with irinotecan (5-7). Regorafenib is 
approved for refractory mCRC patients (8), for locally advanced, unresectable or metastatic 
GIST patients and for HCC patients previously treated with sorafenib. The recommended 
dose is 160 mg (40 mg × 4 tablets) orally, once daily for the first 21 days of each 28-day 
cycle. Two phase III trials demonstrated a significant overall survival benefit for regorafenib 
over placebo in patients with mCRC who progressed on standard therapies (8, 9). Two 
phase II trials studied the safety and efficacy profile of regorafenib when combined to 
chemotherapy in patients with mCRC (10, 11). In vitro data indicate that both regorafenib and 
its metabolite M-2 inhibit glucuronidation mediated by UGT1A1 and UGT1A9 (whereas M-5 
only inhibits UGT1A1), hence triggering potential pharmacokinetic interactions. The study 

        
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from Schultheis et al. (10) was designed to explore whether addition of regorafenib to 
FOLFOX or FOLFIRI could be feasible as a treatment of mCRC, in terms of safety and 
pharmacokinetic interactions of the various drug components of the regimen.  Forty-five 
patients were treated every 2 weeks with 5-fluorouracil 400 mg/m²  bolus then 2400 mg/m² 
over 46 h, folinic acid 400 mg/m², and either oxaliplatin 85 mg/m² or irinotecan 180 mg/m². 
On days 4–10, patients received regorafenib 160 mg orally once daily. Drug-related adverse 
events resulted in dose modification, dose interruption, or permanent discontinuation of study 
treatment in 31 (69%) patients overall (18 [72%] FOLFOX and 13 [65%] FOLFIRI). Dose 
reduction or dose interruption of at least one of the chemotherapy components was observed 
in 52% of patients treated with FOLFOX and 65% of patients receiving FOLFIRI. A dose 
reduction of 5-fluorouracil due to AEs was necessary in 18% of administered cycles. 5-
Fluorouracil administration was omitted in 8% of cycles. Oxaliplatin and irinotecan doses 
were reduced in 11% and 12% and interrupted in 11% and 5% of administered cycles, 
respectively. Actually, regorafenib had acceptable tolerability in combination with 
chemotherapy. The most frequent grade 3-4 AEs were: neutropenia (45%), Hand-Foot Skin 
Reaction 
(15%), 
diarrhea 
(10%), 
and 
hypophosphatemia 
(12%). 
Regarding 
pharmacokinetics, area under the curve (AUC) of irinotecan was significantly higher in cycle 
2 (following regorafenib dosing) than in cycle 1 (before regorafenib dosing); the ratio of AUC 
values (cycle 2:cycle 1) was 1.28 (90% confidence interval [CI] 1.06 –1.54). Cmax of irinotecan 
was only slightly increased, and t½ was unchanged. For SN–38, AUC was significantly higher 
in cycle 2 than in cycle 1 (ratio 1.44, 90% CI 1.12–1.85), while Cmax was unchanged. In line 
with the known elimination pathways of platinum and 5-fluorouracil, no pharmacokinetic 
interaction with regorafenib was seen (10). The study from O’Neil et al. (11) was designed to 
show whether the addition of regorafenib to FOLFIRI improves PFS (over a placebo-FOLFIRI 
arm) when given as second-line therapy for patients treated initially with oxaliplatin and 
fluoropyrimidine-based therapy. The regorafenib/FOLFIRI schedule that was used was the 
one proposed by Schultheis et al. (10) (i.e. standard FOLFIRI with irinotecan 180 mg/m² plus 
regorafenib 160 mg daily from day 4 to 10). The study met its primary endpoint of 
demonstrating that the addition of regorafenib to FOLFIRI prolongs PFS compared to 
FOLFIRI alone with a HR of 0.72. When looking at tumor response, authors found that 
regorafenib (combined to chemo) provided more partial responses than placebo plus chemo 
(35% vs. 19%, p= 0.045). The combination was very tolerable, with little increase in toxicity 
compared to the control chemotherapy regimen. Of note, regarding the top-3 reported severe 
(gr. 3-4) AEs, neutropenia, diarrhea, and hypophosphatemia were reported in 41%, 15%, 

        
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and 14% of the patients, respectively (as compared to 30%, 5%, and 0% in the placebo 
group) (11). 
 There is room to combine regorafenib with a chemo triplet such as 
FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin) on the following conditions: 
controlling patients on UGT1A polymorphisms (at least UGT1A1), stepwise dose-
escalation of irinotecan and regorafenib, mandatory granulocyte growth-factor 
injections. 
FOLFIRINOX or FOLFOXIRI: A matter of dose of irinotecan and of 5-fluorouracil. 
 
FOLFOXIRI is a 60-minute infusion of irinotecan at a dose of 165 mg/m², and a 
120-minute infusion of oxaliplatin at a dose of 85 mg/m² and a concomitant 120-
minute infusion of Leucovorin at a dose of 200 mg/m² followed by a 48-hour 
continuous infusion of fluorouracil to a total dose of 3200 mg/m². Cycles are 
repeated every 14 days. This regime has been developed by Italian investigators in 
mCRC (2, 3). 
 
FOLFIRINOX is a 120-minute IV infusion of oxaliplatin at a dose of 85mg/m² on day 
1, immediately followed by folinic acid 400 mg/m² (or calcium levofolinate 200 mg/m²) 
given as a 2-hour IV infusion, with the addition, after 30 minutes, of irinotecan 180 
mg/m², given as a 90-minute intravenous infusion through a Y-connector immediately 
followed by 5-Fluorouracil 400mg/m² IV bolus then 2400mg/m² over 46 hours 
continuous infusion. Cycles are repeated every 14 days. This regime has been 
developed by french investigators in metastatic pancreatic cancer and in mCRC (11, 
12). 
 We have selected FOLFIRINOX rather than FOLFOXIRI as a backbone of our 
experimental treatment because 1) french investigators are used to treat 
patients with such regimen, and because 2) the FOLFIRI-regorafenib that had 
been investigated by O’Neil et al (11) used the same irinotecan and 5-
fluorouracil doses than the FOLFIRINOX regimen. 
 
Why having chosen 48-week disease-control rate, rather than overall response 
rate as the primary objective of the phase II part of this FOLFIRINOX-R trial (see 
page 7)? Overall response rate could have been the primary objective of this trial, as 
we are confident with the postulate that regorafenib is able to induce some additional 
tumour shrinkage to FOLFIRINOX backbone, but we are also cautious with that 
hypothesis. However, the 48-week disease-control rate includes not only the effect of 

        
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tumor responses that are awaited but also stable disease. In addition, this 48-week 
data cutoff (i.e.48-week disease-control rate) is also the median PFS (actually, 12.2 
months) that had been reported in RAS-mut mCRC treated with the FOLFOXIRI-
bevacizumab that we want to benchmark. To conclude, we think that the 48-week 
disease-control rate carries more valuable informations than overall response rate, as 
it captures the true effect of the addition of regorafenib to FOLFIRINOX. 
 
DDR1 activity as a predictor of efficacy of regorafenib  
Serge ROCHE, Ph.D., Centre de Recherche en Biologie cellulaire de Montpellier 
Antoine ADENIS, M.D., Ph.D., ICM, IRCM, Montpellier 
DDR1 is a tyrosine kinase receptor for collagens, which are major components of 
CRC microenvironment. DDR1 functions as a central extracellular matrix sensor to 
regulate cell adhesion and to promote tumor cell invasion and cancer stem cell 
survival in a collagen rich microenvironment (14, 15). Interestingly, the DDR1 kinase 
activity seems to be dispensable for several DDR1 functions reported in human 
cancers (16). Our group recentely reported important DDR1 kinase-dependent 
function in CRC metastasis formation and also showed that DDR1 inhibition provided 
significant anti-tumor activity in this cancer (17). Actually, we showed that DDR1 
pharmacological inhibition by a potent DDR1 inhibitor (i.e.nilotinib) inhibits the 
invasive and metastatic behavior of CRC cells through a RAS-independent 
mechanism. We were able to inhibit the DDR1-mediated metastatic potential of CRC 
cells in a liver metastasis mouse model and of patient-derived cell lines originating 
from metastatic tumors and circulating CRC cells. DDR1 inhibition displayed too anti-
tumor activity in mice that have already developed DDR1-dependent metastatic 
nodules, revealing an additional important role of DDR1 activity in metastatic growth 
(17). Clinical relevance of our findings is further supported by showing that DDR1 
expression level is an independent marker of poor prognosis in stage IV patients, and 
is not correlated with already described variables like tumor location, grade, number 
of metastatic sites, and CMS transcriptional subtypes. Besides, its relative kinase 
activity was dramatically increased in CRC metastatic nodules (mean > 10 fold) from 
a small cohort of patient with mCRC (12/20 patients), when compared to non-
transformed tissue or primary tumors of the same patients. This observation is 
consistent with a DDR1 kinase role in liver metastatic development of CRC patients 
(17). We thus propose that targeting tumor signaling emanated from the 

        
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microenvironment through inhibition of DDR1 activity could be an effective strategy to 
treat mCRC. 
Interestingly, regorafenib is also a potent inhibitor of DDR1 (as well as its M2 and M5 
metabolites), with a Kd identified (0.9 nmol/L) as the lowest of all the kinases being 
inhibited (18). Based on our previous experience with another DDR1 inhibitor, we 
postulate that the antioncogenic properties of regorafenib (as opposed to its inhibitory 
properties against various stromal and angiogenic targets) are mainly driven by 
DDR1 inhibition.  
 
Taking avantage of the present FOLFIRINOX-R trial, we would like to: 
1. assess the baseline activity of DDR1 in colorectal samples,  
2. to compare the baseline DDR1 activity to the one of patients (actually those who 
present some degree of tumor shrinkage) who undergo primarily unplanned 
hepatectomy and let liver metastases available to study,  
3. to correlate baseline DDR1 activity to FOLFIRINOX-R efficacy (response rate, PFS, 
progression-free survival since maintenance therapy onset with regorafenib),  
4. to correlate DDR1 activity on resected liver metastases to the time to recurrence. 
5. To proceed to the following additional in vitro and in vivo experiments in order to 
strengthen the importance of DDR1 inhibition provided by regorafenib: 
 
Test the capacity of regorafenib (1-10nM) to inhibit invasive properties of 
colorectal tumor cells induced by DDR1 overexpression in collagen matrix in vitro. 
 
Test in vivo the capacity of regorafenib treatment (10mg/kg) to block metastatic 
development induced by DDR1 overexpression in colorectal tumor cells that were 
transplanted in the spleen of nude mice. 
 Actually, with this translational research, we aim to assess DDR1 activity as a 
predictor of efficacy in mCRC patients treated with a regorafenib-based 
therapy. 
 
Expected results: Our hypothesis is that a high DDR1 kinase activity level is associated with 
a shorter PFS/OS in patients with CRC, as already reported at the DDR1 transcript level and 
suggested on DDR1 activity from a small cohort of patients with metastatic CRC (17). Based 
on the metastatic function of DDR1 in CRC, the level of DDR1 activity may be a marker of its 
metastatic function in patient tumor samples. Regorafenib may reduce metastatic growth in 
“DDR1 high” CRC and a correlation is expected between high DDR1 tumor activity and 
tumor response to regorafenib.  We also predict that, due to the high affinity of regorafenib to 

        
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DDR1, this kinase inhibitor may block all DDR1 invasive/metastatic activities in CRC 
experimental models described above. 
 
cfDNA monitoring 
 
Alain Thierry, Ph.D., Institut de Recherche sur le Cancer de Montpellier (IRCM) 
 
Antoine Adenis, M.D., Ph.D., ICM, IRCM 
 
Marc Ychou, M.D., Ph.D., ICM, IRCM 
Our group developed a Q-PCR based-method (Intplex) which is a mutation targeted test that 
enables rapid, highly sensitive, cost effective and repetitive analysis (19, 20). We carried out 
the first clinical validation of cfDNA analysis in oncology, i.e. in colorectal cancer (21) using 
this test. Thus, we performed a blinded prospective multicenter study to compare KRAS and 
BRAF mutation status data obtained from the analysis of tumor tissue by routine gold-
standard methods and of plasma DNA from mCRC patients before initiation of anti-EGFR 
therapy. The mutation status was determined by both methods from 106 patient samples. 
cfDNA analysis showed 100% specificity and sensitivity for the BRAF V600E mutation. For 
the seven tested KRAS point mutations, the method exhibited 98% specificity and 92% 
sensitivity with a concordance value of 96%. Mutation load, expressed as the proportion of 
mutant alleles in cfDNA, was highly variable (0.5–64.1%, median 10.5%) among mutated 
samples. CfDNA was detected in 100% of patients with mCRC. This study carried out under 
the most stringent criteria for determining performance of a diagnostic test (STARD criteria) 
shows that liquid biopsy through cfDNA analysis could advantageously replace tumor-section 
analysis and expand the scope of personalized medicine for patients with cancer (21, 
22).Considering the results we accumulated, works from other groups, clinical use of cfDNA 
analysis in general or in the context of the selection of mCRC patients toward targeted 
therapy is warranted in the coming years. 
In this context, we are currently investigating, within the PANIRINOX trial (sponsor: 
UNICANCER), the clinical efficacy reached with an intensified regimen combining 
FOLFIRINOX plus panitumumab in mCRC patients with RAS wild-type status determined by 
cfDNA analysis in comparison with the standard treatment ofFOLFOX6 plus panitumumab 
(23).  
 Considering this active screening of mCRC patients with RAS wild-type cfDNA, 
we have an obvious opportunity to select for research purpose, mCRC patients 
with RAS-mutant cfDNA. 

        
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Because cfDNA analysis has the capacity to reflect tumor load, it has also been used to 
monitor the efficacy of response of mCRC patients to treatment, in a few retrospective series 
with a small number of patients (24-26) 
 
 Actually, with this translational research, we aim to better understand the 
changes of RAS-mutant cfDNA concentration along a regorafenib-based 
therapy 
 
2. Study objectives and Endpoints 
2.1 Objectives 
2.1.1 Primary objectives 
 
Phase I:  
-To determine the maximum tolerated dose (MTD) and the recommended phase II 
dose (RP2D), based on the Dose Limiting Toxicities (DLT) of the combination 
evaluated during the three first cycles following initiation of therapy (observational 
period) 
-To evaluate the safety profile of the combination. 
 
Phase II: To evaluate the efficacy (48-week disease-control rate) of study 
combination 
 
 
2.1.2 Secondary objective 
 
These apply to phase II part of the project. 
 
They include the following evaluations: 
- 
Safety of combination (NCI-CTC v5, neurotoxicity being also evaluated with the Levi’s 
scale – appendix 2) 
- 
Overall response rate and disease control rate according to RECIST 1.1 
- 
Duration of response in patients who were not operated on for their metastases 
- 
Study of variations in the concentration of Ras-mutant cfDNA during treatment, 
- 
8-weeks response rate according to RECIST 1.1 
- 
Deepness of response 

        
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- 
Resectability (R0,R1) and unresectability rates (including R2) among patients with 
liver-only metastases 
- 
Progression-free survival  
- 
Progression-free survival since maintenance therapy onset with regorafenib 
- 
Overall survival 
As translational studies: 
- 
Impact of DDR1 kinase activity on response, PFS and progression-free survival since 
maintenance  therapy  onset  with  regorafenib,  and study  of  the variation  of  DDR1 
activity in patients whom liver mets are deemed resectable. 
- 
Select a population of mCRC with RAS-mutant cfDNA (already done in the 
PANIRINOX trial) 
- 
Describe the distribution of baseline genotype(s) of RAS-mutant cfDNA  
- 
Monitor the RAS mutant-allele concentration along FOLFIRINOX-R therapy  
- 
Correlate the baseline RAS mutant-allele concentration and the deepness of 
decrease of this concentration during FOLFIRINOX-R with PFS and with the 
progression-free survival since maintenance therapy onset with regorafenib. 
 
2.2 Endpoints  
 
 
2.2.1 Primary endpoint 
 
Phase I: Adverse events as graded using the common toxicity criteria from the NCI-CTCAE 
V5 and incidence rates of DLT at each dose level during the 3 first cycles of combination 
therapy, 
Dose-limiting toxicities (DLT) are defined as the occurrence of one or more of the following 
drug-related toxicities during the three fist cycles of treatment:  
 
Non-Hematologic DLT:  
 Missing > 7 days daily doses of regorafenib due to drug-related toxicity 
(scheduled treatment pause of regorafenib will not be counted),  
 Grade ≥ 3 (NCI-CTCAE V5) non-hematologic toxicity, except:  
   -Grade 3 nausea, vomiting, diarrhea and grade 2 alopecia  
   -any  untreated  HFSR  that  can  be  adequately  controlled  with  medical 
   intervention,  
   -Grade ≥ 3 lipase elevation without signs of pancreatitis,  

        
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 Grade ≥ 2 posterior reversible encephalopathy syndrome (PRES), 
 Grade ≥ 2 retinopathy,  
 Liver-specific DLTs are: 
               -Drug-related gr. 3-4 bilirubin increase 
               -Drug-related gr. 3-4 AST and/or ALT increase 
               -Drug-related AST and/or ALT increase > 3 x ULN and associated with  
               concurrent bilirubin increase(> 2 x ULN) 
 
Hematologic DLT:  
 Grade 4 (NCI-CTCAE V5) neutropenia lasting > 3 days, 
 Febrile neutropenia Grade 3 (ANC < 1,000/mm3 with fever ≥ 38.5 °C) 
(CTCAE V5),  
 Febrile 
neutropenia Grade 
4 
(life-threatening 
consequences; 
urgent 
intervention indicated),  
 Grade 4 (NCI-CTCAE V5) anemia (i.e life-threatening consequences; urgent 
intervention indicated),  
 Platelets < 25 000 /mm3 or platelets < 50 000 /mm3 associated with bleeding,  
 INR or PTT elevation of Grade ≥ 3 (NCI-CTCAE V5) with associated bleeding,  
 Grade ≥ 3 hemorrhage/bleeding events (NCI-CTCAE V5).  
 
Phase II: 48-week disease-control rate (defined as the rate of non-progressing patients  after 
central review, at 48-week post-initiation of therapy, to all treated patients. 
Treated patients who have progressed or died before the 48-week evaluation will be 
considered as failure. 
 
2.2.2 Secondary endpoints 
 
 
Progression-free survival (PFS), defined as the time from date of inclusion to date of 
first observed disease progression (investigator’s radiological or clinical assessment) 
or death due to any cause, if death occurs before progression is documented. A 
central review of CT-scans is planned for patients found progression-free at 48 
weeks. Patients without tumor progression or death at the time of analysis will be 
censored at their last date of tumor assessment. 
 
Disease control rate (DCR), defined as the rate of patients with non-progressive 
disease (i.e., CR, PR or SD), to all includes patients. 

        
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 
Objective response rate (ORR), defined as the rate of patients with CR or PR, to all 
patients included.  
 
Deepness of response (DpR) is defined as the relative change in the sum of longest 
diameters of RECIST target lesions at the nadir, in the absence of new lesions or 
progression of non-target lesions, as compared to baseline. 
 
Time to recurrence under maintenance, defined as the time (days) from date of 
chemotherapy discontinuation (for protocolar reasons) and regorafenib continuation 
(as maintenance treatment) to date of first observed disease progression 
(investigator’s radiological or clinical assessment) or death due to any cause, if death 
occurs before progression is documented. Patients without tumor progression or 
death at the time of analysis will be censored at their last date of tumor assessment. 
 
Overall survival (OS), defined as the time (months) from date of inclusion to date of 
death. Patients lost for follow-up at the time of analysis will be censored at their last 
news. 
 
Resection (R) rates: R relates to resection margins. R0/R1 are classified by the 
pathologist and R2 is classified by the surgeon. R0 is defined as the absence of 
cancer cells seen microscopically at the resection margin. R1 is defined as the 
presence of cancer cells microscopically at the resection margin (microscopic positive 
margin). R2 is defined at gross examination with the presence of tumor tissue at the 
resection margin. 
Resectability rate (R0R1) and unresectability rate (including R2) among patients with 
liver-only metastases. 
As translational studies: 
 
 
Central determination of cfDNA levels at baseline, every 8 weeks during treatment 
and at the end of treatment. 
 
Impact of DDR1 kinase activity on response and PFS, and study of the variation of 
DDR1 activity in patients whom liver metastases are deemed resectable. 
 
3. Experimental plan  
3.1 Study design 
This will be a prospective, Interventional, multicenter, open-label, uncontrolled phase I/II trial. 
87 (18 phase I and 69 phase II including 6 patients treated at the RP2D during the phase I) 
patients will be included in several centers. 

        
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Phase I 
 
DLT monitoring must be performed during the first three cycles of treatment. Patients will be 
treated until disease progression. 
In case of patient withdrawal before completing the entire third cycle for reasons other than 
DLT, a new patient will be included at this dose level. 
 
The phase I part of this study will be designed as a standard 3+3 design for dose 
escalation/de-escalation and 3 to 6 patients will be enrolled in each cohort sequentially, 
depending on occurrence of dose limiting toxicities (Figure 1). 
 
A standard 3 + 3 design will be followed in the dose escalation part of study. 
Three dose levels for Irinotecan/Regorafenib (IRI 150/REGO 120, IRI 180/REGO 120, IRI 
180/REGO 160) are planned as well as a -1 level (IRI 150/REGO 80) to be opened in case of 
maximum tolerated dose (MTD) was reached at level 1 (Table 1).  
 
Table 1 : 
 
Steps 
Dose Levels 
Number of patients 
DL-1 
 
IRI 150/REGO 80 
 
 
0-6 
DL1 
 
IRI 150/REGO 120 
 
 
3-6 
DL2 
 
IRI 180/REGO 120 
 
 
3-6 
DL3 
 
IRI 180/REGO 160 
 
 
3-6 
At each dose level, three patients will be included. Three additional patients will be enrolled 
at the same dose level if one dose limiting toxicity (DLT) is observed in the first three patients 
of this dose level (Figure 1).  
 
Figure 1 : 

        
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Table 2 : Dose escalation rules 
Outcome (# DLT / #  Patients) 
Action 
0 DLT out of the first 3 patients 
Include 3 patients at the next dose level 
1 DLT out of 3 patients 
Include 3 additional patients at the same dose level. 
≥ 2 DLT out of 3 patients 
Stop dose escalation. Include 3 additional patients at 
the previous dose level (unless 6 subjects were already 
treated). 
≥ 2 DLT out of 6 patients 
Stop dose escalation. Include 3 additional patients at 
the previous dose level (unless 6 patients were already 
treated). 
 
The MTD is defined as the dose at which at least two out of three to six patients experienced 
a DLT during the first three cycles of treatment. 
 
Dose escalation will be stopped if MTD is reached or the last dose level (IRI 180/REGO 160) 
is reached (MTD not reached).  
Initial dose 
To treat 3 pts* at 
this dose level 
Total 
DLT
To treat to next 
dose level 
To treat 3 more 
pts at the same 
dose level 
Total 
DLT
Last Dose 
level reached 
MTD identified 
MTD identified 
MTD not 
identified 
Yes 
No 
0/3 
>1/3 
1/3 
>1/6 
1/6 

        
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The recommended phase II dose (RP2D) is defined as the dose closest to the MTD at which 
a DLT is observed in 0/3 or 1/6 patients. 
 
Should any patient discontinue the study prior to completing the entire (3 cycles) for reasons 
other than a DLT then a replacement patient will be added at that dose level. 
 
DLT recording and assessment 
 
• 
Study sites will document any DLT immediately and report a DLT event to the 
Sponsor within 24 hours of site’s awareness. 
• 
Once recruitment of 3 or 6 patients per dose level has been completed, recruitment 
will be halted by default until the 3-cycle dose-finding treatment has been completed for each 
patient and sites have reported all relevant safety findings. 
• 
The decision to stop, modify or continue escalation will be made by the project team 
(coordinator, statistician, project manager, safety vigilance head and vigilance manager) if 
there are no SUSARs. In the event of SUSARs, we will refer the matter to the independent 
scientific committee. 
• 
The Sponsor will communicate further dosage information (dose escalation or de-
escalation)  and additional safety measures to all participating sites/investigators. 
                                    
Phase II : 
The 6 patients treated at the RP2D in the phase I part will be included in the phase II part. 
The multicenter, phase II trial is planned to enroll 69 patients. The patients who meet the 
study eligibility criteria will be included to receive the study drug. 
 First inclusion:  april 2019 
 Inclusion period:12 months Phase I + 12 months Phase II 
 End of the inclusion period: march 2021 
 Expected end of study: june 2022 
 Report: september-december 2022  
 Poster/public: phase I (2020), phase II (april 2023 and july 2023) 
 
3.2 Study period 
 
3.3 Compensation modalities  
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.  

        
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4. Population  
4.1 Number of planned patients  
 
-87 patients included out of approximately 174 screened patients. 
4.2 Inclusion criteria 
 
Eligibility criteria for prescreening 
 
The following criteria must be met at the time of prescreening: 
1. Written informed consent for prescreening. 
2. Prescreening of patients will be performed at the investigators’ discretion up to a 
maximum of 21 days prior to full study screening. Investigators should ensure all 
patients will be eligible in terms of disease status within this timeframe.  
3. Age ≥18 years. 
4. Histological documentation of adenocarcinoma of the colon or rectum. 
5. Synchronous or metachronous metastatic colorectal cancer not amenable to surgical 
resection with curative intent. 
6. No prior therapy for metastatic disease. 
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤1. 
8. Life expectancy of at least 3 months. 
 
Besides these basic criteria, any criterion as outlined below under inclusion eligibility criteria 
for full study and exclusion criteria, already known to prohibit the patient’s participation in the 
study  should  be  considered.  No  study-related  procedures will be performed that are not 
covered by the prescreening informed consent form. 
 
Eligibility criteria for full study 
 
1. Written informed consent for full study 
2. Documentation of tumor RAS mutation, wild-type homozygous, heterozygous status 
of UGT1A1 gene. The status of UGT1A1 gene will be performed by the laboratory 
chosen by the investigator (for information, appendix 1). 
3. Serum uracile < 16 ng/ml 
4. Measurable disease, defined as at least one unidimensional measurable lesion on a 
CT scan, according to RECIST version 1.1.  
5. ECOG performance status ≤1. 
6. Life expectancy of at least 3 months. 

        
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7. Adequate bone marrow, renal and liver functions as evidenced by the following 
laboratory requirements within 7 days prior to study treatment initiation: 
a. Absolute neutrophil count (ANC) ≥ 1 500/ mm3 without biologic response 
modifiers such as granulocyte colony-stimulating factor (G-CSF), within 21 
days before the start of study treatment, 
b. Platelet count ≥ 100 000/mm3 , without platelet transfusion within 21 days 
before the start of study treatment, 
c. Hemoglobin (Hb) ≥ 9 g/dL, without blood transfusion or erythropoietin 
within 21 days before the start of study treatment, 
d. Serum creatinine ≤ 1.5 x upper limit of normal (ULN), 
e. Serum calcium ≥ LLN and ≤ 1.2 x UNL ; Serum magnesium ≥ LLN and ≤ 1.2 x 
UNL ; Kalemia ≥ LLN, 
f. Glomerular filtration rate as assessed by the estimated glomerular filtration 
rate (eGFR) ≥ 50 mL/min per 1.73 m2 calculated by the Modification of Diet in 
Renal Disease (MDRD) abbreviated formula, 
g. Total bilirubin ≤ 1.5 x ULN, 
h. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
ULN (≤ 5 x ULN for patients with liver involvement of their cancer), 
i. 
Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver 
involvement for their cancer and/or bone metastases). 
8. Lipase ≤1.5 x ULN.  
9. Adequate coagulation, as assessed by the following laboratory test results: 
c. International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 x 
ULN, 
d. Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN, 
Note: Patients on stable dose (dose has not been changed in at least 28 
days) of anticoagulation therapy will be allowed to participate if they have no 
sign of bleeding or clotting and INR / PT and PTT / aPTT test results are 
compatible with the acceptable benefit-risk ratio at the investigator’s 
discretion. In such case, limits as noted would not apply. 
10. For   women   of   reproductive   potential,   negative   serum   beta   human   chorionic 
gonadotropin (β-HCG) pregnancy test obtained within 7 days before the start of study 
treatment. 

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
Women not of reproductive potential are female patients who are postmenopausal or 
permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy). 
11. For women of childbearing potential and men, agreement to use an adequate 
contraception for the duration of study participation and up to 4 months following 
completion of therapy for women and 6 months for male patients. Females of 
childbearing potential who are sexually active with a non-sterilized male partner must 
use 2 methods of effective contraception. The investigator or a designated associate is 
requested to advise the patient on how to achieve an adequate birth control. Adequate 
contraception is defined in the study as any medically recommended method (or 
combination of methods) as per standard of care. 
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests 
and other study procedures. 
13. Affiliation to the Social Security System. 
 
4.3 Non-inclusion criteria 
 
1. Previous or concurrent cancer that is distinct in primary site or histology from 
colorectal cancer within 5 years prior to study inclusion, except for curatively treated 
cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta 
(non invasive tumor), Tis (carcinoma in situ) and T1 (lamina propria invasion)]. 
2. Discovery of metastases within 6 months after the termination of adjuvant 
chemotherapy. 
3. Previous treatment for metastatic disease. 
4. Radiotherapy within 28 days prior to first dose of treatment. 
5. Active cardiac disease including any of the following: 
a. Congestive heart failure New York Heart Association (NYHA) class 2 
(appendix 3), 
b. Unstable angina (angina symptoms at rest), new-onset angina (begun within 
the last 3 months), 
c. Myocardial infarction less than 6 months before first dose of treatment, 
d. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin 
are permitted). 
6. ECG with a QT/QTc interval higher than 450 ms for men and higher than 470 ms for 
women.  

        
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INTERVENTIONAL STUDY OF CATEGORY 1 
7. Uncontrolled hypertension. (Systolic blood pressure 140 mmHg or diastolic 
pressure 90 mmHg despite optimal medical management). 
8. Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism 
within 6 months before start of treatment. 
9. Persistent proteinuria of National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE V5) grade 3 (i.e. urinary protein ≥ 3.5 g/24 hrs) 
10. Peripheral neuropathy > grade1 (NCI-CTCAE v5). 
11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to first dose of treatment. 
12. Ongoing infection grade 2 (NCI-CTCAE v5). 
13. Known history of human immunodeficiency virus (HIV) infection. 
14. Chronic hepatitis B or C infection (if hepatitis status cannot be obtained from medical 
records, re-testing is required). 
15. Seizure disorder requiring medication. 
16. Symptomatic metastatic brain or meningeal tumors. 
17. Evidence or history of any grade 3-4 bleeding diathesis. Any hemorrhage or bleeding 
event Grade 3 (NCI-CTCAE v5) within 4 weeks prior to the start of study 
medication. 
18. History of organ allograft. 
19. Non-healing wound, ulcer, or bone fracture. 
20. Dehydration Grade 1 (NCI-CTCAE v5). 
21. Substance abuse, medical, psychological, or social conditions that may interfere with 
the patient’s participation in the study or evaluation of the study results. 
22. Known hypersensitivity to any of the study drugs, study drug classes, or any 
constituent of the products. 
23. Interstitial lung disease with ongoing signs and symptoms. 
24. Concomitant intake of St. John's wort. 
25. Live attenuated vaccines are prohibited 10 days before the treatment, during the 
treatment and 3 months after the termination of treatment 
26. History of gastrointestinal fistula or perforation 
27. Inability to swallow oral medication. 
28. Any malabsorption condition. 
29. Pregnant or breast-feeding subjects. 

        
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30. Any condition that, in the opinion of the investigator, would interfere with the 
evaluation of study treatment or interpretation of patient safety or study results. 
31. Participation in another clinical study with an investigational product during the last 30 
days before inclusion. 
32. Patients who might be interconnected with or dependent on the sponsor site or the 
investigator. 
33. Legal incapacity or limited legal capacity. 
4.4  Procedure  
Before the inclusion of the patient in the study, the investigator must verify :  
-that the screening inclusion and non-inclusion criteria have been met  
-that the molecular test consent has been obtained.  
There’s no paper form for this step and no registering. 
Inclusion:  
The inclusion request will be performed by fax for phase I. After the consent form has been 
signed and all inclusion/ non-inclusion criteria have been met, the investigator will proceed 
with the inclusion through the paper inclusion form. It will be send by fax to the biostatistics 
unit 04-67-61-31-18 and project manager 04-67-61-47-02.  
In the absence of a request for derogation, the biostatistics unit will return by fax the 
response to the investigator with the inclusion number and the dose level of the patient. 
Then the CRA will immediately fill out the data in the e-CRF via 
https://ecrfcval.icm.unicancer.fr/CSOnline/ in order that an automatic reply can be sent by e-
mail to confirm the success of the inclusion procedure to the:  
 
Representative of Sponsor – project manager, 
 
Investigator, 
 
Data manager, 
 
Statistician, 
 
Pharmacist 
Once the patient is registered, he/she is considered to be enrolled in the study. 
 
5. Visit Schedule 
5.1 Tabulated overview

 
 
 
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Tabulated overview 
 Folfirinox-R -  Phase I/II 
 
 
Screening 
 
 
 
 
 
 
 
Treatment 
 
 
 
Evaluation  
(Every 8 
weeks) 
 
 
 
End of 
treatment 
 
 
    
    Safety 
 Follow-up 
 
 
Follow-up 
 
 
 
 
 
 
End of 
study 
D-21 
D-7 
Cycle 1 
Cycle 2 
Cycle 3 
≥Cycle 4 
Cycles 
 
 
C1D1 
C1D8 
C2D1 
C2D8 
C3D1 
C3D8 
≥C4 
 
 
 
 
 
Baseline documentation 
 
Informed consents1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria checked 2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination3 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
β-HCG blood test4  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Studies 
 
12-lead ECG5 
X 
 
X8 
 
X 
 
X 
 
X 
 
X 
 
 
 
Complete blood count  
 
X 
X8 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Coagulation 
 
X 
X8 
 
X 
 
X 
 
X 
 
X 
 
 
 
Electrolyte panel 
 
X 
X8 
 
X 
 
X 
 
X 
 
X 
 
 
 
Chemistry panel6 
 
X 
X8 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Liver function test7 
 
X 
X8 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Tumor markers (ACE and CA 19-9) 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Tabulated overview 
 Folfirinox-R - Phase I/II 
 
 
Screening 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
Evaluation  
(Every 8 
weeks) 
 
 
 
End of 
treatment 
 
 
    
    Safety 
 Follow-up 
 
 
Follow-up 
 
 
 
 
 
End of 
study 
D-21 
D-7 
Cycle 1 
Cycle 2 
Cycle 3 
≥Cycle 4 
Cycles 
 
 
C1D1 
C1D8 
C2D1 
C2D8 
C3D1 
C3D8 
≥C4 
 
 
 
 
 
Urinary analysis9 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
cfDNA analysis for RAS. UGT1A1 
and serum uracil for evaluating DPD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging assessments 
 
Radiologic Tumor assessment10 
X 
 
 
 
 
 
 
 
 
X11 
X12 
X13 
 
 
Other Clinical Assessments 
 
DLT assessment14 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
ECOG  
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Body weight, BSA, height15 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
Blood pressure16 
 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
Concomitant medications 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Adverse events17 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
  X21 
 
Drug dispensing 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Drug accountability  
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Post-study survival status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Anti-cancer medications 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Patient’s diary checking18 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Ancillary studies 
 
EDTA tubes (3 X 7 ml) cfDNA19 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
Paraffin block for analysis of DDR120 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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1Written informed consent will be obtained for pre-screening and for full study 
2Eligibility criteria will be checked for pre-screening and for full study 
3Including skin assessment for toxicities 
4Pre-menopausal women of childbearing potential only 
                     512-lead ECG will be performed before and after the administration of Oxaliplatin during the  
             three first cycles (Phase I and II) beyond cycle 3, ECG will be performed before 
             administration of oxaliplatin 
6Includes: albumin, creatinine, creatinine clearance calculated according MDRD, lipase, 
glucose, TSH (every 6 weeks of CXD1), , total protein and uric acid 
7Liver function tests will be performed weekly during the three first cycles of treatment 
8Not required at day 1 of cycle 1 if those were completed within 7 days  
9 Dipstick assessment with pH, protein, glucose, bilirubin, ketones, blood cells and leucocytes 
10CT scan of the abdomen, pelvis and chest or if the patient is allergic to iodine contrast 
agents, hepatic MRI and CT scan of the pelvis and chest without injection; RECIST criteria  
version 1.1 
            11CT-Scans will be performed every 8 weeks  
            12If the last radiological tumor assessment > 1 month 
            13CT-Scan of safety follow-up will be performed if only it weren’t done at the EOT visit  
14Period for DLT assessment is the three first cycles (only Phase I) 
15Height only at screening 
16Blood pressure will be monitored every other week during the first 3 cycles of treatment 
17Continuously from screening until FU visit, 30 days after last administration of study drug 
                18A treatment diary will be handed over to patient on cycle 1 day 1 
19Three EDTA tubes will be collected at baseline, every 8 weeks during treatment and at the  
end of treatment 
20Paraffin-embedded human solid tissue blocks will be sent off at room temperature at the 
end of the enrollments 
21Only for unstabilized adverse events since the end of treatment 
5.2 Screening period 
 
Enrollment into FOLFIRINOX-R will be performed in two stages with two separate informed 
consent forms. Initially, all potential patients will consent to undergo molecular testing. 
 
Molecular testing : 
Only patients with RAS mutated tumor status, wild-type homozygous status of DPD and wild-
type homozygous, heterozygous status of UGT1A1will be screened for the study treatment. 
Each centre will choose its DPD and UGT1A1 genotyping laboratory. For your 
information a list is provided by the sponsor (cf appendix 1). The sponsor will bear the 
cost of the genotyping analysis (we draw your attention to the analysis of phenotyping 
which will not be reimbursed by the sponsor). 
A second consent form to screen for the clinical study (Clinical Trial Consent).  
Both consent processes are independent of each other. 

 
 
 
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The following procedures and assessments will be performed around 21 days of starting 
study Drug :  
 
 
Obtainment of two informed consents  
 
 
A blood sample will be collected then will be shipped to laboratory that you will have 
chosen. To determine the DPD and UGT1A1 status (cf appendix 1). Check with the 
laboratory for the number, type and volume of blood tubes 
 
 
Documentation of RAS mutation 
 
 
Eligibility criteria checked 
 
 
Physical examination including review of all organ systems, examination of pertinent 
organ systems). 
 
 
Radiological tumor assessment using the RECIST criteria, version 1.1 (see appendix 
4) must be performed. (CT scan of the abdomen, pelvis and chest or hepatic MRI and 
CT scan of the pelvis and chest without injection). 
A PET scan is not acceptable for radiological evaluation 
 
 
All additional suspected sites of disease should be imaged. An appropriate 
radiological evaluation should be obtained if bone metastases are suspected (e.g., 
bone scan) 
 
 
12-lead ECG 
 
 
Complete medical history including demographics, allergies, prior surgery and prior 
chemo/radiation therapy with documentation of treatment response. See section XX 
for detailed instructions on the differentiation between medical history and adverse 
events 
 
The following procedures and assessments will be performed within 7 days of starting 
study drug: 
 

 
 
 
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 
Eligibility criteria checked 
 
 
ECOG performance status (appendix 5) 
 
 
Adverse events  
 
 
Physical examination including review of all organ systems, examination of pertinent 
organ systems, weight, BSA and height. 
 
 
A CBC with differential should be performed: RBC, hemoglobin, hematocrit, platelet 
count and WBC. WBC must include differential neutrophil, lymphocyte, monocyte, 
basophil and eosinophil counts 
 
 
Coagulation panel: Prothrombin time (PT) or the International Ratio of PT (PT-INR) 
and Partial Thromboplastin Time (PTT) 
 
 
Electrolyte panel: sodium, potassium, calcium, magnesium, chloride, phosphate, 
bicarbonate 
 
 
Chemistry panel : albumin, lipase, glucose, serum creatinine, clearance calculated 
according MDRD, uric acid, , protein total, TSH  
 
 
Liver function test panel: Aspartate Amino-Transferase (AST), Alanine Amino-
Transferase (ALT), bilirubin (total and direct), alkaline phosphatase, GGT, Lactic 
Dehydrogenase (LDH)  
 
 
Three 7-ml EDTA tubes for cfDNA (not supplied).  After centrifugation, the plasma will  
be  frozen at -80°c until shipment. 
 
 
Tumor markers : CEA (Carcino-Embryogenic Antigen), CA 19.9 (Carbohydrate 
Antigen 19-9) 
 
 
Urine analysis: PH, protein, glucose, bilirubin, ketones, blood cells and leukocytes 
 
 
The blood pressure must be monitored every other week for the three first cycles of 
study treatment. 

 
 
 
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The blood pressure will be recorded by the patient and entered onto his treatment 
diary. Blood pressure measurements will be performed in patients sitting for 5 
minutes prior to the evaluation.  
 
 
A β-HCG dosage for women of childbearing potential. Post-menopausal women with 
no menses for at least 1 year or surgically sterilized women will not be required to 
undergo a pregnancy test. 
 
 
Record of all concomitant medications except Homeopathy. All medicines and 
significant non-drug therapies taken within 7 days before study treatment must be 
recorded in the e-CRF. 
 
5.3 Treatment period 
 
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented, the patient will be enrolled. 
 
The following assessments should be performed on the first day of each cycle 
(FOLFIRINOX + Regorafenib except C1D1 prior to receiving study treatment (+/- 3 
days) : 
 
DLTs assessment for phase I from C2D1 to C4D1 (three first cycles), 
 
 
Physical examination with weight, body surface area (if the patient’s body weight 
changes by more than 10 % then BSA will be recalculated for Regorafenib and it will 
be recalculated for any change of weight for Irinotecan). The physical examination 
includes skin assessment for toxicities,  
 
 
ECOG performance status, 
 
 
Adverse events documentation (including Start/Stop dates, seriousness, CTC  
notation and grading, relationship to study drug, outcome and action taken) using 
CTCAE V5.0, 
 
 
Concomitant medications (including start/stop dates, dose, indication), 
 
 

 
 
 
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 12-lead ECG : It will be performed before and after oxaliplatine administration during 
the three first cycles of Phase I/II, 
 
 
The following laboratory evaluations are not required at Day 1 of Cycle 1 if these 
were completed within 7 days of starting study drug treatment. Otherwise, these 
laboratory evaluations are required on Day 1 of each cycle: 
 
 
 CBC with differential should be performed: RBC, hemoglobin, 
hematocrit, platelet count and WBC. WBC must include differential 
neutrophil, lymphocyte, monocyte, basophil and eosinophil counts, 
 
 Coagulation panel: Prothrombin time (PT) or the International Ratio of 
PT (PT-INR) and Partial Thromboplastin Time (PTT) 
If a patient is on warfarin or phencoumarone with stable PT/INR at 
baseline, the PT/INR should be assessed on Day 15 of Cycle 2. If 
either of these values is above the acceptable range, the doses should 
be modified and the assessments should be repeated every fortnight 
until it is stable, 
 
 Electrolyte panel: sodium, potassium, chloride, magnesium, calcium, 
bicarbonates, phosphate, 
 
 Chemistry panel : albumin, lipase, glucose, serum creatinine, 
clearance calculated according MDRD, uric acid, , protein total, TSH 
every 6 weeks, 
 
 Hepatic panel: Aspartate Amino-Transferase (AST), Alanine Amino-
Transferase (ALT), bilirubin (total and direct), GGT, alkaline 
phosphatase, Lactic Dehydrogenase (LDH). 
 
 Urine analysis: PH, protein, glucose, bilirubin, ketones, blood cells and leukocytes 
  
 
Drug dispensing,  
 

 
 
 
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 
Drug accountability (pharmacy). To have complete control over the distribution 
and use of the study drug, the drug accountability must be performed on Day 1 for 
(Regorafenib) of each cycle. 
A patient’s diary is given on C1D1. It will allow to patient to write down his oral 
intakes and blood pressure values. It will be checked out at each cycle by C2D1. 
 
 
The blood pressure must be monitored every other week for the three first cycles 
of study treatment, 
The blood pressure will be recorded by the patient and entered onto his treatment 
diary. Blood pressure measurements will be performed in patients sitting for 5 
minutes prior to the evaluation.  
 
The following assessments should be performed on day 8 of cycle 1, 2 , 3 : 
 
 
A CBC with differential should be performed: RBC, hemoglobin, hematocrit, platelet 
count and WBC. WBC must include differential neutrophil, lymphocyte, monocyte, 
basophil and eosinophil counts 
 
 
Chemistry panel: albumin, total protein, lipase, glucose, serum creatinine, clearance 
calculated according MDRD, uric acid  
 
 
Liver function test panel: Aspartate Amino-Transferase (AST), Alanine Amino-
Transferase (ALT), bilirubin (total and direct), GGT, Lactic Dehydrogenase (LDH)  
 
The following assessments should be performed at each evaluation i.e (every 8 
weeks): 
 
 
Tumor markers CEA (Carcino-Embryogenic Antigen), CA 19.9 (Carbohydrate 
Antigen 19-9) 
  
 
Radiological tumor assessment using the RECIST criteria, version 1.1 (see 
appendix 4) must be performed. (CT scan of the abdomen, pelvis and chest or 
hepatic MRI and CT scan of the pelvis and chest without injection) 
 
 
Physical examination with weight, BSA   
 

 
 
 
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 
Three 7-ml EDTA tubes for cfDNA (not supplied). After centrifugation, the 
plasma will be frozen at -80°c until shipment. 
 
5.4 End of treatment Visit 
 
The end of treatment corresponds to the last treatment administered. 
 
When a patient is taken off treatment, the following assessments should be performed within 
14 days after study treatment has stopped provided the last clinical and laboratory 
evaluations > 7 days. 
 
 
Physical examination with weight, BSA   
 
 
ECOG performance status 
 
 
Adverse events documentation (including Start/Stop dates, seriousness, CTC  
notation and grading, relationship to study drug, outcome and action taken) 
using CTCAE V5.0  
 
 
Concomitant medications 
 
 
12-lead ECG 
 
 
A CBC with differential should be performed: RBC, hemoglobin, hematocrit, 
platelet count and WBC. WBC must include differential neutrophil, 
lymphocyte, monocyte, basophil and eosinophil counts 
 
 
Coagulation panel: Prothrombin time (PT) or the International Ratio of PT (PT-
INR) and Partial Thromboplastin Time (PTT) 
 
 
Electrolyte panel: sodium, potassium, calcium, magnesium and chloride   
 
 
Chemistry panel : albumin, lipase,  phosphate,  glucose, serum creatinine, 
clearance calculated according MDRD, uric acid, protein total, 
 

 
 
 
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 
Liver function test panel: Aspartate Amino-Transferase (AST), Alanine Amino-
Transferase (ALT), bilirubin (total and direct), GGT, alkaline phosphatase, 
Lactic Dehydrogenase (LDH) 
 
 
Tumor markers: CEA (Carcino-Embryogenic Antigen), CA 19.9 (Carbohydrate 
Antigen 19-9) 
 
 
Three 7-ml EDTA tubes for cfDNA (not supplied).  After  centrifugation,  the  
plasma  will  be  frozen  at -80°c until shipment. 
 
 
Urine analysis: PH, protein, glucose, bilirubin, ketones, blood cells and 
leukocytes 
 
 
A radiological tumor assessment using the RECIST criteria, version 1.1 (see 
appendix 4) must be performed if the last radiological assessment > 1 months. 
(CT scan of the abdomen, pelvis and chest or hepatic MRI and CT scan of the 
pelvis and chest without injection) 
 
 
The blood pressure will be recorded by the patient and entered onto his 
treatment diary. Blood pressure measurements will be performed in patients 
sitting for 5 minutes prior to the evaluation.  
 
 
Drug accountability (pharmacy) 
 
 
Patient’s diary checking 
 
5.5 Follow-up  
 
Safety Follow-Up Visit 
 
Patients have to be evaluated for symptoms and adverse events in a visit 30 days (+/- 7 
days) after permanently stopping study treatment. This contact may be completed via 
telephone. The following assessments should be performed: 
 
 
Vital status 
 
 
Anti-cancer medications 
 
 
Physical examination 

 
 
 
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 
A radiological tumor assessment using the RECIST criteria, version 1.1 (see 
appendix 4) must be performed if only it weren’t performed at the end of 
treatment visit. 
(CT scan of the abdomen, pelvis and chest or hepatic MRI and CT scan of the 
pelvis and chest without injection). 
 
 
Tumor markers : CEA (Carcino-Embryogenic Antigen), CA 19.9 (Carbohydrate 
Antigen 19-9) if not done at the EOT visit 
 
 
Concomitant medications (including anti-cancer medication) 
 
 
Adverse events documentation 
 
 
 
The blood pressure must be performed if only it weren’t performed at the end 
of treatment visit. 
 
Follow-up every three months for 3 years 
 
 
Vital status 
 
 
Anti-cancer medications 
 
 
Physical examination 
 
 
Adverse events documentation (only for unstabilized adverse events since the 
end of treatment) 
 
5.6 End of study 
 
 
Paraffin-embedded human solid tissue blocks will be sent off at room 
temperature at the end of the enrollments. 
 
6. Treatments  
6.1 Experimental treatment or procedures 
 
Patients having signed informed consent form will receive after registration the treatment. 
Patients are eligible for repeated treatment cycles in the absence of disease progression and 
non-manageable adverse events. 
The IV investigational products (IP) will be prepared according to the chemotherapy safety 
standards (appendix 6). 

 
 
 
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FOLFIRINOX administration (Phase I and II): 
FOLFIRINOX will be administered as per standard procedures: every 14 days (1 cycle = 14 
days): 
 
- Oxaliplatin (Eloxatin® or generic drug): 85mg/m² on day 1, IV infusion over 2 hours, 
immediately followed by 
- Folinic acid 400 mg/m² or Calcium Levofolinate 200mg/m² given as a 2-hour IV infusion, 
with the addition, after 30 minutes of 
- Irinotecan (Campto® or generic drug): 150-180 mg/m² as per dose-level, given as a 90-
minute intravenous infusion through a Y-connector immediately followed by 
- 5-Fluorouracil: 400mg/m² IV bolus then 2400mg/m² over 46 hours continuous infusion. 
Irinotecan infusion has to be preceded by a subcutaneous injection of atropine: 0.25mg to 
prevent cholinergic syndrome (in absence of contraindication). 
The next cycle starts on day 15. Each cycle will be delivered every 2 weeks.  
 
With this treatment, prophylactic G-CSF will be systematically given after each course 
from Day 7 to Day 12. 
 
REGORAFENIB administration (Phase I and II): 
-On days 4–10 of each cycle, all patients will receive Regorafenib orally once daily 
depending on dose levels for phase I and RPD2 for phase 2. 
 - 1 cycle = 15 days 
         
 
6.2 Drug packaging and labelling 
5-FU, Oxaliplatin, Irinotecan  
Oxaliplatin, irinotecan, 5-Fluorouacil and calcium levofolinate will be taken in the usual stock.  

 
 
 
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Regorafenib  
 
For  List of excipients and Storage: See Investigator’s brochure (appendix 7). 
 
The investigational drug regorafenib must be exclusively used for the investigation specified 
in this protocol, and it will only be accessible to authorized staff. The sponsor delegate 
labelling, packaging and shipping of product during the study to Sodia. Sodia will perform this 
prestation in accordance with applicable Good Manufacturing Practices. 
 
Regorafenib will be provided by Sponsor as film-coated tablets of 40 mg in 30-tablet bottles. 
 
The investigational product(s) label will bear sponsor’s name, address and telephone 
number, the EudraCT number, product name, dosage form and strength, batch number, 
expiration date, required storage conditions and required caution statements  as applicable. 
 
6.3 Shipment, storage conditions and accountability and destruction 
 
The experimental drug regorafenib, provided by the sponsor, will be distributed to the 
pharmacy at the investigational center by Sodia in accordance with the current Good 
Distribution Practices guidelines. 
The pharmacist of the trial site will receive numbered treatment and will aknowledge receipt 
of all the shipments by sending to the distributor a form duly completed. 
Investigational medicinal products will have to be stored in locked room with limited access 
and in accordance with the recommendations of the manufacturer. 
The pharmacist of the health care site will keep accurate records of the drugs delivered, 
used, unused or destroyed. 
The clinical research assistant mandated by the sponsor will be in charge of verifying the 
accounting records for the supplied medicinal products and ensure that an accounting form is 
validated and signed by the pharmacist of the health care center prior to any demand for 
destruction. 
Sites will be provided with an initial supply when activated, and after sites can order supplies 
as and when they need them. A form will be provided to the site when they are activated. 
The pharmacist is responsible for a safe and proper handling and storage of the 
investigational medicinal products at the investigational center. The investigational products 
must be stored in a locked facility with restricted access to the pharmacist and authorized 
personnel, and under environmental conditions consistent with the drug manufacturer 
recommendations (SmPC for FOLFIRINOX or IB for Regorafenib). 

 
 
 
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Storage requirements of regorafenib: Regorafenib bottles must be stored in the original 
carton under refrigeration at a temperature between 2°C and 25° C until the time of use. 
Bottles will be kept tightly closed. 
 
Storage requirements of irinotecan:  Irinotecan must be kept in the outer carton in order to 
protect from light. 
The Irinotecan concentrate for solution for infusion should be diluted and used immediately 
after opening. However, if dilution takes place in controlled and validated aseptic conditions, 
the Campto® solution for infusion can be used (infusion time included) within 12 hours when 
stored at room temperature, or within 24 hours when stored in a refrigerator at 2°C to 8°C 
after dilution/reconstitution. 
 
Storage requirements of oxaliplatin: after dilution in 5% glucose, chemical and physical in-
use stability has been demonstrated for 48 hours at +2°C to +8°C and for 24 hours at +25°C. 
From a microbiological point of view, this infusion preparation should be used immediately. If 
not used immediately, in-use storage times and conditions prior to use are the responsibility 
of the user and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has 
taken place in controlled and validated aseptic conditions. 
 
Storage requirements of 5-Fluorouacil: do not store above 25°C. Keep container in the 
outer carton to protect from light. Do not refrigerate. 
Store the preparation at a temperature between + 15°C and +25°C. After dilution, immediate 
use is recommended. However, chemical and physical in-use stability has been 
demonstrated for 8 hours at a temperature between + 15°C and +25°C. 
 
Storage requirements of calcium levofolinate: The lyophilisat must be kept at a 
temperature <30°C, protected from light and humidity. After preparation, the solution may be 
kept for 24 hours below 30°C. It may be conserved longer in a refrigerator at a temperature 
between 2°C and 8°C and in the dark. 
 
All Temperature excursions relating to the shipping or storage of regorafenib (in line with the 
below table 3) will be reported to ICM as soon as the site becomes aware. In terms of what 
constitutes a temp excursion for regorafenib, this is summarized below: 
 
Table 3 : Storage Instructions : 

 
 
 
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Between 2°C - 25°C.  
Permitted temperatures: not limited between > 25°C and ≤ + 30°C, 15 days between > + 
30°C and ≤ + 40°C, less than 5 days between 40°C and ≤ + 60°C, less than 5 days between 
> - 18°C and ≤ + 2°C. 
 
Temperature logs should be kept updated by the pharmacist, to document adequate storage 
during the trial. 
The investigator/pharmacist must ensure that the investigational product is administrated 
only to patients enrolled in this trial. The investigational product must not to be used outside 
the context of the trial protocol. 
The pharmacist or the authorized staff must document the receipt, the dispensation, and the 
return or destruction of all investigational products received during this trial. Records on 
investigational products delivery to the center, the inventory at the center, the use by each 
patient, and the return to the sponsor or destruction by the site must be implemented and 
maintained by the pharmacist or another appropriately trained individual at the investigational 
center. Will be reported on these records at least dates, quantities, batch numbers of the 
investigational  products  Forms  will  be  provided  by  the  sponsor  to  ensure trial treatment 
accountability. 
The pharmacist will implement an accounting of medicinal products dispensed, used and 
unused. 
This process will be monitored by the ICM CRA during the trial. The CRA will check that the 
accountability documentation has been filled in and signed by the pharmacist before the 
investigational products, used and unused, are destroyed. 
The destruction will take place in the investigator centers under the responsibility of their 
pharmacist in accordance with national regulatory requirements, and with prior formal 
agreement from the sponsor. A certificate of destruction, identifying concerned products, will 
be given to the sponsor. 
 
6.4 Treatment duration  
 
12 cycles have to be delivered consecutively or not.  
Indeed, treatment can be temporarily stopped to perform surgical resection or regional 
procedures (radiofrequency, cryoablation, radiation therapy) if the disease become 
accessible to them but if it happens, before the end of the 12 planned cycles, the treatment 

 
 
 
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has to be resumed within 4 to 8 weeks after the loco-regional procedure has been completed 
in order to reach a total number of 12 cycles delivered. 
If a surgery or a regional procedure is considered, we recommend respecting a time period 
of 4 weeks between the last chemotherapy and the procedure. 
 
After 12 cycles, patients whose metastases are not progressing and are still unresectable  
will receive regorafenib (experimental regimen and at the same dose) until progression or 
toxicity. 
6.5 Expected Toxicities  
 
The expected adverse events of Oxaliplatine, 5 FU and Irinotecan are described in the 
respective Summaries of Product Characteristics (SmPC). Refer to the latest current version 
on the public drug database website (appendix 7) for: 
- Elvorin 
- 5 FU   
- OXALIPLATINE 
- IRINOTECAN  
Refer to the latest investigator’s brochure for Regorafenib. 
6.6 Dose modification and Dose delay  
 
FOLFIRINOX 
 
Table 4 : Hematological criteria for dose modification/interruption of Folfirinox 
 
  
 
Measures in case of hematological toxicity during the inter-cycle interval (nadir): 
 

 
 
 
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Table 5 : Dose modifications in case of digestive toxicities  
 
 
  
Table 6 : Dose modifications in case of Peripheral neuropathy: 
 
 
  
 
 
 
 
Table 7 : Dose modifications in case of other specific toxicities: 
 

 
 
 
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Recommendations in case of QT/QTc prolongation > 500msec: 
Oxaliplatin will be stopped. Patients will be referred to a cardiologist and monitored in a 
hospital with continuous cardiac activity recording performed until resolution to grade 1 or 
baseline. 
 
Recommendations in case of mucositis or hand-foot syndrome: 
These toxicities are caused by 5-FU. If grade 3-4 toxicity occurs, continuous 5-FU IV infusion 
will be reduced by 25% for the remaining cycles. 
Dose adaptation in case of bilirubin elevation: 
If bilirubin increase is > 1.5 ULN, it is preferable to postpone chemotherapy, because 
irinotecan is eliminated via biliary pathway, and check the presence of a tumoral relapse or 
obstruction of bile duct. Indication of chemotherapy will be retained if these two diagnoses 
are eliminated. However, it will be preferable to stop irinotecan if bilirubin elevation is 
persistent. 
 
Recommendations in case of Other toxicities: 
 
Other toxicities with > grade 2, except anemia and alopecia, may justify a dose reduction of 
25%. If it is medically indicated, for instance, reduction of irinotecan to 120 mg/m2 and/or 
oxaliplatin to 60 mg/m2 and/or 5-FU decreased by 25 % in function of the type of toxicity. 
 
 
 
REGORAFENIB 
 

 
 
 
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Table 8 : Dose modification/interruption for non-hematological adverse events related 
to regorafenib (except hand-foot skin reaction, hypertension, and liver function test 
abnormalities) 
 
 
Severity 
grade 
Dose interruption  
Dose reduction  
Dose for subsequent 
cycles  
Grade 0-2 
No interruption of 
therapy 
No change 
No change 
Grade 3 
Interrupt therapy until 
toxicity resolves to 
Grade ≤ 2 
Decrease dose by 
40 mg (one tablet) 
If toxicity remains ≤ 
Grade 2, dose re-
escalation 
may 
be 
considered 
at 
the 
discretion 
of 
the 
investigator. If dose is 
re-escalated 
and 
toxicity (≥ Grade 3) 
recurs, 
institute 
permanent 
dose 
reduction  
Grade 4 
Interrupt therapy until 
toxicity resolves to 
Grade ≤ 2 
Decrease dose 
by 40 mg (one 
tablet). 
Permanent 
discontinuation 
may be 
considered at 
the investigator’s 
discretion. 
_ 
a Excludes alopecia, non-refractory nausea/vomiting, non-refractory hypersensitivity, and non-clinically 
significant and asymptomatic laboratory abnormalities  
 
 
Table 9 : Hematological criteria for dose modification/interruption of regorafenib 
 
Gradea 
ANC 
(109/L) 
Platelets 
(109/L) 
Dose interruption 
Dose modification 
0-2 
>1.0 
≥50 
No interruption of 
therapy 
No change 
3 
<1.0 – 0.5 
<50 – 25 
Interrupt therapy 
until toxicity resolves 
to Grade ≤ 2b 
1st and 2nd occurence: no 
change 
3rd occurrence : 
Decrease dose by 40 mg 
(one tablet) 
4 
<0.5 
<25 
Interrupt therapy 
until toxicity resolves 
to Grade ≤ 2b 
1st and 2nd occurence: no 
change 
3rd occurrence : 
Decrease dose by 80 mg 
(two tablets) 
a Applies to all hematological toxicities; absolute neutrophil count (ANC) and platelet count displayed 
as examples.  
b If no recovery after 28 day interruption, treatment will be discontinued  

 
 
 
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c Dose will not be re-escalated to original dose level after reduction for toxicity. If more than 2 dose 
reduction steps are required, treatment will be discontinued 
 
Dose modifications required for study drug-related increases in ALT and/or AST levels and 
requirements for monitoring are provided in Table 10. During the first 3 cycles of treatment, 
ALT, AST, and bilirubin must be obtained at baseline and monitored weekly, even if values 
are normal. 
  
Table 10 : Dose modifications in case of drug-related liver function test abnormalities  
 
Observed 
elevations 
of ALT and/or AST 
Occurrence 
Recommended measures and dose 
modification 
≤5 times upper limit 
of normal (ULN)  
(maximum Grade 2) 
Any occurrence 
Continue regorafenib treatment.  
Monitor liver function weekly until transaminases 
return to < 3 times ULN (Grade 1) or baseline. 
> 5 times ULN ≤ 
20 times ULN 
(Grade 3) 
1st occurrence 
Interrupt regorafenib treatment.  
Monitor transaminases weekly until return to < 
3 times ULN or baseline. 
 
Restart: If the potential benefit outweighs the 
risk of hepatotoxicity, re-start regorafenib 
treatment, reduce dose by 40 mg (one tablet), 
and monitor liver function weekly for at least 
4 weeks.  
 
Re-occurrence 
Discontinue treatment with regorafenib 
permanently. 
>20 times ULN  
(Grade 4) 
Any occurrence 
Discontinue treatment with regorafenib 
permanently. 
>3 times ULN 
(Grade 2 or higher) 
with concurrent 
bilirubin >2 times 
ULN 
Any occurrence 
Discontinue treatment with regorafenib 
permanently.  
Monitor liver function weekly until resolution or 
return to baseline.  
Exception: patients with Gilbert’s syndrome who 
develop elevated transaminases should be 
managed as per the above outlined 
recommendations for the respective observed 
elevation of ALT and/or AST. 
 
Dose modifications and measures in case of hand-foot skin reaction (HFSR)/palmar-plantar 
erythrodysesthesia syndrome are provided in Table 11. 
 
 
 
Table 11 : Dose modifications and measures for HFSR 
 
 

 
 
 
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Skin toxicity grade 
Occurrence 
Recommended dose modification and 
measures 
Grade 1 
Any 
Maintain dose level and immediately  
institute supportive measures for  
symptomatic relief.  
Grade 2 
1st occurrence 
Decrease dose by 40 mg (one tablet) and  
institute supportive measures. 
If no improvement occurs despite dose 
reduction, interrupt therapy for a minimum of 
7 days, until toxicity resolves to Grade 0-1.  
A dose re-escalation is permitted at the 
discretion of the investigator. 
No 
improvement 
within 7 days or 2nd 
occurrence 
Interrupt therapy until toxicity resolves to 
Grade 0-1. 
When re-starting treatment, decrease dose 
by 40 mg (one tablet).  
A dose re-escalation is permitted at the 
discretion of the investigator. 
3rd occurrence 
Interrupt therapy until toxicity resolves to 
Grade 0-1. 
When re-starting treatment, decrease dose 
by 40 mg (one tablet).  
A dose re-escalation is permitted at the 
discretion of the investigator. 
4th occurrence 
Discontinue 
treatment 
with 
regorafenib 
permanently. 
Grade 3 
1st occurrence 
Institute supportive measures immediately. 
Interrupt therapy for a minimum of 7 days 
until toxicity resolves to Grade 0-1.  
When re-starting treatment, decrease dose 
by 40 mg (one tablet).  
A dose re-escalation is permitted at the 
discretion of the investigator.  
2nd occurrence 
Institute supportive measures immediately. 
Interrupt therapy for a minimum of 7 days 
until toxicity resolves to Grade 0-1.  
When re-starting treatment, decrease dose 
by 40 mg (one tablet). 
3rd occurrence 
Discontinue 
treatment 
with 
regorafenib 
permanently. 
 
 
 
Suggestions: 
 
 
Control of calluses 
Before initiating treatment with regorafenib: 
 
 
Check condition of hands and feet 
 
 
Suggest a manicure/pedicure, when indicated 

 
 
 
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 
Recommend pumice stone use for callus or ‘rough spot’ removal. 
 
During regorafenib treatment: 
 
 
Avoid pressure points 
 
 
Avoid items that rub, pinch or create friction 
 
 
Use of creams 
 
Apply non-urea based creams liberally, e.g., 
 
 
Cetaphil 
 
 
Aveeno 
 
 
Norwegian Formula 
 
 
Eucerin 
 
 
Keratolytic Creams: Use sparingly and only to affected (hyperkeratotic) areas 
 
 
Urea-based creams 
 
 
Salicylic acid 6% 
 
 
Alpha Hydroxy Acids (AHA) based creams 
 
 
Approximately 5-8% provide gentle chemical exfoliation 
 
 
Apply liberally two times each day 
 
 
Topical analgesics like lidocaine 2% to be considered for pain control  
 
Topical corticosteroids should be considered for subjects with Grade 2 or 3 hand-foot skin 
reaction. Avoid systemic steroids. 
 
Cushions 
 
Protect tender areas 
 
 
Use socks/gloves to cover moisturizing creams 
 
 
Wear well-padded footwear 
 
 
Use insole cushions or inserts (e.g., silicon, gel) 

 
 
 
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 
Foot soaks with tepid water and Epsom salts 
 
 
Table 12 : Dose modification/interruption and management of treatment-emergent 
hypertension 
Severity grade 
Definition 
Antihypertensive 
therapy 
Dose 
modification/interruption 
Grade 1 
Prehypertension: 
SBP 
120-139 
mmHg or DBP 80-
89 mmHg  
None 
Continue study drug.  
Consider 
increased 
BP 
monitoring  
Grade 2 
SBP 140-159 mmHg 
or DBP 90-99 mmHg  
or 
symptomatic 
increase in DBP >20 
mmHg or to >140/90 
mmHg if previously 
within normal limits  
Treat with the aim to 
achieve DBP ≤ 90 
mmHg.  
If S/DBP previously 
within normal limits, 
start 
antihypertensive 
monotherapy.  
If subject is taking 
antihypertensive 
medication, 
titrate 
the dosage up.  
Continue study drug. 
If symptomatic, delay dose 
until 
symptoms 
resolve 
AND diastolic BP ≤ 90 
mmHg 
Restart dose at same dose 
level. 
Grade 3 
SBP ≥ 160 mmHg or  
DBP ≥ 100 mmHg  
or ≥1 antihypertensive 
drug or more intensive 
antihypertensive 
therapy required than 
previously 
Treat to DBP ≤ 90 
mmHg. 
Start 
antihypertensive 
medication. 
and/or 
Increase 
dose 
of 
current 
antihypertensive 
medication. 
and/or 
add 
additional 
antihypertensive 
medication(s) 
Delay dose until DBP ≤ 90 
mmHg and, if symptomatic, 
until symptoms resolve. A  
restart dose will be at the 
same dose level.  
If BP not controlled with 
more 
intensive 
therapy, 
reduce 
dose 
to 
Dose 
reduction step -1  
If Grade 3 hypertension 
recurs after dose reduction 
and 
antihypertensive 
therapy, reduce dose to 
Dose reduction step -2  
Grade 4 
Life-threatening 
consequences 
(malignant 
hypertension): 
transient 
or 
permanent neurologic 
deficit, 
hypertensive 
crisis  
-- 
Discontinue therapy 
In cases only one value is >Grade 1 (e.g., 155/88 mmHg), the guidelines provided for the highest 
grade should be followed. Patients requiring interruption of study treatment > 4 consecutive weeks 
must discontinue study drug.  
If BP remains controlled for ≥ one full cycle, dose re-escalation is permitted at the investigator’s 
discretion 
 
Blood pressure will be recorded by the treating physician and entered onto the e-CRF. 

 
 
 
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Any blood pressure that is out of normal range must be reported to the treating physician. 
Blood pressure measurements considered out of normal range are diastolic ≥100 mmHg and 
systolic ≥ 150 mmHg, or a ≥ 20 mmHg increase in diastolic measurement if the measurement 
was previously within normal limits. 
 
The dose modification schedule for treatment emergent hypertension during regorafenib 
dosing should be followed (see [Table 12]). Patients’ blood pressure (BP) measurements will 
be monitored and appropriate treatment to effectively control hypertension under regorafenib 
treatment is strongly recommended. 
The selection of anti-hypertensive medication used in this setting should be performed at the 
investigator's discretion, considering possible site-specific treatment guidelines. All medication 
should be recorded in the subjects e-CRF. 
 
Termination of regorafenib : 
 
In the event of gastrointestinal perforation or fistula develops 
In the event of reversible Posterior Encephalopathy Syndrome (REPS) 
-In the event of the appearance of cardiac ischemia and/or infarction, severe bleeding, 
severe hypertensive crisis 
 
6.7 Authorized associate procedures and treatment 
 
All medication which is considered necessary for the patient’s welfare, and which is not 
expected to interfere with the evaluation of the study drug, may be given at the discretion of 
the Principal Investigator. All concomitant medications (including start/stop dates, dose 
frequency, route of administration and indication) must be recorded in the patient’s source 
documentation, as well as in the appropriate pages of the e-CRF.  
 
6.7.1 Other treatments/procedures 
 
Authorized concomitant medications: 
 
 
Atropine 
 
 
Anti-emetics 
 
 
Alpha hydroxyl acids, keratolytic, non urea creams 
 
 
Topical corticoids 

 
 
 
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 
Antihistaminics 
 
 
Contrast agent 
 
 
Treatment with non-conventional therapies (for example homeopathy, vitamins or 
acupuncture), and vitamin/mineral supplements is acceptable provided that they do 
not interfere with the study endpoints, in the opinion of the Investigator.  
 
 
It is advised not to use the association of warfarine (Coumadine®) with 
chemotherapy. It is preferable to use heparin and therapeutic anticoagulation with 
low-molecular weight heparin. If warfarine cannot be avoided, the rate of prothrombin 
must be checked more frequently and INR monitored every fortnight until INR/PTT is 
stable. 
 
 
Bisphosphonates 
 
 
G-CSF and other hematopoietic growth factors may be used during the study in the 
management of acute toxicity such as febrile neutropenia when clinically indicated or 
at the discretion of the investigator.  
 
 
Patients taking chronic erythropoietin are authorized. 
 
6.8  Prohibited treatment 
 
-Other antitumor treatments (chemotherapy, hormonotherapy, immunotherapy, biological 
response modifier, targeted therapy) or approved therapies during this trial or within 30 days 
are prohibited.  
 
-St-John’s wort 
 
-Herbal medicine and grapefruit juice 
 
-Yellow fever vaccine.  
 
-live attenuated vaccines 
 
-Pimozide (Orap®) and cisapride (Prepulsid®) are strictly contraindicated: they are 
associated with a major risk of disorder of the ventricular rhythm (notably twisting spuces). 

 
 
 
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-Immunosuppressive agents (eg ciclosporin, tacrolimus): Excessive immunosuppression with 
risk of lymphoproliferation. 
 
-Bone marrow transplant or stem cell rescue. 
 
 
-Radiotherapy within 28 days prior to first dose of treatment. 
 
6.9  Main medications that can interact with regorafenib 
 
Inhibitors of CYP3A4 and UGT1A1/UGT1A9/inducers of CYP3A4  
In vitro data indicate that regorafenib is metabolized by cytochrome CYP3A4 and uridine 
diphosphate glucuronosyl transferase UGT1A9.  
Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a 
single dose of regorafenib (160 mg on day 5) resulted in an increase in mean exposure 
(AUC) of regorafenib of approximately 33%, and a decrease in mean exposure of the active 
metabolites, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), of approximately 90%. It is 
recommended to avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. 
clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and 
voriconazole) as their influence on the steady-state exposure of regorafenib and its 
metabolites has not been studied.  
Co-administration of a strong UGT1A9 inhibitor (e.g. mefenamic acid, diflunisal, and niflumic 
acid) during regorafenib treatment should be avoided, as their influence on the steady-state 
exposure of regorafenib and its metabolites has not been studied.  
Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single 
dose of regorafenib (160 mg on day 7) resulted in a reduction in AUC of regorafenib of 
approximately 50%, a 3- to 4-fold increase in mean exposure of the active metabolite M-5, 
and no change in exposure of active metabolite M-2. Other strong CYP3A4 inducers (e.g. 
phenytoin, carbamazepine, phenobarbital and St. John’s wort) may also increase metabolism 
of regorafenib. Strong inducers of CYP3A4 should be avoided, or selection of an alternate 
concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be 
considered.  
 
UGT1A1 and UGT1A9 substrates  
In vitro data indicate that regorafenib as well as its active metabolite M-2 inhibit 
glucuronidation mediated by UGT1A9 whereas M-5 only inhibits UGT1A1 at concentrations 

 
 
 
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which are achieved in vivo at steady state. This indicates that co-administration of 
regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates.  
 
Breast cancer resistance protein (BCRP) and P-glycoprotein substrates  
Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of 
rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure 
(AUC) of rosuvastatin and a 4.6-fold increase in Cmax.  
This indicates that co-administration of regorafenib may increase the plasma concentrations 
of other concomitant BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin).  
  
Inhibitors of P-glycoprotein and BCRP/Inducers of P-glycoprotein and BCRP 
In vitro studies indicate that the active metabolites M-2 and M-5 are substrates for P-
glycoprotein and BCRP. Inhibitors and inducers of BCRP and P-glycoprotein may interfere 
with the exposure of M-2 and M-5. The clinical significance of these findings is unknown.  
 
CYP isoform-selective substrates 
In vitro data indicate that regorafenib is a competitive inhibitor of the cytochromes CYP2C8 
(Ki value of 0.6 micromolar), CYP2C9 (Ki value of 4.7 micromolar), CYP2B6 (Ki value of 
5.2 micromolar) at concentrations which are achieved in vivo at steady state (peak plasma 
concentration of 8.1 micromolar). The in vitro inhibitory potency towards CYP3A4 (Ki value of 
11.1 micromolar) and CYP2C19 (Ki value of 16.4 micromolar) was less pronounced.  
A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing 
with 160 mg regorafenib on the pharmacokinetics of probe substrates of CYP2C8 
(rosiglitazone) CYP2C9 (S-warfarin), CYP 2C19 (omeprazole) and CYP3A4 (midazolam). 
Pharmacokinetic data indicate that regorafenib may be given concomitantly with substrates 
of CYP2C8, CYP2C9, CYP3A4, and CYP2C19 without a clinically meaningful drug 
interaction. 
 
Antibiotics  
The concentration-time profile indicates that regorafenib and its metabolites may undergo 
enterohepatic circulation (see section 5.2). Co-administration with neomycin, a poorly 
absorbed antimicrobial agent used for eradicating the gastrointestinal microflora (which may 
interfere with the enterohepatic circulation of regorafenib) had no effect on the regorafenib 
exposure, but there was an approximately 80% decrease in the exposure of the active 
metabolites M-2 and M-5 which showed in vitro and in vivo comparable pharmacological 
activity as regorafenib. The clinical significance of this neomycin interaction is unknown, but 

 
 
 
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may result in a decreased efficacy of regorafenib. Pharmacokinetic interactions of other 
antibiotics have not been studied.  
 
Bile salt-sequestering agents  
Regorafenib, M-2 and M-5 are likely to undergo enterohepatic circulation. Bile salt-
sequestering agents such as cholestyramine and cholestagel may interact with regorafenib 
by forming insoluble complexes which may impact absorption (or reabsorption), thus 
resulting in potentially decreased exposure. The clinical significance of these potential 
interactions is unknown, but may result in a decreased efficacy of regorafenib. 
 
6.10  Main medications that can interact with irinotecan  
 
-Concomitant treatments based on St-John’s wort (alternative medecine) are absolutely 
contraindicated with irinotecan (Campto® or generic drug); this plant decreases the serum 
concentration of SN-38, the active metabolite of irinotecan. 
 
-The interaction between irinotecan and neuromuscular blocking agents cannot be 
established. Because of the anticholinesterase activity of IRINOTECAN, drugs with 
anticholinesterase 
activity 
may 
prolong 
the 
neuromuscular 
blocking 
effects 
of 
suxamethonium and neuromuscular blockade of non-depolarizing agents may be 
antagonized. 
 
-Several studies have shown that concomitant administration of cytochrome CYP450 3A4-
inducing anti-convulsants (such as carbamazepine, phenobarbital or phenytoin) decreased 
exposure to irinotecan, SN-38 and SN38 glucuronide and reduced their pharmacodynamic 
effects. The effects of these anti-convulsants result in a 50% or greater decrease in areas 
under the curve (AUC) of SN-38 and SN-38 glucuronide. In addition to induction of 
cytochrome CYP450 3A4 enzymes, increased glucuronidation and biliary excretion may play 
a role in reducing exposure to irinotecan and its metabolites. 
 
-One study showed that co-administration of irinotecan with ketoconazole compared to 
irinotecan alone resulted in an 87% decrease in AUC of APC and a 109% increase in AUC of 
SN-38. 
 
-Special attention is required in patients receiving drugs known to simultaneously inhibit 
(such as ketoconazole) or induce (such as rifampin, carbamazepine, phenobarbital, or 

 
 
 
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phenytoin) cytochrome CYP450 3A4 metabolism. Concomitant administration of irinotecan 
with an inducer or inhibitor of this metabolic pathway may alter irinotecan metabolism and 
should be avoided. 
 
6.11  Main medications that can interact with 5 FU  
 
Metronidazole (Flagyl®) and ornidazole: the concomitant administration of metronidazole can 
enhance toxicity of 5-FU by decreasing its clearance. 
- Allopurinol (Zyloric®): concomitant administration of this product must be avoided (loss of 5-
FU efficacy). 
-Phenytoin : Risk of convulsions due to decreased digestive absorption of phenytoin alone by 
the cytostatic, or risk of increased toxicity or loss of cytotoxic efficacy due to increased 
hepatic metabolism by phenytoin or fosphenytoin. 
-Antivitamin K : Significant increase in the effect of antivitamin K and hemorrhagic risk. If 
association cannot be avoided, more frequent monitoring of INR. Dosage adjustment of 
antivitamin K during cytotoxic treatment and 8 days after discontinuation. 
-Interferon alpha : Increased gastrointestinal toxicity of 5-FU. 
-Drugs that may affect dihydropyrimidine dehydrogenase (DPD) activity : 
A clinically significant interaction between the antiviral Sorivudine and fluorouracil prodrugs 
has been observed, resulting from the inhibition of dihydropyrimidine dehydrogenase, the 
enzyme responsible for the catabolism of fluorouracil and its prodrugs, by Sorivudine or 
chemically related analogues. Precautions should be taken when using fluorouracil in 
combination with drugs that may affect the activity of dihydropyrimidine dehydrogenase. 
-Cimetidine may increase the blood concentration of fluorouracil. 
In the majority of cases, cytostatics are given in combination, which leads to an increase in 
efficacy, but at the cost of a possible increase in toxicity. 
-Yellow fever vaccine is absolutely contraindiqued 
Risk of fatal generalized vaccine disease. 
-Live attenuated vaccines (except antiamarile) is not recommended 
Risk of life-threatening, widespread vaccine-preventable disease. This risk is increased in 
subjects already immunocompromised by the underlying disease. Use inactivated vaccine 
when available (polio). 
6.12  Main medications that can interact with Oxaliplatin 
 

 
 
 
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The drugs that prolong QTc and/or cause twisting spikes have to be used with caution (see 
appendix 8). 
 
7.  
Blinded independent central review (BICR) 
 
A central review of CT-scans is planned for patients found progression-free at 48 weeks. 
They will be submitted to a independent panel of radiologists for review of tumor response. 
7.1. Shipment procedure and storage 
Compact Discs (CDs) will be anonymized and sent by postmail or transferred to PACS 
server of ICM if it’s possible technically. 
It is important to the integrity of the study that all imaging studies are forwarded to the 
independent panel of radiologist in a timely manner throughout the study (by the end of 
treatment of patient). 
 
8. Ancillary Studies  
8.1.   Activity of DDR1 as a predictor of efficacy of regorafenib 
 
Paraffin-embedded human solid tissue blocks will be sent off at room temperature at the end 
of the inclusions and addressed to:  
 
 
Mrs Catherine VIGLIANTI 
collection manager 
Institut régional du cancer de Montpellier 
Centre de ressources biologiques 
208, rue des Apothicaires – Parc Euromedecine 
34298 Montpellier CEDEX 5 
Tel : +33 (0) 4.67.61.25.31 – Fax : +33 (0) 4.67.63.28.73 
catherine.viglianti@icm.unicancer.fr 
 
Paraffin-embedded human solid tissue blocks will be returned to the home institution upon 
completion of ancillary study. 
 
Actually, with this translational research, we aim to assess DDR1 activity as a 
predictor of efficacy in mCRC patients treated with a regorafenib-based therapy. 

 
 
 
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The research will be led by Serge Roche, Centre de Recherche en Biologie cellulaire 
de Montpellier 
 
Methodology: DDR1 activity in CRC samples: DDR1 activity will be measured from tumor 
protein-lysates with the pathscan phospho-DDR1 (panTyr) ELISA kit (CST Company). 
Inhibition of DDR1 metastatic activity by regorafenib: DDR1 kinase overexpression in 
HCT116 and SW620 CRC cells increases their invasive capacities in Boyden chambers and 
their capacity to form colosphere when cultured in suspension in the presence of collagen 
(17). We will test the capacity of regorafenib (1-500nM) to block these DDR1 transforming 
properties in vitro. DDR1 kinase overexpression in Luc+ SW620 cells increases their 
metastatic abilities when spleen-injected in nude mice (17). We will test the capacity of 
regorafenib (50mg/kg/d) to block this DDR1 metastatic function. Drug treatment will be 
started when metastatic nodules are already developed in recipient animals (i.e. at day 7). 
Metastatic development will be analyzed by measuring over time luciferase activity in live 
animals (imaging of the whole animal) and a metastatic index will be deduced from livers of 
sacrified animals. 
8.2. cfDNA monitoring 
8.2.1. Sample timeline 
 
Three EDTA tubes will be collected at baseline, every 8 weeks during treatment and at the 
end of treatment (not supplied). 
 
 
8.2.2. Processing of samples 
 
Three 7-ml EDTA tubes will be taken at various times and centrifuged within 4 hours at 
1200g  for  10 minutes at 4°c. After  centrifugation,  the  plasma  will  be  frozen  at -80°c until 
shipment.            

 
 
 
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8.2.3. Shipment and analysis 
Mrs Catherine VIGLIANTI 
Blood collection manager 
Institut régional du cancer de Montpellier 
Centre de ressources biologiques 
208, rue des Apothicaires – Parc Euromedecine 
34298 Montpellier CEDEX 5 
Tel : +33 (0) 4.67.61.25.31 – Fax : +33 (0) 4.67.63.28.73 
catherine.viglianti@icm.unicancer.fr 
 
The second centrifugation at 16 000 g for 10 minutes at 4°c and analysis will be carried out 
by : 
Dr Alain Thierry 
Equipe de recherche intégrée en Cancérologie de 
Montpellier (INSERM) 
Institut de Recherche du Cancer de Montpellier (IRCM) 
208, rue des Apothicaires – Parc Euromédecine 
34298 Montpellier CEDEX 5 
Tél : +33 (0) 4.67.61.24.42 ; +33 (0) 6.63.82.19.94  
Fax : +33 (0) 4.67.61.24.53 
Alain.thierry@inserm.fr 
 
cfDNA will be extracted using either the QIAmp DNA blood Mini kit (Qiagen, CA) or the 
Maxwell automatic extractor according to the standardized guidelines which were defined for 
pre-analytical conditions (unpublished data). 
CfDNA total concentrations and fragmentation level will be determined by either by targeted 
or sequencing methods. 

 
 
 
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A banking sample is planned at ICM-CRB, Montpellier. 
 
9. Subject withdrawal/end of study 
9.1. DISCONTINUATION OF TREATMENT 
Discontinuation of treatment does not represent withdrawal from the trial. As certain data on 
clinical events beyond treatment discontinuation are important to the study, they must be 
collected through the subject’s last scheduled follow-up, even if the subject has discontinued 
treatment. Therefore, all subjects who discontinue trial treatment prior to completion of the 
treatment regimen will still continue to participate in the trial. 
 
Patient may be discontinued from study treatment at any time if the patient, the Investigator, 
or the Sponsor feels that it is not in the patient’s best interest to continue on study. The 
following is a list of possible reasons for early discontinuation of study treatment:  
 
Disease progression (unless there is reasonable evidence of clinical benefit to justify 
continuation on treatment – to be discussed with the Sponsor)  
 
In the investigator's opinion, continuation in the study treatment would be detrimental 
to the patient's well-being  
 
Protocol violation requiring discontinuation of study treatment  
 
Patient is not compliant with study procedures  
 
Patients with a β-HCG test consistent with pregnancy. Pregnancy will be notified to 
the sponsor. 
 
Any adverse event that cannot be adequately managed with dose modifications, 
including dose interruption > 28 days (unless there is reasonable evidence of clinical 
benefit to justify continuation on the protocol – to be discussed with the Sponsor)  
 
Discontinuation of treatment during more than 4 weeks 
 
Patient death 
 
New cancer 
 
Lost to follow-up 
(The Investigators should make every effort to recontact the patient to identify the 
reason why he/she failed to attend the visit, and to determine the patient health 
status, including at least the vital status. Attempts to contact such patients must be 
documented in the patient’s records (e.g., times and dates of attempted telephone 
contact, receipt for sending a registered letter). 

 
 
 
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9.2. WITHDRAWAL FROM THE TRIAL 
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial. 
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits. 
9.3. END OF STUDY 
The end of the trial corresponds to the last follow-up of the last patient. 
9.4. ASSESSMENT CRITERIA 
Phase I:  Identify  the  maximum-tolerated dose  (MTD)  of  Folfirinox  combination  with  
regorafenib in Patients with metastatic colorectal cancer. 
 
Phase II: 
Non-progression rate (OR+SD): The tumor response will be assessed by the investigator 
using RECIST guidelines v1.1 (2009). The non-progression rate will be presented as a 
percentage with a 95% confidence interval. 
Objective response (OR): The tumor response will be assessed by the investigator using 
RECIST v1.1 criteria, from the first course of chemotherapy, until disease progression. 
Patients with suggestive symptoms of disease progression should be evaluated at the time of 
onset of symptoms. An objective response is defined as a complete (CR) or a partial (PR) 
response. 
The best objective response rate will be reviewed at the end of treatment and presented as a 
percentage with a confidence interval of 95%. 
Survival: 
Progression-free survival (PFS): Survival Delays will be calculated in months from the date of 
inclusion to the date of the considered event: First documented disease progression or death 
from any cause. 
Living patients without disease progression will be censored at the last known date. 
Rates and median PFS will be estimated using Kaplan-Meier method and presented with its 
95% confidence interval. 
Overall survival (OS): The overall survival time will be calculated in months from the date of 
inclusion to the date of death from any cause. Living patients will be censored at the last 
known date. 
Rates and median overall survival will be estimated using the Kaplan-Meier product limit 
method and presented with its 95% confidence interval. 

 
 
 
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The median follow-up will be calculated using the "reverse Kaplan-Meier method". 
10. 
Statistical considerations 
10.1. SAMPLE SIZE  
 
Phase I 
 
A standard 3 + 3 design will be followed in the dose escalation. A maximum of 24 patients 
will be enrolled in phase I. 
 
Phase II 
 
With a one-stage Fleming design,  = 5%,  = 20%, p0 (the probability of inefficiency 
maximum) = 35% and p1 (the probability of minimum efficiency) = 50%, it would be 
necessary to include 65 evaluable patients (69 patients/ 5% non-evaluable patients).  
 
The association can be considered sufficiently effective (reject null hypothesis) if there are at 
least 29 success (48 weeks disease control rate) out of 65 evaluable patients, the success 
rate is significantly greater than 35%. 
 
The association can be considered insufficiently effective (reject alternative hypothesis) if 
there are 28 or less success out of 65 evaluable patients, the success rate is significantly 
lower than 50%. 
 
In total, a maximum of 87 (=18 patients for phase I + 69 patients for phase II including 6 
patients treated at the RP2D during the phase I) patients will be included. 
 
10.2. STUDY POPULATIONS 
 
Different population of patients may be defined for the analysis: 
 
Intent To Treat (ITT) population: all included patients.  
 
Per-Protocol (PP) population: all eligible patients (patients with no major violations of 
the inclusion/exclusion criteria) and evaluable patients (included treated patients with 
evaluation at 48 weeks or without evaluation at 48 weeks if progressive or dead 
patient). 
 
Safety population: all treated patients who received at least one dose of treatment. 
 

 
 
 
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10.3. STATISTICAL METHODS 
 
A statistical analysis plan (PAS) will be written before the closed database. All statistical 
analyses will be performed on ITT population, on PP population for efficacy analysis and on 
Safety population for safety analysis. Populations are defined in section 10.2. 
 
Descriptive analyses will be performed using median and range for continuous parameters, 
frequency and percentage for categorical variables. 
 
Incidence rate of DLT and Incidence rates of adverse events and serious adverse events will 
be carried using frequencies and percentages at each dose level  for phase 1. 
 
The primary phase II endpoints 48 weeks disease control rates, will be described using 
percentage and its associated 95% confidence interval. 
 
The median follow-up will be calculated using the reverse Kaplan-Meier method with its 
confidence interval of 95%. 
 
All event free survival (PFS, OS) will be estimated using the Kaplan-Meier method, and then 
described using medians and rates with their associated 95% confidence interval.  
 
Statistical analyses will be performed with STATA software (Stata Corporation, College 
Station, TX, USA). 
11. 
Vigilance and safety control  
11.1. ADVERSE EVENTS 
11.1.1. DEFINITION 
 
An Adverse Event (AE) is defined as “Any untoward medical occurrence in a patient 
or clinical investigation subject administered an investigational product and which does not 
necessarily have a causal relationship with this treatment”. An AE can therefore be any 
unfavorable and unintended sign (for example: an abnormal laboratory finding), symptom, 
disease, or worsening of a pre-existing medical condition temporally associated with the use 
of an investigational product, whether or not considered related to the investigational product. 
 

 
 
 
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Only abnormal laboratory findings which are clinically significant should be 
considered an AE. Abnormal laboratory findings are clinically significant if an active medical 
intervention is indicated, such as a dose modification of the investigational product ; an 
interruption of the investigational product; the withdrawal of the investigational product; the 
introduction of a (symptomatic) treatment; the performance of additional diagnostic 
procedures; the increase in monitoring frequency. 
An AE related to the investigational product is also called an adverse reaction. 
 
11.1.2. COLLECTION AND REPORTING 
 
Every AE occurring during the clinical trial should be recorded on the corresponding 
page of the Case Report Form. Every AE should be documented, monitored and followed 
until the AE is recovered or until the safety follow-up visit is performed at 30 days after the 
withdrawal of the investigational product. 
 
Clinically significant abnormal laboratory findings should be monitored regularly by 
specific analysis until their values return within the normal reference ranges, to the baseline 
value or until an adequate explication of the out of range value has been found. Per the 
applicable regulations, AEs are collected from the moment of signature of the informed 
consent form until up to 30 days after the withdrawal of the investigational product. 
 
For every AE, the following parameters will be documented by the investigator: 
 
A clear description of the event using the adequate medical terms; 
 
The seriousness of the event; 
 
The severity or grade of the event (severity criteria are described in the next 
paragraph); 
 
The onset and end dates of the event; 
 
The actions taken and the necessity to introduce a corrective treatment or not; 
 
Whether the AE caused or not the withdrawal of the subject from the study; 
 
The outcome of the event. In case of a non-fatal outcome, the AE should be 
documented until recovered, until  the return to baseline conditions of the event or 
until stabilization of the event’s sequelae (the nature of the sequelae should be 
documented) ; 
 
The causality between the event and the investigational product ; 

 
 
 
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 
The eventual causality between the event and the study procedures (time laps 
without treatment, complementary assessments required by the protocol, etc.…), the 
study indication, a concomitant treatment, a concomitant pathology or another factor. 
 
11.1.3. SEVERITY CRITERIA 
 
The severity criteria should not be mistaken with the seriousness criteria which determine the 
conditions of notification. The severity or grade of adverse events is evaluated by the 
investigator following the NCI-CTCAE classification version 5.0 (appendix 9). 
 
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each 
AE based on this general guideline: 
 
Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 
Grade 2 = Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental ADL*. 
 
Grade 3 = Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
 
Grade 4 = Life-threatening consequences; urgent intervention indicated. 
 
Grade 5 = Death related to AE. 
 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
11.2. SERIOUS ADVERSE EVENTS AND NEW EVENT 
11.2.1.  DEFINITION 
 
A Serious Adverse Event (SAE) is an adverse event which: 
 
results in death 
 
is life-threatening 
 
requires in-patient hospitalization or prolongation of existing hospitalization,  
 
results in persistent or significant disability or incapacity  

 
 
 
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 
Is a congenital anomaly or birth defect 
 
Is medically relevant 
 
Life-threatening in this context refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to a reaction that hypothetically might have caused 
death if more severe.  
 
A hospitalization scheduled by the protocol (biopsy, chemotherapy...) is not considered a 
SAE. A hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE is not considered a  SAE.  A  hospitalization  planned  prior  to  
patient enrollment is not considered a SAE, provided that his occurrence/outcome is clearly 
not aggravated by the investigational product.  
 
The terms “disability” and “incapacity” match with all physical/psychological temporary or 
permanent handicaps, clinically significant with consequences for the physical or mental 
functioning and/or the quality of life of the patient. 
 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious events, such as important medical events that might not be 
immediately life-threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. Such 
events are considered serious with seriousness criterion “medically relevant”. Examples of 
such events are allergic bronchospasm, torsade de pointes (appendix 8) or convulsions.  
 
Other examples of serious adverse events with seriousness criterion “medically 
relevant” are second primary malignancies and any suspected transmission via a medicinal 
product of an infectious agent. 
 
For every SAE the investigator and the sponsor evaluate separately the possible 
causal relationship to the investigational product. These evaluations might be different one 
from the other (for example: in the investigator’s opinion the SAE is not related to the 
investigational product and in the sponsor’s opinion the SAE is related to the investigational 
product). 
 
A New event (article R1123-46 du CSP) is: 

 
 
 
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Any new data that may lead to a re-assessment of the benefit/risk ratio of the clinical trial or 
the investigational medicinal product (IMP), to modifications of the use of the IMP or the 
conduct of the trial or modifications of documents regarding the trial or to the suspension or 
termination of the clinical trial or to modify the protocol of the trial concerned or other similar 
trials.  
 
For a first in man study conducted in healthy volunteers: any serious adverse reaction (SAR) 
of the IMP is considered to be a new event  
 
 
11.2.2. URGENT SAFETY MEASURE (USM) (ARTICLES L.1123-10 ET R. 1123-62 CSP)  
 
When a suspicion of an Unexpected Serious Adverse Reaction (SUSAR) or a New Event is 
likely to affect the safety of the subjects, or the IMP is likely to affect the safety of the 
participant who lend themselves to it with immediate endangerment, the sponsor and 
investigator put in place Urgent Safety Measure (USM) to protect the subjects against this 
immediate hazard, the sponsor and the investigator concerned take the necessary 
appropriate Urgent Safety Measures (USM). 
 
 
11.2.3. SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION 
 
A SAE is qualified as a Suspected Unexpected Serious Adverse Reaction (SUSAR) when a 
causal relationship between the investigational product and the SAE is suspected and when 
the nature, the severity, the frequency or the evolution of the reaction does not match with 
the information available in the reference document. The sponsor evaluates the 
unexpectedness of the SAE by consulting the SmPC of Oxaliplatin, 5 FU, Irinotecan and the 
investigator’s brochure in force for Regorafenib. 
 
11.2.4.     PREGNANCY 
For female patients treated with the investigational product, the treatment with this product 
 should be discontinued immediately at the occurrence or suspicion of occurrence of 
pregnancy and the patient should be withdrawn from the study (after confirmation of the 
pregnancy by a urine or blood test). 
 

 
 
 
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The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.  
 
In accordance with the recommendations for fertility preservation, the investigator may 
propose to the patient a protocol of conservation of ovocytes for women and of sperm cells 
for men.  
 
11.2.5. SAE, NEW EVENT, URGENT SAFETY MEASURE, PREGNANCY NOTIFICATION 
PROCEDURE 
 
11.2.5.1.            SAE NOTIFICATION PROCEDURE 
 
Every SAE, expected or unexpected, occurring during the study period (from the moment of 
signature of the informed consent form until up to 30 days after the withdrawal of the 
investigational product) should be notified to the sponsor without any delay using the 
“Serious Adverse Event Notification Form” (appendix 10). This form should be completed 
following the completion instructions (appendix 10) and sent by email to the Clinical 
Research Pharmacovigilance Unit of ICM.  
 
Clinical Research Vigilance Unit 
 
ICM – Institut régional de Cancérologie de Montpellier 
208, rue des Apothicaires, 34298 Montpellier 
Tel: +33 4 67 61 45 68 – Fax: +33 4 67 61 31 04 
                      E-Mail: Notification-EIG-DRCI@icm.unicancer.fr 
 
 
Every SAE occurring beyond the 30 days period after the withdrawal of the investigational 
product, judged by the investigator to be related to the investigational product, should also be 
notified to the sponsor in the same conditions as every other SAE. 
 
The “Serious Adverse Event Notification Form” should be completed in English and only one 
diagnosis or one symptom (except for linked symptoms) should be reported to enable 
MedDRA coding. If several symptoms are documented in the source documents, only the 
main symptom will be reported as verbatim on the notification form.  

 
 
 
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After the initial notification, a follow-up report should be completed and faxed every time 
complementary information on the SAE becomes available. Finally, when the case is closed, 
a final report with the complete information should be completed and sent by email to the 
Clinical Research PharmacoVigilance Unit : 
 
E-Mail: Notification-EIG-DRCI@icm.unicancer.fr 
 
Complementary information or clarification could be requested by the sponsor using Data 
Clarification Forms (DCFs). The sponsor could also ask the site to send the anonymized 
medical records or laboratory findings corresponding to the SAE. In case of a SUSAR a 
narrative of the case in English is to be provided by the investigator.  
         
11.2.5.2.           NEW EVENT / URGENT SAFETY MEASURE (USM)/ NOTIFICATION 
PROCEDURE 
 
Any New Event and/or Urgent Safety Measure  occurring during the study period should be 
notified to the sponsor without any delay, to Clinical Research Pharmacovigilance Unit:  
E-Mail: Pharmacovigilance-icm105@icm.unicancer.fr 
 
Clinical Research Vigilance Unit 
ICM – Institut régional de Cancérologie de Montpellier 
208, rue des Apothicaires, 34298 Montpellier 
Phone: +33 4 67 61 45 68 
11.2.5.3.       PREGNANCY NOTIFICATION PROCEDURE 
 
Pregnancies and suspected pregnancies occurring during the study period from the 
signature of the informed consent form until up to 4 months after withdrawal of investigational 
medicinal products for female patients and 6 months after withdrawal of investigational 
medicinal products for female partners of male patients, are immediately reportable events. 
Every pregnancy or suspicion of pregnancy should be notified to the Sponsor without any 
further delay. 
Pregnancy notification will be done using the "pregnancy notification form" (appendix 11). 
This form should be completed using the filling instruction guide (appendix 11) and sent by 
email to the pharmacovigilance unit (see above). 
The Investigator should inform the Sponsor of the pregnancy follow-up by using the same 
“Pregnancy Notification Form” (appendix 11) as for the initial notification. If the outcome of 
the pregnancy falls within the scope of the definition of serious adverse event (spontaneous 

 
 
 
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abortion requiring hospitalization, fetal death, congenital abnormality…) the investigator 
should follow the Serious Adverse Event notification. 
If it is a paternal exposure, the investigator must obtain the agreement of the pregnant 
women to collect the information on pregnancy. 
11.2.5.4.      SUMMARY CHART OF NOTIFICATION BY TYPE OF EVENT 
 
Type of Event 
 
Notification requirements.  
 
Notification period to the 
sponsor 
Adverse Event 
Case Report Form 
No Immediately reportable events  
 
Serious Adverse 
Event  
SAE Notification Form ( initial+ 
Follow up, if necessary) + Case 
Report Form 
Immediately reportable events  
without any delay to the sponsor 
New Event 
Written report  
Immediately reportable events  
without any delay to the sponsor 
Urgent Safety 
Measure (USM)  
Written report  
Immediately reportable events  
without any delay to the sponsor  
Pregnancy 
Pregnancy notification form 
From confirmation of pregnancy 
 
 
11.2.6. OBLIGATION OF THE SPONSOR 
 
        The ICM, as the sponsor of the trial, receives all SAE Notification Forms and 
evaluates the imputability and the expectedness of the SAEs. In case of a “New event” or 
any urgent safety measures, the sponsor shall inform immediately ANSM and the concerned 
CPP of the new events and the measures taken. 
The declaration of eventual SUSARs and “New event” or any urgent safety measures (USM) 
to the competent authorities is delegated to UNICANCER, 101 rue de Tolbiac 75013 Paris 
(Tel: +33 1 44 23 04 04). UNICANCER submits the SUSARs within the required regulatory 
timelines to the European Medicine Agency (EMA) via EudraVigilance and the competent 
national authorities (ANSM).  
 
        The risk-benefit balance of the study is evaluated continuously by the Clinical Research 
Vigilance Unit of ICM and this risk-benefit balance will be discussed in the periodic safety 
reports. These reports will contain all required regulatory aspects and will be submitted to the 
competent authority (ANSM) and CPP within  the regulatory timeframe. 
  

 
 
 
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SUMMARY CHART OF NOTIFICATION BY TYPE OF EVENT 
ART. R1123-53 
 
 
Type of Event 
Initial notification period to the 
Competent Authority 
(ANSM, CPP) 
Follow up notification 
period to the Competent 
Authority 
(ANSM, CPP) 
SUSARs 
(Death, or life threatening) 
Immediately reportable events 
With any delay after the 
sponsor has taken notice of 
this event 
Within maximum   7 days 
after the sponsor has taken 
notice of this event 
Other SUSARs 
Within 15 days after the 
sponsor has taken notice of 
this event 
Within maximum  8 days 
after the sponsor has taken 
notice of this event 
New Safety Event 
Immediately reportable events 
With any delay after the 
sponsor has taken notice of 
this event 
Within maximum 8 days 
after the sponsor has taken 
notice  
 
Urgent Safety Measures 
(USM)  
 
Immediate implementation of 
MUS  
Immediate information  
(without any delay)  
Request for substantial 
modification Within 
maximum 15 days after the 
sponsor has taken notice  
 
 
11.2.7. INDEPENDENT SAFETY COMMITTEE (ISC)   
   
An Independent Safety Committee (appendix 12) is organized as an Independent 
Data Monitoring Committee, comprising independent experts in clinical research and/or the 
study indication. 
The ISC will be constituted of 3 persons: two oncologists and a methodologist not 
participating in the trial.  
 
The first scheduled time point will be at the end of phase I. According to the number of DLTs 
and after the advice of the IDMC, the sponsor will decide to continue on to phase II or stop 
the trial. The sponsor could ask to organise an additional independent safety committee in 
the event of SUSARs during Phase I. 
During a trial the ISC could be requested to review:   
 
Real-time and cumulative safety data for evidence of study-related adverse events;    
 
Adherence to the protocol;   
 
Factors that might affect the study outcome or compromise the trial data (such as 
protocol violations, losses to follow-up, etc.);  

 
 
 
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 
Data relevant to proceeding to the next stage of the study, if applicable.  
The safety data will be provided to the ISC members by the Biostatistics Unit, and / or the 
Clinical Research Pharmacovigilance Unit and / or the Study Coordinator.  
 
12. 
Quality assurance and control 
12.1. Data collection 
 
Database management 
 
The Database will be hosted by the Institut du Cancer Montpellier (ICM) – Val d’Aurelle, 
Unité de Biométrie – CTD INCa, 208 rue des Apothicaires – Parc Euromédecine – 34298 
Montpellier cedex 5 – France under the responsibility of Sophie Gourgou.  
Database management will be provided by an electronic Case Report Form (eCRF) 
developed using the CSOnline module of Ennov Clinical® software. 
In case of a technical problem on the eCRF, the investigator may refer to the specific 
operating procedure of the eCRF or contact directly:  
 
ICM – Unité de Biométrie – CTD INCa 
From Monday to Friday 9am-5pm 
Email: support.ecrf@icm.unicancer.fr  
Fax: +33 (0)4 67 61 37 18   Tél. : +33 (0)4 67 61 45 48 / 24 52 
 
Secure access password 
 
Each user will receive in his/her personal mailbox an access code (login) and a personal 
password automatically generated from CSOnline to connect to the eCRF via the following 
website: https://ecrfcval.icm.unicancer.fr/CSOnline/. 
 
A password non-disclosure certificate is signed by the principal investigator engaging his/her 
responsibility regarding the confidentiality of the access codes for all users of the eCRF in 
his/her center.  
 
Data collection 

 
 
 
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The study data will be recorded directly by the identified and declared persons of each 
center, via the eCRF, and will be controlled and validated according to specific procedures.  
At the end of the study and once all the eCRF data are validated, the investigator will log in 
and sign all the pages in order to validate the data entered for each patient.  
The sponsor will create and send an electronic copy (PDF file) to the investigator. This copy 
must be printed and signed by the investigator, to be archived at the investigator’s site. 
 
12.2 Trial monitoring 
 
To ensure the authenticity and credibility of all data, in accordance with the “Décision portant 
sur les Bonnes Pratiques Cliniques, 24 November 2006”, the sponsor establishes a system 
of quality assurance consisting in: 
 
 
The management and monitoring of the trial according to the sponsor's (ICM) 
procedures; 
 
The data quality control of the investigational centers by the monitor which involves: 
 verifying that the protocol, as well as the current ICH-GCP guidelines and the 
national regulatory requirements are accurately followed, 
 verifying the informed consent and the eligibility of each patient  
 verifying that the e-CRF data is consistent and in concordance with the source 
documents, 
 verifying the notification of each SAE,  
 verifying the drug traceability (dispatching, storage and accountability), 
 verifying (if applicable) that patients are not already participating in another 
research trial which may exclude their inclusion in the present protocol. The 
monitor will also verify that patients have not participated in another trial 
following with, if applicable, an exclusion period before they can participate in 
another protocol, 
 
The audit of the participating investigational centers when deemed necessary; 
 
The monitors and CRAs in charge of the trial monitoring will be mandated by the sponsor. 
They must have access to all the patients' data as necessary for their duty, in accordance 
with the national regulatory requirements. The monitors and CRAs are bound by professional 
secrecy under the national regulatory requirements. Written reports must be issued to ensure 
monitoring visit traceability. 

 
 
 
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In order to ensure the optimal research quality control, the investigator commits to provide 
the monitor with direct access to all the patients' files.  
 
12.3 Audits and inspection 
 
As part of its audit program, the sponsor may need to audit some investigational centers. The 
center and the investigator agree that audits can be carried out by the sponsor or any person 
duly authorized for at least fifteen years after the trial.  
 
More generally, the investigator center and the investigator undertake to devote the time 
necessary to audit procedures, control and additional information requested by the sponsor 
or by a Concerned Competent Authority. 
 
A Competent Authority may also wish to conduct an inspection (during the trial or after its 
completion). If a Competent Authority requests an inspection, the investigator must inform 
the sponsor immediately that this request has been made. The investigator must provide a 
direct access to all source documents. 
 
13. 
Administrative, ethical and regulatory aspects  
13.1. Conduct of the study and responsibilities  
 
The Sponsor 
 
The sponsor undertakes according to the law in force to: 
 Take out civil liability insurance, 
 Request the approval as well as for any substantial modifications to ANSM 
(agence nationale de sécurité du médicament et des produits de santé), 
 Request the favorable opinion as well as for any substantial modifications to the 
Committee for the Protection of Persons (CPP), 
 Declare to the CPP and the ANSM the beginning and the end of the study, 
 Write the final report of the study, 
 Inform the competent authority, the CPP and the participants of the research of 
the results of the study, 

 
 
 
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 Archive the essential documents of the study in the trial master file for a minimum 
of 15 years after the end of the research. 
 
The Investigator 
 
It is the responsibility of each investigator to: 
 Provide the sponsor with his curriculum vitae, 
 Conduct the clinical trial according to the protocol approved by the ANSM, 
 Collect written informed consent from each patient entering the trial. One copy is 
given to the patient, the original is to be kept by the investigator, the last copy will 
be kept by the sponsor, 
 Regularly complete the e-CRF for each patient included in the trial, 
 Make available to the CRA mandated by the sponsor the source documents of 
the patients in order to confront the data with those entered in the e-CRF and to 
allow their validation, 
 Archive all study documents (informed consents) for a period of 15 years, 
 Respect the confidentiality of the documents provided to him. 
13.2. Subject information and consent  
 
The written informed consent of the patient must be obtained by the investigator or a person 
designated by the investigator before collecting any personal data. The consent must be 
signed and dated by the patient and the investigator or the person designated by the 
investigator to conduct the informed consent interview. 
 
Obtaining informed consent requires the subject to be provided with sufficient information by 
the investigator. Information for the patients, prepared in accordance with the ICH 
recommendations, will be made available by the sponsor for the purposes of informed 
consent collection. 
 
The signature of the consent will be confirmed in the e-CRF by the investigator. The signed 
and dated statement of this informed consent will be archived in the investigator site file (ISF)  
so that forms can be retrieved at any time for surveillance, audit and inspection. A signed 
and dated copy of the subject information and consent form must be given to the subject as 
soon as it is signed.  
The subject information will be revised at each update of important new information that may 
influence the subject's consent. 

 
 
 
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13.3. Regulatory authorizations 
 
The research will be carried out in accordance with the French regulations in force, in 
particular the provisions relating to biomedical research of the Public Health Code, articles 
L1121-1 and following, the laws of Bioethics, the data protection law, the declaration of 
'Helsinki (appendix 13), the Jardé law n ° 2012-300 of March 5, 2012 relating to the 
research involving the human person (application by the decree 2016-1537 and 1538) and 
Good Clinical Practices. 
 
Pursuant to the provisions of articles 39 and 40 of the Law (Computing and Liberties) of 
August 6, 2004 and that of April 27, 2016, patients have a right of access and rectification 
on the data concerning them and the European Regulation 2016/679 on the protection of 
individuals with regard to the processing of personal data and on the free movement of such 
data known as the "GRDP" (General Regulation on Data Protection). They also have a duty 
to oppose the transmission of these data. These rights are exercised with their investigator 
who will inform the coordinating center of research as soon as possible. 
13.4. Authorization of the biological resource center 
 
The CRB involved in the research has received authorization to preserve and prepare 
tissues and cells from the human body for transfer for scientific use, Permit No. AC-2014-
2196. 
13.5. Processing of research data 
 
In accordance with the Decree No. 2016-1872 of December 26th, 2016 published in the 
Official Journal on December 28th, 2016, the ICM follows the reference methodology MR001 
of the National Commission for Data Processing and Freedoms. 
13.6. Amendments of the protocol 
 
The sponsor alone is authorized modifying the protocol, in consultation with the trial 
coordinator. 
 
In accordance with the Articles L.1123-9 and R.1123-35 of the French Public Health Code, 
any change occurring after the beginning of the research, having an impact on any aspect of 

 
 
 
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the research, especially on protection of persons, including with regard to their safety, on the 
conditions for the validity of research, if any, on the quality and safety of experimental drugs, 
on the interpretation of scientific documents which support the development of research or  
the modalities of conduct of this one. 
 
A substantial modification request is sent by the sponsor to the ANSM for approval and/or 
CPP for favorable opinion. Upon receipt of the approval and favorable opinion, the amended 
version of the protocol is then forwarded to all investigators by the sponsor. 
 
A non-substantial change to the protocol is a minor change or unrestricted clarification of the 
conduct of the test. These modifications will not be submitted to the competent authorities 
but will be subject to an agreement between the sponsor and the investigator and will be 
clearly documented in the follow-up file of the study and will be forwarded to the ANSM and/ 
or CPP for information. 
 
13.7. Sponsor discontinuation criteria  
 
Premature termination of this study may occur because of a regulatory authority decision, 
change in approval of ANSM or opinion of the CPP, drug safety problems, or at the discretion 
of the Sponsor.  
If the study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
Investigator. After notification, the Investigator must notify the respective CPP, and contact 
all participating patients and the hospital pharmacy (if applicable) within a 4-week time 
period. As directed by the Sponsor, all study materials must be collected and all eCRFs 
completed to the greatest extent possible. 
 
14. 
Financing and Insurance  
14.1. Financing of Research 
We have a partnership contract with Bayer HealthCare that will finance this study. 
14.2. Insurance 
Insurance has been subscribed by the sponsor (ICM) to SHAM (Contract No. 140.474) for all 
subjects included in the study as of their inclusion (that is, from the date of signing of the 
consent enlightened) in accordance with the provisions of Decree 2006-477 of 26 April 2006, 

 
 
 
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in order to cover the obligations placed on them under Article L 1121-10 of the French Public 
Health Code. 
 
15. Publication policy and communication  
15.1. PUBLICATION POLICY 
 
The coordinator will attempt to submit a publication within one year from the presentation of 
the final results by biostatistician. No publication or presentation of the results of this trial may 
be made without the agreement of the sponsor and the coordinator. 
The authors of the publication are as follows: 
- the main writer (in principle the coordinator unless specifically requested by the latter); 
- a limited number of investigators limited to 1 per center according to the order of 
recruitment. A weighting may be envisaged for large recruiting centers; 
An investigator who has not included will be thanked at the end of the article; 
-the biostatistician will be in 3rd author ranking and may be 1st or 2nd author according to 
the publications derived; 
-a representative of the DRCI will be included in the authors (scientific writer, director of the 
DRCI or project manager depending on their involvement); 
-the last author is usually the coordinator of the study (if not the principal author) or someone 
who has taken decisive action in the design and/or conduct of the study; 
 
If the maximum number of authors authorized by journals is very limited, a restriction will be 
made by the coordinator with the assistance of the DRCI as the sponsor's representative. 
In the case of a derived publication, the authors may be different and reflect the specialty 
concerned by the article, but the latter must always include at least the name of the 
coordinator or a clinician of the ICM. 
Similarly, when submitting abstracts, the order of authors may vary according to the 
conference at which the paper is presented. 
Acknowledgements: 
It may appear in the acknowledgements at the end of the article: 
-patients and their families; 
-the project manager (s) of the DRCI; 
-the data manager (s) and the investigating CRA(s); 
-all participants and representatives of the DRCI not included in the authors; 

 
 
 
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-partners and funders in accordance with the partnership agreements signed with the ICM 
promoter; 
 
The CRB - ICM should be mentioned either in the "Materials and Methods" section or in the 
acknowledgements with N°BB-033-00059. 
15.2. DATA SHARING STATEMENTS 
Will individual participant data be available? Yes 
 
What data in particular will be shared? All of the individual participant data collected during 
the trial, after deidentification. 
 
What other documents will be available? Study protocol, statistical analysis plan, clinical 
study report, analytic code. 
 
When will data be available (start and end dates)? Immediately following publication. No end 
date. 
 
With whom? Anyone wishes to access the data. 
 
For what type of analyses? Any purpose. 
 
By what mechanism will data be made available?  The datasets generated during and/or 
analysed during the current study are available from the corresponding author on reasonable 
request. 
 
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17. Appendices