Conditions: Neuroendocrine Tumors Hepatic Metastases Metastases
Keywords: cancer neuroendocrine tumors gastrointestinal tract metastases liver hepatic
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 74
Healthy volunteers: no

Brief summary:
Determine wether 24 months treatment with everolimus prolongs progression free survival rate (based on a central assessment) after embolisation ou chemoembolisation for liver metastases.

* H0 a 24 months progression free survival rate less than 35% is unacceptable
* H1 a 24 months progression free survival rate greater than 35% would show that everolimus treatment is beneficial, the expected 24 months progression free survival rate being 50%

Detailed description:

Arms:
arm 1: After 2 sessions of embolization with microsphere of 100 to 500 µm or chemoembolization with 100 mg of doxorubicine and 10 ml of lipiodol, administered every day, 10 mg of everolimus during 24 months or until progression (hepatic and other site).

Interventions: intervention 1: Everolimus intervention 2: embolization intervention 3: Doxorubicin
Intervention descriptions: intervention 1: 10 mg per day of everolimus during 24 months or until progression disease intervention 2: 2 sessions embolization with spheric particles intervention 3: 2 sessions chemoembolization with 10 mg of lipiodol with 100 mg of doxorubicine

Protocol document:
Prot_000.pdf: 
FFCD 1104-EVACEL 
 
 
 
 
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FFCD 1104 - EVACEL 
EVEROLIMUS AS A TREATMENT AFTER EMBOLISHMENT OR 
CHEMIOEMBOLIZATION OF HEPATIC METASTASIS OF DIGESTIVE ENDOCRINE 
TUMOR  
PHASE II - MONOBRAS- MULTICENTER 
 
Eudract number: 2012-002224-32 
 
 
COORDINATOR : 
Dr Thomas WALTER 
 
 
 
 
EDOUARD HERRIOT 
Medical Oncology Department CHU LYON  
Hôpital Edouard Herriot  
Oncology Department  
Pavillon E5 - 5 Place Arsonval  
69437 LYON 
Tel: 04 72 11 00 94- Fax: 04 72 11 91 53 
E-mail : thomas.walter@chu-lyon.fr 
 
 
CO-COORDINATOR:  
Pr Thierry de Baere 
Imaging Department - Therapeutic Imaging 
Gustave Roussy Institute 
39 rue Camille Desmoulins 
94805 VILLEJUIF 
Tel: 01 42 11 54 28 - Fax: 01 42 11 52 78 
E-Mail: debaere@igr.fr 
 
  
 
Protocol Writing Committee: 
Thierry de Baere, Michel Ducreux, Olivia Hentic, Karine Le Malicot, Catherine Lombard-Bohas, Emmanuel 
Mitry, Marie Moreau 
 
PROMOTER AND RANDOMIZATION-GESTION-ANALYSIS CENTER (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: 03 80 66 80 13 - Fax: 03 80 38 18 41 
 
 
 
 
 
E-mail: cecile.girault@u-bourgogne.fr 
 
 
Statistician :   
 
Karine LE MALICOT 
 
 
 
 
 
Tel: 03 80 39 34 71 - Fax: 03 80 38 18 41 
 
 
 
E.mail: karine.le-malicot@u-bourgogne.fr  
 
Project manager:  
 
 
Marie MOREAU 
 
 
 
 
Tel: 03 80 39 34 04 - Fax: 03 80 38 18 41 
 
 
 
 
 
Email : marie.moreau@u-bourgogne.fr 
 
Data manager FFCD :  
 
Carole MONTERYMARD 
 
Subscribe to DeepL Pro to edit this document. 
Visit www.DeepL.com/profor more information. 


FFCD 1104-EVACEL 
 
 
 
 
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Tel: 03 80 39 34 84 - Fax: 03 80 38 18 41 
 
 
 
 
 
Email : carole.monterymard@u-bourgogne.fr 
 
 
 
 
SUMMARY 
I. 
OBJECTIVES OF THE TRIAL ............................................................................................................................................. 11 
1. 
Main objective ........................................................................................................................................................................ 11 
2. 
Secondary objectives .............................................................................................................................................................. 11 
II. 
PATIENT SELECTION ......................................................................................................................................................... 11 
1. 
Inclusion criteria .................................................................................................................................................................... 11 
2. 
Non-inclusion criteria ............................................................................................................................................................ 12 
III. 
INCLUSION ASSESSMENT ................................................................................................................................................. 12 
IV. 
INCLUSION............................................................................................................................................................................. 13 
V. 
THERAPEUTICAL SCHEME .............................................................................................................................................. 13 
VI. 
TREATMENT ......................................................................................................................................................................... 13 
VII. EXPECTED TOXICITIES AND DOSE ADJUSTMENT ................................................................................................... 18 
1. 
Dose adjustment after the first embolization or chemoembolization................................................................................. 18 
2. 
Everolimus dose adjustment ................................................................................................................................................. 18 
a. 
Dose adjustment for non-hematologic and hematologic toxicities ....................................................................................... 19 
b. 
Known adverse effects of everolimus ................................................................................................................................... 21 
c. 
Management of stomatitis/ oral mucositis/ mouth ulcers ..................................................................................................... 22 
d. 
Management of hyperlipidemia and hyperglycemia ............................................................................................................. 22 
e. 
Management of non-infectious lung disease ......................................................................................................................... 22 
f. 
Management of a hepatitis reactivation/flare-up .................................................................................................................. 25 
 
Hepatitis C Outbreak Surveillance ....................................................................................................................................... 26 
VIII. MONITORING OF PATIENTS DURING TREATMENT AND AFTER TERMINATION OF TREATMENT .......... 27 
1. 
Monitoring during treatment ................................................................................................................................................ 27 
2. 
Monitoring after discontinuation of the protocol treatment .............................................................................................. 28 
IX. 
DISCONTINUATION OF THE STUDY ............................................................................................................................... 28 
X. 
CENTRALIZED PROOFREADING OF TDM .................................................................................................................... 28 
XI. 
MANAGEMENT OF SERIOUS ADVERSE EVENTS (SIA) ............................................................................................. 28 
XII. STATISTICAL ANALYSIS ................................................................................................................................................... 30 
1. 
Provisional schedule of the study .......................................................................................................................................... 30 
2. 
Analysis ................................................................................................................................................................................... 30 
Main criterion ................................................................................................................................................................................. 30 
Secondary criteria ........................................................................................................................................................................... 31 
Calculation of the number of subjects needed ................................................................................................................................. 31 
3. 
Statistical Analysis Plan ......................................................................................................................................................... 31 
4. 
Independent Committees ....................................................................................................................................................... 32 
XIII. JUSTIFICATION OF THE TEST ......................................................................................................................................... 32 
XIV. LEGAL AND ETHICAL ASPECTS ADMINISTRATIVE CONSIDERATIONS ............................................................ 35 
XV. PUBLICATION RULES ......................................................................................................................................................... 36 
XVI. APPENDICES .......................................................................................................................................................................... 36 
APPENDIX 1: INFORMATION NOTE AND CLINICAL CONSENT ................................................... Erreur ! Signet non défini. 
ANNEX 2: CLASSIFICATION OF NEUROENDOCRINE TUMORS - WHO 2010 ............................. Erreur ! Signet non défini. 
APPENDIX 3: RECIST CRITERIA V1.1 ................................................................................................... Erreur ! Signet non défini. 
APPENDIX 4: TOXICITY ASSESSMENT - NCI-CTC SCALE Version 4.0 ......................................... Erreur ! Signet non défini. 
APPENDIX 5: WHO - Calculation of clearance ......................................................................................... Erreur ! Signet non défini. 
APPENDIX 6: PRODUCT CHARACTERISTICS SUMMARY Everolimus, (Afinitor ®), Doxorubicin, Streptozotocin, 
Lipiodol .......................................................................................................................................................... Erreur ! Signet non défini. 


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APPENDIX 8: FFCD PUBLICATION RULES ......................................................................................... Erreur ! Signet non défini. 
APPENDIX 9: CERTIFICATE OF INSURANCE .................................................................................... Erreur ! Signet non défini. 
ANNEX 10: OPINION OF THE COMMITTEE FOR THE PROTECTION OF INDIVIDUALS (CPP) ....... Erreur ! Signet non 
défini. 
APPENDIX 11: ANSM (formerly AFSSAPS) AUTHORIZATION ......................................................... Erreur ! Signet non défini. 
 
 
 


FFCD 1104-EVACEL 
 
 
 
 
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CONTACTS FFCD 
 
  
 
 
NAME 
FUNCTION 
PHONE 
TELECOPIE 
E-MAIL 
ADMINISTRATIVE MANAGEMENT  
Cécile GIRAULT 
Administrative 
Director 
03 80 39 33 87 
03 80 38 18 41 
cecile.girault@u-bourgogne.fr 
Martina SCHNEIDER 
Assistant 
Administrative 
Director 
03 80 39 34 83 
03 80 38 18 41 
martina.schneider@u-bourgogne.fr 
Aurélie DUBREU 
Executive secretary 03 80 38 13 14 
03 80 39 34 85 
Aurelie.Dubreu@u-bourgogne.fr 
RANDOMIZATION CENTER - MANAGEMENT - ANALYSIS 
Karine LE MALICOT 
Statistician 
03 80 39 34 71 
03 80 38 18 41 
karine.le-malicot@u-bourgogne.fr 
Emilie MAILLARD 
Statistician 
03 80 39 34 81 
03 80 38 18 41 
emilie.maillard@u-bourgogne.fr 
Fadil MASSKOURI 
Data Manager 
03 80 39 34 05 
03 80 38 18 41 
fadil.masskouri@u-bourgogne.fr 
Carole 
MONTERYMARD 
Data Manager/Stat 
03 80 39 34 84 
03 80 38 18 41 
carole.monterymard@u-
bourgogne.fr 
Elodie GAUTIER 
Data Manager/Stat 
03 80 39 34 53 
03 80 38 18 41 
elodie.gautier@u-bourgogne.fr 
Charles FUCHEY 
Data Manager 
03 80 39 34 05 
03 80 38 18 41 
Charles.Fuchey@u-bourgogne.fr 
Marie MOREAU 
Project Manager 
03 80 39 34 04 
03 80 38 18 41 
marie.moreau@u-bourgogne.fr 
Jaïque CARIO 
Assistant Project 
Manager 
03 80 39 34 86 
03 80 38 18 41 
jcario@u-bourgogne.fr 
Géraldine VAUDRIT 
Assistant Project 
Manager 
03 80 39 33 86 
03 80 38 18 41 
Geraldine.Vaudrit@u-bourgogne.fr 
Gaëlle DELIGNETTE 
Assistant Project 
Manager 
03 80 39 34 86 
03 80 38 18 41 
Gaelle.Delignette@u-bourgogne.fr 
Caroline CHOINE-
POURRET 
ARC coordinator 
04 69 18 19 02 
09 74 44 22 47 
ffcd.choinecaroline@sfr.fr 
FFCD ARC Team 
Florence GUILIANI-
KPODOH 
Hicham FATTOUH 
Nicolas LE 
PROVOST 
 
E-mail and telephone contact 
information in the investigator's 
binder 
Nouredine LASMI 
Guillaume 
ARNOULD 
 
 


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PROTOCOL AGREEMENT AND BPC 
 
FFCD 1104 - EVACEL 
EVEROLIMUS AS A TREATMENT AFTER EMBOLISHMENT OR 
CHEMIOEMBOLIZATION OF HEPATIC METASTASIS OF DIGESTIVE ENDOCRINE 
TUMOR  
PHASE II - MONOBRAS- MULTICENTER  
EudraCT N°: 2012-002224.32 
Version 1.1 of 15.04.2013 amendment 2-3 
 
This version of the protocol is approved by : 
 
The Promoter :   
Ms. Cecile GIRAULT  Date:  15.04.2013Signature 
: 
 
The Coordinator : Dr Thomas WALTER  
 
Date: 
04/15/2013Signature 
:                     
 
 
I, the undersigned, Doctor :   .........................................................................  
 
 
 
 
After having read the requirements of this research, the protocol and its annexes, I hereby certify that I will 
conduct this trial in accordance with Good Clinical Practice and in compliance with the applicable provisions 
of the Public Health Code. 
 
In particular, I agree to: 
• 
comply with the protocol and any modifications notified to it by the promoter 
• 
agree to supervise research in the center and to train collaborators in the conduct of research and 
provides a list of names.  
• 
have each patient sign a written consent after having read the information note intended for him/her, 
before any research is carried out 
• 
Report serious adverse events or developments within 24 hours of learning of them, and as specified 
in the research protocol 
• 
respect the inclusion and non-inclusion criteria, as well as the start and end dates of the study 
• 
participate in the translational part of the study subject to the patient's signature of the specific consent 
and to send the samples according to the recommendations,  
• complete all the items in the observation book, ensure the quality of the data collection and the proper 
management of the products  
• 
retain research data and documents until notified by the sponsor that they are no longer required  
• 
inform the sponsor of any conflict of interest situation that may affect its scientific independence in 
the context of the research 
• 
inform the sponsor without delay of any action, whether amicable or contentious, brought by a person 
involved in the research or his or her beneficiaries, which may call into question the sponsor's liability 
• 
accept periodic visits from the sponsor's representatives, and make available to them all source 
documents and materials relating to the research in order to ensure quality control of the data recorded 
in the case report form. The investigator accepts control in the form of an audit by the sponsor and/or 
inspection by the health authorities.  
• 
respond by phone or mail to requests for corrections or clarifications regarding the observation book, 
• 
Allow time for the ARC FFCD to sign the forms, answer any questions and take action 
 
Date:  
 
 
 
           Signature: 
 
 
 
 
 
CENTER STAMP: 
 
 
Send the original to the CRGA of the FFCD - 7 bd Jeanne d'Arc - BP 87900 - 21079 Dijon Cedex 
 
 


FFCD 1104-EVACEL 
 
 
 
 
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LIST OF ABBREVIATIONS USED IN THE TEXT 
 
AFSSAPS :  French agency for the sanitary safety of health products 
ALAT : alanine amino transferase 
ANSM :  
National Agency for the Safety of Medicines and Health Products 
ASAT :  
aspartate amino transferase 
CPP :   
Committee for the Protection of Persons 
CRGA:  
Centre for Randomization, Data Management and Analysis 
ECG :   
electrocardiogram 
INR :  
International Normalized Ratio 
IV : 
 
intravenous 
LNS :  
upper limit of normal 
PNN :   
neutrophilic polynuclear cells 
RCP :  
multidisciplinary consultation meeting 
TAP :  thoracoabdomino-pelvic 
APTT :  
 
activated partial thromboplastin time  
CT : 
 
CT scan 
NET :   
neuroendocrine tumor 
PT :   
prothrombin rate 
5HIAA : 
5-hydroxyindoleacetic acid 
 
 
 
 
 
 
 
 
 
 
 
 


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SYNOPSIS 
Essay title:  
 
EVEROLIMUS AS A TREATMENT AFTER EMBOLISHMENT OR 
CHEMIOEMBOLIZATION OF HEPATIC METASTASIS OF 
DIGESTIVE ENDOCRINE TUMOR  
PHASE II - MONOBRAS- MULTICENTER   
Trial number 
FFCD 1104 - EVACEL 
Developer 
French-speaking Federation of Digestive Oncology (FFCD) 
Coordinator(s) 
Dr Thomas WALTER 
Objectives 
Principal:  
The primary objective of the study is to determine whether treatment with 
everolimus for 24 months prolongs progression-free survival according to 
RECIST 1.1 criteria. The primary endpoint will be progression-free survival at 
24 months in patients receiving hepatic embolization or chemoembolization 
followed by everolimus therapy. 
Secondary:  
- 
Progression-free survival at 24 months (hepatic and non-hepatic) 
- 
Overall survival at 24 months 
- 
Tolerance of the treatment during the 24 months of treatment   
Inclusion criteria  
- 
Histologically proven metastatic endocrine tumor of the gastrointestinal 
tract (TENPATH review mandatory), well differentiated (grade 1 and 2 
according to the WHO 2010 classification, appendix 2) 
- 
Predominantly hepatic involvement compared to other metastatic 
locations requiring embolization or chemoembolization 
- 
Hepatic metastasis(es) measurable according to RECIST V1.1 criteria, 
unresectable or not accessible to local radiofrequency treatment 
- 
Indication, validated in RCP, for hepatic arterial embolization or 
chemoembolization for antitumor purposes due to the progressive nature 
of liver metastases (morphological progression over the last 12 months 
according to RECIST V1.1 criteria) 
- 
Age ≥ 18 years 
- 
General condition WHO ≤ 2  
- 
Adequate biological workup: 
o Neutrophils ≥ 1,500/mm3 , platelets ≥ 100,000/mm, Hb > 10 g/dL 
o Serum bilirubin ≤ 1.5 x upper normal limit (UL), INR < 1.3 (or 
< 3 on anticoagulants), ALT and AST ≤ 5 x UL  
o PAL < 5 N 
o Creatinine ≤ 1.5 x LNS 
o 24-hour proteinuria (for patients who will receive streptozotocin 
for chemoembolization) < 1.5 N  
o Fasting serum cholesterol ≤ 300 mg/dL or 7.75 mmol/L and 
triglycerides ≤ 2.5 x LNS (in the event that one or both of these 
thresholds are exceeded, the patient can be included in the study 
only after initiation of appropriate lipid-lowering therapy) 
- 
Complete resolution or persistence with a maximum grade of 1 (except 
for transaminases or INR if anticoagulant) of toxicities from any 
previous treatments (NCI CTC version 4.0)  
- 
Minimum time to previous treatment: 28 days 
- 
Information to the patient and signature of an informed consent, after 
verification of the eligibility criteria 
- 
Affiliation to a social security system 
Non-inclusion 
criteria  
 
- 
Duodeno-pancreatic endocrine tumor 
- 
Poorly differentiated and/or grade 3 endocrine tumor 


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- 
Indication for embolization or chemoembolization for symptomatic 
purposes only 
- 
Previous 
treatment 
with 
hepatic 
arterial 
embolization 
or 
chemoembolization 
- 
Previous treatment with an mTOR inhibitor (somatostatin analogues for 
anti-secretory purposes are allowed) 
- 
Symptomatic bone metastasis(es) 
- 
Any progressive unbalanced condition: hepatic insufficiency, renal 
insufficiency, respiratory insufficiency, congestive heart failure NYHA 
III-IV, unstable angina, myocardial infarction, significant arrhythmias  
- 
Interstitial lung disease 
- 
Patients with uncontrolled diabetes defined as HBa1C > 8  
- 
Patients receiving chronic corticosteroids or immunosuppressants 
- 
Hypersensitivity to everolimus, other rapamycin derivatives or any of 
the excipients 
- 
Major surgery, open biopsy, or significant traumatic injury within 28 
days prior to initiation of study treatment. Incompletely healed wound 
or anticipated need for major surgery during the course of the study 
- 
Patient with contraindication to vascular occlusion procedures 
o Portal thrombosis 
o Bilio-digestive anastomosis 
- 
HIV patients on antiretroviral therapy 
- 
Malignant pathology within the last 5 years except for basal cell skin 
carcinoma or cervical cancer in situ treated curatively 
- 
Pregnant or breastfeeding woman 
- 
Lack of effective contraception (for men or women of childbearing age) 
- 
Predictable non-compliance 
- 
Medical, geographical, sociological, psychological or legal situation that 
would prohibit the patient from completing the study or signing an 
informed consent 
- 
Concurrent patient participation in other experimental research that 
could influence the primary endpoint of the study 
Study design and 
treatment plan  
 
Hepatic arterial embolization or chemoembolization followed by 24 months of 
everolimus treatment. 
Possibility of performing hepatic arterial embolization alone or in combination 
with doxorubicin or streptozotocin chemotherapy. The modalities and the 
treatment plan (number of sessions planned to obtain a complete hepatic 
treatment, maximum 2 sessions authorized) must be defined before the patient's 
inclusion in the trial and specified in the report of the PCR. 
Everolimus (10 mg/d) will be started 7 days after embolization or 
chemoembolization or after improvement of liver toxicity to a grade ≤1. 
Treatment should not be initiated beyond 30 days after embolization or 
chemoembolization. 
Duration of everolimus treatment: 24 months after the first embolization or 
chemoembolization in the absence of unacceptable toxicity. 
In the situation where several embolization or chemoembolization sessions are 
planned, everolimus will be stopped for the time of the embolization or 
chemoembolization 
(stopped 
the 
day 
before 
the 
embolization 
or 
chemoembolization and restarted as described above) 
Morphological evaluation every 3 months by triphasic thoraco-abdomino-pelvic 
CT scan 
Statistical 
methods 
 
According to the literature, the median progression-free survival after 
embolization or chemoembolization ranges from 15 to 19 months with a 
progression-free survival rate of approximately 35%. As there is no information 


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on progression-free survival in the literature, the hypotheses were built on the 
progression-free survival data. 
 The assumptions used to calculate the number of subjects are as follows: 
H0: a 24-month progression-free survival rate of less than 35% is not acceptable  
H1: A 24-month progression-free survival rate of more than 35% would 
demonstrate the utility of adjuvant everolimus therapy with an expected 24-
month progression-free survival rate of 50%. 
To obtain a power of 80% with a first-species risk of 5% (one-sided), it is 
required to include 68 patients according to the assumptions established above 
(using the exact binomial distribution). 
Taking into account a rate of lost to follow-up or patients not evaluable for any 
reason except death, 72 patients will be included. 
The data will be described according to the usual methods detailed in the 
statistical analysis plan. The analysis will be performed on an intention-to-treat 
basis. 
Number of 
subjects needed 
72 patients 
Planned study 
period 
Expected start date of inclusion: November 2012 
Expected completion date of inclusion: April 2016 
Primary endpoint analysis: April 2018 
End of study: January 2019 
 


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EXAMINATION AND FOLLOW-UP SCHEDULE 
 
 
BEFORE 
TREATMENT 
DURING EMBOLIZATION OR 
CHEMOEMBOLIZATION   
DURING TREATMENT 
WITH EVEROLIMUS (24 
months maximum)  
AFTER STOPPING 
TREATMENT WITH 
EVEROLIMUS (after 24 
months)  
Within 4 
weeks prior to 
inclusion 
Within 7 days prior 
to each embolization 
or 
chemoembolization  
After embolization or 
chemoembolization  
Every 3 months +/- 1 
week 
Every 3 months +/- 1 
week   
Informed consent 
X 
 
 
 
 
CLINICAL EXAMINATION 
Weight, general condition WHO 
X 
X 
 
X 
X 
Functional 
symptoms 
related 
to 
hormonal 
hypersecretion  
X 
 
 
 
 
Medical and surgical history and treatments related to 
the endocrine tumor 
X 
 
 
 
 
MORPHOLOGICAL EXAMINATION 
Triphasic thoracoabdomino-pelvic CT (to be 
performed in the investigating center, without injection, 
arterial time, portal time) *with measurement of liver 
metastases according to RECIST v1.1 criteria 
X* 
 
X**  
X*  
X*** 
ECG ± cardiological opinion if necessary 
X 
 
 
 
 
BIOLOGICAL ASSESSMENT 
CBC/platelets, total and conjugated bilirubin, AST, 
ALT, PAL, creatinine, 24-hour proteinuria if treated 
with streptozotocin 
X 
X 
 
X 
 
INR, TCA 
X 
X 
 
X 
 
albumin, urea, blood ionogram, GGT  
X 
 
 
X 
 
Serum cholesterol and triglycerides, fasting blood 
glucose and HbA1c  
X 
 
 
X 
 
Chromogranin A, urinary 5HIAA  
X 
 
 
X 
 
B viral serology (HBV-DNA, HBsAg, anti-HBsAb, anti-
HBcAb) and C**** 
X 
 
 
X**** 
 
Pregnancy test for women of childbearing age 
X (within 7 days of 
starting treatment) 
 
 
 
 
*With target measurement according to RECIST v1.1 criteria  
**To be performed for technical reasons only. Measurements should not be used for evaluation of tumor response 
*** If everolimus is discontinued for reasons other than hepatic progression, continue morphological monitoring until hepatic progression occurs 
**** In case of B and C viral serology, follow up the DNA and RNA load respectively every 3 to 6 weeks (see table 2-2 and 2-3) 


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I. 
OBJECTIVES OF THE TRIAL 
1. 
Main objective 
The primary objective of the study is to determine whether treatment with everolimus 
for 24 months prolongs progression-free survival according to RECIST 1.1 criteria. The 
primary endpoint will be progression-free survival at 24 months in patients receiving 
hepatic embolization or chemoembolization followed by everolimus therapy. 
 
2. 
Secondary objectives 
Secondary objectives will be the 24-month assessment of: 
- 
Progression-free survival (hepatic and non-hepatic) 
- 
Overall survival 
- 
Tolerance of the treatment during the 24 months of treatment 
 
II. 
PATIENT SELECTION 
1. 
Inclusion criteria 
 
- 
Histologically proven metastatic endocrine tumor of the gastrointestinal tract 
(TENPATH review mandatory), well differentiated (grade 1 and 2 according to the 
WHO 2010 classification, appendix 2) 
- 
Predominantly hepatic involvement compared to other metastatic locations requiring 
embolization or chemoembolization 
- 
Hepatic metastasis(es) measurable according to RECIST V1.1 criteria, unresectable or 
not accessible to local radiofrequency treatment 
- 
Indication, validated in RCP, for hepatic arterial embolization or chemoembolization 
for antitumor purposes due to the progressive nature of liver metastases (morphological 
progression over the last 12 months according to RECIST V1.1 criteria) 
- 
Age ≥ 18 years 
- 
General condition WHO ≤ 2  
- 
No contraindication to embolization or chemoembolization  
- 
No contraindication to everolimus treatment 
- 
Adequate biological workup: 
o Neutrophils ≥ 1,500/mm3 , platelets ≥ 100,000/mm3 , Hb > 10 g/dL 
o Serum bilirubin ≤ 1.5 x upper normal limit (UL), INR < 1.3 (or < 3 on 
anticoagulants), ALT and AST ≤ 5 x UL  
o Creatinine ≤ 1.5 x LNS 
o 24-hour proteinuria (for patients who will receive streptozotocin for 
chemoembolization) < 1.5N  
o Fasting serum cholesterol ≤ 300 mg/dL or 7.75 mmol/L and triglycerides ≤ 2.5 
x LNS (in the event that one or both of these thresholds are exceeded, the patient 
can be included in the study only after initiation of appropriate lipid-lowering 
therapy) 
- 
Complete resolution or persistence with a maximum grade of 1 (except for 
transaminases or INR if anticoagulant) of toxicities from any previous treatments (NCI 
CTC version 4.0)  
- 
Minimum time to previous treatment: 28 days 
- 
Information to the patient and signature of an informed consent, after verification of the 
eligibility criteria 


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- 
Affiliation to a social security system 
 
2. 
Non-inclusion criteria  
 
- 
Duodeno-pancreatic endocrine tumor 
- 
Poorly differentiated and/or grade 3 endocrine tumor 
- 
Indication for embolization or chemoembolization for symptomatic purposes only 
- 
Previous treatment with hepatic arterial embolization or chemoembolization  
- 
Previous treatment with an mTOR inhibitor (somatostatin analogues for anti-secretory 
purposes are allowed) 
- 
Symptomatic bone metastasis(es) 
- 
Any progressive unbalanced condition: hepatic insufficiency, renal insufficiency, 
respiratory insufficiency, congestive heart failure NYHA III-IV, unstable angina, 
myocardial infarction, significant arrhythmias  
- 
Interstitial lung disease 
- 
Patients with uncontrolled diabetes defined as HbA1c > 8  
- 
Patients receiving chronic corticosteroids or immunosuppressants 
- 
Hypersensitivity to everolimus, other rapamycin derivatives or any of the excipients 
- 
Major surgery, open biopsy, or significant traumatic injury within 28 days prior to 
initiation of study treatment. Incompletely healed wound or anticipated need for major 
surgery during the course of the study 
- 
Patient with contraindication to vascular occlusion procedures 
o Portal thrombosis 
o Bilio-digestive anastomosis 
- 
HIV patients on antiretroviral therapy 
- 
Malignant pathology within the last 5 years except for basal cell skin carcinoma or 
cervical cancer in situ treated curatively 
- 
Pregnant or breastfeeding woman 
- 
Lack of effective contraception (for men or women of childbearing age) 
- 
Predictable non-compliance 
- 
Medical, geographical, sociological, psychological or legal situation that would prohibit 
the patient from completing the study or signing an informed consent 
- 
Concurrent patient participation in other experimental research that could influence the 
primary endpoint of the study 
 
III. 
INCLUSION ASSESSMENT  
 
• 
Within 4 weeks prior to the first embolization or chemoembolization and before 
inclusion   
 
o Complete clinical examination: weight, general condition WHO (Appendix 5), 
functional symptoms related to hormonal hypersecretion  
o Medical and surgical history and treatments related to the endocrine tumor 
o Biological workup (the biological workup for the first two points should be 
performed before inclusion and repeated 7 days before the 1ière embolization 
or chemoembolization if inclusion beyond 7 days):  
• 
CBC/platelets, urea and creatinine + calculated creatinine clearance 
(Cockcroft formula appendix 5), blood ionogram 
• 
INR, aPTT, albumin, alkaline phosphatases, AST, ALT, bilirubin (total 
and conjugated), gamma-GT, 24-hour proteinuria (for patients who will 
receive streptozotocin for chemoembolization) 


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• 
Serum cholesterol and triglycerides 
• 
Fasting blood glucose and HbA1c 
• 
B viral serology (test for HBsAg, if positive test for HBV-DNA, anti-
HBsAb, anti-HBcAb) and C 
• 
Chromogranin A, urinary 5HIAA 
• 
Pregnancy test for women of childbearing age (to be performed within 
7 days before the first day of treatment) 
o Triphasic thoracoabdomino-pelvic CT (without injection, arterial time, portal 
time) with measurement of liver metastases according to RECIST V1.1 criteria 
(Appendix 3). The examination must be performed in an expert center (ideally 
the investigating center). 
o ECG +/- cardiological consultation if necessary 
IV. 
INCLUSION  
 
Inclusion will be performed after the assessment to define eligibility and after signing the 
patient's informed consent.  
 
The inclusion number will be assigned by faxing the inclusion form in the observation booklet 
to the FFCD's Randomization - Management - Analysis Center (CRGA) in Dijon: FAX number: 
03 80 38 18 41. The CRGA is open from Monday to Friday from 9:00 am to 6:00 pm.  
 
At the same time, confirmation of inclusion will be sent to LC2, the company responsible for 
the distribution of everolimus, within 48 hours from Monday to Thursday.  
 
An advance observation booklet will be sent out at the opening of the center. An observation 
booklet will be sent after each inclusion.  
 
After inclusion, treatment should be started within 30 days after 1ière embolization or 1ière 
chemoembolization. 
 
V. 
THERAPEUTICAL SCHEME 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VI. 
TREATMENT 
 
1- Embolization or Chemoembolization 
 
INCLUSION 
INCLUSION 
REVIEW 
CPR 
 Embolization or 
chemoembolization for hepatic 
progression 
 Treatment plan specifying the 
number of sessions required to 
obtain a complete treatment of 
the liver (1 to 2 sessions) 
Embolization or 
chemoembolization 
(1 to 2 sessions) + 
Everolimus (10 mg/d) 
 
Everolimus 
(10 mg/d for 24 
months or until 
progression)  
+  
Morphological 
evaluation every 3 
months 


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Possibility of performing hepatic arterial embolization alone or associated with chemotherapy 
with doxorubicin or streptozotocin. 
The two embolization or chemoembolization sessions should be spaced 4 to 8 weeks apart.  
The modalities and the treatment plan (number of sessions planned to obtain a complete hepatic 
treatment, maximum 2 sessions authorized) must have been defined before the inclusion of the 
patient in the trial and specified on the report of the PCR. 
When 2 embolization or chemoembolization sessions are planned, a CT scan may be performed 
before the 2ème session if necessary for technical reasons. This CT scan should not be used to 
evaluate the tumor response. 
 
DESCRIPTION OF THE TECHNIQUE 
 
Pre-therapeutic angiography should always be performed to confirm portal system patency and 
tumor hypervascularity and to rule out a significant arteriovenous shunt.  
Identification and protection of the cystic and gastric arteries is recommended. 
 
We will always try to favor chemoembolization versus simple embolization. If the choice is 
simple embolization, it should be performed with particles of 500 microns maximum and until 
complete stagnation in the targeted arteries. 
 
Desirable doses for chemoembolization injections 
- 
100 mg doxorubicin (reconstituted in 5 mL or the smallest possible volume of fluid). 
Doxorubicin may be reconstituted in X-ray contrast medium to increase density and promote 
emulsion stability or 1500 mg of streptozotocin  
- 
10 ml of lipiodol ideally  
- 
Spherical embolization particles: from 100 to 700 microns depending on the 
operator's preference and should always be performed until complete stasis. 
 
PREPARATION AND INJECTION TECHNIQUE 
 
Chemoembolization 
The use of loaded microspheres is not allowed chemoembolization must involve the use of 
an emulsion of doxorubicin or streptozotocin and Lipiodol 
- 
Preparation of the emulsion with two 20CC uher lock syringes connected by a three-
way valve. The mixing process should be initiated by pushing the doxorubicin or 
streptozotocin towards the Lipiodol (the aim is to promote a water-in-oil emulsion) and 
by making about 20 back and forth syringes. The mixture obtained must be injected 
before embolization under scopic control and with a flow rate avoiding arterial reflux.   
- 
The use of a microcatheter is recommended in case of localized disease in order to obtain 
an ultra-selective positioning. 
- 
It is imperative to try to perform the embolization in addition to the chemopiodol and 
therefore to stop the injection of the drug/Lipiodol emulsion before complete stagnation, 
or failing that to wait at least 10 minutes after injection of the chemopiodol to obtain a 
flow capable of allowing the embolization.  
- 
Subsequent particle embolization should result in complete stasis in the targeted arteries 
at least to the second-order arteries in case of lobar involvement. 
 
Embolization 
The use of spherical embolization particles of 100 to 500 microns according to the 


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operators' choice. The injection is done in a slow way with spheres suspended in the 
saline/contracts mixture in order to avoid aggregation of particles responsible for 
proximal occlusions. Embolization is complete to the second and third order branches. 
Stasis should be observed for 10 minutes before deciding to terminate the procedure. 
There is no limitation in the volume of embolization that can be used. 
- 
For patients with bilobar involvement, each lobe must be treated separately. A 
catheter is placed in a lobar hepatic artery for total embolization. The second 
session should be performed on the other lobe. 
- 
The use of a microcatheter is recommended in case of localized disease in order to 
obtain an ultra-selective positioning      
 
Patients with localized lesion(s) should be treated with an even distribution of the dose of 
doxorubicin or streptozotocin within the lesion(s). If possible, chemoembolization should be 
repeated in the same manner. The two sessions should be separated by 4 to 8 weeks. 
For patients with bilobar involvement, each lobe should be treated separately. A catheter is 
placed in a lobar hepatic artery and the full dose of doxorubicin/lipiodol or 
streptozotocin/lipiodol is administered. The second session should be performed in the other 
lobe.  
 
Embolization or chemoembolization must always be associated with appropriate analgesic 
treatment, prophylactic antibiotic therapy and/or premedication with corticosteroids, the 
modalities of which are left to the discretion of the investigator. 
 
Repeat chemoembolization sessions:  
Three sessions are planned with intervals of 6 to 8 weeks. 
The second and third session will be performed depending on the initial tumor response. An 
additional session is not recommended in case of complete lipiodolated fixation of all tumor 
targets. 
In case of bleeding and/or severe liver failure secondary to an embolization or 
chemoembolization session, the following session(s) will be cancelled.  For any other toxicity 
secondary to a TACE session, the performance of one (or two) additional sessions will be left 
to the discretion of the investigator. 
 
Lipiodol and doxorubicin or streptozotocin are reported to health authorities as non-
investigational drugs. 
However, the tolerance of 2 embolization or chemembolization sessions will be collected in the 
observation booklet. 
 
2- Everolimus treatment 
 
Everolimus, an investigational treatment, is being provided as part of the study. It will be 
supplied in boxes of 30 tablets. The tablets will be either 10 mg or 5 mg. The boxes will be 
labeled "clinical trial" as recommended. 
 
The dosage is 10 mg/day, i.e. 1 tablet of 10 mg or 2 tablets of 5 mg. In case of toxicity, refer 
to paragraph VII for dose adjustments. 
 
Everolimus treatment will be continued for a maximum of 24 months after the first embolization 
or chemoembolization. 
 


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Everolimus will be started 7 days after embolization or chemoembolization or when liver 
toxicities have returned to a grade ≤1 according to the NCI CTIC version 4.0 toxicity scale. 
Treatment should not be initiated beyond 30 days after embolization or chemoembolization. 
 
If embolization or chemoembolization cannot be performed after patient inclusion, everolimus 
MUST NOT be started.   
If embolization or chemoembolization is postponed, wait for embolization or 
chemoembolization to start everolimus as described above. If embolization or 
chemoembolization is definitely cancelled, DO NOT ADMINISTER everolimus and follow the 
patient according to the recommendations (see paragraph VIII-2: monitoring after cessation of 
treatment).  
 
For the second session, everolimus will be stopped the day before the session and restarted in 
the same manner as initially, i.e., 7 days after embolization or chemoembolization or when liver 
toxicities have returned to a grade ≤1 according to the NCI CTIC toxicity scale version 4.0 and 
within a maximum of 30 days after embolization or chemoembolization. 
 
Method of administration 
Everolimus should be taken orally once a day at the same time each day, with or without food. 
The tablets should be swallowed whole with a glass of water. The tablets should not be chewed 
or crushed. 
If a dose is missed, the patient should not take an additional dose, but should take the next 
prescribed dose.  
 
 
3- Concomitant treatments to be avoided  
 
Everolimus is a substrate of CYP3A4 and a moderate inhibitor of P-glycoprotein (PgP). 
Therefore, the absorption and subsequent elimination of everolimus may be influenced by drugs 
that act on CYP3A4 and/or PgP.  In vitro, everolimus is a competitive inhibitor of CYP3A4 
and a mixed inhibitor of CYP2D6. 
Known and theoretical interactions with selective inhibitors and inducers of CYP3A4 and PgP 
are described in the Table below. 
 
CYP3A4 and PgP inhibitors that may increase everolimus concentrations: CYP3A4 or PgP 
inhibitors may increase blood levels of everolimus by decreasing the metabolism or efflux of 
everolimus from intestinal cells. 
CYP3A4 and PgP inducers that may decrease everolimus concentrations: Substances that are 
CYP3A4 and PgP inducers may decrease blood levels by increasing everolimus metabolism or 
efflux of everolimus from intestinal cells. 
 
Effect of other active substances on everolimus 
 
Active substances by interaction 
Recommendations for Concomitant 
Administration 
Potent CYP3/PgPA INHIBITORS 
Ketoconazole 
Concomitant administration of everolimus 
not recommended 
Itraconazole, posaconazole, voriconazole 
Telithromycin, clarithromycin 
Nefazodone 
Ritonavir, atazanavir, saquinavir, 
darunavir, indinavir, nelfinavir 
Moderate CYP3A4/PgP INHIBITORS 


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Erythromycin 
Use with caution when concomitant 
administration with moderate CYP3A4 or 
PgP inhibitors cannot be avoided. If co-
administration with a moderate CYP3A4 or 
PgP inhibitor is required, a dose reduction 
to 5 mg daily and 5 mg every other day may 
be 
considered. 
However, 
there 
is 
insufficient 
clinical 
data 
on 
dose 
adjustment. Due to inter-subject variability, 
the recommended dose adjustments may 
not be optimal for all individuals, so close 
monitoring 
for 
adverse 
effects 
is 
recommended. 
Verapamil 
Ciclosporin oral 
Fluconazole 
Diltiazem 
Amprenavir, fosamprenavir 
Grapefruit juice or other foods that affect 
CYP3A4/PgP 
The combination should be avoided 
 
Potent CYP3/PgPA INDUCTORS 
Rifampicin 
Avoid 
concomitant 
use 
with 
strong 
CYP3A4 inducers. If co-administration 
with a strong CYP3A4 inhibitor is required, 
an everolimus dose increase of 10 mg daily 
up to 20 mg daily, using a 5 mg step 
increase, is applied on day 4ième and day 
8ième after initiation of inducer therapy. This 
dose of everolimus is established to adjust 
the AUC to the range of values observed 
without inducer. However, there are no 
clinical data available with this dose 
adjustment. When treatment with the potent 
inducer is stopped, the dose of everolimus 
should be returned to the dose used prior to 
initiation of concomitant administration. 
Corticosteroids  
(e.g. dexamethasone, prednisone, 
prednisolone) 
Carbamazepine, 
Phenobarbital, 
Phenytoin 
Efavirenz,  
Nevirapine 
St. John's wort (Hypericum Perforatum) 
with an effect on CYP3A4/PgP 
Preparations containing St. John's wort 
should not be used during everolimus 
treatment 
 
The use of live vaccines should be avoided during everolimus treatment (examples of live 
vaccines: intranasal influenza vaccine, measles vaccine, mumps vaccine, rubella vaccine, oral 
polio vaccine, BCG (Bacillus Calmette-Guérin), varicella vaccine, and Typhoid Ty21a vaccine) 
 
 
4- Treatment with somatostatin analogues  
 
In patients who were receiving somatostatin analogue therapy for symptomatic purposes prior 
to embolization or chemoembolization, this therapy should be continued after embolization or 
chemoembolization unless determined by the investigator. In the absence of carcinoid 


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syndrome, somatostatin analogue therapy is not permitted after embolization or 
chemoembolization. 
 
VII. 
EXPECTED TOXICITIES AND DOSE ADJUSTMENT 
 
1. 
Dose adjustment after the first embolization or chemoembolization 
 
No dose adjustment of doxorubicin or streptozotocin is planned for chemoembolization 
sessions. There are no plans to adjust the dose of lipiodol for embolization sessions. 
 
Embolization or chemoembolization will only be performed if hematological, renal and hepatic 
functions are satisfactory i.e. if: 
- 
PNN > 1.5 109 /L, 
- 
Platelets > 75 x 109 /L 
- 
Hemoglobin > 10 g/dL 
- 
INR < 1.3N or < 3 on anticoagulants or PT > 50  
- 
Creatinine level < 1.5N 
- 
Total bilirubin < 1.5N  
- 
ASAT, ALAT < 5N 
- 
PAL < 5N  
In case of grade 3 or 4 non-hematological toxicity attributable to the first embolization or 
chemoembolization session, no further embolization or chemoembolization is performed. Only 
everolimus will be continued for a maximum of 24 months.  
 
2. 
Everolimus dose adjustment 
 
All toxicity will be assessed according to the NCI-CT v4.0 scale (Appendix 4). 
The rules for everolimus dose adjustment in case of observed hematological and non-
hematological toxicities are defined in Tables 1.1, 1.2.   
All interruptions or changes to the study drug must be recorded 
 
Monitoring of suspected everolimus toxicity 
Patients whose treatment is temporarily or permanently discontinued due to an adverse event 
or laboratory abnormality suspected to be related to everolimus should be monitored at least 
weekly until the adverse event resolves or returns to grade 1. If the patient's treatment is to be 
delayed for more than 21 days from the day of the next scheduled dose, the patient should be 
excluded from the study. 
 
Table 1.0 Guidelines for Everolimus Dose Level Changes 
 
Dose level 
Dose and frequency of administration 
0 (initial dose) 
10 mg per day 
-1 
5 mg per day 
-2 
5 mg every 2 days 
 


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a. 
Dose adjustment for non-hematologic and hematologic toxicities 
 
Table 1-1 
Dose adjustment criteria for everolimus toxicity and reinstatement of 
everolimus therapy  
 
NON-HEMATOLOGICAL AND NON-
HEPATIC Toxicity (NCI-CTC V4.0) 
Actions 
Grade 2  
 
(except pneumonia - see Table 1-4) 
If toxicity is tolerable to the patient, maintain the 
same dose.  
In case of intolerable toxicity for the patient, 
discontinue everolimus until recovery to grade 1. 
Then reintroduce everolimus at the same dose. 
If an event returns to grade 2, discontinue 
everolimus until recovery to grade 1. Then 
reintroduce everolimus at the lower dose level. 
Grade 3 
(except hyperlipidemia*) 
(except pneumonia - see Table 1-4) 
Interrupt everolimus until recovery to grade 1. 
Then reintroduce everolimus at the lower dose 
level.  
For pneumonia, consider short-term steroid therapy. 
Grade 4 
Stopping everolimus 
Any non-hematologic toxicity requiring 
interruption for a period ≥ 3 weeks 
Stopping everolimus 
*Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be 
managed with medical treatments. 
 
Table 1-2 
HEMATOLOGICAL 
Toxicity (NCI-CTC V4.0) 
Grade 
Actions 
Thrombocytopenia 
Grade 2  
(platelets < 75, ≥ 50 x 109 
/l) 
Interrupt everolimus until 
recovery to grade 1 (> 75 x 
109 /l). Then reintroduce 
everolimus at the initial 
dose. 
If thrombocytopenia returns 
to grade 2, discontinue 
everolimus until recovery to 
grade 1. Then reintroduce 
everolimus at the lower dose 
level.  
Grade 3  
(platelets < 50, ≥ 25 x 109 
/l) 
Interrupt everolimus until 
recovery to grade ≤ 1 
(platelets ≥ 75 x 109 /L).  
Then resume everolimus at a 
lower dose level. 


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If thrombocytopenia recurs 
at grade 2, discontinue 
everolimus. 
Grade 4  
(platelets < 25 x 109 /L) 
Stopping everolimus 
Neutropenia 
Grade 3 
(neutrophils < 1, ≥ 0.5 x 
109 /L) 
Interrupt everolimus until 
recovery to grade 1 
(neutrophils ≥ 1.5 x 109 /l). 
Then resume everolimus at 
the initial dose.   
If PNN returns to grade 3, 
withhold everolimus until 
PNN is ≥ 1.5 x 109 /l.  Then 
resume everolimus at the 
lower dose level.   
Discontinue study treatment 
if a third episode of Grade 3 
neutropenia occurs 
Grade 4 
 (neutrophils < 0.5 x 109 
/L) 
Interrupt everolimus until 
recovery to grade 1 
(neutrophils ≥ 1.5 x 109 /l). 
Then resume everolimus at 
the lower dose level. 
If Grade 3 or 4 neutropenia 
occurs despite this dose 
reduction, discontinue 
everolimus 
Febrile neutropenia  
Grade 3  
 
Discontinue everolimus until 
fever resolves and grade ≤ 1 
neutropenia returns.  
Continue everolimus 
interruption until PNN is ≥ 
1,500/mm3 and fever 
disappears. Then resume 
everolimus at the lower dose 
level.  
If febrile neutropenia recurs, 
discontinue everolimus. 
Grade 4  
(life-threatening) 
Stopping everolimus 
Any hematological toxicity  
Requiring an interruption 
for a period ≥ 3 weeks 
Stopping everolimus 
 
 
 
 
 
 
 


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Table1-3:  
 
Toxicity ANEMIA 
(Hemoglobin decrease) 
NCI-CTC v4.0 
Grade 
Dose adjustment 
Anemia  
Grade 1 or 2 
No change in dose 
Grade 3 
Interrupt everolimus until 
recovery to grade < 2, then 
resume everolimus at the same 
dose. If return to grade 3, 
withhold everolimus until grade 
< 2, then resume at lower dose 
level. Discontinue everolimus 
in case of 3ième grade 3 episode. 
Grade 4 
Permanent discontinuation of 
everolimus 
 
b. 
Known adverse reactions to everolimus  
 
-The most common grade -34 adverse events -(frequency ≥ 2% in at least one pivotal study) 
were anemia, fatigue, diarrhea, infections, stomatitis, hyperglycemia, thrombocytopenia, 
lymphopenia, neutropenia, hypophosphatemia, hypercholesterolemia, diabetes mellitus, and 
pneumonitis. Grades follow the CTCAE version 4.0 classification. 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, 
viral or protozoal infections, including infections with opportunistic pathogens. Localized and 
systemic infections, including pneumonia, other bacterial infections, invasive fungal infections 
such as aspergillosis or candidiasis, and viral infections, including cases of hepatitis B 
reactivation, have been described in patients treated with everolimus. Some of these infections 
have been severe (e.g., leading to respiratory or hepatic failure), sometimes with fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with everolimus. Pre-
existing infections should be treated before starting everolimus therapy.  During treatment with 
everolimus, vigilance for signs and symptoms of infection should be exercised; if an infection 
is diagnosed, appropriate treatment should be initiated as soon as possible and temporary or 
permanent discontinuation of everolimus should be considered. If a diagnosis of invasive 
systemic fungal infection is made, everolimus must be discontinued and appropriate antifungal 
therapy initiated. 
Hypersensitivity reactions with symptoms including anaphylaxis, dyspnea, flushing, chest pain, 
or angioedema (e.g., swelling (edema) of the airways or tongue, with or without respiratory 
failure) have been observed with everolimus. 
Hyperglycemia has been reported in clinical trials.  It is recommended that fasting blood 
glucose be monitored prior to initiation of everolimus therapy and periodically thereafter. 
Optimal glycemic control should be achieved prior to initiating everolimus therapy in a patient. 
Mouth ulcers, stomatitis and oral mucositis have been observed in patients treated with 
everolimus. In these cases, topical treatments are recommended, but alcohol or hydrogen 
peroxide mouthwashes should be avoided. 
Elevations in serum creatinine, usually mild, have been reported in clinical trials. It is 
recommended that renal function be monitored before starting everolimus therapy and 
periodically thereafter. 
Decreases in hemoglobin, lymphocytes, platelets and neutrophils have been reported in clinical 


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trials. It is recommended that complete blood counts be monitored prior to the initiation of 
everolimus therapy and periodically thereafter. 
The use of live vaccines and close contact with individuals who have received live vaccines 
should be avoided during treatment with everolimus. 
Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have been reported.  
c. 
Management of stomatitis/oral mucositis/aphthae  
Oral stomatitis/mucositis/ mouth ulcers due to everolimus should be treated with local 
symptomatic therapy. It should be noted that investigators in previous trials have described oral 
toxicities associated with everolimus in terms of mouth ulcers rather than mucositis or 
stomatitis. If your examination reveals canker sores rather than more general inflammation of 
the mouth, please classify the adverse event as such. Please follow the template below for 
treatment of oral stomatitis/mucitis/aphthas: 
1. For mild toxicity (Grade 1), use conservative measures such as alcohol-free mouthwash 
or salt water mouthwash (0.9%) several times a day until resolved. 
2. For more severe toxicity (grade 2, in which case patients are able, despite pain, to maintain 
adequate oral nutrition, or grade 3 in which case patients cannot maintain adequate oral 
nutrition), the proposed treatments are analgesic topical oral treatments (i.e., local 
anesthetics such as benzocaine, butylaminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone 
acetonide 0.1% gingival paste (Orabase Kenalog® ). 
3. Agents containing hydrogen peroxide, iodine and thyme derivatives may tend to exacerbate 
mouth ulcers. It is best to avoid these agents. 
4. Antifungal agents should be avoided unless a fungal infection has been diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, 
etc.) should be avoided in all patients as they are potent inhibitors of everolimus 
metabolism, resulting in higher everolimus exposures. Therefore, topical antifungal agents 
are preferable if an infection is diagnosed. Similarly, antiviral agents such as acyclovir 
should be avoided unless a viral infection is diagnosed. 
d. 
Management of hyperlipidemia and hyperglycemia  
Hyperlipidemia and hypertriglyceridemia should be treated according to local best clinical 
practice.  
e. 
Management of non-infectious lung disease 
Non-infectious pneumonitis is a class effect of rapamycin derivatives.  Non-infectious lung 
disease (including interstitial lung disease) has also been described in patients treated with 
everolimus. A diagnosis of non-infectious lung disease should be considered in patients 
presenting with non-specific respiratory signs and symptoms such as cough or dyspnoea, 
hypoxia, pleural effusion, and when infectious, neoplastic or other non-drug causes have been 
excluded by appropriate investigations. Patients should be asked to report promptly any new or 
worsening respiratory symptoms.  
Patients with radiological changes suggestive of non-infectious lung disease with few or no 
symptoms may continue everolimus therapy without a change in dosage. In the presence of 
moderate symptoms (Grade 2), discontinuation of treatment should be considered until 
symptoms improve. Administration of corticosteroids may be indicated. Everolimus may be 
reintroduced at a reduced dose until recovery to Grade 1 or higher.  
When symptoms of non-infectious lung disease are severe (Grade 3), everolimus treatment 
should be discontinued and corticosteroids may be indicated until clinical symptoms resolve. 
Everolimus treatment may be reintroduced at a reduced dose depending on individual clinical 
circumstances. 
 


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Table 1-4Management of  non-infectious lung disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PNEUMOPATH
Y (NCI-CT V 4.0) 
INVESTIGATION 
REQUIRED 
CARE  
EVEROLIMUS DOSE 
ADJUSTMENT 
Grade 1 
Chest CT in the lung 
window and 
respiratory function 
tests, including 
spirometry, DLCO, 
and room air O2  
saturation at rest.  
Repeat chest x-
ray/computed 
tomography every 2 
cycles until normal.  
No specific 
treatment is 
required 
Administer 100% of the 
everolimus dose. 
Grade 2 
Chest CT in lung 
windows and 
pulmonary function 
tests, including 
spirometry, DLCO, 
and room air O2  
saturation at rest. 
Repeat with each 
subsequent cycle 
until normalcy is 
achieved. 
Bronchoscopy is 
recommended *  
Symptomatic 
only. Prescribe 
corticosteroids 
if cough is 
troublesome. 
Reduce everolimus dose 
until recovery to a grade≤ 
1.  
Everolimus may also be 
discontinued if 
troublesome symptoms 
occur.  
Patients will discontinue 
treatment if they fail to 
recover to a grade ≤ 1 
within 3 weeks 
Grade 3 
Prescribe 
corticosteroids 
if an infectious 
origin is 
excluded.  
Gradually 
reduce the 
dose according 
to medical 
indication. 
Withhold treatment until 
recovery to a grade ≤ 1.  
The treatment protocol 
may be restarted within 2 
weeks at a reduced dose 
(by one level) if there is 
evidence of clinical 
benefit. 
Patients will discontinue 
treatment if they fail to 
recover to a grade ≤1 
within 2 weeks.  
Grade 4 
Prescribe 
corticosteroids 
if an infectious 
origin is 
excluded.  
Gradually 
reduce the 
dose according 
to medical 
indication. 
Stop the treatment. 
*Bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 
 


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f. 
Management of reactivation /flare-up of hepatitis  
In cancer patients with hepatitis B virus, either carrier or chronic, the administration of antivirals 
during cancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) reactivation 
and associated morbidity and mortality (Loomba et al. 2008). 
• Monitoring and prophylaxis for hepatitis B reactivation 
 
Table 2-1 provides detailed information on monitoring and prophylactic treatment based on 
initial viral load and serologic marker test results. 
 
Table 2-1:  
Actions to be Taken for Initial Positive Hepatitis B Results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV DNA 
+ 
+ or -. 
- 
- 
- 
HBsAg 
+ or -. 
+ 
- 
- 
- 
HBsAb 
+ or -. 
+ or -. 
+ 
and without 
prior HBV 
vaccination 
+ or -. 
- 
or + with 
previous HBV 
vaccination 
HBsAb 
+ or -. 
+ or -. 
+ or -. 
+ 
- 
Recommendation 
Prophylaxis should be 
initiated 1-2 weeks prior to 
the first dose of study drug 
Monitor HBV DNA 
approximately every 6 
weeks 
 
No prophylaxis 
Monitor HBV DNA 
approximately every 3 weeks 
 
No specific 
action 
Antiviral prophylaxis should be continued for at least 4 weeks after the last dose of study drug. 
For the definition of hepatitis B reactivation and guidelines for its management, refer to Table 
2-2.   
 
Table 2-2: Hepatitis B Management Guidelines  
 
HBV reactivation (with or without clinical signs and symptoms)*. 
For patients with initial 
findings:  
HBV DNA positive 
OR 
HBsAg positive 
-------------------------------
------- 
Reactivation is defined 
as:    
[1-log increase in HBV 
DNA from baseline HBV 
Treat: Start a second antiviral  
AND 
Discontinue study drug until resolution:  
 
≤ baseline levels of HBV DNA 
In case of resolution within ≤ 28 days the study drug should be 
restarted at a lower dose, if available. If the patient is already 
receiving the lowest dose of study drug per protocol, the patient 
should restart the study drug at the same dose after resolution. 
Both antiviral therapies should be continued for at least 4 weeks 
after the last dose of study drug is administered.  


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DNA OR new onset of 
measurable HBV DNA] 
 
If resolution occurs within >28 days patients should discontinue 
study drug but continue both antiviral treatments for at least 4 
weeks after the last dose of study drug. 
For patients with initial 
results:  
HBV DNA and HBsAg 
negative 
AND  
[HBsAb positive (with no 
prior history of HBV 
vaccination), OR HBcAb 
positive]  
-------------------------------
------ 
reactivation is defined as 
follows: 
New appearance of 
measurable HBV DNA 
Treat: Start antiviral medication  
AND 
Discontinue study drug until resolution:  
  ≤ baseline levels of HBV DNA 
In case of resolution within ≤ 28 days the study drug should be 
restarted at a lower dose, if available. If the patient is already 
receiving the lowest dose of study drug per protocol, the patient 
should restart the study drug at the same dose after resolution. 
Antiviral therapy should be continued for at least 4 weeks after 
the last dose of study drug is administered.  
In case of resolution within > 28 days patients should 
discontinue study drug, but continue antiviral therapy for at least 
4 weeks after the last dose of study drug. 
* All hepatitis B reactivations should be recorded as a Grade 3 adverse event (CTCAE v 4.0 
Other Adverse Events Associated with Metabolic or Biological Abnormalities: Viral 
Reactivation), unless the investigator considers them life-threatening in which case they should 
be recorded as a Grade 4 adverse event (CTCAE v 4.0 Other Adverse Events Associated with 
Metabolic or Biological Abnormalities: Viral Reactivation). The date of viral reactivation is the 
date on which both the DNA and ALAT criteria are met (e.g., for a patient with HBV DNA 
positive on 01-01-10 and an ALAT level ≥ 5 x ULN on 01-04-10, the date of viral reactivation 
is 01-04-10). 
• Hepatitis C Outbreak Surveillance 
The following two categories of patients should be monitored every 6 weeks for HCV 
reactivation: 
- 
Patients with detectable HCV RNA by PCR analysis in basal state. 
- 
Patients with a known history of hepatitis C virus (HCV) infection, despite a negative 
baseline viral load test (including those who have been treated and considered "cured") 
For the definition of hepatitis C reactivation and guidelines for its management, see Table 2-3 
Guidelines for the Management of Hepatitis C. 
 
Table 2-3: Guidelines for the Management of Hepatitis C 
 
HCV outbreak 
For patients with baseline results: detectable HCV 
RNA, an HCV outbreak is defined as follows:  
Discontinue study drug but continue 
monitoring as part of the study.  


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Increase in HCV RNA by 2 log10 IU/ml 
AND 
ALT elevation: 5 x ULN or 3 x baseline, whichever 
is higher 
 
 
For patients with baseline results: Known history of 
hepatitis C without detectable HCV RNA, an HCV 
outbreak is defined as:  
New appearance of detectable HCV RNA  
AND 
ALT elevation: 5 x ULN or 3 x baseline, whichever 
is higher 
Discontinue study drug but continue 
monitoring as part of the study.  
. 
 
* All hepatitis C outbreaks should be recorded as a Grade 3 event (CTCAE v 4.0 Other Adverse 
Events Associated with Metabolic or Biological Abnormalities: Viral Outbreak), unless the 
investigator considers them life-threatening, in which case they should be recorded as a Grade 
4 event (CTCAE v 4.0 Other Adverse Events Associated with Metabolic or Biological 
Abnormalities: Viral Outbreak)  
 
VIII. 
PATIENT MONITORING DURING TREATMENT AND 
AFTER WITHDRAWAL OF TREATMENT 
 
1. 
Monitoring during treatment 
 
Within 7 days prior to each embolization or chemoembolization session   
 
o Clinical assessment: weight, general condition (WHO) 
o Evaluation of the tolerance of the previous embolization or chemoembolization 
o Biological check-up:  
o CBC-platelets 
o INR, aPTT, creatinine, bilirubin (total, conjugated), AST, ALT, PAL 
 
NB: An abdominal CT scan may be performed if necessary for technical reasons before the 2nd 
embolization or chemoembolization session. Caution: this imaging should not be used to 
evaluate the response to treatment of metastases. 
 
Every 3 months (+/- 1 week) from the date of the first embolization or 
chemoembolization (except DNA and ARC monitoring for positive serology)  
 
o Clinical assessment: WHO, weight, evaluation of side effects 
o Bioassay:  
• 
CBC/platelets, urea and creatinine + calculated creatinine clearance 
(Cockcroft formula), blood ionogram 
• 
INR, aPTT, albumin, alkaline phosphatase, AST, ALT, bilirubin (total 
and conjugated), gamma-GT 
• 
Serum cholesterol and triglycerides 
• 
Fasting blood glucose and HbA1c 
• 
Chromogranin A, urinary 5HIAA 
o If HBV positive, monitor DNA approximately every 3 weeks or 6 weeks depending on 
the result (see Table 2-2)   


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o If HCV positive, monitor RNA every 6 weeks (see Table 2.3)  
o Morphological assessment: triphasic thoracic-abdominal-pelvic CT scan with target 
measurement according to RECIST V1.1 criteria (Appendix 3). Evaluation CT scans 
should be performed in the same center as the initial examination 
 
NOTE: Patients whose treatment is temporarily or permanently discontinued due to an 
adverse event or laboratory abnormality suspected to be related to everolimus should be 
monitored at least weekly until the adverse event resolves or returns to Grade 1 
2. 
Post-treatment monitoring protocol 
 
- 
After discontinuation of treatment for hepatic progression  
o After hepatic progression, the clinical, biological and morphological 
monitoring of the patient will be left to the investigator's discretion 
 
- 
After discontinuation of treatment for a reason other than hepatic progression 
(e.g. toxicity, extra-hepatic progression, patient's wish, : 
o Morphological surveillance: CT every 3 months until liver progression occurs, 
according to the same modalities as the initial morphological evaluation 
(triphasic thoraco-abdomino-pelvic CT with target measurement according to 
RECIST V1.1 annex 3) 
 
IX. 
STOP PROCESSING THE STUDY  
 
The processing of the study will be stopped in case of: 
- Investigator's decision 
- Major toxicity requiring discontinuation of treatment (despite protocol adaptations) 
- Serious or unexpected event requiring discontinuation of protocol treatment 
- Disease progression (hepatic, extra-hepatic, clinical) 
- Patient refusal 
- Death of the patient 
 
X. 
CENTRALIZED PROOFREADING OF TDM  
 
To address the primary endpoint of efficacy of everolimus treatment after embolization or 
chemoembolization, a centralized review of morphological examinations of the inclusion 
workup and follow-ups will be performed by an independent review committee. 
 
To do this, make a copy of the imaging to be kept in the patient's file. The FFCD CRA in charge 
of your center will make an anonymized copy of the CD ROM and send the imaging to the 
FFCD imaging platform.  
 
XI. 
  MANAGEMENT OF SERIOUS ADVERSE EVENTS (SIA)  
 
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, by regular blood tests. 
Toxicities will be assessed using the NCI-CTC-AE version 4.0 toxicity scale (see Appendix 4). 
 


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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. 
 
b. Serious Adverse Event (SAE) 
A serious adverse event is any event that   
• Resulting in death, 
• Life-threatening, 
• Leading to hospitalization or prolonged hospitalization, 
• Causing permanent disability or severe temporary incapacity, 
• Causing a birth defect, fetal malformation or abortion, 
• Medically significant   
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 above mentioned severity criteria (e.g. overdose, second cancers, 
pregnancies and new events may be considered as medically significant). 
 
Pregnancy is an exclusion criterion in this trial. However, if a pregnancy is discovered after 
inclusion, the patient must be excluded from the trial. The sponsor should be informed without 
delay via the serious adverse event reporting form (no severity criteria should be checked). The 
patient should be followed until the outcome of the pregnancy and this outcome, whatever it 
may be, should be reported to the sponsor. 
 
Hospitalizations included in the protocol will not be considered an SAE. 
 
c. Undesirable Effect  
Any noxious and undesired response to an investigational drug at any dose or to any 
investigational component. The adverse reaction is serious if it meets the severity criteria (see 
above). 
 
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's reference document (Investigator's Brochure 
or RCPs). 
 
In this essay the reference documents will be: 
• For everolimus, the Summary of Product Characteristics for Afinitor® (Appendix 6) 
 
The versions of the Investigator's Brochure and PCR (used for the definition of expected or 
unexpected everolimus) will be the latest available on the anniversary date of the start of the 
trial. 
 
What to do  
 


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The investigator informs the sponsor of all Serious Adverse Events (Expected and Unexpected), 
whether or not attributable to the research, that occur during treatment and within 30 days of 
the last treatment administration.  
 
All Delayed Serious Adverse Events (occurring after this 30-day period) considered reasonably 
related to the protocol treatment(s) or research should be reported without time limitation. 
 
The report is made by faxing the "notification of a serious adverse event" form (Appendix 7), 
documented as precisely as possible, dated and signed, within 24 working hours of their 
discovery to the FFCD's Randomization Management Analysis Center (CRGA): by fax to 
03 80 38 18 41 
 
Modalities and duration of follow-up of individuals following the occurrence of adverse 
events 
The investigator is responsible for appropriate medical follow-up of patients until resolution or 
stabilization of the effect or until the patient's death. This may sometimes mean that this follow-
up extends beyond the patient's discharge from the trial. 
 
He/she transmits the additional information to the sponsor using an SAE reporting form 
(checking the Follow-up No. X box to specify that it is a follow-up report and not an initial 
report) within 24 hours of obtaining it. It also forwards the last follow-up to the resolution or 
stabilization of the SAE.  
He keeps the documents concerning the suspected adverse reaction in order to allow, if 
necessary, to complete the information previously transmitted. 
 
 
XII. 
STATISTICAL ANALYSIS 
 
 
1. 
Provisional timetable for the study 
 
The end of the trial will be 4 years after the inclusion of the last patient included. For the 
purposes of the study, the follow-up time for patients will be 24 months after inclusion. 
 
The rate of inclusion is estimated at 3 patients per month, so the duration of inclusion is 24 
months. 
 
The study duration to meet the primary and secondary endpoint is 24 months. 
 Six months will be required to clean the base and perform the analysis + final report (March 
2015).  
 
Expected start date of inclusions: November 2012 
Expected completion date of inclusion: April 2016  
Primary endpoint analysis: April 2018 
Theoretical end of study: January 2019 
 
2. 
Analysis  
Main criterion  
The primary endpoint will be to assess liver progression (death will be considered as 
progression) during the 24 months of everolimus treatment according to RECIST V1.1 criteria 
(Appendix 3). 


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The time to progression-free survival (based on review or on the opinion of the investigator if 
review is not possible) will be defined as the time interval between the date of inclusion and the 
date of liver progression or death (regardless of cause). For living patients without hepatic 
progression, the time interval between the date of inclusion and the date of last morphological 
evaluation will be taken. 
 
Secondary criteria  
The secondary endpoints will be:  
- 
Progression-free survival (hepatic or non-hepatic) at 24 months 
- 
Overall survival at 24 months 
- 
Tolerance of the treatment during the 24 months of treatment  
 
Progression-free survival will be defined as the time interval between the date of inclusion and 
the date of progression (hepatic or non-hepatic) as assessed by RECIST V1.1 criteria or death 
(regardless of cause) or the date of the last morphological assessment for patients alive without 
progression. 
 
Overall survival will be defined as the time interval between the date of inclusion and the date 
of death regardless of the cause of death or the date of last news for living patients. 
 
Tolerance to treatment will be assessed by: 
- duration of treatment, doses received, dose reductions and deferrals 
- Toxicities collected at each monthly visit, and described according to NCI-CTC version 
4.0 criteria; Grade 3, Grade 4 and Grade 5 toxicities will be reviewed. 
- the number and description of SAEs 
- the evolution of the WHO performance index. 
 
Calculation of the number of subjects needed 
According to the literature, the median progression-free survival after embolization or 
chemoembolization ranges from 15 to 19 months with a progression-free survival rate of 
approximately 35%. As there is no information on progression-free survival in the literature, 
the hypotheses were built on the progression-free survival data. 
The assumptions used to calculate the number of subjects are as follows: 
H0: a 24-month progression-free survival rate of less than 35% is not acceptable  
H1: A 24-month liver progression-free survival rate greater than 35% would demonstrate the 
utility of everolimus therapy with an expected 24-month liver progression-free survival rate of 
50%, 
To obtain a power of 80% with a first-species risk of 5% (one-sided), it is required to include 
68 patients according to the assumptions established above (using the exact binomial 
distribution). 
Taking into account a rate of lost to follow-up or patients not evaluable for any reason except 
death, 72 patients will be included. 
3. 
Statistical analysis plan 
 
Populations of analysis 
 


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Patients included in the study will be described (ITT) as well as patients not evaluable for the 
primary endpoint.   
 
A patient is considered evaluable if he or she has received at least one dose of everolimus and 
one evaluation. 
 
All efficacy analyses will be performed on a modified intention-to-treat basis (evaluable 
patients) included in the study regardless of eligibility criteria and treatment received. 
 
Tolerability population: the ITT population that received at least one dose of the treatments. 
 
In all cases of discontinuation, the patient remains in the intention-to-treat analysis. There is no 
exclusion period for a subsequent therapeutic trial. 
 
Main analyses 
 
A statistical analysis plan will be written prior to freezing the database. 
The description of clinical and medical variables will be done using percentages (95% 
confidence interval) and mean (standard deviation) and median (Min-Max) as well as the inter-
quartile range (Q1-Q3). 
 
Survivals and times will be estimated by the Kaplan Meier (KM) method. They will be 
described by medians and rates at different time points with their 95% confidence intervals. 
Median follow-up time will be calculated using the reverse Kaplan Meir method. 
 
The results for the primary endpoint will also be described by a Water Fall plot representing for 
each patient the percentage change at 24 months in liver metastasis size since the measurement 
at inclusion according to the response according to the RECIST V1.1 criteria. 
 
The time to onset of grade 3/4/5 toxicity will be estimated using the Kaplan Meier method. 
 
Exploratory analyses 
 
- 
research into factors predictive of progression-free survival and/or overall survival 
- 
comparison 
of 
progression-free 
survival 
between 
embolization 
alone 
and 
chemoembolization 
4. 
Independent committees 
 
An independent committee will be formed and will include at least: two physicians (onco-
gastroenterologists), a statistician, a pharmacovigilance expert. The independent committee 
may meet at any time during the protocol when deemed necessary by the Sponsor. 
XIII. 
JUSTIFICATION OF THE TEST  
 
Neuroendocrine tumors (NETs) are a heterogeneous group of rare tumors. The prevalence of 
these tumors is estimated to be between 0.4 and 1 per 100,000 inhabitants per year. In the 
gastrointestinal tract, the most frequent locations are the appendix (19%), the small intestine 
(15%) and the rectum (11%). Neuroendocrine tumors of the small intestine mainly affect young 
adults between 30 and 35 years of age, while those of the colon tend to occur around 60 years 
of age [[1]. 
 
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There are many therapeutic options, and the choice of treatment depends primarily on the 
location of the primary tumor, the stage of extension, and the tumor's progression [[2]. Given 
the great variability of cases, it is difficult to establish a precise decision tree for the treatment 
of digestive NETs. In all cases, the decision should be made after multidisciplinary discussion. 
Symptomatic management of hormonal hypersecretion is imperative and should be initiated 
without waiting for the extension workup. Surgery, the only curative treatment, should always 
be discussed initially, and secondarily, after obtaining a therapeutic response. Surgical removal 
of the primary tumor is usually recommended, even in cases of advanced NET. In the metastatic 
situation, the therapeutic indications must be discussed taking into account the location of the 
primary tumor and the metastases, the cellular differentiation, the evolution with evaluation of 
the speed of growth of the metastases. In the case of well-differentiated NETs with little 
progression, an initial surveillance can be proposed with a first evaluation at a few weeks to 
assess the tumor evolution. 
If the tumor is slowly progressive (tumor stability without new localization), monitoring, 
possibly associated with treatment with somatostatin analogues, may be proposed. If the tumor 
is progressive (morphological progression or new metastatic sites), antitumor treatment should 
be considered. In the case of NET of the digestive tract, which is not very chemosensitive, 
(chemo)-embolization in case of isolated or predominant liver metastases is often the preferred 
option. 
 
Place of (chemo)embolization 
 
The principle of intra-arterial chemoembolization is to combine chemotherapy administered via 
the hepatic intra-arterial route with embolization [[3]. As metastases are, contrary to normal 
liver, mainly vascularized by the arterial route, this approach allows to induce a targeted anoxia, 
potentiated by the administration of a cytotoxic agent. 
Chemoembolization is effective in controlling clinical manifestations related to hormonal 
hypersecretion, especially during carcinoid syndrome, in 70 to 100% of patients depending on 
the series. 
The ENETS-01 trial, the only prospective randomized trial that compared embolization and 
chemoembolization, included only 26 patients. There was no difference in progression-free 
survival at 24 months (the primary endpoint) between the chemoembolization (38%) and 
embolization (44%, p=0.9) groups[4]. In the larger retrospective non-randomized series, 
progression-free survival rates are not always specified [5, 6, 7]. In the MD Anderson study (81 
patients), the 24-month progression-free survival rate was 35% with a median progression-free 
survival of 17 months. [6]. In a French study, the median progression-free survival was 14.5 
months with a 24-month progression-free survival rate of about 35% in 67 patients [7]. 
A post-embolization syndrome (fever, abdominal pain, nausea, vomiting, hepatic cytolysis) is 
frequent and requires appropriate symptomatic treatment. The possibility of an acute carcinoid 
crisis justifies the prescription of a treatment with somatostatin analogues. These techniques are 
contraindicated in case of biliary-digestive anastomosis or biliary prosthesis because of a major 
risk of infectious complication with hepatic abscess. Portal vein thrombosis and hepatocellular 
insufficiency are also contraindications. 
 
 
Rationale for antiangiogenic therapy after (chemo)embolization 
 
Digestive NETs are characterized by their hypervasculariation. Endocrine tumor cells secrete 
excess VEGF which is likely to play an important role in the angiogenic process associated 
with endocrine tumorigenesis [8, 9]]. However, the mechanisms that regulate the angiogenic 
process associated with endocrine tumorigenesis in digestive NETs remain poorly understood. 
 


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Embolization stimulates angiogenesis with an increase in circulating VEGF levels [10] levels, 
and the main mechanism associated with a progressive recovery after (chemo)embolization is 
tumor revascularization from collateral vessels. In this context, a treatment with antiangiogenic 
action administered after (chemo)embolization could improve tumor control. A recent phase II 
study evaluated sunitinib therapy in this setting with encouraging results [10].  
 
Everolimus 
 
Inhibitors of the mTOR pathway have antiangiogenic activity, which partly explains their 
antitumor effect in vitro and in vivo [11]. Regarding everolimus, promising initial results have 
led to a development program in digestive NETs. In a phase II study, Yao et al. reported the 
use of everolimus combined with delayed octreotide in 60 patients with well differentiated NET 
[12]. The objective response was 30% in the 30 patients treated with the 10-mg dose versus 
13% for patients treated with 5 mg. Among patients with "carcinoid" tumors, the objective 
response rate was 17%, with stabilization achieved in 80% of patients, at the cost of moderate 
side effects. This study led to the selection of the 10 mg everolimus dose for further 
development of the product in the RADIANT I, II and III studies [12, 13, 14]. Only the 
RADIANT II study involved NET of the gastrointestinal tract [13]. This international 
multicenter phase III study randomized everolimus (10 mg/d) to placebo, combined in both 
arms with octreotide LP30 mg/28 d. Four hundred and thirty patients with documented 
progression within 12 months prior to inclusion were included. One-third of the patients had 
been previously treated with chemotherapy and nearly 80% with a delayed somatostatin 
analogue. Progression-free survival was 16.4 months in the everolimus plus delayed octreotide 
arm versus 11.3 months in the placebo plus delayed octreotide arm (HR = 0.77; 95% CI = 0.59-
1.00; p = 0.026) in centralized readout (primary objective of the trial), not statistically 
significant according to the study analysis design since the expected predefined p was 0.0246. 
The center-read analysis (12.0 months versus 8.6 months, HR = 0.78; 95% CI = 0.62-0.98; p = 
0.018) and after predefined statistical adjustments (HR = 0.60; 95% CI = 0.44-0.84; p = 0.0014), 
which were secondary objectives of the trial, supported the superiority of everolimus. The 
interim analysis of overall survival showed no difference between the two groups (HR = 1.22; 
95% CI = 0.91-1.62; p = 0.908). The safety profile of this molecule is quite acceptable, with 
mainly grade 1-2 toxicities and less than 7% grade 3-4 toxicities.  
 
Bibliographic references:  
1Lepage  
C, Guigay J. Epidemiology of endocrine tumors. In: Baudin E, Ducreux M, eds. Thoracic and 
digestive endocrine tumors. Paris: Springer, 2008:21-6. 
2Ramage  
JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, et al. Guidelines for the management of 
gastroenteropancreatic neuroendocrine (including carcinoid) tumors (NETs). Gut 2012;61:6-32. 
3Ruszniewski  
P, O'Toole D. Ablative therapies for liver metastases of gastroenteropancreatic endocrine tumors. 
Neuroendocrinology 2004;80:74-8. 
4Maire  F, Lombard-Bohas C, O'Toole D, Vullierme MP, Rebours V, Pelletier AL, et al. Embolization versus 
hepatic intra-arterial chemoembolization for the treatment of hepatic metastases of digestive endocrine tumors: the 
first prospective randomized study (Poster 227).  JFHOD. Paris, 2011. 
5Eriksson  
BK, Larsson EG, Skogseid BM, Lofberg AM, Lorelius LE, Oberg KE. Liver embolizations of 
patients with malignant neuroendocrine gastrointestinal tumors. Cancer 1998;83:2293-301. 
6Gupta  S, Yao JC, Ahrar K, Wallace MJ, Morello FA, Madoff DC, et al. Hepatic artery embolization and 
chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience. 
Cancer J 2003;9:261-7. 
7Marrache  
F, Vullierme MP, Roy C, El Assoued Y, Couvelard A, O'Toole D, et al. Arterial phase 
enhancement and body mass index are predictors of response to chemoembolisation for liver metastases of 
endocrine tumours. Br J Cancer 2007;96:49-55. 
8Terris  B, Scoazec JY, Rubbia L, Bregeaud L, Pepper MS, Ruszniewski P, et al. Expression of vascular 
endothelial growth factor in digestive neuroendocrine tumors. Histopathology 1998;32:133-8. 
9Katoh  R. Angiogenesis in endocrine glands: special reference to the expression of vascular endothelial growth 
factor. Microsc Res Tech 2003;60:181-5. 


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10Strosberg  
JR, Weber JM, Choi J, Campos TL, Valone TL, Han G, et al. A phase II clinical trial of sunitinib 
following hepatic transarterial embolization for metastatic neuroendocrine tumors. Ann Oncol 2012. 
11Couderc  
C, Poncet G, Villaume K, Blanc M, Gadot N, Walter T, et al. Targeting the PI3K/mTOR pathway 
in murine endocrine cell lines: in vitro and in vivo effects on tumor cell growth. Am J Pathol 2011;178:336-44. 
12Yao  JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, et al. Efficacy of RAD001 (everolimus) and 
octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin 
Oncol 2008;26:4311-8. 
13Pavel  ME, Hainsworth JD, Baudin E, Peeters M, Horsch D, Winkler RE, et al. Everolimus plus octreotide long-
acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome 
(RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011;378:2005-12. 
14Yao  JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic 
neuroendocrine tumors. N Engl J Med 2011;364:514-23. 
 
XIV. 
LEGAL AND ETHICAL ASPECTS ADMINISTRATIVE 
CONSIDERATIONS 
 
STUDY SPONSOR 
 
The sponsor of the study is the Fédération Francophone de Cancérologie Digestive (FFCD). 
The study was registered under the number EudraCT 2012-002224-32. 
  
REMINDER OF THE TEXTS IN FORCE 
 
This test will be carried out according to the new European Directive 2001/20/EC.  
 
LIABILITY INSURANCE 
 
Insurance was taken out by the sponsor on 14/05/2012 with SCHAM insurance (Société 
Hospitalière d'Assurance Mutuelle) under the number 137.681, in accordance with Article L 
1121-10 of the Public Health Code (Appendix 9).  
 
APPLICATION FOR AUTHORIZATION TO THE CPP AND AFSSAPS 
 
This protocol has been authorized by the CPP (Committee for the Protection of Individuals) XI 
of St Germain en Laye, 5/07/2012 (Appendix 10) 
This protocol received a favorable opinion from the ANSM (Agence Nationale de Sécurité du 
médicament et des produits de santé, formerly AFSSAPS (Agence Française de Sécurité 
Sanitaire des Produits de Santé)) on 29/06/2012 (Appendix 11). 
 
COLLECTION OF THE PATIENT'S CONSENT 
 
The investigator undertakes to collect, after information, the clinical consents of the patient in 
writing (information sheets and consent forms in Appendix 1). A copy of this consent 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. 
 
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 no-cost research agreement will be established between the investigating center administrator 
and the sponsor.  


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DATA ARCHIVING 
 
The files will remain confidential and can only be consulted under the responsibility of the 
doctors in charge of the patients. The sponsor and the health authorities in case of inspection 
will have direct access to these documents. 
At the end of the trial, the observation book will be kept for 15 years by the investigator. 
 
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 data bank of the Center of Randomization and Management Analysis of the FFCD, 
with the exception of the elements relating to the identity of the patients. 
 
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 trial may be 
consulted by a person mandated by the FFCD and/or by the health authorities to conduct an 
audit. On-site visits to the files, scheduled after agreement by the investigator, may take place 
during or after the period of inclusion in the trial 
This protocol will be monitored by the FFCD's mobile ARCs.  
 
XV. 
PUBLICATION RULES 
They shall be in accordance with those established by the FFCD (Appendix 8).  
 
XVI. 
APPENDICES 
  
 
 
 
 

SAP_001.pdf: 
 
 
                                                                                                                     
 
 
 
 
 
 
 
 
 
 
 
Everolimus as treatment after embolization or chemoembolization of 
liver metastases of digestive endocrine tumor. 
Phase II single arm multicenter 
EVACEL - FFCD 1104 
 
 
 
Statistical Analysis Plan 
Final analysis 
 
 
 
 
 
 
 
 
 
Version: 1.4 
Date: June 19, 2018 
 
 
 
Editor: E. Barbier 
Review committee: T. Walter, T. De Baere, K. Le Malicot, C. Montérymard, P. Carni.  
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Developer 
FFCD 
Faculty of Medicine,  
7 boulevard Jeanne d'Arc, 
BP 87900, 21079, Dijon Cedex 
 
Scientific coordinator Dr. Thomas Walter 
HGE and Medical Oncology Department 
E. Herriot Hospital,  
Place d'Arsonval 
69437 LYON 
Tel: 04 72 11 73 98 - Fax: 04 72 11 91 53 
Email: thomas.walter@chu-lyon.fr 
 
Coordinator   
Dr Thierry de Baere 
 
Imaging Department - Therapeutic Imaging 
Gustave Roussy Institute 
39 rue Camille Desmoulins 
94805 VILLEJUIF 
Tel: 01 42 11 54 28 - Fax: 01 42 11 52 78 
Email: debaere@igr.fr 
 
Project Manager  
Ms. Marie Moreau 
FFCD 
Faculty of Medicine,  
7 boulevard Jeanne d'Arc, 
BP 87900, 21079, Dijon Cedex 
Tel: 03 80 39 34 04 - Fax: 03 80 38 18 41 
Email : marie.moreau@u-bourgogne.fr 
 
Biostatistics Manager Mrs. Karine Le Malicot 
FFCD 
Faculty of Medicine,  
7 boulevard Jeanne d'Arc, 
BP 87900, 21079, Dijon Cedex 
Tel: 03 80 39 34 71 - Fax: 03 80 38 18 41 
Email : karine.le-malicot@u-bourgogne.fr 
 
 
 


 
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1 Table of contents 
1 
TABLE OF CONTENTS .................................................................................................................... 3 
2 
ABBREVIATIONS AND DEFINITIONS ............................................................................................ 5 
3 
INTRODUCTION ............................................................................................................................ 6 
3.1 
Rationale for the study .......................................................................................................................................... 6 
3.2 
Objectives of the trial............................................................................................................................................. 7 
3.2.1 Main objective ............................................................................................................................................................................... 7 
3.2.2 Secondary objectives ................................................................................................................................................................. 7 
3.2.3 Exploratory analyses.................................................................................................................................................................. 7 
4 
STUDY POPULATION ..................................................................................................................... 8 
4.1 
Inclusion criteria ..................................................................................................................................................... 8 
4.2 
Criteria for non-inclusion .................................................................................................................................... 8 
5 
EXPERIMENTAL DESIGN ............................................................................................................... 9 
5.1 
Scheme of the study ................................................................................................................................................ 9 
5.2 
Treatment arms ....................................................................................................................................................... 9 
5.3 
Randomization and blinding .............................................................................................................................. 9 
5.4 
Chronological sequence ..................................................................................................................................... 10 
5.5 
Justification of the number of subjects needed ........................................................................................ 10 
5.6 
Steps of the test ..................................................................................................................................................... 11 
5.6.1 Final Analysis ............................................................................................................................................................................. 11 
5.6.1 Late analysis................................................................................................................................................................................ 11 
5.7 
Judging criteria ..................................................................................................................................................... 11 
5.7.1 Main criterion ............................................................................................................................................................................. 11 
5.7.2 Secondary efficacy criteria ................................................................................................................................................... 11 
5.7.3 Secondary safety criteria ....................................................................................................................................................... 12 
5.7.1 Other criteria .............................................................................................................................................................................. 12 
5.7.2 Exploratory analyses............................................................................................................................................................... 12 
6 
STUDY POPULATION FOR ANALYSIS .......................................................................................... 12 
6.1 
Definition of Analysis Populations ................................................................................................................ 12 
6.1.1 Intent-to-treat (ITT) population ........................................................................................................................................ 13 
6.1.2 Analysis population for primary endpoint (PI)........................................................................................................... 13 
6.1.1 Population per protocol (PP) .............................................................................................................................................. 13 
6.1.2 Population for Tolerance Analysis (SP) .......................................................................................................................... 13 
6.2 
Definition of analysis subgroups .................................................................................................................... 13 
7 
STATISTICAL METHODS ............................................................................................................. 13 
7.1 
General information on statistical analysis methods ............................................................................. 13 
7.1.1 Software ........................................................................................................................................................................................ 14 
7.1.2 Adjustments to SSP .................................................................................................................................................................. 14 
7.1.3 Agreements concerning dates and durations .............................................................................................................. 14 


 
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7.1.4 Outlier Conventions ................................................................................................................................................................. 14 
7.1.5 Missing Data Conventions .................................................................................................................................................... 14 
7.1.6 Definition of the baseline ...................................................................................................................................................... 14 
7.1.7 Statistics ........................................................................................................................................................................................ 14 
7.2 
Patient characteristics at inclusion ............................................................................................................... 15 
7.2.1 Eligibility ...................................................................................................................................................................................... 15 
7.2.2 Demographic characteristics ............................................................................................................................................... 15 
7.2.3 Clinical characteristics ........................................................................................................................................................... 15 
7.2.4 Biological characteristics ...................................................................................................................................................... 16 
7.2.5 Disease-related characteristics .......................................................................................................................................... 16 
7.3 
Monitoring characteristics ............................................................................................................................... 17 
7.4 
Evaluation of the primary endpoint .............................................................................................................. 17 
7.5 
Evaluation of effectiveness ............................................................................................................................... 17 
7.5.1 Rate of living patients without liver progression in mRECIST at 24 months ................................................ 17 
7.5.2 Survival without liver progression ................................................................................................................................... 17 
7.5.3 Progression-free survival...................................................................................................................................................... 17 
7.5.4 Overall survival ......................................................................................................................................................................... 17 
7.5.5 Best response ............................................................................................................................................................................. 17 
7.6 
Evaluation of tolerance ...................................................................................................................................... 18 
7.6.1 Embolization or chemoembolization............................................................................................................................... 18 
7.6.2 Administration of oral everolimus therapy .................................................................................................................. 18 
7.6.3 ISG .................................................................................................................................................................................................... 19 
7.6.4 Toxicities ...................................................................................................................................................................................... 19 
7.6.5 WHO................................................................................................................................................................................................ 19 
7.7 
Exploratory Analysis Evaluations .................................................................................................................. 19 


 
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2 Abbreviations and definitions 
 
CHE  
Chemoembolization 
CP 
 
Main criterion 
SEE   
Serious Adverse Event 
 
5HIA5-hydroxyindoleacetic acid  
INR 
International Normalized Ratio 
ITTIntention to  treat 
NCI-CTCNational  
Cancer Institute Common Toxicity Criteria 
 
RCMultidisciplinary consultation meeting 
RECIST 
Response evaluation criteria in solid tumors 
SPPopulation of  tolerance 
 
NeuroEndocrine tumor 
 
 


 
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3 Introduction 
 
3.1 Rationale for the study 
 
Neuroendocrine tumors (NETs) are a heterogeneous group of rare tumors (estimated prevalence between 
0.4 and 1 per 100,000 population per year).  
Treatment of digestive endocrine tumors 
There are numerous therapeutic options and the choice of treatment depends essentially on the location of 
the primary tumor, the stage of extension and the tumor's evolution. In all cases, the decision must be taken 
after multidisciplinary discussion. Symptomatic management of hormonal hypersecretion is imperative. 
Surgical removal of the primary tumor is usually recommended. In the case of well-differentiated NETs with 
little progression, initial surveillance may be proposed with an evaluation of the tumor's evolution. If the 
tumor is slowly progressive (tumor stability without new localization), surveillance, possibly associated 
with treatment with somatostatin analogues, may be proposed. If the tumor is progressive (morphological 
progression or new metastatic sites), antitumor treatment should be considered. In the case of NET of the 
digestive tract, which is not very chemosensitive, (chemo)embolization in case of isolated or predominant 
liver metastases is often the preferred option. 
Place of (chemo)embolization 
The principle of intra-arterial chemoembolization is to combine intra-arterial hepatic chemotherapy with 
embolization. As metastases are mainly vascularized by the arterial route, this approach allows to induce a 
targeted anoxia. Chemoembolization is effective in controlling clinical manifestations related to hormonal 
hypersecretion. The ENETS-01 trial, the only prospective randomized trial comparing embolization and 
chemoembolization (26 patients included), showed no difference in progression-free survival at 24 months 
between the chemoembolization (38%) and embolization (44%) groups. In the MD Anderson study (81 
patients), the 24-month progression-free survival rate was 35%. In a French study (67 patients), the 24-
month progression-free survival rate was about 35%.  
Rationale for antiangiogenic therapy after (chemo)embolization 
Digestive NETs are characterized by their hypervasculature. Tumor endocrine cells secrete excess VEGF 
which is likely to play an important role in the angiogenic process associated with endocrine tumorogenesis. 
Embolization stimulates angiogenesis with an increase in circulating VEGF levels and the main mechanism 
associated with a progressive recovery after (chemo)embolization is tumor revascularization from 
collateral vessels. Therefore, treatment with antiangiogenic action after (chemo)embolization could 
improve tumor control.  
Everolimus 
Inhibitors of the mTOR pathway have antiangiogenic activity, which explains in part their antitumor effect. 
In the phase II study by Yao et al., the everolimus dose of 10 mg was retained for further development. Only 
the phase III RADIANT II study concerned NET of the digestive tract. This study randomized 430 patients 
between everolimus (10 mg/d) and placebo, combined in both arms with octreotide LP30mg/28d. 
Progression-free survival was 16.4 months in the everolimus arm versus 11.3 months in the placebo arm 
(HR = 0.77; 95% CI = 0.59-1.00; p NS) on centralized review. The center-read analysis (12.0 months versus 


 
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8.6 months, HR = 0.78; 95% CI = 0.62-0.98; p S) supported the superiority of everolimus with a very 
acceptable safety profile.  
 
 
3.2 Objectives of the trial 
 
3.2.1 
Objective main 
The primary objective of the study is to determine whether treatment with everolimus for 24 months 
prolongs progression-free survival according to RECIST 1.1 criteria. The primary endpoint will be 
progression-free survival at 24 months in patients receiving hepatic embolization or chemoembolization 
followed by everolimus therapy. 
 
3.2.2 
Secondary objectives 
The secondary objectives of the study are to evaluate: 
• 
Progression-free survival at 24 months (hepatic and non-hepatic) 
• 
Overall survival at 24 months 
• 
Tolerance of the treatment during the 24 months of treatment   
 
3.2.3 
Exploratory analyses 
An exploratory analysis is planned to: 
• Search for factors predictive of progression-free survival and/or overall survival 
• To compare liver progression-free survival between embolization alone and chemoembolization. 


 
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4 Study population 
The study includes patients with well-differentiated metastatic NET of the gastrointestinal tract. 
 
4.1 Inclusion criteria  
• 
Histologically proven metastatic endocrine tumor of the gastrointestinal tract (TENPATH review 
mandatory), well differentiated (grade 1 and 2 according to WHO 2010 classification) 
• 
Predominantly hepatic involvement compared to other metastatic locations requiring embolization or 
chemoembolization 
• 
Hepatic metastasis(es) measurable according to RECIST V1.1 criteria, unresectable or not accessible to local 
radiofrequency treatment 
• 
Indication, validated in RCP, for hepatic arterial embolization or chemoembolization for antitumor 
purposes due to the progressive nature of liver metastases (morphological progression over the last 12 
months according to RECIST V1.1 criteria) 
• 
Age ≥ 18 years 
• 
General condition WHO ≤ 2  
• 
No contraindication to embolization or chemoembolization  
• 
No contraindication to everolimus treatment 
• 
Adequate biological workup: 
o Neutrophils ≥ 1.5 x 109 /L, platelets ≥ 100 x 109 /L, Hb > 10 g/dL 
o Serum bilirubin ≤ 1.5 x upper normal limit (UL), INR < 1.3 (or < 3 on anticoagulants), ALT and AST 
≤ 5 x UL  
o Creatinine ≤ 1.5 x LNS 
o 24-hour proteinuria (for patients who will receive streptozotocin for chemoembolization) < 1.5 N  
o Fasting serum cholesterol ≤ 300 mg/dL or 7.75 mmol/L and triglycerides ≤ 2.5 x LNS (in the event 
that one or both of these thresholds are exceeded, the patient can be included in the study only after 
initiation of appropriate lipid-lowering therapy) 
• 
Complete resolution or persistence with a maximum grade of 1 (except for transaminases or INR if 
anticoagulant) of toxicities from any previous treatments (NCI CTC version 4.0)  
• 
Minimum time to previous treatment: 28 days 
• 
Information to the patient and signature of an informed consent, after verification of the eligibility criteria 
• 
Affiliation to a social security system 
 
4.2 Non-inclusion criteria 
• 
Duodeno-pancreatic endocrine tumor 
• 
Poorly differentiated and/or grade 3 endocrine tumor 
• 
Indication for embolization or chemoembolization for symptomatic purposes only 
• 
Previous treatment with hepatic arterial embolization or chemoembolization  
• 
Previous treatment with an mTOR inhibitor (somatostatin analogues for anti-secretory purposes are 
allowed) 
• 
Symptomatic bone metastasis(es) 


 
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• 
Any progressive unbalanced condition: hepatic insufficiency, renal insufficiency, respiratory insufficiency, 
congestive heart failure NYHA III-IV, unstable angina, myocardial infarction, significant arrhythmias  
• 
Interstitial lung disease 
• 
Patients with uncontrolled diabetes defined as HBa1C > 8  
• 
Patients receiving chronic corticosteroids or immunosuppressants 
• 
Hypersensitivity to everolimus, other rapamycin derivatives or any of the excipients 
• 
Major surgery, open biopsy, or significant traumatic injury within 28 days prior to initiation of study 
treatment. Incompletely healed wound or anticipated need for major surgery during the course of the study 
• 
Patient with contraindication to vascular occlusion procedures 
o Portal thrombosis 
o Bilio-digestive anastomosis 
• 
HIV patients on antiretroviral therapy 
• 
Malignant pathology within the last 5 years except for basal cell skin carcinoma or cervical cancer in situ 
treated curatively 
• 
Pregnant or breastfeeding woman 
• 
Lack of effective contraception (for men or women of childbearing age) 
• 
Predictable non-compliance 
• 
Medical, geographical, sociological, psychological or legal situation that would prohibit the patient from 
completing the study or signing an informed consent 
• 
Concurrent patient participation in other experimental research that could influence the primary endpoint 
of the study 
 
5 Experimental design 
 
5.1 Scheme of the study 
This is a single-arm, multi-center Phase II trial.  
 
5.2 Treatment arm 
There is a single study treatment arm consisting of: 
- 
1 to 2 embolization or chemoembolization sessions (sessions spaced 4 to 8 weeks apart).  
- 
10 mg/day everolimus (started 7 days after embolization or chemoembolization) 
The maximum treatment period is 24 months. 
 
5.3 Randomization and blinding  
The trial is an open-label trial. There is no randomization in this trial. 


 
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5.4 Chronological sequence 
Each patient will follow the chronological sequence described below: 
 
 
5.5 Justification of the number of subjects needed 
According to the literature, the median progression-free survival after embolization or chemoembolization 
ranges from 15 to 19 months with a progression-free survival rate of approximately 35% at 24 months. As 
there is no information on hepatic progression-free survival in the literature, the hypotheses were built on 
the progression-free survival data. 
The assumptions used to calculate the number of subjects are as follows: 
• H0: a 24-month progression-free survival rate of less than 35% is not acceptable  
• H1: A 24-month liver progression-free survival rate of more than 35% would demonstrate the utility 
of adjuvant everolimus therapy with an expected 24-month liver progression-free survival rate of 
50%, 
Inclusion assessment 
Within 4 weeks prior to the first embolization or 
chemoembolization and before inclusion 
CPR 
- 
Embolization or chemoembolization for hepatic 
progression 
- 
Treatment plan specifying the number of 
sessions required to obtain a complete 
treatment of the liver (1 to 2 sessions) 
Inclusion 
Everolimus (10mg/d) for 24 months or until 
progression 
Monitoring Morphological evaluation 
Every 3 months until progression 
1 to 2 sessions embolization or chemoembolization 
+ 
Everolimus (10mg/d) 


 
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To obtain a power of 80% with a first-species risk of 5% (one-sided), it is required to include 68 patients 
according to the assumptions established above (using the exact binomial distribution). 
Taking into account a 5% rate of lost to follow-up or patients who cannot be evaluated for any reason except 
death, 72 patients will be included. 
 
5.6 Steps of the test 
 
5.6.1 
Analysis Final 
The final analysis will be performed 24 months after the inclusion of the 72ème patient. The point date for 
the analysis is therefore: 01/09/2017 
Out of 68 evaluable patients, if 31 or more patients are alive without liver progression at 24 months, the 
treatment will be declared worthwhile. 
 
5.6.1 
Late analysis 
Not applicable. 
 
5.7 Judging criteria 
 
5.7.1 
Main criterion 
The primary endpoint is the rate of living patients without liver progression 24 months after inclusion. 
Hepatic progression is defined according to RECIST V1.1 criteria and is based on centralized review (or on 
the investigator's opinion in case of impossible review). 
 
5.7.2 
Secondary endpoints of effectiveness 
5.7.2.1 
Rate of living patients without liver progression in mRECIST at 24 months 
The rate of living patients without liver progression 24 months after inclusion will also be described 
according to mRECIST criteria and based on centralized review. 
5.7.2.2 
Survival without liver progression 
It is defined as the time from the date of inclusion to the date of first hepatic progression (based on 
centralized review or on the investigator's opinion in case of impossible review) or the date of death 
(regardless of cause). Living patients without hepatic progression will be censored at the point date or the 
date of last morphological evaluation. 
Live patients for whom no morphological evaluation is available will be censored at inclusion date + 1 day. 
 
5.7.2.3 
Progression-free survival 
It is defined as the time between the date of inclusion and the date of first hepatic or extrahepatic 
progression (based on centralized review or on the investigator's opinion in case of unavailable review) or 


 
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the date of death (regardless of cause). Patients alive without progression will be censored at the point date 
or the date of last morphological evaluation. 
Live patients for whom no morphological evaluation is available will be censored at inclusion date + 1 day. 
5.7.2.4 
Overall survival 
It is defined as the time 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. 
 
5.7.3 
Secondary tolerability criteria 
The following secondary safety endpoints will also be analyzed: 
Regarding Embolization/Chimioembolization: 
▪ 
The number of embolizations and chemoembolizations actually performed per patient; 
▪ 
The number of embolizations or chemoembolizations planned in PCR; 
▪ 
The territories of (chemo) embolisations 
▪ 
Complications during the procedure; 
▪ 
Post-session complications. 
Regarding Everolimus treatment: 
▪ 
Duration of treatment; 
▪ 
The time between the end of 1ère (chemo)embolization and the resumption of everolimus therapy; 
▪ 
The time between the end of 2ème (chemo)embolization and the resumption of everolimus treatment; 
▪ 
Treatment compliance; 
▪ 
The number of patients who had at least one dosage change; 
▪ 
The number of patients who had at least one temporary stop or deferral; 
▪ 
Toxicities (graded according to NCI-CTC v 4.0).  
 
5.7.1 
Other criteria 
▪ 
The evolution of the WHO performance index 
▪ 
Best response under treatment (based on centralized review) 
▪ 
The administration of G-CSF 
 
5.7.2 
Exploratory analyses 
▪ 
An analysis of the predictive factors for overall survival and progression-free survival will be 
performed; 
▪ 
In an exploratory manner, the progression-free survival between embolization alone and 
chemoembolization will be compared (if the number of patients in each group is sufficient). 
 
6 Study population for analysis 
 
6.1 Definition of Analysis Populations 
 


 
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6.1.1 
Intent-to-treat (ITT) population 
The intention-to-treat population is defined as all patients included in the study, regardless of eligibility 
criteria and treatment received. All analyses will be performed on an intention-to-treat basis, unless 
specifically mentioned for certain criteria. 
 
6.1.2 
Population of analysis for primary endpoint (PC) 
The analysis population for the primary endpoint is defined as the ITT population of evaluable patients. A 
patient is considered evaluable if he or she has received at least one dose of everolimus and at least one 
treatment-related imaging. 
A patient who dies (from any cause after treatment) or progresses in liver function before 24 months is 
evaluable and considered a failure for the primary endpoint. 
Patients without a 24-month evaluation will be reviewed according to the following rules:  
- 
If the patient has a later assessment (27 months or more) and is not progressing at that time, then 
they will be considered progression-free at 24 months  
- 
The other patients will be reviewed at a medical review to decide, in view of the patient's entire 
file, whether they can be considered as failed or as truly non-evaluable (a rate of 5% of additional 
patients has been planned for these situations).  
 
A listing of patients excluded from the CP population will be provided with the reasons for their exclusion. 
  
6.1.1 
Population per protocol (PP) 
The per-protocol population is defined as all patients included in the study without major protocol deviation 
(i.e. meeting the criterion "Endocrine tumor of the gastrointestinal tract"), having at least one 
(chemo)embolization and at least 1 month of everolimus treatment (started within 30 days post-HEC). 
A listing of patients excluded from the PP population will be provided with the reasons for exclusion. 
 
6.1.2 
Population for tolerance analysis (SP) 
It is defined as the ITT population that received at least one dose of everolimus. The safety criteria will be 
evaluated in this population. 
A listing of patients excluded from the PP population will be provided with the reasons for exclusion. 
 
6.2 Definition of analysis subgroups 
Not applicable 
 
7 Statistical methods 
 
Statistical analyses will be performed by the CRGA. 
 
7.1 General information on statistical analysis methods 
 


 
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7.1.1 
Software 
Statistical analyses will be performed with SAS software version 9.4 or later. Some graphs can be made with 
R software version 2.11 or later. 
7.1.2 
Adjustments to SSP 
Adjustments may be made to this analysis plan in case of amendments to the protocol, or if phenomena not 
initially foreseen require statistical adaptations. In all cases, these modifications must be made before the 
database is frozen. 
 
7.1.3 
Agreements concerning dates and durations 
Time since inclusion will be defined as the time since the day of inclusion, with the day of inclusion 
considered as day 1. 
The time since the start of treatment will be defined as the time since the day of the first treatment, the day 
of the first treatment being considered as day 1.  
Therefore, the durations will be calculated according to the following rule, for example for the duration 
between death and inclusion: day of death - day of inclusion + 1. 
The day before the day of inclusion (resp. the day before the day of treatment) will be considered as day -1 
(day 0 does not exist). 
The last date of news will be by default the date of the last examination/monitoring performed. 
The following conversion rules will be used to convert the number of days into months or years: 1 month = 
30.4375 days; 1 year = 365.25 days. 
 
7.1.4 
Outlier Conventions 
Outliers will be subject to a confirmation request to the investigating center. In case of confirmation, their 
value will not be modified and will be taken into account as it is during the analysis. 
 
7.1.5 
Missing Data Conventions 
Except in the cases specified, missing data will not be replaced. 
In case of partially missing data concerning dates, the following rule will be applied: when the day is missing, 
the day will be considered as the 15th of the month. 
 
7.1.6 
Definition of the baseline 
Baseline measurements will be the last measurements taken at inclusion. In case of missing data, the last 
measurement performed before the first administration of the treatment will be used. 
 
7.1.7 
Statistics 
Quantitative variables will be described using the number, median, mean, standard deviation of the mean, 
minimum, maximum, and interquartile range (Q1-Q3). Quantitative variables may be categorized using 
their median or a cut-off known from the medical literature. 
 


 
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Categorical variables will be described using percentages, and if necessary their two-sided 95% 
confidence intervals (calculated using the exact method). 
Missing values will not be included in the calculation of frequencies and percentages. 
 
The confidence intervals provided will be two-sided 95% confidence intervals, except for the primary 
criterion where a one-sided 95% confidence interval will be given. 
 
Survival data will be estimated and plotted using the Kaplan-Meier method (Kaplan and Meier, 1958).  
This will be described by the median and rates calculated at different times. Two-sided 95% confidence 
intervals will be provided. Confidence intervals for the rates will be constructed from the Greenwood 
variance calculated using the log-log transformation. 
The median follow-up time will be calculated using the reverse Kaplan-Meier method (Shemper, 1996). 
 
For uni 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 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. 
 
7.2 Patient characteristics at inclusion 
 
7.2.1 
Eligibility 
Population ITT 
Patient eligibility at inclusion will be verified and described by: 
▪ Number and percentage of patients who met all inclusion criteria  
▪ Number and percentage of patients who met all non-inclusion criteria  
▪ Number and percentage of patients who met all criteria (inclusion and non-inclusion)  
 
 
7.2.2 
Demographic characteristics 
Population ITT and CP 
The following characteristics at inclusion will be described: 
▪ Inclusion center (number of patients included per center) 
▪ Age (year) 
▪ Gender (Male vs Female) 
 
7.2.3 
Clinical characteristics 
Population ITT and CP 
The following characteristics at inclusion will be described: 
▪ WHO general status (0 vs 1 vs 2) 
▪ BMI (kg/m2 )  


 
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▪ Presence of carcinoid heart disease (Yes vs. No) 
 
7.2.4 
Biological characteristics 
Population ITT and CP 
The following characteristics at inclusion will be described: 
▪ Presence of anti-coagulant (Yes vs No) 
▪ Chromogranin A (ng/mL) 
▪ Urinary 5HIAA (mg/24h) 
▪ Albumin (g/L) 
▪ Total bilirubin (µmol/L) 
▪ Conjugated bilirubin (µmol/L) 
▪ PAL (Number of x the normal) 
▪ ALT (Number of x normal)  
▪ ASAT (Number of x normal) 
▪ Hemoglobin (g/dL),  
▪ PNN (/mm3 ) 
▪ Wafers (x103 /mm3 ) 
▪ Creatinine clearance (ml/min) 
▪ B Viral serology: HBsAg (Negative vs. Positive); and if Positive : 
- HBV-DNA (Negative vs Positive)  
- Anti-HBs Ac (Negative vs Positive)  
- Anti-HBc Ac (Negative vs Positive); 
▪ Viral C serology: HCV antibody (Negative vs. Positive)  
 
7.2.5 
Characteristics related to the disease 
Population ITT and CP 
The following characteristics at inclusion will be described: 
▪ The grade of the tumor (G1 vs G2)  
▪ The site of the primary tumor (Esophagus vs Jejunum-Ileon vs Appendix vs Stomach vs Colon vs Rectum 
vs Other); A listing of other locations will be provided. 
▪ The presence of bilateral liver metastases (Yes vs. No)  
▪ Percentage of liver invasion; 
▪ The presence of extrahepatic metastases (Yes vs. No), and if yes, the location; 
▪ Presence of previous treatments:  
- Surgery of the primary (Yes vs. No),  
- Locoregional treatment of liver metastases (Yes vs. No) and if yes,  
Type of treatment (Surgery and/or Radiofrequency and/or Other) 
- History of somatostatin analogue treatment (Yes vs. No) and if yes, 
Treatment in progress (Yes vs. No) 
The aim of the treatment (anti-tumor vs functional) 
- Other previous treatment (Yes vs. No)  


 
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7.3 Monitoring characteristics 
Population ITT 
The median follow-up time and its 95% confidence interval will be calculated in months.  
 
7.4 Evaluation of the primary endpoint 
Population CP 
The rate of patients alive without progression at 24 months will be calculated and presented using its one-
sided 95% confidence interval (exact confidence interval, binomial distribution). 
The results for the primary endpoint will also be described by a Water Fall plot representing for each patient 
the percentage change at 24 months in liver metastasis size since the measurement at inclusion according 
to the response according to the RECIST V1.1 criteria. 
 
7.5 Evaluation of effectiveness 
 
7.5.1 
Rate of living patients without liver progression in mRECIST at 24 months 
Population CP 
The 24-month live progression-free rate in mRECIST will be calculated and presented using its one-sided 
95% confidence interval (exact confidence interval, binomial distribution). 
 
7.5.2 
Survival without liver progression 
CP, ITT and PP population (if the number of patients allows it) 
The time scale considered will be the month. 
Progression-free survival will be plotted using the Kaplan Meier estimator. Median survival and rates at 
different time points will be calculated along with their 95% confidence intervals. 
 
7.5.3 
Progression-free survival 
CP, ITT and PP population (if the number of patients allows it) 
The time scale considered will be the month. 
Progression-free survival (hepatic or not) will be plotted using the Kaplan Meier estimator. Median survival 
and survival rates at 4, 8, 12, 18, 24 months will be calculated along with their 95% confidence intervals. 
 
7.5.4 
Overall survival 
CP, ITT and PP population (if the number of patients allows it) 
The time scale considered will be the month. 
Overall survival will be plotted using the Kaplan Meier estimator. Median survival and survival rates at 4, 8, 
12, 18, 24 months will be calculated along with their 95% confidence intervals. 
7.5.5 
Best response 
Population CP, ITT and PP 


 
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The best response under treatment (CR, PR, S, P) will be calculated and described according to the usual 
descriptive statistics. The objective response rate (OR = CR and PR) will also be described. 
 
7.6 Assessment of tolerance 
 
7.6.1 
Embolization or chemoembolization 
Population ITT  
Treatment by (chemo)embolization will be described by: 
▪ 
The number of embolizations (1 vs 2) per patient and the total number of embolizations performed 
▪ 
The number of chemoembolizations performed and the type: by doxorubicin or streptozotocin 
▪ 
The number and percentage of patients who had (of the population of patients who had at least one 
embolization/chemoembolization):  
- 1 single embolization session 
- 1 single chemoembolization session 
- 2 embolization sessions 
- 2 sessions of chemoembolization  
▪ 
Cross-tabulation of the number of embolizations or chemoembolizations planned in the PCR (at 
inclusion) and the number of embolizations or chemoembolizations actually performed. 
 
Will also be described (percentage on the total number of embolisations and/or chemoembolisations 
performed): 
▪ 
The territory of (chemo)embolisations 
▪ 
The presence of a complication during the procedure (No vs. Yes), and if so: 
- presence of hepatic arterial occlusion by dissection or spasm (No vs. Yes) 
- presence of bleeding at the puncture site (No vs. Yes) 
- presence of another complication (No vs. Yes)  
▪ 
The presence of a post-session complication (No vs. Yes), and if yes, a listing of these complications. 
 
7.6.2 
Administration of oral everolimus treatment 
7.6.2.1 
Duration of treatment 
Population SP 
The duration of treatment (converted into months) will be calculated by the formula : 
Start date of last intake - start date of first intake + 1 day 
Temporary stoppages and any deferral days during this period will not be subtracted from this duration. It 
will be described according to the usual descriptive statistics. 
7.6.2.2 
Doses administered 
Population SP 
Compliance will be calculated according to the formula: cumulative dose received (in mg) / protocol dose 
(in mg) 


 
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The theoretical protocol dose being equal to 10 mg x treatment duration (in days). 
It will be described according to the usual descriptive statistics. 
7.6.2.1 
Modified dosage and temporary discontinuation 
Population SP 
The number of patients who had at least one dosage change and the number of patients who had at least 
one temporary stop or deferral will be described according to standard descriptive statistics. 
7.6.2.2 
Permanent cessation of treatment 
Population SP 
The number and percentage of patients permanently discontinuing protocol treatment and the reasons for 
discontinuing protocol treatment (% of the number of patients discontinuing treatment) will be described 
according to standard descriptive statistics. . 
7.6.2.1 
Other criteria 
Population SP 
The time from the end of 1ère (chemo)embolization to the resumption of everolimus treatment will be 
calculated in days and described according to standard descriptive statistics. 
Similarly, the time between the end of the 2ème (chemo)embolization and the resumption of everolimus 
treatment will be calculated and presented. 
 
7.6.3 
ISG 
The summary of the SAEs will be provided by pharmacovigilance. 
 
7.6.4 
Toxicities 
Population SP 
Toxicities (graded according to NCI-CTC v 4.0) will be described by: 
▪ The total number of patients by maximum grade of toxicity (grade 1-2-3-4-5); 
▪ The number of patients and the maximum toxicity grade achieved (grade 1-2-3-4-5) by SOC and type of 
toxicity; 
▪ Total number of patients by maximum grade of toxicity by grouping grades (grade 1-2 and grade 3-4-5); 
▪ The number of patients and the maximum grade of toxicities achieved by grouping the grades (grade 1-
2 and grade 3-4-5) by SOC and type of toxicities. 
 
7.6.5 
WHO 
Population SP 
The evolution of the WHO performance index during treatment will be described by cross-tabulating the 
WHO index at inclusion with the WHO index of the last available on-treatment assessment. 
 
7.7 Evaluations of exploratory analyses 
 


 
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▪ 
An analysis of predictive factors for overall survival and progression-free survival will be performed 
using univariate and multivariate Cox models. The predictive factors studied will be the parameters 
identified at inclusion: 
- 
Previous treatment (yes vs. no) 
- 
WHO (0 vs 1-2)  
- 
Age (< vs. ≥ median) 
- 
Gender (Male vs Female) 
- 
Presence of carcinoid heart disease (yes vs. no) 
- 
Tumor grade (G1 vs G2) 
- 
Tumor site (appendix vs. jejunum/ileum vs. colon/rectum vs. other) 
- 
Bilateral liver metastases (yes vs. no)  
- 
Extrahepatic metastases (yes vs no)  
- 
BMI (< 25 vs ≥ 25)  
- 
Chromogranin A (>2N vs < 2N with N=200 ng/mL) 
- 
Decrease from Chromogranin A inclusion at M3 (2 thresholds will be tested: > 50% vs ≤ 50% and > 
30% vs ≤ 30%) 
- 
Decrease from baseline in urinary 5HIAA at M3 (2 thresholds will be tested: > 50% vs ≤ 50% and > 
30% vs ≤ 30%) 
 
▪ 
As an exploratory measure, progression-free survival between embolization alone and 
chemoembolization will be compared by a logrank test (if the number of patients in each group is 
sufficient).