Clinical trial NCT02788006
Conditions: Colorectal Adenocarcinoma
Sponsor: Federation Francophone de Cancerologie Digestive
Start date: 2016-01-01; Completion date: 2017-09-01
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Multicenter prospective phase II study evaluating regorafenib in older patients with metastatic colorectal cancer

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Regorafenib 160 mg
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Protocol FFCD 1404 - REGOLD version 1.1 of 17.08.. 2015 for 
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Page 1 on 28 
 
 
 FFCD 1404 - REGOLD 
 
PHASE II STUDY EVALUATING THE EFFICACY AND TOLERABILITY OF 
REGORAFENIB IN PATIENTS 70 YEARS AND OLDER WITH METASTATIC 
COLORECTAL ADENOCARCINOMA 
 
EudraCT number: 2015-002086-29 
 
COORDINATOR 
Pr Thomas APARICIO  
Department of Gastroenterology and Digestive Oncology 
Avicenne Hospital 
125 rue de Stalingrad - 93009 BOBIGNY cedex 
Tel : 01 48 95 54 31 Fax : 01 48 95 54 39  
email: thomas.aparicio@avc.aphp.fr 
 
CO-SCIENTIFIC MANAGER  
Dr Gaëtan DES GUETZ  
Medical Oncology Department  
Avicenne Hospital 
125 rue de Stalingrad - 93009 BOBIGNY cedex 
Tel : 01 48 95 50 31 Fax : 01 48 95 50 35  
email: gaetan.des-guetz@avc.aphp.fr  
 
PROTOCOL DRAFTING COMMITTEE  
T. APARICIO, G. DES GUETZ, M HEBBAR, T LANDRE, K LE MALICOT, M SCHNEIDER , F 
PAMOUKDJIAN, J TAIEB, D TOUGERON 
 
PROMOTER:  
Fédération Francophone de Cancérologie Digestive (FFCD) - 7 Bd Jeanne d'Arc - 
BP87900 - 21079 Dijon Cedex 
 
CENTER FOR RANDOMIZATION-MANAGEMENT-ANALYSIS (CRGA)  
 
Fédération Francophone de Cancérologie Digestive (FFCD) : Faculté de Médecine, 7 
Boulevard Jeanne d'Arc, BP 87900, 21079 Dijon Cedex, France  
 
Administrative Director : 
 
Cécile GIRAULT 
 
 
 
  
 
 
 
Tel: + 33 (0)3 80 66 80 13 - Fax: + 33 (0)3 80 38 18 41 
 
 
 
E-mail : cgirault@u-bourgogne.fr  
 
Statistician:   
 
Carole MONTERYMARD 
 
 
 
 
 
 
Tel: + 33 (0)3 80 39 34 84 - Fax: + 33 (0)3 80 38 18 41 
 
 
 
E-mail: carole.monterymard@u-bourgogne.fr 
 
Project Manager:  
 
 
Martina SCHNEIDER 
 
 
 
 
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Tel: + 33 (0)3 80 39 34 83 - Fax: + 33 (0)3 80 38 18 41 
 
 
 
E-mail : martina.schneider@u-bourgogne.fr 


 
 
 
 
 
 
 
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SUMMARY 
 
SUMMARY .................................................................................................................................................... 3 
LIST OF ABBREVIATIONS ........................................................................................................................... 4 
CONTACTS ......................................................................................................... Erreur ! Signet non défini. 
PROTOCOL AGREEMENT AND BPC ............................................................... Erreur ! Signet non défini. 
Send the original to the CRGA of the FFCD - 7 bd Jeanne d'Arc - BP 87900 - 21079 Dijon Cedex . Erreur ! 
Signet non défini. 
SYNOPSIS .......................................................................................................... Erreur ! Signet non défini. 
EXAMINATION AND FOLLOW-UP SCHEDULE .......................................................................................... 6 
1. BACKGROUND INFORMATION AND RATIONALE FOR THE STUDY .................................................. 7 
1.1 General information ................................................................................................................................. 7 
2. OBJECTIVES OF THE STUDY ................................................................................................................. 8 
2.1 Main objective .......................................................................................................................................... 8 
2.2 Secondary Objectives.............................................................................................................................. 8 
3. PATIENT SELECTION .............................................................................................................................. 8 
4. INCLUSION ASSESSMENT ................................................................................................................... 10 
5. INCLUSION ............................................................................................................................................. 10 
6. DIAGRAM OF THE STUDY .................................................................................................................... 10 
7. TREATMENT ........................................................................................................................................... 11 
8. PATIENT MONITORING ......................................................................................................................... 13 
9. CENTRALIZED REVIEW AND ANCILLARY STUDY ............................................................................. 14 
10. MANAGEMENT OF SERIOUS ADVERSE EVENTS (SIA) .................................................................. 14 
10.1 Security assessment parameters ........................................................................................................ 14 
10.2 Definitions ............................................................................................................................................ 14 
11. STATISTICAL ANALYSIS ..................................................................................................................... 17 
11.1 Judging Criteria ................................................................................................................................... 17 
11.2 Exploratory assessment of geriatric parameters ................................................................................. 18 
12. ANCILLARY STUDY ............................................................................................................................. 23 
13. STUDY COMMITTEES ......................................................................................................................... 24 
13.1 Board of Directors ........................................................................................................................ 24 
13.2 Independent Data Review Committee ......................................................................................... 24 
14. BIBLIOGRAPHIC REFERENCES ......................................................................................................... 24 
15. ADMINISTRATIVE CONSIDERATIONS ............................................................................................... 26 
16. PUBLICATION RULES.......................................................................................................................... 27 
17. APPENDICES ....................................................................................................................................... 27 
APPENDIX 1: Clinical Study Information Sheet and Informed Consent Form .... Erreur ! Signet non défini. 
APPENDIX 2: "Patient" self-questionnaire .......................................................... Erreur ! Signet non défini. 
APPENDIX 3: "Team" Questionnaire .................................................................. Erreur ! Signet non défini. 
APPENDIX 4: RECIST 1.1 Criteria ..................................................................... Erreur ! Signet non défini. 
APPENDIX 5: ECOG ........................................................................................... Erreur ! Signet non défini. 
APPENDIX 6: Measurement of creatinine clearance using the Cockcroft and Gault formula : ......... Erreur ! 
Signet non défini. 
APPENDIX 7: NCI-CTC Toxicity Criteria Version 4.0 ......................................... Erreur ! Signet non défini. 
APPENDIX 9: SAE form ...................................................................................... Erreur ! Signet non défini. 
APPENDIX 10: FFCD Publication Rules ............................................................. Erreur ! Signet non défini. 
SCHEDULE 11: Certificate of Insurance ............................................................. Erreur ! Signet non défini. 
APPENDIX 12: Favourable opinion of the PPC .................................................. Erreur ! Signet non défini. 
APPENDIX 13: Authorization from the ANSM ..................................................... Erreur ! Signet non défini. 


 
 
 
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LIST OF ABBREVIATIONS 
 
ACE 
Carcinoembryonic antigen 
DNA 
Deoxyribonucleic acid 
ALAT  
Alanine aminotransferase (or SGPT: serum glutamic pyruvic transaminase) 
ASAT 
Aspartate-aminotransferase (or SGOT: serum glutamic oxaloacetic transaminase) 
BPC 
Good Clinical Practice 
JRC 
Colorectal carcinoma 
CCRm 
Metastatic colorectal carcinoma 
CIRD 
Independent Data Review Committee 
CO 
Observation booklet 
ECG 
Electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
EI 
Adverse event 
ISG 
Serious adverse event 
FFCD 
French-speaking Federation of Digestive Oncology 
HR 
Hazard ratio 
IC 
Confidence interval 
MRI 
Magnetic resonance imaging 
ITT 
Intent To Treat   
NCI-CTCAE 
National Cancer Institute - Common Toxicity Criteria for Adverse Events 
p.o.  
Per os 
PAL 
Alkaline phosphatases 
QDV 
Quality of life 
RECIST 
Criteria for assessing tumor response in solid tumors 
SG 
Overall survival 
CT 
PA 
VKAS 
NFS 
GGT 
ARC 
INR 
CPR 
CT scan 
Blood Pressure 
Anti-vitamin K 
Blood Count 
Gamma GT 
Clinical Research Associate 
International Normalized Ratio 
Summary of product features  
 
 


 
 
 
 
 
 
 
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EXAMINATION AND FOLLOW-UP SCHEDULE 
 
 
Before inclusion 
During treatment (until progression) 
After treatment 
J -21 
J -14 
J -7 
C1 : D1, D7 
and D14  
 
C2 : D1, D7 
and D14 
 
D1 of each 
cycle (every 4 
weeks) 
D14 of each 
cycle 
Every 8 weeks 
after the start of 
treatment 
End of 
treatment visit 
Every 8 weeks 
Informed consent 
X 
 
 
 
 
 
 
 
 
Clinical examination 
 
X 
 
X 
X 
 
X 
X 
X 
Weight, height, BP 
 
X 
 
X 
X 
 
X 
X 
 
ECOG 
 
X 
 
 
X 
 
X 
X 
X 
Geriatric questionnaires, 
quality of life 
 
X 
 
 
X 
 
X 
 
 
Biological check-up 11 
 
 
X 
 
X 
 
X 
 
 
Biological check-up 21 
 
 
 
 
 
X 
 
X 
 
Urine dipstick ± 24h 
proteinuria 
 
X 
 
 
X 
 
X 
 
 
ECG  
 
X 
 
 
X2 
 
 
 
 
Thoracic and abdominal-
pelvic CT 
X 
 
 
 
 
 
X 
 
 
ACE 
 
 
X 
 
X 
 
X 
 
 
Cardiac ultrasound or 
myocardial scintigraphy ± 
cardiological opinion  in case 
of cardiopathy3 
X 
 
 
 
 
 
 
 
 
Assessment of treatment 
toxicity 
 
 
 
X 
X 
 
X 
X 
 
 
Biological check-up 1: CBC-PQ, natraemia, kalemia, calcemia, magnesemia, phosphoremia, uricemia, creatininemia, albuminemia, ASAT, ALAT, PAL, total and 
conjugated bilirubinemia, GGT, TP, TSH, lipase, INR for patients treated with AVK. 
Biological check-up 2: CBC-Pq, natraemia, kalemia, creatinine, creatinine clearance, ASAT, ALAT, PAL, total and conjugated bilirubin, GGT INR for patients treated with 
AVK. 
1 For patients treated with an anti-coagulant, a coagulation test should be performed, if the values are outside the therapeutic range the dose of anticoagulant should be 
modified and a coagulation check should be done every week until stabilization. 
² During treatment, an ECG will be done according to the investigator's choice. 
3 In case of heart disease, cardiac echography or myocardial scintigraphy, completed by a cardiologist's opinion if necessary, dated less than 3 months before 
inclusion. 
 
 


 
 
 
 
 
 
 
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1. BACKGROUND INFORMATION AND RATIONALE FOR THE STUDY 
 
 
1.1 General 
 
In France, the incidence of colorectal cancer (CRC) continues to increase. Approximately 
50% of CRCs occur in patients over the age of 70. Cancers in general are the second 
most common cause of death in patients over 70 years old.  
With the aging of the population expected in the coming years, the proportion of patients 
over 70 years of age will increase further. On the other hand, life expectancy is increasing 
among elderly patients. It reaches 12 years for patients over 75 years old and more than 
8 years for those over 80 years old. The discussion of a CRC in a patient over 70 years 
of age in a multidisciplinary consultation meeting is therefore frequent and the course of 
action is often difficult to determine because of the lack of consensus data specific to 
elderly patients.  
Elderly people are a heterogeneous population. Some people age well, have few chronic 
pathologies and remain independent. But many suffer from several organ pathologies, 
malnutrition, functional walking disorders, sensory deficits, but also cognitive or 
psychological disorders such as depression (linked to bereavement, disabilities...). 
Polymedication, as a consequence of comorbidities, is therefore frequent with a risk of 
iatrogeny increased by the side effects of the drugs and their interactions. All these 
elements, in close interaction with social and economic conditions, determine the health 
status of elderly subjects. The presence of co-morbidities reduces life expectancy and 
may in itself be a contraindication to treatment (2). There is also a risk of decompensation 
of comorbidities in the presence of a new pathology or its treatment.  
The question of adapting treatment to the patient takes on its full meaning in 
oncogeriatrics; treatment must necessarily be personalized. The recent recommendations 
of the INCa propose a geriatric evaluation of elderly patients undergoing cancer treatment. 
When carried out, it will modify the therapeutic management of approximately 20% of 
patients, particularly in the case of loss of autonomy or malnutrition (3).  
Assessment of geriatric parameters may allow treatment to be tailored. In the FFCD 2001-
02 study, which compared 5-fluorouracil monotherapy with FOLFIRI in first-line metastatic 
colorectal cancer in patients over 75 years of age, loss of autonomy and cognitive 
impairment were associated with the occurrence of toxicity (4). Recently, a screening tool 
has been proposed to select patients for geriatric evaluation (5). 
 
1.2 Treatment of metastatic colorectal cancer with regorafenib 
 
Regorafenib is an oral multitargeted inhibitor with initial hepatic metabolism, targeting both 
the tumor and its vasculature. Regorafenib inhibits VEGFR-2 and -3, and kinases located 
in tumor cells (RET, KIT, PDGFR, and Raf). In preclinical studies, regorafenib has shown 
antitumor activity in a broad spectrum of animal tumor models including CRC. In a Phase 
Ib study, regorafenib showed an acceptable toxicity profile and initial evidence of 
antitumor efficacy in patients with metastatic CRC (6). In a Phase III study (CORRECT), 
regorafenib treatment significantly increased overall survival in patients with metastatic 
CRC who had received all previously approved therapies (1). Other efficacy parameters 
such as progression-free survival (PFS) and tumor control rate were also improved. 


 
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Subgroup analyses, including patients over 65 years of age, showed an improvement in 
these parameters compared to placebo. 
A retrospective analysis specifically studied the impact of regorafenib treatment in patients 
over 65 years of age compared with younger patients (7). The hazard ratio for overall 
survival (regorafenib/placebo) was 0.72 (95% CI 0.56-0.91) in patients younger than 65 
years and 0.86 (95% CI 0.61-1.19) in patients older than 65 years (interaction test p = 
0.405). Treatment exposure was similar in both groups (<65 years vs. >65 years) with 
respect to median treatment duration (7.6 weeks vs. 7.1 weeks), median daily dose (160 
mg in each group), and median proportion of planned dose taken of regorafenib (83.3% 
vs. 78.6%). Most patients had treatment-related side effects (<65 years: 93.8%; ≥65 
years: 91.7%). The rate of regorafenib-related grade ≥3 adverse events was 52% in 
patients <65 years, 57% in patients between 65 and 74 years, and 66% in patients >75 
years. In the latter group, hypertension was more common than in younger patients.  
Although data on the use of targeted therapies in metastatic CRC are limited in elderly 
patients, a phase III study specific to elderly patients showed that bevacizumab prolonged 
progression-free survival (8). A randomized phase II study of the FFCD (PRODIGE 20), 
the results of which are currently being analyzed, is designed to evaluate the safety and 
evolution of geriatric parameters during treatment with bevacizumab. 
The objective of the REGOLD study is to better describe the effects of regorafenib in 
elderly patients with metastatic CRC. In addition to safety and efficacy endpoints, quality 
of life and geriatric parameters will be assessed. 
 
  
2. OBJECTIVES OF THE STUDY 
 
2.1 Main objective  
 
Assessment of tumor control rate (defined as the number of patients not progressing i.e. 
with complete tumor response, partial tumor response or tumor stability) on regorafenib 
therapy, 2 months after initiation of therapy, in elderly patients with metastatic colorectal 
cancer (mCRC) who have been previously treated with available therapies. 
 
 
2.2 Secondary Objectives 
 
Evaluate: 
- Overall survival at 1 year 
- Progression-free survival at 1 year 
- Tumor control rate at 2 months (centralized review) 
- Objective response rate assessed from the best response under treatment 
- Time to therapeutic failure 
- Time to degradation of autonomy 
- Time to degradation of quality of life 
- Geriatric prognostic and predictive parameters 
- Dose-intensity and its correlation with tumor control rate 
- Tolerance of regorafenib according to the NCI-CTC AE version 4.0 scale 
 
3. PATIENT SELECTION  
 
3.1 Inclusion criteria 
 


 
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- Metastatic colorectal cancer with histological evidence 
- Measurable disease according to RECIST 1.1 criteria 
- Age ≥ 70 years 
- ECOG ≤ 1 
- Life expectancy greater than or equal to 3 months  
- Biological workup: hemoglobin ≥ 9 g/dL, PNN ≥ 1500/mm3, platelets ≥ 100,000/mm3, 
bilirubin ≤ 1.5N, AST, ALT and PAL ≤ 2.5N (≤ 5N if liver metastases), lipase ≤1.5N, PT≥ 
70%, creatinine clearance ≥ 30 mL/min 
- Patients who have failed fluoropyrimidine-based chemotherapy, anti-VEGF therapy, and 
anti-EGFR therapy (if the cancer expresses the non-mutated RAS gene), who have 
progressed on this therapy, or patients who have discontinued this therapy for 
unacceptable toxicity  
- Completed geriatric patient and team questionnaires 
- Signed informed consent 
 
3.2 Criteria for non-inclusion 
 
- Inability to swallow tablets (crushed tablets are not allowed) 
- Previous treatment with regorafenib or another multikinase inhibitor 
- Other cancer within 5 years prior to inclusion, except cervical cancer in situ, non-
melanoma skin cancer and superficial bladder cancer treated curatively 
- Radiation therapy: - with extended fields, within 4 weeks, - with limited fields, within 2 
weeks, prior to inclusion. The site treated in this way must have demonstrated 
progression, if it is the only evaluable site 
- Unresolved > grade 1 toxicity attributed to prior therapy 
- Major surgery within 28 days of starting treatment  
- Unhealed wound, ulcer or bone fracture 
- Congestive heart failure of class >2 according to the NYHA classification 
- Unstable angina or angina that started less than 3 months ago 
- Myocardial infarction less than 6 months before the start of treatment 
- Uncontrolled hypertension (systolic pressure > 150 mm Hg or diastolic pressure > 90 
mm Hg despite optimal treatment) 
- Pheochromocytoma 
- Arterial or venous thromboembolic event within 6 months prior to the start of treatment 
- Clinically active infection of grade >2  
- HIV infection 
- Chronic viral hepatitis B or C requiring antiviral treatment 
- Cirrhosis  
- Known or suspected brain metastasis 
- Bleeding grade >3 within 4 weeks of starting treatment 
- Symptomatic pulmonary fibrosis  
- Proteinuria > grade 3  
- Malabsorption  
- Known hypersensitivity to the study drug or to a drug of the same class or to an excipient 
- Systemic anti-cancer treatment during the study or within 4 weeks prior to initiation of 
treatment 
- Concomitant treatment with a CYP3A4 inhibitor or inducer or a UGT1A9 inhibitor 
- Social, psychological or medical condition that may interfere with participation in the 
study or its evaluation 
 


 
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4. INCLUSION ASSESSMENT 
 
- Within 3 months prior to inclusion: 
In case of a history of heart disease, it is recommended to have the results of a cardiac 
echography or a myocardial scan, completed by a cardiologist's opinion if necessary.  
 
- Within 21 days prior to inclusion: 
 Thoracoabdomino-pelvic CT or hepatic MRI + non-injected thoracic CT scan if 
contraindication to iodinated contrast injection.  
 
- Within 14 days prior to inclusion: 
- medical history, clinical examination (weight, height, BP, ECOG status)  
- completion of the "patient self-questionnaire at inclusion" (Appendix 2) 
- Completion of the "Inclusion Team Questionnaire" (Appendix 3) 
- Urine dipstick, if protein > +, then do the 24h proteinuria 
- ECG  
 
- Within 7 days prior to inclusion: 
- biological assessment including: 
• NFS-Plates  
• natremia, kalemia 
• calcemia, magnesemia, phosphoremia, uricemia  
• creatinine clearance (Cockcroft and Gault) (Appendix 5) 
• creatinine, albumin  
• liver check-up: ASAT, ALAT, PAL, total and conjugated bilirubin, GGT 
• TP  
• ACE  
• TSH  
• Lipase 
• INR for patients treated with VKAs 
 
 
 
 
 
 
5. INCLUSION 
 
Inclusion will be done after a complete eligibility check-up and the signature of the 
informed consent. Inclusion will be carried out by the CRGA of the FFCD after reception 
of the fax of inclusion (form 1 of the observation booklet) at 03 80 38 18 41. The CRGA is 
open from Monday to Friday from 9 am to 6 pm. 
A confirmation of inclusion will be faxed back to the investigator.  
After the patient is enrolled in the study, treatment should be started within 7 days. 
An observation booklet will be sent at the opening of the center. A new observation book 
will be sent after each inclusion. 
 
6. DIAGRAM OF THE STUDY 
 


 
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This is a single-arm Phase II study. All patients included, after verification of the inclusion 
criteria, will be treated according to the same regimen. Each cycle lasts 28 days (21 days 
of treatment and 7 days without treatment). 
 
7. TREATMENT  
 
Regorafenib is not provided as it is in its indication. 
The initial dose will be 160 mg (4 tablets) taken orally once daily for 21 days, followed by 
7 days without treatment.  
They should be taken at a fixed time and in one go at the end of a light meal in a large 
glass of water. 
 Forgotten or vomited tablets should not be taken again. 
Dose modifications will be made according to the protocol in 40 mg steps. The minimum 
recommended dose is 80 mg. 
Reasons for dose reduction or discontinuation of treatment will be collected in the 
observation booklet.  
Compliance with the treatment will be evaluated for each cycle by the investigator, using 
the compliance booklet given to the patient at the beginning of the treatment and reported 
at each consultation. This compliance will be reported in the observation booklet.  
 
7.1 Duration of treatment 
 
Causes of discontinuation are:  
- progress  
- occurrence of a second cancer 
- Dose reduction of more than 2 times 40 mg  
- interruption of treatment for more than 4 consecutive weeks 
- patient refusal 
- withdrawal of consent 
- continuation of the study deleterious to the patient according to the investigator 
 
Patients who discontinue study treatment will be managed according to local guidelines. 
The administration of any other anti-cancer treatment will be collected in the observation 
booklet at a follow-up visit.  
Patients will be followed every 2 months after discontinuation of treatment, regardless of 
the reason for discontinuation, until death except for patients who have withdrawn their 
consent.  
Patients who stopped treatment before progression will be followed to assess the date of 
first progression.   
 
7.2 Dose adjustment  
 
Toxicities will be evaluated by questioning and clinical examination at D1, D7, and D14 of 
the 1st cycle and of the 2e cycle then at D1 of each following cycle. They will be evaluated 
by biology at D14 and D28 of each cycle. They will be graded according to the NCI-CTC 
AE version 4.0 criteria (Appendix 7).  
The decision to reduce the dose is based on toxicity throughout the cycle. 
The doses will be adapted according to the RCP (see table below).  
 


 
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Discontinuation of treatment and/or reduction in dosage may be necessary depending on 
tolerance. Dosage changes should be made in 40 mg (one tablet) increments. The 
minimum recommended daily dose is 80 mg. The dose may be increased if there is 
complete recovery of the side effect after dose reduction. The maximum daily dose is 160 
mg.  
 
A) Dosage modifications and recommended actions for hand-foot syndrome 
(MPS/palmoplantar erythrodysesthesia): 
 
Grade of skin 
toxicity 
Occurrence 
Dosage changes and recommended actions 
Grade 1 
All cases 
Maintain dosage and institute symptomatic treatment immediately. 
Grade 2 
1re occurred 
Reduce the dose by 40 mg (one tablet) and start symptomatic 
treatment immediately. 
No improvement 
within 7 days or 
2e occurred 
Interrupt treatment until toxicity disappears or decreases to a grade ≤ 
1. 
When treatment is resumed, reduce the dose by 40 mg (one tablet). 
3e occurred 
Immediately initiate symptomatic treatment. Interrupt treatment until 
toxicity has resolved or decreased to a grade ≤ 1. 
When treatment is resumed, reduce the dose by 40 mg (one tablet) if it 
had been increased after previous episodes.  
4e occurred 
Stop the treatment permanently. 
Grade 3 
1re occurred 
Immediately institute symptomatic treatment.  
Interrupt treatment for a minimum of 7 days until toxicity disappears or 
decreases to a grade ≤ 1. 
When treatment is resumed, reduce the dose by 40 mg (one tablet). 
2e occurred 
Immediately institute symptomatic treatment.  
Interrupt treatment for a minimum of 7 days until toxicity disappears or 
decreases to a grade ≤ 1. 
When treatment is resumed, reduce the dose by 40 mg (one tablet). 
3e occurred 
Stop the treatment permanently. 
Treatment should be permanently discontinued in case of intolerance to the 80 mg daily 
dose. 
 
B) Dosage modifications and recommended actions for drug-related liver function 
abnormalities 
 
Elevated ALT and/or AST 
levels 
Occurrence 
Dosage changes and recommended actions 
<= 5 times the upper limit of 
normal (ULN) 
(Grade 2 maximum) 
All cases 
Continue regorafenib therapy.  
Monitor liver function weekly until transaminases return to 
<3 times ULN (grade 1) or to baseline. 
> 5 times ULN (Grade 3) 
≤ 20 times ULN 
1re occurred 
Discontinue regorafenib.  
Monitor transaminases weekly until they return to < 3 times 
ULN or to baseline. 
Resumption of treatment: reinstate regorafenib, reduce 
dose by 40 mg (one tablet) if potential benefit outweighs 
risk of hepatotoxicity. Monitor liver function weekly for at 
least 4 weeks. 
New 
occurrence 
Permanent discontinuation of regorafenib. 
> 20 times ULN (Grade 4) 
All cases 
Permanent discontinuation of regorafenib. 


 
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Elevated ALT and/or AST 
levels 
Occurrence 
Dosage changes and recommended actions 
> 3 times ULN (Grade 2 or 
higher) with concomitant 
elevation of bilirubin > 2 
times ULN 
All cases 
Permanent discontinuation of regorafenib.  
Monitor liver function weekly until normalization or return to 
baseline. 
Exception: Patients with Gilbert's syndrome who develop 
elevated transaminases should be managed as described 
above for corresponding elevations in ALT and/or AST. 
 
7.3 Contraindicated treatments  
 
Regorafenib is metabolized by cytochrome CYP3A4 and uridine diphosphate 
glucuronosyl transferase UGT1A9. 
Coadministration of regorafenib with potent CYP3A4 inhibitors (such as clarithromycin, 
grapefruit 
juice, 
itraconazole, 
ketoconazole, 
posaconazole, 
telithromycin 
and 
voriconazole) should be avoided. 
Coadministration of regorafenib with strong inducers of CYP3A4 (such as rifampin, 
phenytoin, carbamazepine, phenobarbital, or St. John's Wort) should be avoided. 
 
8. PATIENT MONITORING 
 
8.1 during treatment : 
 
- Clinical examination: weight, height, BP, collection of toxicities and clinical tumor 
assessment  
- Cycle 1 and 2: at D1, D7 and D14  
- Cycles 3 and following: at D1 of each cycle  
- At the end of treatment visit 
The ECOG is completed on Day 1 of each cycle (cycle 1 and following) and at the end-
of-treatment visit. 
 
- Bioassay: 
At each cycle: at D1 and D14; (for cycle 1, the biological test at D1 can be the 
inclusion test, if it is less than 14 days old).  
The assessment at Day 1: CBC-platelets, natraemia, kalemia, calcemia, 
magnesemia, phosphoremia, uricemia, creatininemia, creatinine clearance, albuminemia, 
ASAT, ALAT, PAL, total and conjugated bilirubinemia, GGT, TP, TSH, lipase, INR for 
patients treated with AVK. 
Assessment at D14: CBC/blood platelets, creatinine clearance, natraemia, 
kalemia, creatinine, ASAT, ALAT, PAL, total and conjugated bilirubin, GGT, INR for 
patients treated with AVK. 
- At the end-of-treatment visit: CBC/blood platelet count, natraemia, kalemia, creatinine, 
creatinine clearance, AST, ALT, PAL, total and conjugated bilirubin, GGT 
A coagulation test should be performed at D1 and D14 of each cycle, if patients are treated 
with anticoagulant. If the values are outside the therapeutic range, the dose of 
anticoagulant should be modified and a coagulation test should be performed every week 
until stabilization. 
 
- Other follow-up: 
During treatment, an ECG will be performed if deemed useful by the investigator. 


 
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Every 4 weeks, until progression, CEA measurement will be performed as well as quality 
of life and geriatric parameters assessment. 
Every 8 weeks, until progression, a thoraco-abdomino-pelvic scan will be performed to 
evaluate the tumor response.  
 
8.2 After treatment : 
 
- If treatment is stopped for progression: the patient will be followed up approximately 
every 8 weeks to collect survival data and subsequent anti-cancer treatments. 
- if the treatment is stopped for another reason: the patient will be followed every 8 weeks 
with a thoraco-abdomino-pelvic scanner, until progression. Then he will be followed 
approximately every 8 weeks to collect survival data and subsequent anti-cancer 
treatments.  
 
9. CENTRALIZED REVIEW AND ANCILLARY STUDY  
 
Radiological responses will be evaluated according to RECIST version 1.1 criteria 
(Appendix 4) and will be reviewed by a panel of independent radiologists.  
Remember to keep the CDs and the CT scan report in the patient's file; the CRA FFCD 
will make a copy of these imaging studies for centralization at the AMRC. 
In addition, ancillary imaging studies will also be performed on these copies. 
 
 
 
10. MANAGEMENT OF SERIOUS ADVERSE EVENTS (SIA)  
 
10.1 Security assessment parameters  
 
Safety will be assessed by evaluating the general and clinical condition of the patients and 
by collecting events occurring between visits during consultations, and by regular blood 
tests. Toxicities will be assessed using the NCI-CTCAE Toxicity Scale version 4.0 
(Appendix 7).  
In case of an emergency, the patient, his family or his physician should call the investigator 
to inform him of an event.  
 
10.2 Definitions  
 
a. Adverse Event (AE)  
An adverse event is a harmful occurrence in a person who is a subject of biomedical 
research, whether or not the occurrence is related to the research or the product being 
investigated.  
All adverse events will be recorded in the observation book on the pages provided for this 
purpose according to their grade.  
 
b. Serious Adverse Event (SAE)  
A serious adverse event is any event that  
- Resulting in death  
- Life-threatening  
- Resulting in hospitalization or prolonged hospitalization  
- Causing permanent disability or severe temporary incapacity  
- Causing a birth defect, fetal malformation or abortion  


 
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- Medically significant (examples: overdoses, second cancers, and new developments 
may be considered medically significant).  
 
The terms disability and incapacity correspond to any temporary or permanent physical 
or psychological handicap, clinically significant and affecting the physical activity and/or 
quality of life of the patient.  
Any clinical event or laboratory result considered serious by the investigator and not 
corresponding to the severity criteria defined above is considered medically significant. 
They may put the patient at risk and require medical intervention to prevent an outcome 
corresponding to one of the severity criteria mentioned above (examples: overdose, 
second cancers, pregnancies and new facts may be considered medically significant).  
 
c. Undesirable Effect  
Any noxious and unintended response to an investigational drug at any dose or to any 
investigational component. An adverse reaction is serious if it meets a severity criterion.  
 
d. Unexpected Serious Adverse Effect  
An unexpected serious adverse reaction is an event that is not mentioned, or that differs 
in nature, intensity, or evolution from the product reference document (or RCPs).  
 
e. New fact  
A new fact can be: an unexpected frequency of an expected SAE, an SAE related to the 
trial procedure. 
f. Intensity (or severity)  
The intensity criterion should not be confused with the severity criterion, which is used as 
a guide to define reporting obligations.  
The intensity of the events will be estimated according to the extract of the NCI CTC-AE 
classification version 4.0 (Appendix 7). The intensity of adverse events not listed in this 
classification will be assessed according to the following qualifiers:  
- Mild (grade 1): does not affect the patient's usual daily activity  
- Moderate (grade 2): disrupts the patient's usual daily activity  
- Severe (grade 3): prevents the patient's usual daily activity  
- Very severe (grade 4): requires resuscitative measures / life threatening  
- Death (grade 5)  
 
g. Causal relationship  
- Related: an event is said to be related when a causal relationship between the event and 
the product under study can reasonably be suspected  
- Unrelated: an event is said to be unrelated when a causal relationship between the event 
and the product under study cannot reasonably be suspected  
- Doubtful: causality is said to be "doubtful" when there is doubt about the causal 
relationship between the event and the product under study (the relationship can then be 
neither formally excluded nor formally affirmed)  
 
10.3 Reference documents for the study   
 
The reference document for assessing the expected or unexpected nature of the SAEs 
will be, for regorafenib, the Summary of Product Characteristics for STIVARGA® 40 mg 
(Appendix 8).  
The version of the PCRs used for the definition of expected/unexpected will be the latest 
available on the anniversary date of the start of the trial.  


 
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10.4 Events of particular interest, to be declared as a SAE  
 
Within the framework of this protocol, we ask you to report on the SAE form, even if none 
of the classic severity criteria are met: 
- 
Grade 3-4 liver function tests 
- 
hepatic insufficiency 
 
10.5 Events not to be considered serious  
 
Disease progression should not be considered an SAE.  
Events that are potentially related to progression but may also be secondary to treatment 
will continue to be reported (e.g. thromboembolic events, bleeding phenomena, 
perforations).  
Due to the severity of the disease in this study, certain conditions defined as an SAE will 
be excluded from the SAE reporting procedure, namely:  
- Hospitalization or surgery specifically related to the treatment of the disease  
- Hospitalization performed to simplify study treatments or procedures.  
 
10.6 Conduct  
 
The investigator informs the sponsor of all Serious Adverse Events (expected and 
unexpected), whether or not attributable to the research, that occur during the study or 
within 30 days of the last treatment administration.  
The investigator informs the sponsor of all Adverse Events of Special Interest (even "non-
serious" ones) that occur during the study or within 30 days of the last treatment 
administration.  
 
All Delayed Serious Adverse Events (occurring after this 30-day period) considered 
reasonably related to the protocol treatment(s) or research should be reported without 
time limitation.  
 
The report is made by faxing the "notification of a serious adverse event" form (Appendix 
9), documented as precisely as possible, dated and signed, within 24 working hours of 
their knowledge to the FFCD's Randomization Management Analysis Center (CRGA) 
by fax to 03 80 38 18 41.  
 
The investigator is responsible for appropriate medical follow-up of patients until resolution 
or stabilization of the effect or until the patient's death. This may sometimes involve 
extending follow-up after the trial patient's protocol treatment has been discontinued.  
It transmits the additional information to the sponsor using an SAE reporting form 
(checking the "Follow-up" box and incrementing the number, to specify that it is a follow-
up report and not an initial report) within 24 hours of obtaining it. It also forwards the last 
follow-up to the resolution or stabilization of the SAE.  
It responds to requests for additional information to document the initial observation. 
 
The sponsor is responsible, upon receipt of the investigator's report of the serious adverse 
event, for issuing an opinion on the causal relationship between the serious adverse event 
and the study product(s).  


 
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If the serious adverse event is linked by the investigator and/or sponsor to one of the study 
products (i.e., it is a serious adverse event), the investigator and/or sponsor must establish 
the expected or unexpected nature of this event.  
In the case of an unexpected serious adverse reaction, or if it is a new event, the sponsor 
prepares an initial report which will be sent to the ANSM, the CPP and the EMA (via 
EudraVigilance) within 7 days in the case of death or life-threatening situation, otherwise 
within 15 days.  
If it is an expected serious adverse event, it will be collected for the semi-annual and 
annual safety reports.  
 
 
 
 
11. STATISTICAL ANALYSIS  
 
11.1 Judging criteria 
 
1) Primary endpoint 
Tumor control rate is defined as the percentage of patients with complete tumor response, 
partial tumor response, or tumor stability on regorafenib therapy at 2 months after initiation 
of therapy as determined by the investigator (RECIST V1.1 criteria) 
 
2) Secondary criteria 
 
The secondary endpoints are defined as follows:  
 
- Overall treatment tolerance will be assessed by the rate of observed toxicities, graded 
according to NCI-CTC v4.  
 
- Overall survival is defined as the time from the date of inclusion to the date of death 
from any cause. Patients lost to follow-up or alive at the time of analysis will be censored 
at the date of last report. A minimum follow-up of 1 year for the last included patient is 
required.   
 
- The tumor control rate assessed in centralized review is defined as the percentage of 
patients with complete tumor response, partial tumor response, or tumor stability on 
regorafenib therapy 2 months after the start of therapy (RECIST criteria V1.1). 
 
- The objective response rate is defined as the occurrence of at least one complete or 
partial response assessed from the best response (according to RECIST v1.1 criteria) 
during the treatment evaluations (Appendix 4). Patients who discontinue the study without 
response assessment will be considered non-responders. 
 
- Time to treatment failure is defined as the time from the date of inclusion to the date 
of treatment discontinuation (regardless of cause) or death (regardless of cause). Living 
patients without treatment discontinuation will be censored at the date of last treatment 
administration. 
 
- Progression-free survival is defined as the time from the date of inclusion to the date 
of first investigator-rated progression (clinical or radiological) or death (from any cause). 
Patients alive without progression will be censored at the date of last news. A minimum 


 
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follow-up of 1 year for the last included patient is required.   
 
- The regorafenib dose intensity will be calculated during the first 2 cycles of treatment 
and over the entire treatment period. The theoretical dose intensity (TDI) (mg/cycle) is 
3360 mg ((160mg/d x 21d ). The dose intensity (DI) actually received is equal to the total 
dose received divided by the total duration of treatment. The relative dose intensity (DIR) 
is equal to DI / DIT. 
 
- Time to deterioration in independence is defined as the time from the date of inclusion 
to the date on which the IADL score (Appendix 2) has decreased by at least 1 point from 
the score calculated at inclusion. Patients alive or deceased without deterioration of 
autonomy will be censored at the date of last IADL assessment or the date of death.  
 
- Time to deterioration in quality of life is defined as the time from the date of inclusion 
to the date of deterioration of the Spitzer QoL Index (9) (Appendix 3) by 2 points from the 
score at inclusion. Patients alive or deceased without deterioration will be censored at the 
date of last QoL assessment or the date of death.  
 
11.2 Exploratory evaluation of geriatric parameters 
 
It is recommended that each patient has had a geriatric consultation prior to 
inclusion.  
An exploratory analysis is planned to look for geriatric prognostic factors for the 
primary endpoint. An analysis of the evolution of geriatric parameters during the follow-up 
will also be performed. 
 
The "patient" self-questionnaire including the collection of activity of daily living and 
the "team" questionnaire including the quality of life (Spitzer QoL Index) will be completed 
at inclusion and at each evaluation (every 4 weeks).  
The self-questionnaire will be completed by the patient. The "team" questionnaire 
will be completed by a clinical research associate, a nurse or the investigator depending 
on the organization of the service.  
 
The 2 questionnaires include the assessment of geriatric parameters with the 
following domains: functional status, mobility, cognition, depression, energy, social 
context and quality of life; physical activity, nutrition, hearing and vision will only be 
completed at inclusion. A cut-off value is determined for each domain.  
 
The questionnaires and self-questionnaires are presented in Appendices 2 and 3. These 
evaluation questionnaires have been used in onco-geriatrics, particularly as self-
questionnaires (10-14).  
 
The geriatric parameters are: 
 
1) Co-morbidity (Self questionnaire and Team) 
To assess the co-morbidity of each patient, the following items will be documented: 
- 
Existence of one or more hospitalizations in the last 12 months for a reason other 
than cancer management.  
- 
Updated Charlson score (15) 
 


 
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2) Functional status   
a) Activities of daily living (Self questionnaire) 
The self-administered questionnaire replicating the items of the Katz index (16) will be 
used to measure basic activities of daily living (ADL). Thus, the ADL score for each patient 
can range from 0 (unable to perform any activity) to 6 (able to perform all activities). 
Disability in a BDA is defined as the need for assistance with at least one activity of daily 
living. 
Threshold value: <6 
 
b) Instrumental activities of daily living (IADL) (Self questionnaire) 
The self-administered questionnaire reproducing the IADL items will be used to measure 
instrumental activities of daily living (IADL) (17). Disability in an IADL is defined as the 
need for assistance to complete at least one IADL. The denominator will be adjusted to 
account for patients not performing certain activities listed in the IADL.  
The threshold value is: <14 when the patient does or did all IADL activities. A score 
lower than 14/14 is considered pathological (e.g., if the patient needs help with housework 
and managing money, the score will be 12/14 and therefore pathological). If the patient 
has never done certain activities, the score is adjusted according to the denominator 
corresponding to the maximum number of points possible on the activities performed by 
the patient (e.g.: if the patient has never done housework, the score will be 12/12, and the 
IADL is considered normal).  
 
c) Eastern Cooperative Oncology Group Functional Index (ECOG-PS) (Case report) 
The ECOG is a five-point scale designed to measure the level of interference of symptoms 
with normal activity and the number of hours awake in bed (18).  An ECOG ≥ 2 is 
considered a decrease in functional status. 
Threshold value = ECOG ≥ 2 
 
3) Mobility (Self questionnaire and Team questionnaire) 
To assess mobility, the unipodal station test (19) and the number of falls reported in the 
last 6 months (or last 2 months at follow-up) will be used. The unipodal station test is 
considered abnormal if the patient is unable to balance on one leg for more than 5 seconds 
or if the patient has had a fall in the last 6 months.  
Threshold value: monopodal support < 5 seconds or fall in the last 6 months (and 
in the last 2 months for follow-up) 
 
Volunteer centers will also measure the 4-meter walking speed (TM-4) (20). The TM-4 is 
done over a distance of eight meters including the two meters of acceleration and 
deceleration. The time is measured for the central 4 meters, to avoid acceleration and 
deceleration at both ends of the course. Precise instructions will be given to the patient: 
"walk at your usual pace, at your ease". The test will be repeated twice. A 4 m walking 
speed test longer than 4 seconds is considered as pathological (21). 
 
4) Nutrition  
a) Body Mass Index (Observation Booklet) 
The body mass index (BMI) will be calculated for each patient as follows: BMI = Weight 
(Kg)/[Height (m)]2 . BMI is an index commonly used to classify overweight and obesity in 
adults. The World Health Organization (1998) classifies normal weight with a BMI of 18.5 
to 24.9 kg/m2 , overweight with a BMI between 25 and 29.9 kg/m2 , and obese with a BMI 


 
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30 kg/m2 . A BMI < 18.5 kg/m2 is considered underweight and indicates severe 
malnutrition (22). A BMI < 21 already indicates undernutrition (HAS 2007) in the elderly.  
Threshold value in geriatrics: BMI < 21 kg/m2 
 
b) Mini nutritional evaluation (Team Questionnaire) 
The Mini Nutritional Assessment (MNA-SF) is a 6-item questionnaire to detect 
malnutrition. These items are already collected in the G8 Mini Assessment. Patients are 
considered at risk of malnutrition if they have a score < 11 out of a total of 14 (23). 
Threshold value: score < 11 
The G8 scale used in the ONCODAGE study will be evaluated (5).  
 
c) Evaluation of weight loss by losing 4kg in 1 year (Self questionnaire) 
"In the past year, have you involuntarily lost more than 10 pounds?" (20) 
 
5) Cognition (Team Questionnaire) 
The Mini-COG will be used to detect cognitive impairment (24).  
Scores:  
• If 3-word recall = 0 positive test for cognitive impairment 
• If the 3 words recall = 1 or 2 
- Either normal clock test: negative test for cognitive impairment 
- Either abnormal clock test: positive test for cognitive impairment  
• If recall of 3 words = 3, negative test for cognitive impairment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6) Depression (Self questionnaire)  
 The mini-cog score algorithm is based on the 3-word recall memory test and the clock test. 
The clock test serves as an "informative disturbance" that helps to clarify the score when the 
memory test score is intermediate. 
MINI-COG 
Memory test = 0 
Memory test = 1-2 
Memory test = 3 
Abnormal clock test 
Normal clock test 
 
positive test 
for cognitive 
impairment 
positive test 
for cognitive 
impairment 
negative test 
for cognitive 
impairment 
negative test 
for cognitive impairment 


 
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The 4-item Geriatric Depression Scale (mini GDS)  is used to suspect depression. A score 
of 1 or higher indicates possible depression (25). 
Threshold value: ≥ 1 
 
7) Energy (Self questionnaire) 
A visual analog scale will be used to assess the energy domain (26). A score < 3 indicates 
a positive fragility marker for this domain.  
Threshold value: < 3  
 
8) Physical activity (Team Questionnaire) 
The validated self-questionnaire derived from the Canadian Study of Health and Aging 
Risk Factor Questionnaire (RFQ) will be used (27). Physical activity will be stratified 
according to 4 levels of exercise that are scored from 1 to 4 :  
4- high level of exercise (more intense than walking at least 3 times a week) 
3- moderate exercise (walking 3 times a week) 
2- low level of exercise (either walking or more intense than walking, less than 3 times a 
week or exercise less intense than walking, any frequency) 
1- No physical exercise 
No exercise or low level of exercise (score 1 or 2) indicates a positive fragility marker for 
this domain.   
Threshold value: < 2  
 
9) Social context (Self questionnaire) 
No reference tool yet exists to measure social context in gerontological research. The 
following question was chosen: Will you have someone to care for you during the 
treatment period? If so, who is it? (Spouse, children, friends, neighbors, caregivers). 
Threshold value: no 
 
10) Quality of life (Team Questionnaire) 
The Spitzer QoL Index questionnaire will be used to assess quality of life (9).  
 
11) Hearing (Self questionnaire) 
The next question will be asked "do you have difficulty hearing or do you have a hearing 
aid?" 
Threshold value: yes  
 
12) Vision (Self questionnaire) (28):  
The following questions will be used:  
Question 1: "Are you able to read a sentence in the newspaper (with or without glasses)?"   
If no to question 1: 
Question 2: "Can you read the headlines in the newspaper?   
Threshold value: answer no to question 1 
 
 
 
 
11.3 Calculation of the number of subjects required  
 
The clinical assumptions are based on data from the CORRECT study and are as follows:  


 
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H0 : A tumor control rate at 2 months after the start of treatment of 25% or less is not 
sufficient  
H1 : A tumor control rate at 2 months after the start of treatment of more than 25% is 
considered sufficient. A rate of 47% is expected.  
 
With a one-sided α risk of 5% and 90% power, 42 patients are required. 
Patients who discontinue the study prior to documented tumor progression at 2 months 
will be considered non-responders for the primary endpoint analysis.  
 
The decision rules after inclusion of 42 patients are: 
If 15 or fewer patients show a complete or partial response or stability, then the 
treatment will be considered not effective. 
If 16 or more patients have a complete, partial or stable response, then the treatment 
is considered effective.  
 
A recruitment of 2 patients per month is planned. 
 
11.4 Statistical analysis 
 
Populations of analysis 
All analyses will be done on an intention-to-treat basis on all included patients who have 
taken at least one treatment tablet.  
 
Descriptive analyses 
Continuous variables will be described using mean, standard deviation, median, minimum 
and maximum, and interquartile range (Q1-Q3).  
Qualitative variables will be described using frequencies and percentages. The 
percentages will be calculated without taking into account the missing modality. 
 
Analysis of the judging criteria 
Censored data will be estimated and plotted using the Kaplan Meier (KM) method. 
Survival times will be described by medians and rates at different time points with their 
95% confidence intervals. The median follow-up time will be calculated using the so-called 
"reverse Kaplan Meier" method. 
 
 
Tolerance analysis  
Toxicities will be described, by the number of patients and toxicities according to the 
different grades and the different SOC. They will also be described by grouping grades 1-
2 versus 3-4-5.  
 
Analysis of geriatric parameters 
An analysis of prognostic factors for overall survival and progression-free survival will be 
performed. These analyses will be performed using univariate and multivariate Cox 
models.  
The geriatric parameters and the inclusion variables considered clinically relevant will be 
studied in univariate. Variables that are significant at the 20% threshold can be introduced 
into the multivariate models. Several multivariate models can be constructed, and the 
comparison of the different models obtained will be carried out according to a measure of 
model adequacy (AIC), a measure of calibration (O'Quigley's R2 ) and a measure of 
accuracy (Breier score). 


 
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Exploratory analysis 
In an exploratory way, in order to study the temporal evolution of geriatric and quality of 
life scores (Spitzer QoL Index, IADL, ...), mixed models of analysis of variance for 
repeated measures of each of the scores will be performed.  
 
12. ANCILLARY STUDY 
 
During this study, copies of the evaluation images will be collected for each patient. It is 
planned to look for predictive markers of response and progression-free survival under 
regorafenib treatment.  
- 
Fat is now considered as an endocrine and paracrine organ (29). Today we distinguish 
2 types of fat, visceral and subcutaneous, because they have a different secretion 
profile (30). Visceral fat secretes adipokines, some of which are pro-angiogenic and 
proliferative. Cross-sectional imaging (CT/MRI) is the only technique to separate 
visceral fat from subcutaneous fat. It has been hypothesized that pro-angiogenic 
adipokines secreted by visceral fat may influence the response and survival of patients 
treated with anti-angiogenic drugs. As an exploratory study, a monocentric study of 
120 patients treated in 1st line metastatic colorectal cancer was performed: 80 patients 
were treated with bevacizumab + chemotherapy and 40 patients with chemotherapy 
alone (31). It is clear that patients treated with bevacizumab with high visceral fat have 
a poorer 2-month response, shorter progression-free survival and overall survival. 
Other studies of the same type are underway for other cancers and the preliminary 
results confirm these initial results. The major objective will be to validate that visceral 
fat area (calculated on the baseline scan) is an independent predictor of response at 
the first assessment (8-week scan) and of progression-free survival.  
 
- 
In addition, an exploratory study of tumor density will be conducted based on the 
analysis of baseline and 8-week scans.  
Three tumor density measurements will be performed for a maximum of 2 targets per 
organ, on axial slices made after injection of iodinated contrast. For each target, a 
density measurement by a global region of interest will be performed on the slice 
showing the largest tumor surface. A density measurement will be performed on the 
tumor area appearing the most hyperdense. Finally, a measurement will be performed 
on the most hypodense tumor area. Finally, a density measurement of the underlying 
healthy organ will also be noted for each scan. The injection time (arterial, portal or 
late) will be noted for each target, as well as the quantity of contrast medium used 
(noted on the radiological report).  These measurements will be repeated on the 8-
week scan. 
The objective will be to determine, with the help of ROC curves, the threshold of 
variation of the tumor density allowing to predict the response and the progression. 
 
- Finally, sarcopenia has been shown to be a predictive factor for toxicity of 
chemotherapy in colorectal cancers (32) and also of sorafenib (another tyrosine kinase 
inhibitor close to regorafenib) in hepatocellular carcinoma (33). Sarcopenia will be 
analyzed on abdominal sections to investigate its predictive value of toxicity and 
efficacy of regorafenib. 
 
 


 
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13. STUDY COMMITTEES 
 
13.1 Board of Directors 
 
A steering committee will be established, chaired by the lead coordinator. This committee 
will include the protocol writing committee, the FFCD president, the project manager and 
the statistician. 
 
13.2 Independent Data Review Committee 
 
An independent monitoring committee will be established, including a physician 
specializing in oncogeriatrics, a gastroenterologist/oncologist, a statistician and a 
pharmacovigilance expert. Their functions will be described in the charter of the 
independent monitoring committee. It will analyze all safety data during the study. It will 
meet 3 months after the inclusion of the fifteenth patient. In case of unexpected toxicity, 
unacceptable the independent committee may recommend:  
- A protocol amendment that could significantly improve treatment tolerability 
- Premature termination of the study if the treatment causes intolerable side effects.     
 
13.3 Centralized proofreading 
 
A panel of radiologists will be responsible for centralized review of radiological imaging 
collected during the study to determine treatment responses and progressions. 
 
 
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abstracts using data from 6 countries. Am J Epidemiol 2011;173:676-682. 
 16.  Katz S. Assessing self-maintenance: activities of daily living, mobility, and instrumental activities of 
daily living. J Am Geriatr Soc 1983;31:721-727. 
 17.  Fillenbaum GG, Smyer MA. The development, validity, and reliability of the OARS multidimensional 
functional assessment questionnaire. J Gerontol 1981;36:428-434. 
 18.  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
 19.  Vellas BJ, Wayne SJ, Romero L, Baumgartner RN, Rubenstein LZ, Garry PJ. One-leg balance is an 
important predictor of injurious falls in older persons. J Am Geriatr Soc 1997;45:735-738. 
 20.  Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop 
WJ, Burke G, McBurnie MA. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci 
Med Sci 2001;56:M146-M156. 
 21.  Abellan vK, Rolland Y, Andrieu S, Bauer J, Beauchet O, Bonnefoy M, Cesari M, Donini LM, Gillette 
GS, Inzitari M, Nourhashemi F, Onder G, Ritz P, Salva A, Visser M, Vellas B. Gait speed at usual 
pace as a predictor of adverse outcomes in community-dwelling older people an International 
Academy on Nutrition and Aging (IANA) Task Force. J Nutr Health Aging 2009;13:881-889. 
 22.  Cook Z, Kirk S, Lawrenson S, Sandford S. Use of BMI in the assessment of undernutrition in older 
subjects: reflecting on practice. Proc Nutr Soc 2005;64:313-317. 
 23.  Rubenstein LZ, Harker JO, Salva A, Guigoz Y, Vellas B. Screening for undernutrition in geriatric 
practice: developing the short-form mini-nutritional assessment (MNA-SF). J Gerontol A Biol Sci 
Med Sci 2001;56:M366-M372. 
 24.  Borson S, Scanlan JM, Watanabe J, Tu SP, Lessig M. Simplifying detection of cognitive impairment: 
comparison of the Mini-Cog and Mini-Mental State Examination in a multiethnic sample. J Am 
Geriatr Soc 2005;53:871-874. 
 25.  Clement JP, Nassif RF, Leger JM, Marchan F. [Development and contribution to the validation of a 
brief French version of the Yesavage Geriatric Depression Scale]. Encephale 1997;23:91-99. 
 26.  Bandeen-Roche K, Xue QL, Ferrucci L, Walston J, Guralnik JM, Chaves P, Zeger SL, Fried LP. 
Phenotype of frailty: characterization in the women's health and aging studies. J Gerontol A Biol Sci 
Med Sci 2006;61:262-266. 
 27.  Davis HS, MacPherson K, Merry HR, Wentzel C, Rockwood K. Reliability and validity of questions 
about exercise in the Canadian Study of Health and Aging. Int Psychogeriatr 2001;13 Supp 1:177-
182. 
 28.  Cacciatore F, Abete P, Maggi S, Luchetti G, Calabrese C, Viati L, Leosco D, Ferrara N, Vitale DF, 
Rengo F. Disability and 6-year mortality in elderly population. Role of visual impairment. Aging Clin 
Exp Res 2004;16:382-388. 
 29.  Cao Y. Angiogenesis modulates adipogenesis and obesity. J Clin Invest 2007;117:2362-2368. 
 30.  Maeda K, Okubo K, Shimomura I, Mizuno K, Matsuzawa Y, Matsubara K. Analysis of an expression 
profile of genes in the human adipose tissue. Gene 1997;190:227-235. 


 
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 31.  Guiu B, Petit JM, Bonnetain F, Ladoire S, Guiu S, Cercueil JP, Krause D, Hillon P, Borg C, 
Chauffert B, Ghiringhelli F. Visceral fat area is an independent predictive biomarker of outcome after 
first-line bevacizumab-based treatment in metastatic colorectal cancer. Gut 2010;59:341-347. 
 32.  Barret M, Antoun S, Dalban C, Malka D, Mansourbakht T, Zaanan A, Latko E, Taieb J. Sarcopenia 
is linked to treatment toxicity in patients with metastatic colorectal cancer. Nutr Cancer 2014;66:583-
589. 
 33.  Mir O, Coriat R, Blanchet B, Durand JP, Boudou-Rouquette P, Michels J, Ropert S, Vidal M, Pol S, 
Chaussade S, Goldwasser F. Sarcopenia predicts early dose-limiting toxicities and 
pharmacokinetics of sorafenib in patients with hepatocellular carcinoma. PLoS One 2012;7:e37563. 
 
 
15. ADMINISTRATIVE CONSIDERATIONS  
 
Study sponsor 
The sponsor of the study is the Fédération Francophone de Cancérologie Digestive 
(FFCD). The study was registered under the EudraCT number: 2015-002086-29. 
 
Reminder of the texts in force 
This test will be conducted according to the French law in force 
 
Liability Insurance 
Insurance has been taken out by the promoter with SHAM (Société Hospitalière 
d'Assurances Mutuelles) under contract number XXX (Appendix 11), in accordance with 
Article L 1121-10 of the Public Health Code.  
 
Request for authorization to the CPP and ANSM 
This protocol received the favorable opinion of the CPP (Committee for the Protection of 
Persons) Ile de France VIII, on 29/06/2015 (Appendix 12). 
This protocol has been authorized by the ANSM (Agence Nationale de Sécurité du 
Médicament) (Appendix 13). 
 
Collection of the patient's consent 
The investigator undertakes to collect, after information, the clinical consent of the patient 
in writing (information sheet and consent form in Appendix 1). A copy of these consents 
must be kept by the investigator for 15 years, to be presented to the supervisory 
authorities in case of inspection. The original should be given to the patient. 
In accordance with the recommendations of the Cancer Plan (Measure 4.3.), this 
document has been submitted for review, advice and guidance to the Patients' Committee 
for Clinical Research (PCCR) of the National League Against Cancer. 
 
Hospital management information and research agreement 
Prior to the implementation of the study, the hospital management will be informed by the 
sponsor of the investigator's interest in participating in this trial. 
A research agreement will be established between the administrator of the investigating 
center and the sponsor.  
 
 
 
 
Data archiving 


 
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                       Page 27 on 28 
 
The files will remain confidential and can only be consulted under the responsibility of the 
doctors in charge of the patients. The sponsor and the health authorities in case of 
inspection will have direct access to these documents. 
At the end of the trial, the observation book will be kept for 15 years by the investigator. 
 
Computer support 
In accordance with the text of the law n° 78-17 of January 6, 1978 modified by the law of 
August 9, 2004, relating to data processing, files and freedoms, the data of the trial will be 
recorded in a computerized database of the FFCD Randomization and Analysis 
Management Center, excluding elements relating to the identity of patients. The FFCD 
has made a simplified declaration (MR01) to the CNIL for the implementation of its 
centralized databases. 
 
Data processing 
The FFCD's Center for Randomization, Management and Analysis (CRGA) will be 
responsible for data management and analysis.  
 
Monitoring, quality assurance and inspections by authorities 
The investigator agrees in advance that the records of the patients included in the study 
may be consulted by an FFCD CRA or a person mandated by the sponsor or the FFCD 
and/or by the health authorities to carry out an audit. On-site visits of the files, scheduled 
after agreement of the investigator, will take place during the protocol period of the study. 
 
16. PUBLICATION RULES 
 
They shall be in accordance with those established by the FFCD (Appendix 10). 
 
17. APPENDICES  
 
 
ANNEXE 1 : Notice d'information et formulaire de consentement éclairé pour l’étude clinique 
APPENDIX 2: "Patient" self-questionnaire  
APPENDIX 3: "Team" Questionnaire  
APPENDIX 4: RECIST 1.1 Criteria 
APPENDIX 5: ECOG 
APPENDIX 6: Measurement of creatinine clearance using the Cockcroft and Gault formula   
APPENDIX 7: NCI-CTC Toxicity Criteria Version 4.0 
APPENDIX 8: Regorafenib CPR 
APPENDIX 9: RSI form 
APPENDIX 10: FFCD Publication Rules 
SCHEDULE 11: Certificate of Insurance 
APPENDIX 12: Favourable opinion of the PPC 
APPENDIX 13: Authorization from the ANSM 


 
 
 
 
 
 
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28 on 28 
 
 

SAP_001.pdf: 
 
Statistical Analysis Plan – Final Analyses – FFCD 1404 - REGOLD – v1.0 : February 2017 
Page 1 over 15 
 
 
 
 
 
 
 
 
 
 
              
 
 
 
 
 
 
 
 
 
PHASE II STUDY EVALUATING THE EFFICACY AND TOLERABILITY OF REGORAFENIB IN 
PATIENTS 70 YEARS AND OLDER WITH METASTATIC COLORECTAL ADENOCARCINOMA 
Phase II non randomized  
FFCD 1404 - REGOLD 
 
 
Statistical Analyses Plan 
Final Analyses 
 
 
 
 
 
 
 
 
Version : 1.0 
Date : 23 February 2017 
 
Writter : Carole Montérymard 
Review committee : Thomas Aparicio, Gaëtan Des Guetz , Lila Gaba, Karine Le Malicot, Charles Fuchey. 
 
 


 
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Promotion 
Fédération Francophone de Cancérologie Digestive (FFCD),  
Faculté de Médecine,  
7, Boulevard Jeanne d’Arc, BP 87900,  
21079 Dijon Cedex 
 
Coordonator 
  
Pr Thomas Aparicio 
Service de Gastro-Entérologie et Cancérologie Digestive 
Hôpital Avicenne 
125 Rue de Stalingrad 
93009 BOBIGNY cedex 
Tel. 01 48 95 54 31 
Email : thomas.aparicio@avc.aphp.fr 
 
Project manager  
 
Mme Lila Gaba 
FFCD 
Faculté de Médecine 
7 boulevard Jeanne d’Arc 
BP 87900, 21079, Dijon Cedex 
Tél. : 03 80 39 34 83  
Email : lila.gaba@u-bourgogne.fr 
  
 
 


 
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Table of contents 
 
1 
Introduction ..................................................................................................................................................................................................................5 
1.1 
Objectives ...........................................................................................................................................................................................................5 
1.1.1 
Main objective .............................................................................................................................................................................................5 
1.1.2 
Secondary objectives ................................................................................................................................................................................5 
1.1.3 
Exploratory studies...................................................................................................................................................................................5 
1.2 
Study design ......................................................................................................................................................................................................5 
1.3 
Treatment ...........................................................................................................................................................................................................5 
1.4 
Sample Size calculation ................................................................................................................................................................................5 
1.5 
Analyses planning ...........................................................................................................................................................................................6 
1.6 
Adjustments.......................................................................................................................................................................................................6 
2 
Study populations .......................................................................................................................................................................................................6 
2.1 
Analyses populations ....................................................................................................................................................................................6 
2.1.1 
Intent-to-treat population (ITT) .........................................................................................................................................................6 
2.1.2 
Modified Intent-to-treat population (ITTm) .................................................................................................................................6 
2.1.3 
Safety population (PT) ............................................................................................................................................................................6 
3 
Statistical Generalities ..............................................................................................................................................................................................6 
3.1 
Software ..............................................................................................................................................................................................................7 
3.2 
Conventions .......................................................................................................................................................................................................7 
3.3 
Conventions for missing data ....................................................................................................................................................................7 
3.4 
Baseline definition ..........................................................................................................................................................................................7 
3.5 
Statistics ..............................................................................................................................................................................................................7 
4 
Analyses statistiques .................................................................................................................................................................................................9 
4.1 
Baseline characteristics ................................................................................................................................................................................9 
4.1.1 
Eligibility........................................................................................................................................................................................................9 
4.1.2 
Demographics .............................................................................................................................................................................................9 
4.1.3 
Clinical characteristics.......................................................................................................................................................................... 10 
4.1.4 
Biological characteristics .................................................................................................................................................................... 10 
4.1.5 
Disease characteristics ......................................................................................................................................................................... 10 
4.2 
Follow-up ......................................................................................................................................................................................................... 11 
4.2.1 
Definition .................................................................................................................................................................................................... 11 
4.2.2 
Evaluation .................................................................................................................................................................................................. 11 
4.3 
Main efficacy criterion ............................................................................................................................................................................... 11 
4.3.1 
Definition .................................................................................................................................................................................................... 11 
4.3.2 
Evaluation .................................................................................................................................................................................................. 11 
4.4 
Secondary efficacy criteriaa .................................................................................................................................................................... 12 
4.4.1 
Overall Survival ....................................................................................................................................................................................... 12 
4.4.2 
Tumoral control (centralised review) ........................................................................................................................................... 12 
4.4.3 
Objective response ................................................................................................................................................................................. 12 
4.4.4 
Time to therapeutic failure ................................................................................................................................................................. 12 
4.4.5 
Progression-Free Survival .................................................................................................................................................................. 13 


 
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4.4.6 
Time to autonomy deterioration ..................................................................................................................................................... 13 
4.4.7 
Time to QOL deterioration ................................................................................................................................................................. 13 
4.5 
Safety ................................................................................................................................................................................................................. 14 
4.5.1 
Regorafnib.................................................................................................................................................................................................. 14 
4.5.2 
Toxicities .................................................................................................................................................................................................... 15 
4.5.3 
SAEs .............................................................................................................................................................................................................. 15 
4.6 
Analyses Exploratoires ......................................................................................................................... Erreur ! Signet non défini. 
4.6.1 
Définition .................................................................................................................................................................................................... 15 
4.6.2 
Evaluation .................................................................................................................................................................................................. 15 
 


 
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1 Introduction 
 
1.1 Objectives 
 
1.1.1 
Main objective 
 
The primary objective of this study is to evaluate the tumor control rate (defined as the number of patients without 
progression, i.e., with complete response, partial response, or stability) under regorafenib treatment, according to the 
investigator (RECIST v1.1), 2 months after the start of treatment. 
 
1.1.2 
Secondary objectives 
 
Secondary objectives are : 
• 
1-year Overall Survival 
• 
1-year Progression-Free survival 
• 
Disease control at 2 months (centralized review) 
• 
Objective response evaluated according to best response under treatment 
• 
Time to therapeutic failure 
• 
Time to autonomy degradation 
• 
Time to quality of life deterioration 
• 
 Geriatric prognostic and predictive parameters 
• 
Dose-intensity and its correlation to disease control 
• 
Safety of regorafenib (NCI-CTC AE version 4.0)  
 
1.1.3 
Exploratory studies 
 
The objective is to search for predictive factors of response and progression-free survival under regorafenib treatment. 
An analysis of the evolution of geriatric parameters during the follow-up will also be performed.Plan expérimental 
 
1.2 Study design 
 
Phase II open-labelled study , multicenter 
 
1.3 Treatment 
 
The dose of regorafenib is 160 mg (4 x 40 mg tablets) taken orally daily (21 days of treatment and 7 days without 
treatment, i.e. 28-day cycles). 
 
1.4 Sample Size calculation 
 


 
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Clinical hypotheses are based on data from the CORRECT study and are as follows:  
H0: A tumor control rate at 2 months after the start of treatment of 25% or less is not sufficient.  
H1: A tumor control rate at 2 months after the start of treatment of more than 25% is considered sufficient. A 
rate of 47% is expected.  
With a one-sided risk α of 5% and power of 90%, 42 patients are needed. 
Patients who stop the study before documented tumor progression at 2 months will be considered non-responders 
for the primary endpoint analysis.  
 
The decision rules after inclusion of 42 patients are: 
• 
If 15 or fewer patients have a complete or partial response or stability then the treatment will be considered 
non-effective. 
• 
If 16 or more patients have a complete or partial response or are stable, then the treatment will be 
considered effective. 
 
1.5 Analyses planning 
 
Analyses will be done once 
 
1.6 Adjustments 
 
Adjustments may be made to this analyses plan in the event of amendments to the protocol, or if phenomena not 
initially foreseen require statistical adaptations. In all cases, these modifications must be made before the database 
is frozen. 
2 Study populations 
 
2.1 Analyses populations 
 
2.1.1 
Intent-to-treat population (ITT) 
The intention-to-treat population is defined as all patients included in the study, regardless of eligibility criteria. 
 
2.1.2 
Modified Intent-to-treat population (ITTm) 
The modified intention-to-treat population is defined as all patients included in the study who received at least one 
regorafenib tablet and had at least one imaging assessment under protocol treatment. 
 
2.1.3 
Safety population (PT) 
The safety population is defined as all patients included in the study who received at least one regorafenib tablet. 
 
3 Statistical Generalities 
 
Analyses will be done by CRGA. 


 
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3.1 Software 
Statistical analyses will be performed with SAS software version 9.4. Some graphs can be made with R software version 
2.11 or later. 
 
3.2 Conventions   
Time since inclusion will be defined as the time elapsed since the day of inclusion, with the day of inclusion being 
considered as day 1. 
Therefore, the durations will be calculated according to the following rule, e.g. for the time from death to inclusion: day 
of death - day of inclusion + 1. 
The day before the day of inclusion (resp. the day before the day of treatment) will be considered as day -1 (day 0 does 
not exist). 
 
The date of last news will be the date of the last examination performed or the last treatment or the last medical 
consultation/visit. 
The following conversion rules will be used for the conversion of the number of days to months or years: 1 month = 
30.4375 days; 1 year = 365.25 days. 
 
3.3 Conventions for missing data 
 
Except in the cases specified, missing data will not be replaced. 
 
3.4 Baseline definition 
 
Baseline measurements will be the last measurement taken prior to inclusion or the last measurement taken prior to the 
first administration of treatment. 
3.5 Statistics 
 
The confidence intervals provided will be two-sided 95% confidence intervals except for the primary criterion where the 
calculated confidence interval will be a one-sided 95% confidence interval. 
 
Quantitative data will be described using the following descriptive statistics: number, mean, standard deviation, median, 
first and third quartile, and minimum and maximum. These statistics will be considered the usual statistics for the 
analysis of quantitative variables. Quantitative variables may be categorized using their median or a cut-off known from 
the medical literature. 
 
Categorical variables will be summarized using the following descriptive statistics: the number, frequencies and 
percentages for each level of the variable. These statistics will be considered the usual statistics for the analysis of 
categorical variables. 
When necessary, the 95% confidence intervals for the proportions can be calculated from the exact binomial distribution. 
  


 
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Survival data will be estimated and plotted using the Kaplan Meier method (Kaplan and Meier., 1958). They will be 
described by the median and rates calculated at different time points with their two-sided 95% confidence intervals. 
Confidence intervals for the rates will be constructed from the Greenwood variance calculated using the log-log 
transformation.   
 
Median follow-up time will be estimated using the inverse Kaplan-Meier method (Shemper, 1996). 
  
As an exploratory measure, for uni and multivariate analyses, the hazard ratios will be estimated using a Cox model (Cox, 
1984). The hypothesis of proportionality of the rates will be tested using the graphical representation and the test based 
on Schöenfeld's residuals (Grambsch, 1994); the linearity of the effect of the continuous variables on the risk will be 
evaluated from the graphical representation of the martingale residuals. Confidence intervals for the coefficient estimates 
of the Cox models will be calculated using the Wald method. 
 
 


 
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4 Analyses statistiques 
 
ITT 
Population 
ITTm 
Population 
Population de 
tolérance 
Baseline description 
 
 
 
Eligibility 
X 
 
 
Demographics 
X 
 
 
Clinical characteristics 
X 
 
 
Biological characteristics 
X 
 
 
Disease characteristics 
X 
 
 
Main criterion 
 
 
 
Tumoral control 
X 
 
 
Critères secondaires 
 
 
 
Follow-up time 
X 
 
 
OS, PFS 
X 
 
 
Tumoral control (Centralised review) 
X 
 
 
Objective response 
X 
 
 
Time to therapeutic failure 
X 
 
 
Time to autonomy deterioration 
X 
 
 
Time to QOL deterioration 
X 
 
 
Safety 
 
 
 
Treatment 
 
 
X 
Toxicities 
 
 
X 
 
4.1 Baseline characteristics 
 
4.1.1 
Eligibility 
 
Population : ITT 
Patient eligibility at inclusion will be described by:  
• 
The number and percentage of patients who met all inclusion criteria 
• 
Number and percentage of patients who met all non-inclusion criteria 
• 
Number and percentage of patients who met all inclusion and non-inclusion criteria 
 
4.1.2 
Demographics 
 
Population : ITT 
Following characteristics will be described : 
▪ Age (years) ; 
▪ Number of patients per center ; 
▪ Sex  
 


 
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4.1.3 
Clinical characteristics 
 
Population : ITT 
Following characteristics will be described : 
▪ Weight (kg) ; 
▪ ECOG (0 vs 1) ; 
▪ Geriatric assessment (yes/no) before starting treatment 
▪ ADL and IADL   
▪ Köhne Score 
Definition :  
Low :  
o 
OMS 0-1 and only one metastatic site 
Intermediate :  
o 
OMS 0-1 and more than one metastatic site and PAL ≤ 300 U/L 
o 
OMS >1 and white blood cells ≤ 10 x 109/L and only one metastatic site  
High :  
o 
OMS 0-1 and more than one metastatic site and PAL > 300 U/L 
o 
OMS >1 and white blood cells > 10 x 109/L 
o 
OMS >1 and white blood cells ≤ 10 x 109/L and more than one metastatic site 
 
 
4.1.4 
Biological characteristics 
 
▪ Haemoglobin (g/dL) 
▪ Creatinin (µmol/L) 
▪ PAL (Ul/L) 
▪ Leucocytes (/mm3) 
▪ CEA (µg/L) 
 
4.1.5 
Disease characteristics 
 
Population : ITT 
Following characteristics will be described : 
▪ Time between primary tumor diagnosis and study inclusion (months) 
▪ Time between metastatic diagnosis and study inclusion (months) 
▪ Primary tumor Localization   
▪ Primary tumor  resection   
▪ Metastatic localization  
▪ BRAF status 
▪ RAS status 
▪ MSI/MSS status 
▪ Previous treatment and description  


 
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4.2 Follow-up 
 
4.2.1 
Definition 
Population : ITT 
Median follow-up time is defined as the time interval between the date of inclusion and the date of last news (patients 
alive or lost to follow-up) or the date of death (regardless of cause). 
4.2.2 
Evaluation  
The median follow-up time (for alive patients) and its 95% confidence interval will be calculated in months. It will be 
estimated by the inverse Kaplan Meier method. 
 
4.3 Main efficacy criterion 
 
Population : ITTm 
 
4.3.1 
Definition 
 
The primary endpoint is to evaluate the tumor control rate. It is defined as the percentage of patients with a complete, 
partial or stable tumor response 2 months after the start of treatment according to the investigator's RECIST v1.1 criteria.  
 
Patients who stopped treatment (due to radiological progression or death) before 2 months after the start of treatment 
will be considered as having failed tumor control. Discontinuations for other causes will be reviewed on a case-by-case 
basis; verify that the patient has not taken any subsequent treatment between the date of discontinuation and the date 
of imaging.  In case of clinical progression, if no imaging is available, the patient will be considered to have failed tumor 
control; otherwise, review the medical record to determine the reason for the clinical progression. 
 
If imaging at 2 months is not available but imaging before 2 months is done then:  
▪ 
Patients with radiological and/or clinical progression on a previous evaluation will be considered to have failed 
tumor control at 2 months. 
▪ 
Patients who have died (regardless of cause) before 2 months will be considered to have failed tumor control. 
 
If 2-month imaging is not available, subsequent imaging will be reviewed if available and the patient record will be 
reviewed. 
 
4.3.2 
Evaluation  
 
The primary endpoint will be assessed on the ITTm population. This criterion will be described according to the usual 
descriptive statistics. A one-sided 95% confidence interval will be calculated using the exact method. 
 
The decision rules to be applied on 42 patients evaluable during the analysis (ITTm population) are :  
- If 15 or less patients have a complete or partial response or stability, then the treatment is judged not effective.   
- If 15 or more patients have a complete or partial response or are stable, then the treatment is considered effective.   
These may be adjusted based on the actual number of evaluable patients included.  


 
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4.4 Secondary efficacy criteriaa 
 
4.4.1 
Overall Survival 
 
4.4.1.1 
Definition 
It is defined as the time interval between the date of inclusion and the date of death (regardless of cause). 
Patients lost to follow-up or alive at the time of analysis will be censored at the date of last news. A minimum follow-up 
of 1 year for the last included patient is required. 
4.4.1.2 
Evaluation  
The time scale considered will be the month. 
Overall survival will be plotted using the Kaplan Meier estimator and survival rates at different time points (3, 6, 9, 12 
and 18 months) will be calculated along with their 95% confidence intervals. 
 
4.4.2 
Tumoral control (centralised review) 
 
4.4.2.1 
Definition 
It is defined as the percentage of patients with a complete, partial, or stable tumor response at 2 months after the start of 
treatment as assessed by centralized review according to RECIST v1.1 criteria.  
Patients who have stopped treatment before the 2-month assessment will be considered as having failed tumor control. 
 
4.4.2.2 
Evaluation   
This criterion will be described according to the usual descriptive statistics. A one-sided 95% confidence interval will be 
calculated using the exact method. 
 
4.4.3 
Objective response 
 
4.4.3.1 
Definition 
It is defined as the percentage of patients in objective response, i.e., complete response (CR) or partial response (PR) as 
assessed by the investigator according to RECIST v1.1 criteria. The objective response will be determined from the best 
response during treatment assessments. Patients who discontinue treatment without response assessment will be 
considered as having no objective response.  
 
4.4.3.2 
Evaluation  
Objective tumor response rates will be described according to standard descriptive statistics. 
 
4.4.4 
Time to therapeutic failure 
 
4.4.4.1 
Definition 
It is defined as the time between the date of inclusion and the date of treatment discontinuation (regardless of cause). 
Living patients without treatment discontinuation will be censored at the date of last treatment administration. 


 
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4.4.4.2 
Evaluation   
The time scale considered will be months. 
The time to treatment failure will be plotted using the Kaplan Meier estimator and the rates at 6, 9, 12, 18 months will be 
calculated along with their 95% confidence intervals. 
 
4.4.5 
Progression-Free Survival 
 
4.4.5.1 
Definition 
Elle est définie comme l’intervalle de temps entre la date d’inclusion et la date de 1ère progression radiologique et/ou 
clinique selon l’investigateur ou la date de décès (quelle qu’en soit la cause). Les patients vivants et sans progression 
seront censurés à la date de dernières nouvelles. Un minimum d’un an pour le dernier patient inclus est nécessaire. 
 
4.4.5.2 
Evaluation de la survie sans progression 
L’échelle de temps considérée sera le mois. 
La survie sans progression sera représentée graphiquement grâce à l’estimateur de Kaplan Meier et les taux de survie à 
différentes temporalités (6, 9, 12 et 18 mois) seront calculés ainsi que leurs intervalles de confiance à 95 %. 
 
4.4.6 
Time to autonomy deterioration 
The analysis will be done if we have the questionnaire at baseline and at least one follow-up for the majority of patients. 
 
4.4.6.1 
Definition 
It is defined as the time between the date of inclusion and the date on which the IADL score decreased by at least one 
point from the score at inclusion. Patients alive or deceased without deterioration of autonomy will be censored at the 
date of last IADL assessment or the date of death. 
 
4.4.6.2 
Evaluation   
The time scale considered will be the month. 
The time to degradation of autonomy will be plotted using the Kaplan Meier estimator and the 6, 9, 12, 18 month rates 
will be calculated along with their 95% confidence intervals. 
 
4.4.7 
Time to QOL deterioration 
 
The analysis will be done if we have the questionnaire at baseline and at least one follow-up for the majority of patients. 
4.4.7.1 
Definition 
It is defined as the time between the date of inclusion and the date of deterioration of the Spitzer QoL Index by 2 points 
from the score at inclusion. Patients alive or deceased without deterioration will be censored at the date of last QoL 
assessment or the date of death. 
 
4.4.7.2 
Evaluation   
The time scale considered will be the month. 
The time to deterioration of quality of life will be plotted using the Kaplan Meier estimator, and the 6-, 9-, 12-, and 18-
month rates will be calculated along with their 95% confidence intervals. 


 
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4.5 Safety 
Population : ITTm 
Safety will be evaluated by:  
▪ 
Duration of treatment, doses received, dose reductions, and deferrals; 
▪ 
Toxicities described according to NCI-CTC version 4.0 criteria; 
▪ 
Number and description of SAEs 
 
4.5.1 
Regorafnib 
 
4.5.1.1 
Treatment duration 
Treatment duration will be described by: 
▪ 
The number of cycles per patient; 
▪ 
The duration of treatment (converted into months) will be calculated by the formula 
Date last tablet taken - date first tablet taken + 1d 
▪ 
The therapeutic breaks and the days without taking tablets during this period will not be subtracted from this 
duration. 
It will be described according to the usual descriptive statistics. 
 
4.5.1.2 
Doses 
Compliance will be calculated according to the formula: 
(Cumulative dose received (in mg) / theoretical protocol dose (in mg)) x 100 
The protocol treatment dose is 4 tablets of 40 mg per day, i.e. 160 mg per day (21 days of treatment and 7 days without 
treatment, i.e. cycles of 28 days).  
 
Compliance will be described according to the usual descriptive statistics. 
 
4.5.1.3 
Postponement of cures, modification of administration and reason 
▪ 
The number and percentage of patients with at least one deferral of treatment and the reasons for these deferrals      
▪ 
The number of patients who had at least one dose change will be described. The causes of dose modifications 
will be presented. A listing of others will be provided. 
▪ 
The number and percentage of patients who have permanently stopped the protocol treatment and the reasons 
for stopping treatment will be described.    
 
All parameters will be described according to standard descriptive statistics. 
 
4.5.1.4 
Subsequent lines 
▪ 
The number of patients who received a subsequent line and subsequent patterns will be described. 
▪ 
The number of patients who had resection of the primary and metastases and the outcome of the resection will 
be described. 
 
All parameters will be described according to standard descriptive statistics. 
 


 
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4.5.2 
 Toxicities 
 
On-treatment toxicities will be described according to NCI-CTC version 4.0 criteria by: 
▪ 
The number and percentage of patients who experienced at least one toxicity over all courses of treatment by 
grade; 
▪ 
The number and percentage of patients who experienced at least one maximum grade 3-4-5 toxicity over all 
courses or at least one maximum grade 1-2 toxicity; 
▪ 
Toxicities will be described according to causality to treatment and by SOC (by preferred term). 
▪ 
The number of toxicities that resulted in an SAE 
 
4.5.3 
SAEs 
A summary of the SAEs will be provided by pharmacovigilance. 
 
4.6 Exploratory analyses 
 
4.6.1 
Definition 
The exploratory analysis will investigate the predictive factors for response, overall survival, and progression-free 
survival with regorafenib therapy.  
 
Prior to any inferential analysis, descriptive statistics of the predictive factors will be performed to assess the feasibility 
of this analysis. 
 
The variables for which the p-value is lower than 0.20 in univariate analysis or judged clinically relevant among the list 
to be defined will be retained for the multivariate analysis. The prognostic factors studied will be the geriatric parameters. 
4.6.2 
Evaluation  
For univariate and multivariate analyses, hazard ratios will be estimated using a Cox model (Cox, 1984). The 
proportionality of the rates will be tested using the graphical representation and the test based on Schöenfeld's residuals 
(Grambsch, 1994); the linearity of the effect of the continuous variables on the risk will be assessed from the graphical 
representation of the martingale residuals. Confidence intervals for the coefficient estimates of the Cox models will be 
calculated using the Wald method. 
 
Several multivariate models can be constructed. The comparison of the different models obtained will be carried out 
according to a measure of adequacy of the model (AIC), a measure of calibration (O'Quigley's R²) and a measure of 
accuracy (Breier score). 
 
In an exploratory way, in order to study the temporal evolution of geriatric and quality of life scores (Spitzer QoL Index, 
IADL, ...), mixed models of analysis of variance for repeated measures of each of the scores will be carried out.