A Randomized Phase III Trial Assessing a Regorafenib-irinotecan Combination (REGIRI) Versus Regorafenib Alone in Metastatic Colorectal Cancer Patients After Failure of Standard Therapies, According to the A/A Genotype of Cyclin D1
Phase: PHASE3
Conditions: Metastatic Colorectal Cancer (mCRC)
Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle

 
 
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A randomized phase III trial assessing a regorafenib-irinotecan combination 
(REGIRI) versus regorafenib alone in metastatic colorectal cancer patients after 
failure of standard therapies, according to the A/A genotype of Cyclin D1 
 
NEXT-REGIRI 
 
N°Study Sponsor 
N°EudraCT  
PROICM 2018-01 NEX 
2018-002231-24 
According to law Jardé study of Category 1 
 
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 
 
 
 
Coordinator 
 
Dr Emmanuelle SAMALIN 
Digestive oncology unit 
ICM 
Phone : 04-67-61-25-92 
Email : Emmanuelle.samalin@icm.unicancer.fr 
Project manager 
 
Patrick CHALBOS 
ICM 
Phone : 04 67 61 25 74 
Fax :     04 67 61 23 55 
Email : Patrick.chalbos@icm.unicancer.fr 
Biostatistician 
Simon Thezenas  
ICM 
Phone : 04 67 61 30 35 
Fax :     04 67 61 37 18 
Email : Simon.Thezenas@icm.unicancer.fr 
 
Date & Name of CPP: IDF III, on 11/09/2018 
 
The information provided in this document is confidential and the property of ICM. It is intended solely for parties associated with the clinical investigation or for regulatory 
purposes. Reproduction and/or distribution of the information contained therein is not authorized without the consent of ICM, except the information necessary to obtain 
informed consent of individuals participating in this clinical trial. 
 
 
 
 

 
 
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ABBREVIATIONS 
 
 
 
 
List of 
abbreviations 
Explanation 
5-FU 
5 FluoroUracil 
AE  
Adverse Event 
ALT  
Alanine aminotransferase/glutamic pyruvic transaminase/sGPT 
ANC 
Absolute neutrophil count 
ANSM 
Agence nationale de sécurité du médicament et des produits de santé 
(French National Agency fo Medicines and Health Products Safety) 
AST  
aspartate aminotransferase/glutamic oxaloacetic transaminase/sGOT 
β-HCG 
Beta human chorionic gonadotropin 
BSA 
Body surface area 
CA 19-9 
Carbohydrate Antigen 19-9 
CCDN1 
Cyclin D1 
CEA 
Carcino-Embryogenic Antigen 
CPP 
Ethic Comittee 
CKD-EPI 
Chronic Kindney Disease – Epidemiology Collaboration 
CRA 
Clinical Research Associate 
CR 
Complete response 
CT Scan 
Computed Tomography Scanner 
DCF  
Data clarification form 
DCR  
Disease control rate 
ECG 
ElectroCardioGram 
ECOG 
Eastern Cooperative Oncology Group 
EOF 
End of treatment 
EORTC 
European organisation for research and treatment of cancer 
e-CRF  
Case report form 
EUDRACT 
European Union Drug Regulating Authorities Clinical Trials 
G-CSF 
Granulocyte colony-stimulating factor 
GGT  
Gamma-glutamyl transferase 
HB 
Hemoglobin 
HR  
Hazard Ratio 
HRQOL 
Health-related quality of life 
ICM 
Montpellier Cancer Institute 
ISC 
Independent scientific committee 
INCA 
Institut national du cancer 
INR  
International Normalized Ratio 
ITT 
Intention-To-Treat 
LDH 
Lactate Dehydrogenase 
mCRC 
Metastatic colorectal cancer 

 
 
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MRI  
Magnetic Resonance Imaging 
NCI/ CTCAE 
National Cancer Institute (US) Common terminology criteria for 
adverse events 
NYHA 
New-York Heart Association 
PET-Scan 
Positron emission tomography 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial Thromboplastin Time 
RAS 
Rat sarcoma viral oncogene homolog 
RBC 
Red Blood Count 
RECIST  
Response Evaluation Criteria in Solid Tumors 
RS 
Reference sequence 
SAE  
Serious Adverse Event 
SD  
Stable Disease 
SmPC 
Summary of Product Characteristics 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit normal 
WBC 
White Blood Count 
WT 
Wild type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table of contents 
SYNOPSIS (English) .................................................................................................. 7 
1. 
Background and rationale .................................................................................. 16 
2. 
Study objectives and Endpoints ........................................................................ 18 
2.1 Objectives..................................................................................................................... 18 
2.1.1 Primary objective ................................................................................................. 18 
2.1.2 Secondary objective ............................................................................................ 18 
2.2 Endpoints ..................................................................................................................... 18 
2.2.1 Primary endpoint .................................................................................................. 18 
2.2.2 Secondary endpoints .......................................................................................... 18 
3. 
Experimental plan .............................................................................................. 19 
3.1 Study design ................................................................................................................ 19 
3.2 Study period ................................................................................................................. 20 
3.3 Compensation modalities .......................................................................................... 20 
4. 
Population ......................................................................................................... 20 
4.1 Number of planned patients ...................................................................................... 20 
4.2 Inclusion criteria .......................................................................................................... 20 
4.3 Non-inclusion criteria .................................................................................................. 21 
4.4  Procedure .................................................................................................................... 23 
5. 
Visit Schedule .................................................................................................... 24 
5.1 Tabulated overview..................................................................................................... 24 
5.2 Screening period ......................................................................................................... 27 
5.3 Treatment period ......................................................................................................... 30 
5.4 End of treatment Visit ................................................................................................. 35 
5.5 Follow-up ...................................................................................................................... 36 
6. 
Treatments ........................................................................................................ 37 
6.1 Experimental treatment or procedures .................................................................... 37 
6.2 Expected Toxicities ..................................................................................................... 41 
6.3 Dose modification and Dose delay........................................................................... 41 
6.4 Authorized associate procedures and treatment ................................................... 59 
6.4.1 Other treatments/procedures ............................................................................. 59 
6.5 Non permitted treatment ............................................................................................ 60 
7. 
Ancillary Studies ................................................................................................ 63 
7.1. Immunohistochemistry Study ................................................................................ 63 
8. 
Discontinuation criteria/Subject withdrawal/end of study ................................... 64 

 
 
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8.1. Discontinuation of treatment ................................................................................. 64 
8.2. Withdrawal from the trial ........................................................................................ 65 
8.3. end of study ............................................................................................................. 65 
9. 
Statistical considerations ................................................................................... 65 
9.1 Sample size ................................................................................................................. 65 
9.2 Study populations ....................................................................................................... 65 
9.3 Statistical methods ...................................................................................................... 66 
10. 
Vigilance and safety control ............................................................................ 68 
10.1 Adverse Events ......................................................................................................... 68 
10.1.1 Definition ................................................................................................................. 68 
10.1.2   Collection and Reporting .................................................................................... 69 
10.1.3 Severity Criteria ..................................................................................................... 70 
10.2 Serious Adverse Events, New Event and Urgent Safety Measure (USM) ...... 70 
10.2.1 Definition ............................................................................................................. 70 
10.2.2 Suspected Unexpected Serious Adverse Reaction ..................................... 72 
10.2.3 
Pregnancy ..................................................................................................... 72 
10.2.4 SAE, New Event, Urgent Safety Measure, and Pregnancy Notification 
Procedure ....................................................................................................................... 73 
10.2.5 Obligation of the sponsor ................................................................................. 76 
10.3 Independent Safety Committee (ISC) ................................................................... 77 
11. Quality assurance and control ............................................................................ 77 
11.1. Data collection .......................................................................................................... 77 
11.2 Trial monitoring ......................................................................................................... 78 
11.3 
Audits and Inspection ......................................................................................... 79 
12. Administrative, ethical and regulatory aspects .................................................... 80 
12.1. 
Conduct of the Study and Responsibilities...................................................... 80 
12.2. 
Subject Information and Consent ..................................................................... 81 
12.3. 
Regulatory Authorizations .................................................................................. 81 
12.4. 
Authorization of the Biological Resource Center............................................ 82 
12.5. 
Processing of Research Data............................................................................ 82 
12.6. 
Amendments of the Protocol ............................................................................. 82 
12.7. 
Sponsor Discontinuation Criteria ...................................................................... 83 
13. 
Financing and Insurance ................................................................................ 83 
13.1. 
Financing of Research........................................................................................ 83 
13.2. 
Insurance .............................................................................................................. 83 
14. Publication policy and communication ................................................................ 84 

 
 
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14.1. 
Publication policy ................................................................................................. 84 
14.2. 
Data sharing statements .................................................................................... 85 
14.3. ..................................................................................................................................... 85 
15. References ......................................................................................................... 85 
 
 
 

 
 
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                                     SYNOPSIS  
TITLE 
A randomized phase III trial assessing a regorafenib-
irinotecan combination (REGIRI) versus regorafenib 
alone in metastatic colorectal cancer patients after 
failure of standard therapies, according to the A/A 
genotype of Cyclin D1  
SYNOPSIS VERSION 
 5.0 
PATHOLOGY 
Metastatic colorectal cancer 
 
PROTOCOL CODES 
Acronym: NEXT-REGIRI 
Sponsor Code: PROICM 2018-01 NEX 
EUDRACT: 2018-002231-24 
 
STUDY SPONSOR 
ICM – Institut régional du cancer de Montpellier 
Clinical, Translational and innovation Research Department  
Dr JP Bleuse 
208 rue des Apothicaires 
34298 Montpellier Cedex 05 – France  
Mail: DRCI-icm105@icm.unicancer.fr 
Phone: 04 67 61 31 02 
Fax: 04 67 41 30 23 
 
STUDY COORDINATOR  
Dr Emmanuelle Samalin 
ICM 
Digestive oncology 
208 rue des Apothicaires 
34298 Montpellier Cedex 05 – France 
Phone: 04 67 61 25 92 
E-mail: emmanuelle.samalin@icm.unicancer.fr 
 
METHODOLOGY AND DATA 
MANAGEMENT CENTER  
ICM -   Institut régional du cancer de Montpellier 
Biometric Unit  
208 rue des Apothicaires 
34298 Montpellier Cedex 05 – France 
Contact Name: Mr Simon Thezenas 
Phone: 04 67 61 30 35 
E-mail: simon.thezenas@icm.unicancer.fr 
 
CLINICAL RESEARCH 
VIGILANCE UNIT 
ICM -    Institut régional du cancer de Montpellier 
208 rue des Apothicaires 
34298 Montpellier Cedex 05 – France 
Contact Name : Nadia BENSMAIL 
Phone: 04 67 61 45 68 
E-mail: Pharmacovigilance-icm105@icm.unicancer.fr 
STUDY DESIGN 
Multicenter randomized Phase III study 
 
NUMBER OF PLANNING 
PATIENT 
78 patients out of about 312 screened patients 
 

 
 
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BACKGROUND AND 
RATIONALE  
Patients with metastatic colorectal cancer (mCRC) who have 
received all approved standard treatments (except Regorafenib 
and TAS 102) no longer have treatment options available while 
maintaining a good performance status which would allow them to 
receive a new treatment. 
 
A Phase III randomized trial that compared Nexiri (Nexavar® + 
Irinotecan) vs irinotecan or versus Sorafenib alone showed a 
progression-free survival at two-months which was favorable to 
the  NEXIRI  combination  ;  59%  ( IC95% : 39-66 )  versus  23% 
(IC95% : 10-33) and 22% (IC95%: 8-30) respectively. 
 
The patients treated with Irinotecan or Sorafenib alone could 
receive 
NEXIRI 
combination 
after 
progression 
and 
the 
progression-free survivals were 3,7 months (IC95% : 2,2-4,9) and 
3,5 months (IC95% : 2,1-3,7) in patients treated with NEXIRI or 
after progression and 1,9 months (IC95% : 1,7-2,1) and 2,1 
months (IC95% : 1,9-2,5) in patients treated only with Irinotecan 
and Sorafenib respectively. 
 
The median overall survival was higher with NEXIRI : 7,2 months 
(patients treated from the beginning of the study) and 7,9 months 
(patients treated after progression and crossover) versus 3 
months in patients treated only with Irinotecan and 3,2 months in 
patients receiving only Sorafenib.  
 
The A870A rs603965 polymorphism of cyclin D1, a molecule 
involved in the initiation of cell division, was favorable to the 
NEXIRI combination on overall survival with a median of 19.6 
months versus 6.2 months for two other genotypes A/G and G/G. 
 
Regorafenib, which is an oral signal deactivation agent with a 
chemical structure very similar to Sorafenib, is a standard 
treatment in heavily pretreated mCRC patients since the results of 
CORRECT study which compared Regorafenib to placebo on 
overall survival showed a superiority of Regorafenib : 6,4 months 
versus 5 months (HR 0,774 [IC95% 0,63, 0,94]). 
 
Sorafenib isn’t approved in mCRC so the objective of this NEXT-
REGIRI trial is compared REGIRI combination (Regorafenib-
Irinotecan) to Regorafenib alone in a phase III trial in patients in 
progression after having received all standard treatments and 
bearing genotype A/A of cyclin D1. 
 

 
 
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STUDY OBJECTIVES 
Primary objective  
Comparison of overall survival in the Regorafenib and REGIRI 
combination (Regorafenib + Irinotecan) arms in mCRC patients of 
Cyclin D1 A/A genotype.  
Secondary objectives 
-Progression-free survival 
-Time to deterioration 
-Objective response rate 
-Disease control rate according to Recist criteria (version 1.1) 
 
-Toxicity (according to the NCI-CTCAE v5.0) 
-Quality of life (EORTC QLQ-C30)  
STUDY ENDPOINTS  
 
Primary endpoint:  
Overall survival presented with its median and confidence interval 
at 95%, estimated from randomization date to the date of death, 
whatever the cause, using the Kaplan-Meier method. 
Secondary endpoints:  
The secondary efficacy endpoint include: 
- Progression-free survival (PFS), defined as the time (days) from 
date of randomization 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. 
-  Time to Deterioration is defined as the time between the date of 
randomization and the first time the patient has a WHO ≥  2 during 
treatment.  
- Disease control rate (DCR), defined as the rate of patients, 
whose best response was not progressive disease (i.e., CR, PR or 
SD), to all randomized patients in the treatment group 
- Objective response rate (OOR), defined as the rate of patients 
with CR or PR,  to all randomized patients in the treatment group. 
Patients prematurely discontinuing without an assessment will be 
considered non-responders for the analysis. 
- Safety will be evaluated using the NCI-CTCAE version 5.0 scale; 
at each visit for the duration of the treatment. 
-Quality of life will be evaluated, using the EORTC QLQ-C30 
questionnaire. 
The expected benefit is an overall survival improvement of this 
treatment in patients with metastatic colorectal cancer who have 
received 
all 
standard 
treatments 
except 
TAS-102 
and 
Regorafenib. 

 
 
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RISK AND BENEFITS  
 
 
Toxicity and tolerance will be clinically and biologically assessed 
and rated on the NCIC CTCAE V5.0 scale at each visit.  
The expected benefit is an improvement in the overall survival of 
this treatment in patients with metastatic colorectal cancer who 
have received all standard treatments except TAS-102 and 
regorafenib. The risks of the study are continuously assessed by 
the MHI's pharmacovigilance department. This risk-benefit will be 
discussed in periodic safety reports. These reports will include all 
regulatory aspects and will be submitted to the competent 
authorities. 
ELIGIBILITY CRITERIA 
Inclusion criteria 
1. Signed informed consent obtained before any study 
specific procedures 
2. Male or female ≥ 18 years of age  
3. Histological documentation of adenocarcinoma of the colon 
or rectum 
4. Patients with metastatic colorectal cancer 
5. Progression during or within 3 months following the last 
administration of approved standard therapies, which must 
include a fluoropyrimidine (or raltitrexed), oxaliplatin,  
irinotecan, anti-VEGF therapy and an anti-EGFR therapy 
(for RAS wild-type tumors), encorafenib 
6. ECOG performance status ≤1 
7. Life expectancy of at least  3 months 
8. Patients with A/A CCND1 genotype of rs603965 CCND1 
9. Adequate bone marrow, liver and renal function as 
assessed by the following laboratory requirements 
conducted within 7 days of starting study treatment: 
 Lipase ≤ 1.5 x ULN 
 
 Total bilirubin ≤ 1.5 x ULN 
 
 Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤ 3.0 x ULN (≤ 5 x ULN for 
patients with liver involvement of their cancer) 
 

 
 
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 Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN 
for patients with liver involvement for their cancer 
and/or have bone metastases) 
 Platelet count ≥ 100,000/mm3; Hemoglobin (Hb) ≥ 9 
g/dL; Absolute neutrophil count (ANC) ≥ 1,500/ mm3. 
Transfusion to meet the inclusion criterion 
 Serum creatinine ≤ 1.5 x ULN 
10. International normalized ratio (INR) ≤ 1.5 x ULN and partial  
thromboplastin 
time 
(PTT) 
or 
activated 
partial 
thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving  
treatment with therapeutic anticoagulation. Patients being 
treated with anticoagulant, e.g., heparin, will be allowed to 
participate provided no prior evidence of an underlying 
abnormality in these parameters exists. Close monitoring of 
at least weekly evaluations will be performed until INR and 
PTT are stable based on a pre-dose measurement as 
defined by the local standard of care 
11. Women of childbearing potential must have a blood or urine 
pregnancy test performed a maximum of 7 days before 
start of study treatment, and a negative result must be 
documented before start of study treatment  
 
12. Women of childbearing potential and men must agree to 
use adequate contraception before entering the study until 
at least respectively 7 months and 4 months after the last 
study drug administration of Regorafenib and respectively 6 
months and 3 months after the last study drug 
administration of Irinotecan. 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.  
Exclusion criteria 
 
1. Patients with A/G or G/G CCND1 genotype of  rs603965 
CCND1 
2. Prior treatment with regorafenib or sorafenib 
3. Prior treatment with TAS 102 
4. Major surgical procedure, open biopsy, or significant 

 
 
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traumatic injury within 28 days before start of study drug 
5. Pregnant 
or 
breast-feeding 
subjects. 
Women 
of 
childbearing potential must have a pregnancy test 
performed a maximum of 7 days before start of treatment, 
and a negative result must be documented before start of 
study drug 
6. Congestive heart failure ≥ New York Heart Association 
(NYHA) class 2 
7. Unstable angina (angina symptoms at rest), new-onset 
angina (begun within the last 3 months) 
8. Myocardial infarction less than 6 months before start of 
study drug 
9. Cardiac arrhythmias requiring anti-arrhythmic therapy 
(beta blockers or digoxin are permitted)  
10. Uncontrolled hypertension. (Systolic blood pressure > 140 
mmHg or diastolic pressure > 90 mmHg despite optimal 
medical management) 
11. Pleural effusion or ascites that causes respiratory 
compromise (≥ NCI-CTCAE V5.0 Grade 2 dyspnea) 
12. Ongoing infection > Grade 2 NCI-CTCAE V5.0 
13. Known history of human immunodeficiency virus (HIV) 
infection 
14. Active hepatitis B or C, or chronic hepatitis B or C requiring 
treatment with antiviral therapy 
15. Patients with seizure disorder requiring medication 
16. History of organ allograft 
17. Patients with evidence or history of any bleeding diathesis, 
irrespective of severity  
18. Any hemorrhage or bleeding event ≥ NCI-CTC V5.0 Grade 
3 within 4 weeks prior to the start of study medication  
19. Non-healing wound, ulcer, or bone fracture 

 
 
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20. Dehydration NCI-CTCAE V5.0 Grade ≥ 1 
21. Substance abuse, medical, psychological or social 
conditions that may interfere with the subject’s participation 
in the study or evaluation of  the  study  results 
22. Known hypersensitivity to any of the study drugs, study 
drug classes, or excipients in the formulation 
23. Any illness or medical conditions that are unstable or could  
jeopardize the safety of the subject and his/her compliance 
in the study 
24. Persistent proteinuria of NCI-CTCAE V5.0 Grade 3 (> 
3.5g/24 hours) 
25. Patients unable to swallow oral medications 
26. Any malabsorption condition 
27. Chronic inflammatory bowel disease and / or bowel 
obstruction 
28. Unresolved toxicity higher than NCI-CTCAE V.5.0 Grade 1 
attributed to any prior therapy/procedure excluding 
alopecia, 
hypothyroidism 
and 
oxaliplatin 
induced 
neurotoxicity  ≤ Grade 2 
29. Concomitant participation or participation within the last 30 
days in another clinical trial 
30. Systemic anticancer therapy during this trial or within 4 
weeks before randomization 
31. Concomitant intake of St. John's wort 
32. Live attenuated vaccines are prohibited 10 days before the 
treatment, during the treatment and 6 months after the 
termination of treatment 
33. History of gastrointestinal fistula or perforation 
34. 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  

 
 
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bladder tumors [Ta (non invasive tumor), Tis (carcinoma in 
situ) and T1 (lamina propria invasion)]. 
STUDY PRODUCT OR 
MEDICAL DEVICE 
REGORAFENIB  
IRINOTECAN 
ENROLLMENT 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT OR SURGERY  
MODALITIES 
Experimental arm : REGIRI (arm A) 
 
-Irinotecan will be administered every 15 days.  
 
-1st cycle : Irinotecan will be administered at the dose of 120 
mg/m² on D1 by a IV perfusion over 90 minutes. 
 
-2nd cycle : if no diarrheas grade > 1 and any other toxicities grade 
> 2 then the Irinotecan dose will be at 150 mg/m² and 
administered on D1 by IV infusion over 90 minutes. 
 
-From the third cycle : if no diarrheas grade > 1 and any other 
toxicity grade > 2 then the Irinotecan dose will be at 180 mg/m² 
and administered on D1 by IV infusion over 90 minutes. 
D1=D15 
 
-Regorafenib will be given orally at a dose of 160 mg, once daily 
during on days 2–8 and 16–22 of each cycle, D1 = D28 
 A chemotherapy course = 15 days, 1 cycle = 4 weeks 
 
Control arm : STIVARGA® (Regorafenib) (arm B) 
-Regorafenib will be given orally at a dose of 160 mg once 
daily over 3 weeks followed by 1 week off, D1=D28.  
1 cycle = 4 weeks 
 
 
Pre-treated 
patients with 
mCRC and 
wt or mutated 
RAS status  
 
Genotype 
A/A of 
cyclin D1 
(25% of 
patients) 
Screening 
Randomisation 1 :1 
Arm A: 
REGIRI 
(irinotecan + 
regorafenib) 
 Arm B:  
Stivarga® 
(Regorafenib) 

 
 
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ANCILLARY STUDY 
 
Immunohistochemistry : 
The expression of cyclin D1 protein will be sought by 
immunohistochemistry on tissue sections obtained from paraffin-
embedded specimens. 
We will investigate any association between protein expression 
and response to treatment.  
In addition, depending on the progress of knowledge at the time of 
the study is completed, other biomarkers predictive of response to 
treatment can be explored by IHC on the same tumor blocks. 
STATISTICAL 
CONSIDERATIONS 
 
To show an increase of median overall survival from 7 to 15 
months (30% to 57% rates, respectively), with a HR=0.47 and a 
power of 80% and alpha=5%, 55 events are required for the 78 
patients to be randomized considering 15% additional patients for 
lost to follow-up.  
The A/A  Cyclin D1 (A/A CCDN1)  genotype  accounting for 25% 
of the mCRC patients, a screening of 312 patients will be required 
before randomization which will be stratified BY RAS status. 
The inclusion period will last 64 months  
No interim analysis is planned. 
STUDY PERIOD 
 First inclusion : september 2019  
 Inclusion period : 64 months  
 End of the inclusion period:January 2025  
 Expected end of study:  June 2025  
 Report : December 2025   
 

 
 
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1. Background and rationale 
Until recently, there were no treatment options available for patients with metastatic 
colorectal cancer who progress after all approved standard therapies, although many 
patients maintain a good performance status and could be candidates for further therapy. 
The NEXIRI combination (sorafenib + irinotecan) showed promising results in heavily 
pretreated mCRC patients with KRAS mutated tumors (1). A randomized phase II study  
assessed this  combination versus irinotecan or sorafenib as monotherapies, with possible 
cross-over to the NEXIRI arm at progression for patients treated with either monotherapy.  
The progression-free survival at two months, the primary objective of the study, was of 59%. 
The median progression-free survival was of 3.7 months (95% CI: 2.2-4.9) and 3.5 months 
(95% CI: 2.1-3.7) in the NEXIRI and cross-over arms, and of 1.9 (95% CI: 1.7-2.1) and 2.1 
(95% CI: 1.9-2.5) in the irinotecan and sorafenib (monotherapies) groups, respectively. The 
median overall survival was higher in patients treated with NEXIRI, either from the beginning 
of the study or at progression (cross-over patients): 7.2 (95% CI: 5.8-9.4) and 7.9 months 
(95% CI: 7.1-8.7) compared with patients treated only with irinotecan or sorafenib, 
respectively 3 (95% CI: 2.1-3.8) and 3.3 months (95% CI: 2.5-4.2) (2). 
Cyclin D1 (CCND1) is involved in the G1 phase of the cell cycle; the A870G rs603965 
polymorphism is specifically associated with response to anti-cancer treatments (3,4). The 
A/A genotype, which generates a truncated form of CCND1, was favorable to the NEXIRI 
combination on overall survival, with a median of 19.6 months (95% CI: 4.8-/) versus 6.2 
months (95% CI: 4.9-9.4) for the A/G and G/G genotypes; this benefit was not reported in 
patients treated with sorafenib alone.  
This data would have warranted further investigation through a large, randomized phase III 
trial, however, information was given by Bayer that no clinical development was planned in 
the indication of mCRC with sorafenib. 
Regorafenib is an oral tumor deactivation agent – whose chemical structure is close to that of 
sorafenib - which potently blocks multiple protein kinases, including kinases involved in tumor  
angiogenesis, oncogenesis, metastasis and tumor immunity. Unlike sorafenib, regorafenib 
underwent a clinical development program in GI cancers, showing survival benefits in 
metastatic colorectal cancer which has progressed after all standard therapies. In the phase 
III study CORRECT, the addition of regorafenib to best supportive care resulted in 
significantly longer survival, compared to placebo plus best supportive care, with a p value of 
0.005178 from stratified log rank test, a hazard ratio of 0.774 [95% CI 0.636, 0.942] ) and a 
median OS of 6.4 months vs. 5.0 months (5). This study provided evidence for a continuing 
role of targeted treatment after disease progression, with regorafenib offering a potential new 
line of therapy in this treatment-refractory population. 

 
 
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Meanwhile, a combination approach was investigated to create potential synergy with the 
ultimate objective to improve even more survival outcomes in this particular population. 
A combination of FOLFOX or FOLFIRI (oxaliplatin 85 mg/m2 or irinotecan 180 mg/m2, D/L-
folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2 followed by 5-FU 2400 mg/m2 for 46 hours) 
every 2 weeks and regorafenib (160 mg/day administered sequentially to FOLFIRI on days 
4-10 and 18-24 of every 4 week cycle, was explored in a phase Ib trial in patients with 
metastatic colorectal cancer (mCRC) (6). The incidence of drug-related adverse events of 
any grade was similar (no significant differences) between FOLFOX and FOLFIRI groups 
indeed Thrombocytopenia (20% vs 20%), Neutropenia was (44% vs 55%), Diarrhea (52% vs 
60 %), hand-foot reaction skin reaction (36% vs 35%). The most frequent drug-related 
adverse events leading to dose modification were neutropenia (n = 12; 27%), mucositis (n = 
8; 18%), hand–foot skin reaction (n = 8; 18%), and leukopenia (n = 5; 11%). Regorafenib in 
combination with mFOLFOX6 or FOLFIRI showed encouraging anti-tumor efficacy with 
partial response in 7 patients, 4 on regorafenib with mFOLFOX6 and 3 on regorafenib with 
FOLFIRI. Overall, disease control (i.e., partial response or stable disease) was achieved in 
33 patients (87%), 18 on regorafenib with mFOLFOX6 and 15 on regorafenib with FOLFIRI. 
Even though regorafenib increased the exposure to SN-38 in the FOLFIRI group, it was not 
associated with reduced tolerability. 
These findings were confirmed in a multicenter, randomized, double-blind phase II trial of 
FOLFIRI plus regorafenib (A) or FOLFIRI + placebo (B) in mCRC, in which the addition of 
regorafenib on an intermittent schedule (week on, week off) to FOLFIRI as 2nd line therapy, 
was tolerable, and resulted in a statistically significant prolongation of PFS compared to 
FOLFIRI alone.  Grade ≥ 3 adverse events occurring in > 5% of patients (A vs B) included 
neutropenia (40% vs 30%), diarrhea (14% vs 5%), hypophosphatemia (14% vs 0%), fatigue 
(11% vs 7%), mucositis (9% vs 10%), hypertension (8% vs 2%), elevated lipase (8% vs 3%) 
and hand-foot syndrome was grade ≥ 5% on arm A vs 2% on B. The addition of regorafenib 
on an intermittent schedule to FOLFIRI was tolerable, and resulted in a statistically significant 
prolongation of PFS compared to FOLFIRI alone (7). 
 
Altogether, these results and those of the NEXIRI study justify conducting a phase III 
randomized trial assessing a regorafenib – irinotecan (REGIRI) combination versus 
Regorafenib  alone in  mCRC  patients of  CCND1 A/A genotype,  who  have  progressed  
being treated with available therapies.  

 
 
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2. Study objectives and Endpoints 
2.1 Objectives 
2.1.1 Primary objective 
Comparison of overall survival in the Regorafenib and REGIRI combination (Regorafenib + 
Irinotecan) arms in mCRC patients of Cyclin D1 A/A genotype.  
 
 
2.1.2 Secondary objective 
- Progression-free survival 
- Time to deterioration 
- Objective response rate 
- Disease control 
- Toxicity (according to the NCI CTC V5.0) 
- Quality of life (EORTC QLQ-C30 – appendix 2) 
 
2.2 Endpoints  
 
 
2.2.1 Primary endpoint 
Median Overall survival presented with its confidence interval at 95%, estimated from the 
randomization date to the date of death, whatever the cause, using the Kaplan-Meier 
method. 
 
2.2.2 Secondary endpoints 
 
The secondary efficacy endpoints include: 
- Progression-free survival (PFS), defined as the time (days) from date of randomization 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. 
- Time to Deterioration is defined as the time between the date of randomization and the first 
time the patient has a WHO ≥ 2 during treatment. 
- Disease control rate (DCR), defined as the rate of patients, whose best response was not 
progressive disease (i.e., CR, PR or SD), to all randomized patients in the treatment group- 
Objective response rate (OOR), defined as the rate of patients with CR or PR, to all 
randomized patients in the treatment group. Patients prematurely discontinuing without an 
assessment will be considered non-responders for the analysis. 

 
 
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- Safety will be evaluated by clinical and biological means and scored on the NCI-CTCAE 
version 5.0 scale, performed at each visit (every 2 weeks). 
-Quality of life will be evaluated, based on the EORTC QLQ-C30 questionnaire (appendix 2). 
3. Experimental plan  
3.1 Study design 
This is an open, prospective, multicenter, randomized Phase III study.  
78 patients will be randomized in several centers. 
 
Experimental arm : REGIRI (arm A) 
 
                               
 
 
Control arm : Stivarga® (Regorafenib) (arm B) 
 
             
 
 

 
 
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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.  
4. Population  
4.1 Number of planned patients  
 
-78 patients randomized out of approximately 312 screened patients. 
-Patients with wild-type or mutated RAS status and Genotype A/A of cyclin D1 (25% of 
patients). 
 
4.2 Inclusion criteria 
 
1. Signed informed consent obtained before any study specific procedures 
2. Male or female ≥ 18 years of age  
3. Histological documentation of adenocarcinoma of the colon or rectum 
4. Patients with metastatic colorectal cancer 
5. Progression during or within 3 months following the last administration of approved 
standard therapies, which must include a fluoropyrimidine (or raltitrexed), oxaliplatin, 
irinotecan, anti-VEGF therapy and an anti-EGFR therapy (for RAS wild-type tumors), 
encorafenib 
6. ECOG performance status ≤1 
7. Life expectancy of at least  3 months 
8. Patients with A/A CCND1 genotype of rs603965 CCND1 
9. Adequate bone marrow, liver and renal function as assessed by the following 
laboratory requirements conducted within 7 days of starting study treatment: 
 First inclusion : september 2019  
 Inclusion period :  64 months  
 End of the inclusion period: January 2025  
 Expected end of study: June 2025  
 Report : December 2025  
 

 
 
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 
 Lipasémie ≤1.5 x ULN 
 
Total bilirubin ≤ 1.5 x ULN 
 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x 
ULN (≤ 5 x ULN for patients with liver involvement of their cancer) 
 
Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with liver  
involvement for their cancer and/or have bone metastases) 
 
 
Platelet count ≥ 100,000/mm3; Hemoglobin (Hb) ≥ 9 g/dL; Absolute neutrophil  
count (ANC) ≥ 1,500/ mm3. Transfusion to meet the inclusion criterion will not 
be allowed 
 
 
Serum creatinine ≤ 1.5 x ULN 
10. International normalized ratio (INR) ≤ 1.5 x ULN and partial thromboplastin time (PTT) 
or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving 
treatment with therapeutic anticoagulation. Patients being treated with anticoagulant, 
e.g., heparin, will be allowed to participate provided no prior evidence of an 
underlying abnormality in these parameters exists. Close monitoring of at least 
weekly evaluations will be performed until INR and PTT are stable based on a pre-
dose measurement as defined by the local standard of care 
11. Women of childbearing potential must have a blood or urine pregnancy test 
performed a maximum of 7 days before start of study treatment, and a negative result 
must be documented before start of study treatment  
12.  Women of childbearing potential and men must agree to use adequate contraception 
before entering the study until at least  respectively 7 months and 4 months after the 
last study drug administration of Regorafenib and respectively 6 months and 3 
months after the last study drug administration of Irinotecan. 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.  
 
4.3 Non-inclusion criteria 
 

 
 
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1. 
Patients with A/G or G/G CCND1 genotype of rs603965 CCND1 
2. 
Prior treatment with regorafenib or sorafenib 
3. 
 Prior treatment with TAS 102 
4. 
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
before start of study drug 
5. 
Pregnant or breast-feeding subjects. Women of childbearing potential must have a 
pregnancy test performed a maximum of 7 days before start of treatment, and a negative 
result must be documented before start of study drug 
6. 
Congestive heart failure New York Heart Association (NYHA) class 2 (appendix 3) 
7. 
Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 
3 months) 
8. 
Myocardial infarction less than 6 months before start of study drug 
9. 
Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are 
permitted) 
10. 
Uncontrolled hypertension. (Systolic blood pressure 140 mmHg or diastolic pressure 
90 mmHg despite optimal medical management) 
11. 
Pleural effusion or ascites that causes respiratory compromise (CTCAE Grade 2 
dyspnea) 
12. 
Ongoing infection Grade 2 CTCAE V5.0 
13. 
Known history of human immunodeficiency virus (HIV) infection 
14. 
Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral 
therapy 
15. 
Patients with seizure disorder requiring medication 
16. 
History of organ allograft 
17. 
Patients with evidence or history of any bleeding diathesis, irrespective of severity 
18. 
Any hemorrhage or bleeding event CTCAE Grade 3 within 4 weeks prior to the start 
of study medication 
19. 
Non-healing wound, ulcer, or bone fracture 

 
 
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20. 
Dehydration CTCAE V5.0 Grade 1 
21. 
Substance abuse, medical, psychological or social conditions that may interfere with 
the subject’s participation in the study or evaluation of the study results 
22. 
Known hypersensitivity to any of the study drugs, study drug classes, or excipients in 
the formulation 
23. 
Any illness or medical conditions that are unstable or could jeopardize the safety of 
the subject and his/her compliance in the study 
24. 
Persistent proteinuria of CTCAE Grade 3 (> 3.5g/24 hours) 
25. 
Patients unable to swallow oral medications 
26. 
Any malabsorption condition 
27. 
Chronic inflammatory bowel disease and / or bowel obstruction 
28. 
Unresolved toxicity higher than CTCAE (V5.0) Grade 1 attributed to any prior 
therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neurotoxicity 
Grade 2 
29. 
Concomitant participation or participation within the last 30 days in another clinical 
trial 
30. 
Systemic anticancer therapy during this trial or within 4 weeks before randomization  
31. 
Concomitant intake of St. John's wort 
32. 
Live attenuated vaccines are prohibited 10 days before the treatment, during the 
treatment and 6 months after the termination of treatment 
33. 
History of gastrointestinal fistula or perforation 
34. 
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 bladder tumors [Ta (non invasive tumor), Tis 
(carcinoma superficial in situ and T1 (lamina propria invasion) 
4.4  Procedure  
 
Enrollment procedures will be performed using Electronic Case report Form (eCRF). 
The procedure of use of eCRF for randomization will be given to all investigators during the 
study opening of each of the centers.  
This enrolment procedure will be performed in 2 steps:  

 
 
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1/ Inclusion (screening): After inclusion and non-inclusion criteria have been fulfilled and the 
patient consent has been obtained, the patient will be included in the trial.  
2/ Randomization: The randomization procedure will allocate the treatments A or B using list 
algorithm, with a 1:1 ratio and will be stratified by the following criteria: 
-RAS Status 
 
The inclusion / randomization will be performed using the module of the eCRF / Ennov 
Clinical® software. After the consent form has been signed and all inclusion/ non-inclusion 
criteria checked, the investigator will proceed with the randomization through the ICM online 
e-CRF: 
 
https://ecrfcval.icm.unicancer.fr/CSOnline/ 
An automatic reply will be sent by e-mail to confirm the success of the randomization 
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 
 NEXT-REGIRI 
 
 
 
Screening 
 
 
Treatment 
 
 
Evaluation  
(Every 8 
weeks) 
 
 
 
End of 
treatment 
b,c 
 
    
   Safety 
Follow-upc-
d 
 
Follow-up 
 
 
End 
of 
study 
 
Regorafenib 
(1 cycle = 4 
weeks 
 
REGIRI 
(1 course = every 15 days and 
 1 cycle = every 4 weeks) 
Baseline Documentation 
 
As early 
as 
second-
line 
~ 28 
days  
 
 
Within 
28  
days 
 
Within  
14 
days 
Within  
7 
days 
 
 
CX D1a 
 
 
C1, C2 
D8  
 
 
 
CX D1a 
 
 
 
 
 
C1, C2  
D8  
 
 
 
 
Cx D15 
 
 
C1, C2  
D22 
 
 
~8 weeks 
 
 
~14 days 
 
 
~30 days 
Follow-up: 
every other 
month 
  
 
 
Molecular testing informed 
consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical trial informed consent 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete medical history 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
checked
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
β-HCG blood test  
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
Status of Ras, Raf and MSI have 
to be known 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Studies 
 
 
12-lead ECG 
 
 
 
 
X 
 X1 
 
 X1 
 
 
 
X 
X4 
 
 
 
Complete blood count  
 
 
 
 
X 
X 
 
X 
 
X 
 
 
X4 
 
 
 
Coagulation 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
X4 
 
 
 
Electrolyte panel 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
X4 
 
 
 
Chemistry panel 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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     Tabulated overview 
         NEXT-REGIRI 
 
 
 
Screening 
 
Treatment 
    Every 8 
     weeks 
 
 
End of 
treatment 
b,c 
 
SafetyFollo
w-upc-d 
 
Follow-
up 
 
End 
of 
study 
 
Regorafenib 
(1 cycle = 4 
weeks 
REGIRI 
(1 course = every 15 days and 1 cycle = every 4 
weeks) 
Liver function test panel 
 
 
 
X 
 X2 
 
X 
X 
X 
X 
 
X4 
 
 
 
Thyroid function 
 
 
 
X 
X 
 
X 
 
 
 
 
X4 
 
 
 
Tumor markers 
 
 
 
X 
 X3 
 
 X3 
 
 
 
X 
X4 
X5 
 
 
Urinary analysis 
 
 
 
X 
X 
 
X 
 
X 
 
 
X4 
 
 
 
Imaging assessments 
 
Radiologic Tumor assessment d 
 
X 
 
 
 
 
 
 
 
 
X 
 X6 
X5 
 
 
Other Clinical Assessments 
 
ECOG 
 
 
 
X 
X 
 
X 
 
X 
 
 
 X4 
 
 
 
Body weight, BSA, height, and vital 
signs  
 
 
 
X 
X 
 
X 
 X7 
X 
 
 
 X4 
 
 
 
Concomitant medications 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
 
Adverse events 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Drug dispensing  
 
 
 
 
 X8 
 
 X8 
 
 
 
 
 
 
 
 
Drug accountability  
 
 
 
 
 X8 
 
 X8 
 
X 
 
 
X 
 
 
 
Post-study survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Anti-cancer medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Patient’s diary 
 
 
 
 
  X9 
 
 X9 
 
X 
 
 
 
 
 
 
Patient Reported Outcomes 
 
Quality of life questionnaires  
 
 
 
 
   X10 
 
  X10 
 
 
 
X 
 
 
 
 
Phone call : adverse events, blood 
pressure 
 
 
 
 
X 
X 
 
 
 
X 
 
 
 
 
 
Ancillary study 
 
Immunohistochemistrye 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

 
 
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Réf interne ICM : ICM-ENR-432 Version : 001  Date d’application : 24/05/2017  
 
a:  Cycle 1 Day 1 : the laboratory evaluations are not required at day 1 of cycle 1 if those were 
completed within 7 days  
b:  Within 14 days (+/- 7 day) after study treatment has stopped 
 
c:  Within 30 days (+/- 7 day) after study treatment has stopped 
d: CT scan of the abdomen, pelvis and chest or hepatic MRI and CT scan of the pelvis and chest without injection; 
    RECIST criteria version 1.1 
e: Paraffin-embedded human solid tissue blocks will be sent off at room temperature at the end of the inclusions 
 
1: A 12-lead ECG will be performed at the end of every other cycle (8 weeks, if there’s no postponed 
treatment)  
2 : D1 and D15 of the first two cycles for Bras B (Stivarga®) and D1 only at the other cycles 
3: Tumor markers CEA and CA 19-9 at every cycle 
4: If the last clinical and laboratory evaluations > 7 days 
5: if not done at the EOT visit 
6: If the last radiological tumor assessment > 1 month 
7:  C1-C2 D8 (arm A) : vital signs without height, weight and BSA 
8:  As applicable 
9: A treatment diary will be handed over to patient on cycle 1 day 1 
10: EORTC QLQ-C30 questionnaires will be completed by the patient on Day 1 of Cycle 1 then at 
each evaluation (= 8 weeks) for both treatments 
 
5.2 Screening period 
 
Enrollment into NEXT-REGIRI will be performed in two stages with two separate informed 
consent forms. Initially, all potential patients will consent to undergo molecular testing 
(appendix 4). The blood sample for molecular testing will be sent off to :  
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 molecular testing will be carried out by Dr Evelyne Crapez. 
Dr Evelyne Crapez 
Responsable de l’unité de recherche translationnelle 
Institut régional du cancer de Montpellier 

 
 
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Unité de recherche translationnelle 
208, rue des Apothicaires – Parc Euromedecine 
34298 Montpellier CEDEX 5 
Tel : +33 (0) 4.67.61.30.48 – Fax : +33 (0) 4.67.41.08.59 
Evelyne.Crapez@icm.unicancer.fr 
 
Only patients with the Sequence A/A rs603965 of cycline D1 gene can be screened for the 
study treatment (REGIRI vs Regorafenib). A second consent form to screen for the clinical 
study (Clinical Trial Consent).  
Both consent processes are independent of each other. 
 
The following procedure will be able to be performed as early as second-line treatment:  
 
A blood sample will be collected into a PAXGENE DNA tube then will be shipped to 
CRB-ICM for determining the variant A/A genotype of cyclin D1 
 
The following procedures and assessments will be performed around 28 days of starting 
study Drug for both arms of treatment:  
 
 
Status of RAS, RAF and MSI have to be known 
 
 
Obtainment of molecular testing informed consent  
 
The following procedures and assessments will be performed within 28 days of starting 
study Drug for both arms of treatment:  
 
 
Obtainment of written informed consent. No screening procedures may be performed 
unless written informed consent has been obtained 
 
 
Inclusion/Exclusion criteria checked 
 
 
Radiological tumor assessment using the RECIST criteria, version 1.1 (see Appendix 
5) 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 
 

 
 
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 
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) 
 
 
Complete medical history including demographics, allergies, prior surgery and prior 
chemo/radiation therapy with documentation of treatment response.  
 
 
The following procedures and assessments will be performed within 14 days of starting 
study drug: 
 
 
Record of all concomitant medications except Homeopathy. All medicines and 
significant non-drug therapies taken within 14 days before study treatment must be 
recorded in the e-CRF. 
 
The following procedures and assessments will be performed within 7 days of starting 
study drug: 
 
 
12-lead ECG 
 
 
ECOG performance status (Appendix 6) 
 
 
Adverse events  
 
 
Physical examination including review of all organ systems, examination of pertinent 
organ systems, vital signs (heart rate, blood pressure, weight, BSA and height). 
The blood pressure measurements must be performed in a consistent manner using 
a manual cuff on the same arm. The assessment must be made with the patients in 
the sitting position using the same arm for all evaluations. Two additional 
measurements, taken 5 minutes apart, should be conducted if the first blood pressure 
is abnormal 
 
 
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 

 
 
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 
Electrolyte panel: sodium, potassium, calcium, chloride 
 
 
Chemistry panel: albumin, lipase, phosphate, glucose, serum creatinine, clearance 
calculated according CKD-EPI (appendix 7)  
 
 
Liver function test panel: Aspartate Amino-Transferase (AST), Alanine Amino-
Transferase (ALT), bilirubin (total and direct), alkaline phosphatase, GGT, Lactic 
Dehydrogenase (LDH)  
 
 
Thyroid function test: TSH, free T3, and free T4 
 
 
Coagulation panel: Prothrombin time (PT) or the International Ratio of PT (PT-INR) 
and Partial Thromboplastin Time (PTT) 
 
 
Urine analysis: Urine analysis by urinary dipstick. If results of protein ≥ 3+, 
quantification of proteinuria on a 24-hour urine collection 
 
 
Tumor markers : CEA (Carcino-Embryogenic Antigen), CA 19.9 (Carbohydrate 
Antigen 19-9) 
 
 
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. 
 
5.3 Treatment period 
 
REGIRI or Regorafenib: 
 
After all screening assessments have been completed and the patient’s eligibility has been 
confirmed and documented, the patient will be randomized. 
 
The following assessments should be performed on the first day and day 15 of each 
cycle (REGIRI) or cycle (Regorafenib) except C1D1 prior to receiving study treatment 
(+/- 3 days): 
 

 
 
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 
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) and vital signs (heart rate, 
blood pressure)  
 
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) 
 
 
 12-lead ECG. It will be performed every other cycle (8 weeks if there’s no postponed 
treatment) for both arms 
 
 
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 and 15 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) 
 
 Electrolyte panel: sodium, potassium, chloride, calcium 
 
 Chemistry panel : albumin, lipase,  phosphate,  glucose, serum 
creatinine, clearance calculated according CKD-EPI (appendix 7)  
 
 Hepatic panel: Aspartate Amino-Transferase (AST), Alanine Amino-
Transferase (ALT), bilirubin (total and direct), GGT, alkaline 
phosphatase, Lactic Dehydrogenase (LDH) 

 
 
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 Thyroid function test (TSH, free T3, free T4, on day 1 of each cycle for 
both arms)  
 
 Tumor markers CEA (Carcino-Embryogenic Antigen), CA 19-9 (carbohydrate 
 Antigen 19-9) every cycle for both treatments 
 
 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 (on day 1 of each cycle for both arms). 
 
 Urine analysis by urinary dipstick. If results of protein ≥ 3+, then quantification 
    of proteinuria on a 24-hour urine collection must be done. 
 
  EORTC QLQ-C30 (appendix 2) questionnaires will be completed by the patient on 
Day 1 of Cycle 1 (baseline) then on the first day of every other cycle (every 8 
weeks) 
 
 
Drug dispensing  
 
 
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 
arm A (REGIRI) and B (Regorafenib) of each cycle 
 
Provide patient’s diary on C1D1. It will allow to patient to write down his oral 
intakes and blood pressure values 
 
The blood pressure must be monitored weekly for the first six weeks of study treatment. 
The blood pressure will be recorded by the patient and entered onto his treatment diary. In 
the latter case, the patient should be instructed to contact the physician in the event of 
systolic ≥  150  mm Hg  and  / or diastolic ≥ 100 mm Hg. The  physician  should  confirm  the  
reading before recording it into the e-CRF. Blood pressure measurements will be performed 
in patients sitting for 5 minutes prior to the evaluation.  The  patient  should  be instructed to 
take their blood pressure in the morning and repeat two more times for accuracy. 
 

 
 
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The following assessments should be performed on day 8 of cycle 1 and 2: 
 
REGIRI (arm A)  
 
 
Vital signs (Heart rate and blood pressure) 
 
 
these laboratory evaluations are required: Aspartate Amino-Transferase (AST), 
Alanine Amino-Transferase (ALT), bilirubin (total and direct) 
 
 
Stivarga® (Regorafenib) (arm B): 
 
 
Phone call by a treatment nurse for knowing if there are any adverse events and 
blood pressure value (current state of the art) 
 
The following assessments should be performed on day 15 of cycle 1 and 2: 
 
REGIRI (arm A) 
 
 
Physical examination with weight and vital signs (heart rate, blood pressure)  
 
 
ECOG performance status 
 
 
Concomitant medications (including start/stop dates, dose, indication) 
 
 
Adverse events documentation (including Start/Stop dates, seriousness, CTC  
notation and grading, relationship to study drug, outcome and action taken) using 
CTCAE V5.0 
 
 
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, chloride, calcium 
 

 
 
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 
Chemistry panel : albumin, lipase,  phosphate,  glucose, serum creatinine, clearance 
calculated according CKD-EPI (appendix 7)  
 
 
Hepatic panel: Aspartate Amino-Transferase (AST), Alanine Amino-Transferase 
(ALT), bilirubin (total and direct), GGT, alkaline phosphatase, Lactic Dehydrogenase 
(LDH) 
 
 
Urine analysis by urinary dipstick. If results of protein ≥ 3+, then quantification of  
proteinuria on a 24-hour urine collection must be done. 
 
 
Drug accountability (pharmacy) 
Verify patient’s diary. It will allow to patient to write down his oral intakes and blood 
pressure values 
 
 
The following assessments should be performed on day 15 of cycle 1 and 2: 
 
Stivarga® (Regorafenib - arm B): 
 
 
 
these laboratory evaluations are required: Aspartate Amino-Transferase (AST), 
Alanine Amino-Transferase (ALT), bilirubin (total and direct) 
 
The following assessments should be performed on day 22 of cycle 1 and 2: 
 
REGIRI (arm A): 
 
 
 
Phone call by a treatment nurse for knowing if there are any adverse events and 
blood pressure value (current state of the art) 
 
These laboratory evaluations are required: Aspartate Amino-Transferase (AST), 
Alanine Amino-Transferase (ALT), bilirubin (total and direct) 
 
The following assessments should be performed at each evaluation i.e (every 8 
weeks): 
 
REGIRI or Regorafenib: 
 

 
 
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 
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 5) 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. Throughout the 
study, the identical lesions to those identified and measured at baseline must 
be evaluated using the same technique, and preferably by the same 
radiologist. Copies of all CT scans performed for tumor assessment in non-
progressive enrolled patients will be stored on CDs at the site 
 
 
EORTC QLQ-C30 (appendix 2) questionnaires will be completed by the 
patient at each evaluation i.e 8 weeks 
 
5.4 End of treatment Visit 
 
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 and vital signs (heart rate, blood 
pressure)  
 
 
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 

 
 
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 
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, chloride and calcium 
 
 
Chemistry panel: albumin, lipase, phosphate, glucose, serum, creatinine, 
clearance calculated according CKD-EPI (appendix 7)  
 
 
Liver function test panel: Aspartate Amino-Transferase (AST), Alanine Amino-
Transferase (ALT), bilirubin (total and direct), GGT, alkaline phosphatase, 
Lactic Dehydrogenase (LDH) 
 
 
Thyroid function test : TSH, free T3, and free T4 
 
 
Tumor markers: CEA (Carcino-Embryogenic Antigen), CA 19.9 (Carbohydrate  
            Antigen 19-9) 
 
 
Urine analysis by urinary dipstick. If results of protein ≥ 3, then quantification 
of  proteinuria on a 24-hour urine collection must be done 
 
 
A radiological tumor assessment using the RECIST criteria, version 1.1 (see 
Appendix 5) 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) 
 
 
Drug accountability (pharmacy) 
5.5 Follow-up  
 
Safety Follow-Up Visit 
 

 
 
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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: 
 
 
A radiological tumor assessment using the RECIST criteria, version 1.1 (see 
Appendix 5) 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 
 
 
 
Follow-up every other month until Death 
 
 
Vital status 
 
 
Anti-cancer medications 
 
Telephone follow-up is acceptable. Site staff must use caution when contacting the patient’s 
family for this information, especially if they are no longer under the care of the investigator,   
so as to not inadvertently cause any distress to the family of a patient who is no longer alive. 
 
6. Treatments  
6.1 Experimental treatment or procedures 
 
Experimental arm: REGIRI (arm A) 
 

 
 
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                                                            Figure 1 : REGIRI regimen 
 
 
 
The treatment schedule will be as follows:  
 
- Starting on days 1 and 15 of each 28-day cycle, all patients will receive irinotecan as an 
intravenous infusion over a 90 minute period. 
The initial dose of irinotecan will be 120 mg/m2. 
The dose for the second infusion of irinotecan will be 150 mg/m2 over 90 minutes if no 
diarrhea of grade >1 NCI-CTCAE V 5.0 grading or others toxicities of grade >2 occur. 
The dose for the third and subsequent infusions of irinotecan will be 180 mg/m2 over 90 
minutes under the same conditions as for the 2nd infusion.  
 
-On days 2–8 and 16–22 of each cycle, all patients will receive Regorafenib 160 mg orally 
once daily. 
  
-A chemotherapy course = 15 days, 1 cycle = 4 weeks 
 
Control arm: Stivarga® (Regorafenib) (arm B) 
 
-Regorafenib will be given orally at a dose of 160 mg once daily over 3 weeks then one week 
off. 
1 cycle = 4 weeks  
 

 
 
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Figure 2: Regorafenib schedule 
 
 
The following products will be used in the study: 
 
Regorafenib, 40 mg tablets 
 
Irinotecan, 180 mg/m² IV (20 mg/ml) 
 
 
 
 
ARM A : REGIRI (Regorafenib + Irinotecan) 
 
Irinotecan 
See manufacturer’s product information (Appendix 8). 
Irinotecan will be prescribed by each center and used in its marketed form. 
 
The irinotecan will be diluted in a 5 % glucose solution or a 0.9% sodium chloride solution. 
The irinotecan will be delivered over 90 minutes as an intravenous infusion. 
 
Regorafenib 
 
For Packaging, List of excipients and Storage: See Investigator’s brochure (Appendix 8). 
 
Regorafenib® will be provided by Sponsor as tablets of 40 mg. 
 
The investigational product(s) label will bear sponsor’s name, address and telephone 
number, the EudraCT number, product name, dosage form and strength, quantity of 
investigational product par container, batch number, expiration date, dosing instructions, 
required storage conditions and required caution statements and/or regulatory statements as 
applicable. 
 

 
 
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Receipt, distribution, return and destruction (if any) of the study drug must be properly 
documented. 
 
To have complete control over the distribution and use of the study drug, the drug 
accountability must be performed on Day 1 of each cycle starting on Cycle 2. Bottles must be 
returned to the Investigator with all unused medication. Throughout the study, all unused 
study medication will be accounted for. The information will be recorded in the drug 
dispensing log. 
 
The study drug 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. Our partner Bayer will send Regorafenib to 
Sodia which deliver Regorafenib to the investigational site’s pharmacy on behalf of sponsor. 
The renewal of the Regorafenib must be requested by fax or e-mail to Sodia by the 
investigator center.  
 
Regorafenib will be orally administered. It must not be chewed or smashed.  
It should be taken once daily in the morning from day 2 to day 8 and day 16 to day 22 of 
cycle, at the same hour as possible, with approximately 200 mL of water. The Regorafenib 
can be administered after a low-fat (<30% fat) meal. 
 
The Investigator or designated study personnel is responsible for dispensing the study drug 
to patients. 
 
 
ARM B: Stivarga® (Regorafenib) 
 
See manufacturer’s product information (Appendix 8). 
Stivarga® will be delivered in retail pharmacies and used in its marketed form. 
 
To have complete control over the use of the study drug, the drug accountability must be 
performed on Day 1 of each cycle starting on Cycle 2. Bottles must be returned to the 
Investigator with all unused medication. Throughout the study, all unused study medication 
will be accounted for Investigator or pharmacist.  
Regorafenib will be orally administered. It must not be chewed or smashed. 

 
 
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It should be taken once daily in the morning during the first 21 days of cycle, at the same 
hour as possible, with approximately 200 mL of water. The Stivarga® (Regorafenib) should 
be administered after a low-fat (<30% fat) breakfast. 
 
6.2 Expected Toxicities  
 
The expected adverse events of Irinotecan, and Regorafenib are described in the respective 
Summaries of Product Characteristics (SmPC). Refer to the latest current version on the 
public drug database website (Appendix 8) for: 
- Stivarga® in the Regorafenib alone arm   
- Irinotecan in the REGIRI arm  
Refer to the latest investigator’s brochure for Regorafenib in the REGIRI arm. 
 
6.3 Dose modification and Dose delay  
 
ARM A: REGIRI 
 
Regorafenib : Dosage changes should be made in 40 mg increments (1 tablet). The 
recommended daily dose of Regorafenib is 160 mg.  
 
Dose reductions of Regorafenib 
1st reduction : 120 mg 
2nd reduction : 80 mg 
 
 
 
 
 
 
 
Table a*  
 
Digestive toxicity : Diarrhea 
A symptomatic treatment of the diarrhea occurring more than 24 hours after the irinotecan 
administration is possible by diosmectite (Smecta®), 1 sachet/8h and loperamide (Imodium®), 
2 capsules/8h until 24 hours after the last stool which is loose or watery. If, in spite of this 
treatment, the diarrhea is not under control in the first 24 hours then fluoroquinolones as 
antibiotics will be orally given during 7 days. 
In case of diarrhea > grade 1, the patient will receive during the next courses of treatment a 
prophylactic treatment by sucralfate (Keal®) 1 sachet / 6 h et Ercefuryl® 200 at a rate of 3 
capsules/24 h. 
 
Table 1: Action and dose modification during the administration of Irinotecan and 
Regorafenib after the first course of treatment in case of diarrhea 

 
 
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Grade 
During the course of treatment 
dose at the next course of 
treatment 
Grade 1 
NA 
Irinotecan at 150 mg/m². 
Regorafenib at 160 mg per day 
+ prophylactic treatment 
Grade 2 
Interrupt irinotecan until diarrhea 
resolves to Grade ≤ 1 
Irinotecan at 120 mg/m². 
Regorafenib at 160 mg per day 
+ prophylactic treatment 
Grade 3 
Interrupt irinotecan until diarrhea 
resolves to Grade ≤ 1 
Irinotecan at 120 mg/m² and 
Regorafenib at 120 mg per day 
Grade 4 
 
Discontinue treatment permanently 
 
Discontinue treatment permanently 
 
 
Table 2: Action and dose modification during the administration of Irinotecan and 
Regorafenib after the second course in case of diarrhea 
 
 
Grade 
During the course of 
treatment 
Dose at the third course of 
treatment 
Grade 1 
NA 
Dose-escalation of irinotecan is 
permitted. Regorafenib at 160 
mg per day 
+ prophylactic treatment 
Grade 2 
Interrupt irinotecan until 
diarrhea resolves to Grade 
≤ 1 
Dose-escalation of irinotecan is 
not permitted. Regorafenib at 
160 mg per day 
+ prophylactic treatment 
Grade 3 
1st occurrence:  Interrupt 
irinotecan until diarrhea 
resolves to Grade ≤ 1 
 
1st occurrence:  Decrease 
Irinotecan to 120 mg/m². 
Regorafenib to 160 mg per day 
 

 
 
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2nd occurrence:  Interrupt 
irinotecan until diarrhea 
resolves to Grade ≤ 1 
2nd occurrence:  Irinotecan 
dose is not changed at 120 
mg/m2 and decrease 
Regorafenib to 120 mg per day 
3rd occurence : Discontinue 
treatment permanently 
 
3rd occurence : Discontinue 
treatment permanently 
 
Grade 4 
Discontinue treatment 
permanently 
 
Discontinue treatment 
permanently 
 
 
 
 
Table 3: Action and dose modification during the administration of Irinotecan and 
Regorafenib after the third course and beyond in case of diarrhea 
 
Grade 
During the course of 
treatment 
Dose at the third course of 
treatment 
Grade 1-2 
Interrupt irinotecan until 
diarrhea resolves to 
Grade ≤ 1 
No dose modification 
+ prophylactic treatment 
Grade 3 
 
 
 
 
 
 
Patients having 
received the 
irinotecan dose of 
180 mg/m2 
 
1st occurrence:  Interrupt 
irinotecan until diarrhea 
resolves to Grade ≤ 1 
 
2nd occurrence:  Interrupt 
irinotecan until diarrhea 
resolves to Grade ≤ 1 
 
1st occurrence:  Decrease 
Irinotecan to 150 mg/m². 
Regorafenib to 160 mg per day 
 
2nd occurrence:  Decrease 
Irinotecan to 120 mg/m². 
Regorafenib to 160 mg per day 
 
3rd occurence : Interrupt 
irinotecan until diarrhea 
resolves to Grade ≤ 1 
 
3rd occurrence:  Irinotecan is not 
changed at 120 mg/m² and 
decrease Regorafenib to 120 mg 
per day 

 
 
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4th occurence : 
Discontinue treatment 
permanently 
 
4th occurrence:  Discontinue 
treatment permanently 
 
Patients having 
received the 
irinotecan dose  of 
150 mg/m2 
1st occurrence:  Interrupt 
irinotecan until diarrhea 
resolves to Grade ≤ 1 
1st occurrence:  Decrease 
Irinotecan to 120 mg/m². 
Regorafenib to 160 mg per day 
2nd occurrence:  Interrupt 
irinotecan until diarrhea 
resolves to Grade ≤ 1 
2nd occurrence:  Irinotecan is not 
changed at 120 mg/m² and 
decrease Regorafenib to 120 mg 
per day 
3rd occurence : 
Discontinue treatment 
permanently 
3rd occurence : Discontinue 
treatment permanently 
Patients having 
received the 
irinotecan dose of 
120 mg/m2 
1st occurrence:  Interrupt 
irinotecan until diarrhea 
resolves to Grade ≤ 1 
1st occurrence:  Irinotecan is not 
changed at 120 mg/m² and 
decrease Regorafenib to 120 mg 
per day 
2nd occurrence:  
Discontinue treatment 
permanently 
2nd occurrence:  Discontinue 
treatment permanently 
Grade 4 
Discontinue treatment 
permanently 
Discontinue treatment 
permanently 
 
 
 
Hematologic toxicity  
 
Table 4: Action and dose modification during the administration of Irinotecan in case 
of hematologic toxicity 
CBC at D15 
Delayed Treatment  
Decrease the dose for the next 
courses of treatment 
ANC < 1500/mm3 
J21* 
No dose modification + G-CSF 

 
 
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and Platelets > 100 000/mm3 
Platelets < 100 000/mm3 
Whatever the number of ANC 
J21* 
Reduce by 1 dose level 
* or until 28th day as needed (maximum) 
Modalities of Reintroduction of treatment : ANC ≥ 1500/mm3 and Platelets ≥ 100 000/mm3 
If the Platelets and/or ANC values are not correct at D28, the patient will discontinue 
permanently the study treatment. 
 
At the time of Nadir  
In the case of a grade 4 neutropenia, whatever the duration or complication i.e by an 
infection or fever > 38°5, the G-CSF will be administered at the next course of treatment. If 
the same toxicity continues with G-CSF then the irinotecan dose will be reduced at the dose 
immediately inferior. If there is a third occurrence of this toxicity, the patient will permanently 
discontinue the study treatment. 
 
 
Table 5: Action and dose modification during the administration of Regorafenib in 
case of hematological toxicity 
 
Hematological toxicity (Modification dose/delay for Regorafenib) 
Grade 
Treatment delay 
Dose modification  
Grade 0-2 
No delay in Regorafenib 
treatment 
No modification dose 
Grade 3 
No delay in Regorafenib 
treatment 
Reduce by 1 dose levelbc 
Grade 4 
Interrupt Regorafenib 
until hematologic 
toxicity resolves to 
Grade ≤ 2a 
Reduce by 1 dose levelbc 
a 
If no recovery within 30 days, the treatment will be permanently discontinued. 
b If more than 2 dose reductions are necessary, the treatment will be permanently 
discontinued. 
c 
Cf table a. 

 
 
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Table 6: Action and dose modification during the administration of Regorafenib in 
case of non-hematologic toxicity 
Non-hematological toxicity (dose modification/delay for Regorafenib)  
(except hand-foot skin reaction, hypertension, liver function test abnormalities and 
diarrhea)a 
Grade 
Treatment delay 
         Dose modification  
Grade 0-2 
No delay in Regorafenib treatment 
         No dose modification 
Grade 3 
 
Interrupt Regorafenib until non 
hematologic toxicity resolves to Grade 
≤ 2b  
 
         Reduce by 1 dose levelcd 
Grade 4 
Discontinue treatment permanently 
Discontinue treatment permanently       
a 
In the absence of nausea/vomiting prophylaxis and diarrhea not treated. 
b If more than 2 dose reductions are necessary, the treatment will be permanently 
discontinued. 
c 
If no recovery within 30 days, the treatment will be permanently discontinued. 
d Cf table a. 
 
Table 7: Delay and dose modification during the administration of Regorafenib in 
case of hand-foot skin reaction  
 
Skin Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 
1: 
Numbness, 
dysesthesia, 
paraesthesia, 
tingling, painless swelling, 
erythema or discomfort of 
the hands or feet which 
does not 
disrupt the patient’s normal 
activities 
Any 
Maintain dose level and institute immediately 
supportive measures for symptomatic relief 

 
 
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Grade 2: Painful erythema 
and swelling of the hands or 
feet 
and/or 
discomfort 
which affects the patient’s 
normal activities 
1st 
occurrence 
Decreasing dose by one dose levela and 
institute immediately supportive measures. 
If no improvement , interrupt therapy for a 
minimum of 7 days, until toxicity resolves to 
Grade 0-1b.  
No 
improvement 
within 7 days 
or 
2nd 
occurrence 
Interrupt Regorafenib until toxicity resolves to 
 Grade 0-1. When resuming treatment, treat at 
reduced dose levelab 
3rd 
occurrence 
Interrupt Regorafenib until toxicity resolves to 
Grade 0-1. When resuming treatment, decrease 
dose by one additional dose levela b c 
4th 
occurrence 
Discontinue treatment permanently 
Grade 3: Moist 
desquamation, 
ulceration, 
blistering 
or 
severe pain of the hands or 
feet, or severe discomfort 
that causes the patient to 
be 
unable to 
work 
or 
perform activities of daily 
living. 
1st 
occurrence 
Institute supportive measures immediately. 
Interrupt therapy for a minimum of 7 days until 
toxicity resolves to Grade 0-1. When resuming 
treatment, decrease dose by one dose levelab 
2nd 
occurrence 
Institute supportive measures immediately. 
Interrupt therapy for a minimum of 7 days until 
toxicity resolves to Grade 0-1. When resuming 
treatment, decrease dose by one dose levela b c 
        3rd 
occurrence 
Discontinue treatment permanently 
a Cf table a 
b If toxicity returns to Grade 0-1 after dose reduction, dose re-escalation is permitted at the 
discretion of the investigator 
c Subjects requiring > 2 dose reductions should discontinue treatment 
 
Suggestions: 
 
Control of calluses 
Before initiating treatment with regorafenib: 
 

 
 
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 
Check condition of hands and feet 
 
 
Suggest a manicure/pedicure, when indicated 
 
 
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 (114) 
 
Topical corticosteroids should be considered for subjects with Grade 2 or 3 hand-foot skin 
reaction (114). Avoid systemic steroids. 
 
 
Cushions 
 
Protect tender areas 
 
 
Use socks/gloves to cover moisturizing creams 

 
 
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 
Wear well-padded footwear 
 
 
Use insole cushions or inserts (e.g., silicon, gel) 
 
 
Foot soaks with tepid water and Epsom salts 
 
 
Table 8: Management of treatment-emergent hypertension 
 
 
NCI-CTCAE V. 5.0 
grade 
Definition  
Antihypertensive 
therapy 
Regorafenib dosing 
1 
Prehypertension 
(systolic BP 120 - 139 
mmHg or diastolic BP 
80 - 89 mmHg) 
None 
Continue regorafenib  
Consider increased 
BP monitoring 
2 
Systolic BP 140 - 159 
mmHg or diastolic BP 
90 - 99 mmHg, 
 
OR 
 
Symptomatic increase 
by 
> 20 mmHg (diastolic) 
if previously within 
normal limits 
Treat with the aim to 
achieve diastolic BP 
≤ 90 mmHg: 
- If BP previously 
within normal limits, 
start 
antihypertensive 
monotherapy. 
- If subject already 
on 
antihypertensive 
medication, titrate up 
the dose. 
Continue regorafenib 
 
If symptomatic, hold 
regorafenib until 
symptoms resolve 
AND diastolic BP ≤ 
90 mmHg.a When 
regorafenib is 
restarted, continue 
at the same dose 
level. 

 
 
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3 
Systolic BP ≥ 160 
mmHg or 
diastolic BP ≥ 100 
mmHg 
 
OR 
  
More than one drug or 
more 
intensive therapy than 
previously used 
indicated 
Treat with the aim to 
achieve diastolic BP 
≤ 90 mmHg: 
- Start 
antihypertensive 
medication 
AND/OR 
- Increase current 
 
Hold regorafenib 
until diastolic BP 
≤ 90 mm Hg, and if 
symptomatic,  until 
symptoms resolve.a 
When regorafenib is 
restarted, continue 
at the same dose 
level. 
If BP is not 
controlled with the 
addition of new or 
more intensive 
therapy, 
 
 
antihypertensive 
medication 
AND/OR 
- Add additional 
antihypertensive 
medications. 
reduce by 1 dose 
level.bd 
If Grade 3 
hypertension recurs 
despite dose 
reduction and 
antihypertensive 
therapy, reduce 
another dose level. 
cd 
4 
Life-threatening 
consequences (e.g, 
malignant 
hypertension, 
transient or 
permanent neurologic 
deficit, hypertensive 
crisis 
 
Discontinue therapy 
 
BP = blood pressure; NCI-CTCAE=National Cancer Institute-common terminology criteria for adverse events 
a Subjects requiring a delay of study treatment  > 4 weeks should go off  regorafenib. 
b If BP remains controlled for at least one full cycle, dose re-escalation is permitted at the investigator’s discretion. 
c Subjects requiring > 2 dose level reductions (< 80 mg reduction) should go off regorafenib therapy. 
d Cf table a. 
 
 
Blood Pressure should be monitored weekly for the first 6 weeks of treatment. The blood 
pressure will be recorded by the treating physician and entered onto the e-CRF. 
 
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. 

 
 
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The dose modification schedule for treatment emergent hypertension during regorafenib 
dosing should be followed (see [Table 11]). Subjects’ 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. 
 
Table 9: Drug-related liver function test abnormalities 
 
 
 
Elevations of 
alanine aminotransférase (ALT) 
and/or aspartate aminotransférase (AST) 
 Occurence 
Management 
≤ 5 times upper limit of normal (ULN) (Grade 
2) 
Any 
occurence 
Continue 
treatment 
by 
Regorafenib. 
Control 
liver 
function every week until ALT 
and AST values return  to < 3 
times 
ULN 
(grade 
1) 
orbaseline .  
> 5 times ULN AND ≤ 20 times ULN (Grade 3)  
1st occurence
Interrupt 
Regorafenib. 
Control 
ALT 
and 
AST 
values every week until 
they return  to < 3 times 
ULN or baseline.  
Resuming treatment: if the 
potential benefit outweighs 
the risk of hepatic toxicity, 
reintroduce 
Regorafenib 
and reduce the dose of 
one tablet (40 mg) and 
control liver function every 
week for at least 4 weeks.  
2nd 
Discontinue regorafenib 

 
 
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occurence 
permanently 
> 20 times ULN (Grade 4)  
 
Any 
occurence 
Discontinue regorafenib 
permanently 
> 3 times ULN (Grade 2 or higher ) with 
concomitant elevation of bilirubin > 2 times 
ULN  
 
Any 
occurence 
Discontinue regorafenib 
permanently 
Control liver function every 
week 
until 
resolution 
or 
return to baseline  
 
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 
 
Other toxicities 
The other toxicities will have to manage symptomatically, if possible. For any toxicity grade  
2 at D15 except alopecia and anemia, the irinotecan will be delayed up to two weeks and the 
toxicity will have to be grade  1 to perform the course.  
 
 
 
 
ARM B: STIVARGA® (REGORAFENIB) 
 
Dosage changes should be made in 40 mg increments (1 tablet). The recommended daily 
dose of Regorafenib  is 160 mg.  
 
Dose reductions of Stivarga ® 
1st reduction : 120 mg 
2nd reduction : 80 mg 
 
 
 
 
 
 
 
                                                                            Table b 
 
Table 10: Dose modification/Delay for toxicities related to study drug (except hand-
foot Skin reaction and hypertension)a 
 
NCI-CTC V5.0  
Dose 
Interruption 
Dose Modification 
Dose for Subsequent Cycles 
Grade 0-2 
Treat on time 
No change 
No change 
Grade 3 
Delay until < 
Reduce 1 dose levelc 
If toxicity remains < Grade 2, 

 
 
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Grade 2b 
dose re-escalation can be 
considered at the discretion 
of the treating investigator.  
If dose is re-escalated and 
toxicity (Grade 3) recurs, 
institute 
permanent 
dose 
reduction. 
Grade 4 
Delay until < 
Grade 2b 
Reduce by 1 dose levelc. 
Permanent discontinuation 
can 
be 
considered 
at 
treating 
investigator’s 
discretion. 
 
a Excludes alopecia, non-refractory nausea/vomiting, non-refractory hypersensitivity and 
asymptomatic laboratory abnormalities. 
b If no recovery after a 4 week delay, treatment will be permanently discontinued. 
c Cf table b. 
 
 
 
 
Table 11: Dose modifications for hand-foot skin reaction 
 
Skin Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 
1: 
Numbness, 
dysesthesia, 
paraesthesia, 
tingling, painless swelling, 
erythema or discomfort of 
the hands or feet which 
does not 
disrupt the patient’s normal 
activities 
Any 
Maintain dose level and institute immediately 
supportive measures for symptomatic relief 
Grade 2: Painful erythema 
and 
swelling of the hands or feet 
and/or 
discomfort 
which 
affects the patient’s 
1st 
occurrence 
Decreasing dose by one dose level and institute 
immediately supportive measures. 
If no improvement , interrupt therapy for a 
minimum of 7 days, until toxicity resolves to 
Grade 0-1b 

 
 
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normal activities 
No 
improvement 
within 7 days 
or 
2nd 
occurrence 
Interrupt Regorafenib until toxicity resolves to 
Grade 0-1. When resuming treatment, treat at 
reduced dose levelab 
 
3rd 
occurrence 
Interrupt Regorafenib until toxicity resolves to 
Grade 0-1. When resuming treatment, decrease 
dose by one additional dose levela b c 
4th 
occurrence 
Discontinue treatment permanently 
Grade 
3: 
Moist 
desquamation, 
ulceration, 
blistering 
or 
severe pain of the hands or 
feet, or severe discomfort 
that causes the patient to 
be 
unable to 
work 
or 
perform activities of daily 
living. 
1st 
occurrence 
Institute supportive measures immediately. 
Interrupt therapy for a minimum of 7 days until 
toxicity resolves to Grade 0-1. When resuming 
treatment, decrease dose by one dose levelab 
2nd 
occurrence 
Institute supportive measures immediately. 
Interrupt therapy for a minimum of 7 days until 
toxicity resolves to Grade 0-1. When resuming 
treatment, decrease dose by one additional 
dose levela b c 
3rd 
occurrence 
Discontinue treatment permanently 
a Cf table b 
b If toxicity returns to Grade 0-1 after dose reduction, dose re-escalation is permitted at the 
discretion of the investigator 
c Subjects requiring > 2 dose reductions should discontinue treatment 
If no recovery after a 4 week delay, treatment will be discontinued permanently. 
 
For subjects who require a dose reduction for Grade 2 or 3 rash or hand-foot skin reaction 
(HFSR), the dose of study drug may be increased to the starting dose after one full cycle of 
therapy has been Administered with the reduced dose without the appearance of rash or 
HFSR > Grade 1. 
 
The following measurements should be considered for prevention and treatment of hand-foot 
skin reaction: 
 

 
 
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Termination of Stivarga® : 
 
-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 
 
Suggestions: 
 
Control of calluses 
Before initiating treatment with regorafenib: 
 
 
Check condition of hands and feet 
 
 
Suggest a manicure/pedicure, when indicated 
 
 
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 
 
 
Udderly Smooth 
 
 
Gold Bond 
 
 
 
Norwegian Formula 
 
 
Eucerin 
 
 
Keratolytic Creams: Use sparingly and only to affected (hyperkeratotic) areas 
 
 
Urea-based creams 
 
 
Salicylic acid 6% 
 

 
 
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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 (114) 
 
Topical corticosteroids like clobetasol 0.05% should be considered for subjects with Grade 2 
or 3 hand-foot skin reaction (114). 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) 
 
 
Foot soaks with tepid water and Epsom salts 
 
 
Table 12: Management of treatment-emergent hypertension 
 
NCI-
CTCAE 
V5.0 grade 
Definition  
Antihypertensive therapy 
Regorafenib 
dosing 
1 
Prehypertension (systolic 
BP 120 - 139 mmHg or 
diastolic BP 80 - 89 mmHg) 
None 
Continue 
regorafenib.  
Consider 
increased BP 
monitoring. 
2 
Systolic BP 140 - 159 
mmHg or diastolic BP 90 - 
99 mmHg, 
 
OR 
 
Symptomatic increase by 
> 20 mmHg (diastolic) if 
previously within normal 
limits 
Treat with the aim to 
achieve diastolic BP ≤ 90 
mmHg: 
- If BP previously within 
normal limits, start 
antihypertensive 
monotherapy. 
- If subject already on 
antihypertensive 
medication, 
titrate up the dose. 
Continue 
regorafenib. 
 
If symptomatic, 
hold regorafenib 
until symptoms 
resolve AND 
diastolic BP ≤ 90 
mmHg.a When 
regorafenib is 
restarted, 
continue at the 
same dose level. 

 
 
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3 
Systolic BP ≥ 160 mmHg or 
diastolic BP ≥ 100 mmHg 
 
OR 
  
More than one drug or more 
intensive therapy than 
previously used indicated 
Treat with the aim to 
achieve diastolic BP ≤ 90 
mmHg: 
- Start antihypertensive 
medication 
AND/OR 
- Increase current 
antihypertensive 
medication 
AND/OR 
- Add additional 
Antihypertensive 
medications.  
Hold regorafenib 
until diastolic BP 
≤ 90 mm Hg, and 
if symptomatic,  
until symptoms 
resolve.a 
When regorafenib 
is restarted, 
continue at the 
same dose level. 
If BP is not 
controlled with 
the addition of 
new or more 
intensive therapy, 
reduce by 1 dose 
level.be 
If Grade 3 
hypertension 
recurs despite 
dose reduction 
and 
antihypertensive 
therapy, reduce 
another dose 
level. ce 
 
4 
Life-threatening 
consequences (e.g, 
malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis 
 
Discontinue 
therapy 
 
BP = blood pressure; NCI-CTCAE=National Cancer Institute-common terminology criteria for adverse events 
a Subjects requiring a delay of study treatment  > 4 weeks should go off  regorafenib. 
b If BP remains controlled for at least one full cycle, dose re-escalation is permitted at the investigator’s discretion. 
c Subjects requiring > 2 dose level reductions (< 80 mg reduction) should go off regorafenib therapy. 
d Cf table a. 
 
 
Blood Pressure should be monitored weekly for the first 6 weeks of treatment. The blood 
pressure will be recorded by the treating physician and entered onto the e-CRF. 
 
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. 

 
 
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The dose modification schedule for treatment emergent hypertension during regorafenib 
dosing should be followed (see [Table 12]). Subjects’ 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. 
 
 
Table 13 : Drug-related liver dysfunction 
 
Elevations of 
alanine aminotransférase (ALT) 
and/or aspartate aminotransférase (AST) 
 Occurence 
Management 
≤ 5 times upper limit of normal (ULN) (Grade 
2) 
Any 
occurence 
Continue 
treatment 
by 
Regorafenib. 
Control 
liver 
function every week until ALT 
and AST values resolve to < 3 
times ULN (grade 1) or to 
their initial value.  
> 5 times ULN AND ≤ 20 times ULN (Grade 3)  
1st occurence
Interrupt 
Regorafenib. 
Control 
ALT 
and 
AST 
values every week until 
they resolve to < 3 times 
ULN or their initial value.  
Resuming treatment: if the 
benefice is superior to the 
risk of hepatic toxicity, 
reintroduce 
Regorafenib 
and reduce the dose of 
one tablet (40 mg) and 
control liver function every 
week for at least 4 weeks.  
2nd 
occurence 
Discontinue regorafenib 
permanently 

 
 
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> 20 times ULN (Grade 4)  
 
Any 
occurence 
Discontinue regorafenib 
permanently 
> 3 times ULN (Grade 2 or beyond) with 
concomitant elevation of bilirubin > 2 times 
ULN  
 
Any 
occurence 
Discontinue regorafenib 
permanently 
 
Interrupt Regorafenib until 
toxicity resolves to Grade 0-1. 
Control liver function every 
week until ALT and AST 
values resolve to < 3 times 
ULN (grade 1) or to their 
initial value.  
 
6.4 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.  
 
6.4.1 Other treatments/procedures 
 
Permitted concomitant medications: 
 
 
Atropine 
 
 
Anti-emetics 
 
 
Alpha hydroxyl acids, keratolytic, non urea creams 
 
 
Topical corticoids 
 
 
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.  

 
 
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 
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 permitted. 
 
 
 
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.  
 
 
Clinical data indicate that regorafenib has no effect on digoxin pharmacokinetics, 
therefore can be given concomitantly with p-glycoprotein substrates, such as digoxin, 
without a clinically meaningful drug interaction 
6.5 Non permitted treatment 
 
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 

 
 
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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 UGT1A1 and UGT1A9 whereas M-5 only inhibits UGT1A1 at 
concentrations 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.  
 

 
 
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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 
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. 
 
-Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, 
immunotherapy, hormonal therapy and experimental or approved therapies during this trial or 
within 30 days before starting to receive study medication. 
 
-Bone marrow transplant or stem cell rescue. 
 
-Prior radiation and concomitant palliative radiation therapy is allowed if the target        
lesion(s) are not included within the radiation field and no more than 10% of the bone marrow 
is irradiated. 
 
-Use of biologic response modifiers, such as granulocyte colony stimulating factor (GCSF), 
within 3 weeks of study entry.  
 
-Herbal medicine and grapefruit juice 
 
-Yellow fever vaccine: Risk of fatal generalized vaccine disease 
 
-Live attenuated vaccines: Risk of generalized vaccine disease, possibly fatal. Concomitant 
administration during treatment with irinotecan and for 3 months after discontinuation of 

 
 
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chemotherapy is contraindicated. Killed or inactivated vaccines can be administered, 
however the response to these vaccines can be decreased. 
 
-Immunosuppressive agents (eg ciclosporin, tacrolimus): Excessive immunosuppression with 
risk of lymphoproliferation. 
 
-Neuromuscular blocking agents: the interaction between irinotecan and neuromuscular 
blocking agents cannot be ruled out. Due to the anticholinesterase activity of irinotecan, 
drugs with anticholinesterase activity can prolong the neuromuscular blocking effects of 
suxamethonium and the neuromuscular blockade of non-depolarizing agents can be 
antagonized. 
 
-Antivitamin K such as warfarin, phencoumarone etc. 
7. Ancillary Studies  
7.1.            IMMUNOHISTOCHEMISTRY STUDY 
The expression of cyclin D1 protein will be sought by immunohistochemistry on tissue 
sections of paraffin-embedded specimens. 
We will investigate any association between protein expression and response to treatment. 
 
 
In addition, depending on the progress of knowledge at the time of the study is completed, 
other biomarkers predictive of response to treatment can be explored by IHC on the same 
tumor blocks. 
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 
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 
 
 

 
 
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Paraffin-embedded human solid tissue blocks will be returned to the home institution upon 
completion of ancillary study. 
 
8. Discontinuation criteria/Subject withdrawal/end of study 
8.1. 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 reported 
as a serious adverse event. 
 
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 

 
 
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documented in the patient’s records (e.g., times and dates of attempted telephone 
contact, receipt for sending a registered letter). 
8.2. 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. 
8.3. END OF STUDY 
The end of the trial corresponds to the last follow-up of the last patient. 
 
9. Statistical considerations 
9.1 Sample size  
 
The main objective is the comparison of overall survival in the regorafenib and REGIRI 
combination (Regorafenib + Irinotecan) arms in mCRC patients harboring Cyclin D1 A/A 
genotype. 
The aim is to increase the median overall survival from an estimated baseline of 7 to 15 
months corresponding to 1-year OS of 30% to 57%, respectively with a HR=0.47. A total of 
55 events are required to detect this difference if it is true with 80% power and using a 2–
sided log-rank test at the 5% level of significance.  
A total number of required patients is 68 without drop-out. 
Considering 15% additional patients lost to follow-up on estimated patients number, the 
sample size is 78 patients (2*39) to observe the required number of events. 
Because the A/A CCND1 genotype is present in 25% of patients with metastatic colorectal 
cancer, 312 patients will need to be screened. 
No interim analysis was planned. 
9.2 Study populations 
 
Different population of patients may be defined for the analysis: 

 
 
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 
Per-Protocol (PP) population = all patients in the ITT population without major 
protocol deviations that impact assessment of efficacy.  
The PP Analysis will be used to perform sensitivity analysis for the primary endpoint. 
 
Intent To Treat (ITT) population = all randomized patients analyzed in their 
randomized arm. 
 
Eligible population: all patients without major inclusion criteria (CI n°1, n°3, n°4, n°5, 
n°8 ) or non-inclusion violation (n°2, n°3, n°7, n°8). 
 
Safety population = all treated patients who received at least one dose of treatment 
 
Modified Intent To Treat (ITT) population = eligible population in their randomized 
arm. 
 
 
9.3 Statistical methods 
 
A Statistical Analysis Plan (SAP) will be written before the database is locked. Populations 
are defined in section 9.2. 
All statistical analyses will be performed on ITT population. 
Safety analysis will be performed on safety population 
Sensitivity analysis will be performed on Modified Intent To Treat (ITT) population for primary 
endpoint. 
Descriptive analyses (in each arm) will be performed using median and range for continuous 
parameters, frequency and percentage for categorical variables. 
Baseline characteristics of randomized patients in each arm will be compared by Kruskal-
Wallis tests or Wilcoxon for continuous variables, or chi 2 or Fisher exact test for categorical 
variables 
The primary efficacy endpoint of OS will be compared using a two-sided stratified log-rank 
test. The analysis will be stratified by RAS. Kaplan-Meier (KM) estimates for OS and KM 
survival curves will also be presented for each group. The KM estimates at time points such 
as 6 months and 12 months, together with corresponding 95% confidence intervals as well 
as the differences of these estimates will be calculated between the REGIRI and 
Regorafenib arms. 
With regard to the secondary efficacy endpoint PFS, the 2 treatment groups will be 
compared using a log-rank test stratified by RAS. Hazard ratios and 95% CI will be provided. 
KM estimates and KM curves will also be presented for each treatment arm. The KM 
estimates at time points such as 3 months and 6 months, together with corresponding 95% 

 
 
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confidence intervals as well as the differences of these estimates between the REGIRI arm 
and the Regorafenib arm will also be calculated. 
Objective response rate as well as DCR will be compared between treatment groups using 
the Cochran-Mantel-Haenszel test. Estimates and 95% confidence intervals will be computed 
for each treatment arm. The differences in ORR and DCR between the REGIRI and 
regorafenib arms and the corresponding 95% confidence intervals will also be calculated. 
Summary statistics will be displayed for all best response categories: CR, PR and SD. 
Descriptive summary tables will be presented for all safety parameters by each treatment 
group. All AEs, as well as drug-related AEs and SAEs will be summarized by NCI-CTCAE 
version 5 (appendix 9) categories and worst grade. 
PRO data as measured by the EORTC QLQ-C30 (appendix 2) will be analyzed to assess 
differences in health-related quality of life (HRQOL) values between treatment arms.  
 
HRQOL scores were described for each assessment and compared either between 
treatment arms (rank sum test). The missing data pattern was studied by the comparison of 
the baseline characteristics between patients who either completed baseline HRQOL 
questionnaires or not. The compliance of the patients was also described using fill rate at 
each visit and for each questionnaire.  
 
Longitudinal analyses were performed using two approaches:  
(1) A LMM analysed the evolution of scores through time and combined fixed effects [Cnaan 
A, Laird NM, Slasor P. Using the general linear mixed model to analyse unbalanced repeated 
measures and longitudinal data. Stat Med 1997;16:2349-80.+ Fairclough DL. Design and 
analysis of quality of life studies in clinical trials. 2002.] for study group, time factors, 
treatment-by-time interaction effects and random effects allowing specific correlations 
between observations for a particular patient.  This mode l assumed  no  difference between  
the treatment arms at baseline.  
(2) A time to event approach considered the definitive deterioration of a HRQOL score as an 
event. Osoba et al. [Osoba D, Rodrigues G, Myles J, Zee B, Pater J.  
 
Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 
1998;16:139-44.] showed that a mean change of 5-10 pts, 10-20 pts and >20 pts in a 
QLQC30 score corresponds to a “small”, “moderate” and “large” change in HRQOL. This 
definition was applied to indicate the clinical relevance of any differences. TUDD was defined 
as the time from randomisation to the first score deterioration with a 10-point minimal 

 
 
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clinically important difference (MCID) as compared with the baseline score, with no further 
improvement superior to 10 points as compared with baseline or with no available HRQoL 
score [Anota A, Hamidou Z, Paget-Bailly S, Chibaudel B, Bascoul-Mollevi C, Auquier P, et al. 
Time to health-related quality of life score deterioration as a modality of longitudinal analysis 
for health-related quality of life studies in oncology: do we need RECIST for quality of life to 
achieve standardization? Qual Life Res 2015;24:5-18.  + Bonnetain F, Dahan L, Maillard E, 
Ychou M, Mitry E, Hammel P, et al. Time until definitive quality of life score deterioration as a 
means of longitudinal analysis for treatment trials in patients with metastatic pancreatic 
adenocarcinoma. Eur J Cancer e Oxf Engl 1990 2010;46:2753-62. + Hamidou Z, Dabakuyo 
TS, Mercier M, Fraisse J, Causeret S, Tixier H, et al. Time to deterioration in quality of life 
score as a modality of longitudinal analysis in patients with breast cancer. Oncologist 
2011;16:1458-68.].  
Sensitivity analyses were also performed. A survival analysis was also performed to 
determine baseline prognostic factors for PFS and OS. A Cox proportional hazard model was 
performed following the method published in EORTC meta-analyses [Quinten C, Martinelli F, 
Coens C, Sprangers MAG, Ringash J,Gotay C, et al. A global analysis of multitrial data 
investigating quality of life and symptoms as prognostic factors for survival in different tumor 
sites. Cancer 2014;120:302-11., + Quinten C, Coens C, Mauer M, Comte S, Sprangers M, 
Cleeland C, et al. Baseline quality of life as a prognostic indicator of survival: a meta-analysis 
of individual patient data from EORTC clinical trials. Lancet Oncol 2009;10:865-71.]. Baseline 
QLQ-C30 scores were entered as continuous variables. Hazard ratios were calculated for 
every 10-point difference to take into account a 10-point MCID [Osoba D, Rodrigues G, 
Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-of-
life scores. J Clin Oncol 1998;16:139-44. +  Jaeschke R, Singer J, Guyatt GH. Measurement 
of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 
1989;10:407-15.].  
All statistical analyses will be performed with the Stata v13 software. 
 
10. 
Vigilance and safety control  
10.1 Adverse Events 
10.1.1 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 

 
 
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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. 
 
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. 
10.1.2   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 

 
 
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until stabilization of the event’s sequelae (the nature of the sequelae should be 
documented) ; 
 
The causality between the event and the investigational product ; 
 
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. 
 
10.1.3 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. 
 
10.2 Serious Adverse Events, New Event and Urgent Safety Measure (USM) 
10.2.1 Definition 
 

 
 
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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  
 
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 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. 
 

 
 
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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: 
Any new data leading to a reassessment of the benefits / risks balance of the research or 
product of the research, to changes in the use of the product or in the conduct on documents 
related to the research, or to discontinuation, arrest or modification of the research protocol 
or that of similar research. 
For trials assessing first administration or use of a product in persons with no specific 
disease (healthy volunteer): any serious adverse event. 
 
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). 
       10.2.2 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 for Regorafenib alone arm and for Irinotecan  
- The latest version of the investigator’s brochure (IB) for Regorafenib in the 
REGIRI arm. 
 
10.2.3 Pregnancy 
 

 
 
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According to the regulatory recommendations with respect to potential genotoxicity and 
teratogenicity (CFTG 21/09/2020, version 1.1 ) the durations of contraceptives for women of 
childbearing potential (WOCBP) and men to ensure effective contraception during treatment 
with regorafenib  are respectively 7 months and 4 months in men sexually active with women 
of childbearing potentiel after last dose of regorafenib. 
 
For Irinotecan, the durations of contraceptives for women of childbearing potential (WOCBP) 
and men are respectively 6 months and 3 months in men sexually active with women . 
 
 
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). 
 
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. 
 
10.2.4 SAE, New Event, Urgent Safety Measure, and Pregnancy Notification 
Procedure 
 
           10.2.4.1 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 the ICM.  
Clinical Research Vigilance Unit 
ICM – Institut régional de Cancérologie de Montpellier 

 
 
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208, rue des Apothicaires, 34298 Montpellier 
Tel: +33 4 67 61 45 68 – Fax: +33 4 67 61 31 04 
Mail:  
Notification-EIG-DRCI@icm.unicancer.fr 
For other safety information: 
 Pharmacovigilance-icm105@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.  
 
After the initial notification, a follow-up report should be completed and sent 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 Vigilance 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.  
         
             10.2.4.2 New Event / Urgent Safety Measure / Notification Procedure 
 
Any New Event, and 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 

 
 
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Phone: +33 4 67 61 45 68 
 
             10.2.4.3 Pregnancy Notification Procedure 
 
Pregnancies and suspected pregnancies occurring during the study period (from the 
signature of the informed consent form until up to 2 months after the withdrawal of 
Regorafenib, and 3 months after the withdrawal of Irinotecan for female patients and 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 
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. 
 
              10.2.4.4 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 
 
 

 
 
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     10.2.5 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 safety event 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. 
  
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  
Other SUSARs 
Within 15 days after the 
sponsor has taken notice of 
this event 
Within maximum  8 days 
after the sponsor has taken 
notice  
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 delay) 
Request for substantial 
modification Within 
maximum  15 days after the 
sponsor has taken notice 

 
 
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10.3 Independent Safety Committee (ISC)   
   
An Independent Safety Committee (Appendix 12) is organized as an Independent 
Data Monitoring Committee, by some independent experts in clinical research and/or the 
study indication. 
During a trial the ISC can 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.);  
 
Data relevant to proceeding to the next stage of the study, if applicable.  
The scheduled time point will be after the enrolment of the first twenty patients (arm A) and 
will be about the safety of the first two months of treatment.  
 
The Sponsor could ask the ISC for an ad hoc advice throughout the study concerning safety 
and inclusions. 
 
The ISC would be constituted by 3 persons: two oncologists and a methodologist not 
participating in the trial.  
 
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.  
 
11. Quality assurance and control 
11.1. 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.  

 
 
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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 
Data center UNICANCER 
From Monday to Friday 9am-5pm 
Email: support.ecrfbaseicm.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 
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. 
 
11.2 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: 
 

 
 
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 
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. 
 
In order to ensure the optimal research quality control, the investigator commits to provide 
the monitor with direct access to all the patients' files.  
 
11.3 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. 

 
 
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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. 
 
12. Administrative, ethical and regulatory aspects  
12.1. 
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, 
 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, 

 
 
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 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. 
12.2. 
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. 
 
12.3. 
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, 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. They also have a duty to oppose the transmission of these 

 
 
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data. These rights are exercised with their investigator who will inform the coordinating 
center of research as soon as possible. 
European Regulation 2016/619 on the protection of individuals with regard to the 
processing of personal data and on the free movement of such data, known as the "DGPS" 
(General Regulation on Data Protection) will be applicable on May 25, 2018. 
 
12.4. 
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. 
 
12.5. 
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. 
 
12.6. 
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 
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. 
 

 
 
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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. 
 
12.7. 
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. 
 
13. 
Financing and Insurance  
13.1. 
Financing of Research 
We have a partnership contract with Bayer HealthCare that will finance this study. 
13.2. 
Insurance 
Insurance has been subscribed by the sponsor (ICM) to RELYENS (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, in order to cover the obligations placed on them under Article L 1121-10 of the French 
Public Health Code. 

 
 
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14. Publication policy and communication  
14.1. 
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 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; 
-partners and funders in accordance with the partnership agreements signed with the ICM 
promoter; 

 
 
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The CRB - ICM should be mentioned either in the "Materials and Methods" section or in the 
acknowledgements with N°BB-033-00059. 
14.2. 
Data sharing statements 
14.3. 
 
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 and where? 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. 
 
15. References  
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2. Samalin, E. et al. Sorafenib (Soraf) and irinotecan (Iri) combination for pretreated RAS-
mutated metastatic colorectal cancer (mCRC) patients: a multicenter randomized phase II trial 
(NEXIRI 2-PRODIGE 27). 2016 ASCO Annual meeting, in press, abstract 3545, poster 242. 
3. Alt, J. R., Cleveland, J. L., Hannink, M. & Diehl, J. A. Phosphorylation-dependent regulation of 
cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev. 14, 
3102–3114 (2000). 
4. Lu, F., Gladden, A. B. & Diehl, J. A. An alternatively spliced cyclin D1 isoform, cyclin D1b, is a 
nuclear oncogene. Cancer Res. 63, 7056–7061 (2003). 
5. Grothey, A. et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer 
(CORRECT): an international, multicenter, randomized, placebo-controlled, phase 3 trial. 
Lancet Lond. Engl. 381, 303–312 (2013). 
 

 
 
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6. Schultheis B, Folprecht G, Kuhlmann J, et al. Regorafenib in combination with FOLFOX or 
FOLFIRI as first- or second line treatment of colorectal cancer: results of a multicenter phase 
Ib study. Ann Oncol 2013; 24(6): 1560-7. 
7. O’Neil B, O’Reilly S, Kasbari S, et al. A multi-center, randomized, double-blind phase II trial of 
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