Everolimus After (Chemo)Embolization for Liver Metastases From Digestive Endocrine Tumors (EVACEL)
Primary Purpose
Neuroendocrine Tumors, Hepatic Metastases, Metastases
Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Everolimus
embolization
Doxorubicin
Sponsored by
About this trial
This is an interventional treatment trial for Neuroendocrine Tumors focused on measuring cancer, neuroendocrine tumors, gastrointestinal tract, metastases, liver, hepatic
Eligibility Criteria
Inclusion Criteria:
- Well differentiated (grade 1 and 2 according to WHO classification 2010 appendix 2), histologically-proven endocrine tumor of the gastrointestinal tract (TENpath review mandatory),
- Measurable liver metastasis (or metastases) as defined in RECIST v1.1 that are unresectable and inaccessible to radiofrequency ablation-type local treatment
- Hepatic arterial embolization or chemoembolization indicated for tumor size reduction, confirmed in an multidisciplinary team (MDT) meeting, due to the progressive nature of the liver metastases (morphological progression during the past 12 months as defined in RECIST v1.1)
- Age ≥ 18 years
- WHO performance status ≤ 2
- No contraindications to embolization or chemoembolization or everolimus
- Satisfactory laboratory assessments:Neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, Hb > 10 g/dL, serum bilirubin ≤ 1.5 x the upper limit of normal (ULN), INR < 1.3 (or < 3 for patients on anticoagulant therapy) ALT and AST ≤ 5 x ULN, creatinine ≤ 1.5 x ULN, fasting serum cholesterol ≤ 300 mg/dL or 7.75 mmol/L and triglycerides ≤ 2.5 x ULN (if either or both of these limits are exceeded, the patient may only be included into the study after institution of appropriate lipid-lowering therapy)
- Complete resolution of toxic effects of any prior treatments, or persistence at grade 1 at most (CTCAE version 4.0)
- Minimum time since previous treatment: 28 days
- Patient has been informed and has signed an informed consent form, after verification of the eligibility criteria
- Patient covered by a French national health insurance scheme
Exclusion Criteria:
- Duodenopancreatic neuroendocrine tumor
- Poorly differentiated and/or grade 3 endocrine tumor,
- Embolization or chemoembolization indicated for symptomatic control only
- Prior hepatic TACE or embolization
- Prior treatment with an mTOR inhibitor (somatostatin analogs to control secretion are permitted)
- Symptomatic bone metastasis (or metastases)
- Any uncontrolled progressive disease: hepatic failure, renal failure, respiratory failure, NYHA class III-IV congestive heart failure, unstable angina, myocardial infarction, significant arrhythmia
- Interstitial lung disease
- Uncontrolled diabetes, defined by HbA1c > 8%
- Chronic corticosteroid or immunosuppressant therapy
- Hypersensitivity to everolimus, other rapamycin derivatives, or one of the excipients
- Major surgery, open biopsy, or significant traumatic lesion during the 28 days prior to starting the investigational treatment Incompletely healed wound or foreseeable need for major surgery during the study
- Contraindication to vascular occlusion procedures: Portal thrombosis, biliodigestive anastomosis
- Malignancy during the past 5 years, with the exception of curatively treated basal cell skin carcinoma or in situ cervical cancer
- Foreseeable non-compliance
- Medical, geographic, sociological, psychological, or legal situation that would preclude the patient from completing the study or signing an informed consent form
- Pregnant or breast-feeding women
- Men or women of child-bearing potential not using effective contraception
- Concurrent participation in another investigational study that could affect the primary endpoint of this study
Sites / Locations
- CHU - Hôtel Dieu
- Hôpital Avicenne
- Hôpital Saint André
- Hôpital Côte de Nacre
- CHU - Estaing
- Hôpital Beaujon
- Centre GF Leclerc
- CHU - Hôpital François Mitterand
- Hôpital Edouard Herriot
- CHU La Timone
- CHR
- CHU Cochin
- Hôpital Européen Georges Pompidou
- Hôpital Robert Debré
- CHU
- Hôpital Rangueil
- Hôpital Trousseau
- Institut Gustave Roussy
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
embolization or chemoembolization plus everolimus
Arm Description
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).
Outcomes
Primary Outcome Measures
Rate of hepatic progression free survival at 24 months
Hepatic progression free survival rate as defined in RECIST 1.1 (with death considered as progression) during the 24 months of treatment with everolimus (appendix 3).
Progression-free survival rate (PFS) (based on the central assessment) according to RECIST v1.1 according to RECIST v1.1 will be defined as the time from the date of inclusion to the date of hepatic progression or death (due to any cause). For patients who are alive with no hepatic progression, it will be defines as the time from the date of inclusion and the date of the last tumor assessment.
Secondary Outcome Measures
Progression free survival rate (hepatic or not) at 24 months
Progression-free survival rate will be defined as the time from the date of inclusion to the date of disease progression (hepatic or not) evaluated by RECIST V1.1 criteria or death (due to any cause) or the date of the last morphological evaluation for patients who are alive with no disease progression.
Overall survival rate
Overall survival rate shall be defined as the time from the date of inclusion to the date of death, regardless of the cause of death, or the date of last contact for patients who are alive.
Toxicities treatment
the toxicities recorded at each monthly visit, described using -CTCAE version 4.0; grade 3 and 4 toxicities will be reviewed;
Full Information
NCT ID
NCT01678664
First Posted
August 22, 2012
Last Updated
March 27, 2020
Sponsor
Federation Francophone de Cancerologie Digestive
1. Study Identification
Unique Protocol Identification Number
NCT01678664
Brief Title
Everolimus After (Chemo)Embolization for Liver Metastases From Digestive Endocrine Tumors
Acronym
EVACEL
Official Title
Everolimus as Treatment After Embolization or Chemoembolization for Liver Metastases From Digestive Endocrine Tumors
Study Type
Interventional
2. Study Status
Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
October 2012 (Actual)
Primary Completion Date
September 2018 (Actual)
Study Completion Date
April 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Federation Francophone de Cancerologie Digestive
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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%
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroendocrine Tumors, Hepatic Metastases, Metastases
Keywords
cancer, neuroendocrine tumors, gastrointestinal tract, metastases, liver, hepatic
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
74 (Actual)
8. Arms, Groups, and Interventions
Arm Title
embolization or chemoembolization plus everolimus
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Everolimus
Intervention Description
10 mg per day of everolimus during 24 months or until progression disease
Intervention Type
Device
Intervention Name(s)
embolization
Other Intervention Name(s)
spheric particules of 100 to 500 µm
Intervention Description
2 sessions embolization with spheric particles
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Chemoembolization
Intervention Description
2 sessions chemoembolization with 10 mg of lipiodol with 100 mg of doxorubicine
Primary Outcome Measure Information:
Title
Rate of hepatic progression free survival at 24 months
Description
Hepatic progression free survival rate as defined in RECIST 1.1 (with death considered as progression) during the 24 months of treatment with everolimus (appendix 3).
Progression-free survival rate (PFS) (based on the central assessment) according to RECIST v1.1 according to RECIST v1.1 will be defined as the time from the date of inclusion to the date of hepatic progression or death (due to any cause). For patients who are alive with no hepatic progression, it will be defines as the time from the date of inclusion and the date of the last tumor assessment.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Progression free survival rate (hepatic or not) at 24 months
Description
Progression-free survival rate will be defined as the time from the date of inclusion to the date of disease progression (hepatic or not) evaluated by RECIST V1.1 criteria or death (due to any cause) or the date of the last morphological evaluation for patients who are alive with no disease progression.
Time Frame
24 months
Title
Overall survival rate
Description
Overall survival rate shall be defined as the time from the date of inclusion to the date of death, regardless of the cause of death, or the date of last contact for patients who are alive.
Time Frame
24 months
Title
Toxicities treatment
Description
the toxicities recorded at each monthly visit, described using -CTCAE version 4.0; grade 3 and 4 toxicities will be reviewed;
Time Frame
24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Well differentiated (grade 1 and 2 according to WHO classification 2010 appendix 2), histologically-proven endocrine tumor of the gastrointestinal tract (TENpath review mandatory),
Measurable liver metastasis (or metastases) as defined in RECIST v1.1 that are unresectable and inaccessible to radiofrequency ablation-type local treatment
Hepatic arterial embolization or chemoembolization indicated for tumor size reduction, confirmed in an multidisciplinary team (MDT) meeting, due to the progressive nature of the liver metastases (morphological progression during the past 12 months as defined in RECIST v1.1)
Age ≥ 18 years
WHO performance status ≤ 2
No contraindications to embolization or chemoembolization or everolimus
Satisfactory laboratory assessments:Neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, Hb > 10 g/dL, serum bilirubin ≤ 1.5 x the upper limit of normal (ULN), INR < 1.3 (or < 3 for patients on anticoagulant therapy) ALT and AST ≤ 5 x ULN, creatinine ≤ 1.5 x ULN, fasting serum cholesterol ≤ 300 mg/dL or 7.75 mmol/L and triglycerides ≤ 2.5 x ULN (if either or both of these limits are exceeded, the patient may only be included into the study after institution of appropriate lipid-lowering therapy)
Complete resolution of toxic effects of any prior treatments, or persistence at grade 1 at most (CTCAE version 4.0)
Minimum time since previous treatment: 28 days
Patient has been informed and has signed an informed consent form, after verification of the eligibility criteria
Patient covered by a French national health insurance scheme
Exclusion Criteria:
Duodenopancreatic neuroendocrine tumor
Poorly differentiated and/or grade 3 endocrine tumor,
Embolization or chemoembolization indicated for symptomatic control only
Prior hepatic TACE or embolization
Prior treatment with an mTOR inhibitor (somatostatin analogs to control secretion are permitted)
Symptomatic bone metastasis (or metastases)
Any uncontrolled progressive disease: hepatic failure, renal failure, respiratory failure, NYHA class III-IV congestive heart failure, unstable angina, myocardial infarction, significant arrhythmia
Interstitial lung disease
Uncontrolled diabetes, defined by HbA1c > 8%
Chronic corticosteroid or immunosuppressant therapy
Hypersensitivity to everolimus, other rapamycin derivatives, or one of the excipients
Major surgery, open biopsy, or significant traumatic lesion during the 28 days prior to starting the investigational treatment Incompletely healed wound or foreseeable need for major surgery during the study
Contraindication to vascular occlusion procedures: Portal thrombosis, biliodigestive anastomosis
Malignancy during the past 5 years, with the exception of curatively treated basal cell skin carcinoma or in situ cervical cancer
Foreseeable non-compliance
Medical, geographic, sociological, psychological, or legal situation that would preclude the patient from completing the study or signing an informed consent form
Pregnant or breast-feeding women
Men or women of child-bearing potential not using effective contraception
Concurrent participation in another investigational study that could affect the primary endpoint of this study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas WALTER, PhD
Organizational Affiliation
Hôpital Edouard Herriot - Lyon
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU - Hôtel Dieu
City
Angers
Country
France
Facility Name
Hôpital Avicenne
City
Bobigny
Country
France
Facility Name
Hôpital Saint André
City
Bordeaux
Country
France
Facility Name
Hôpital Côte de Nacre
City
Caen
Country
France
Facility Name
CHU - Estaing
City
Clermont Ferrand
Country
France
Facility Name
Hôpital Beaujon
City
Clichy
Country
France
Facility Name
Centre GF Leclerc
City
Dijon
Country
France
Facility Name
CHU - Hôpital François Mitterand
City
Dijon
Country
France
Facility Name
Hôpital Edouard Herriot
City
Lyon
Country
France
Facility Name
CHU La Timone
City
Marseille
Country
France
Facility Name
CHR
City
Orléans
Country
France
Facility Name
CHU Cochin
City
Paris
Country
France
Facility Name
Hôpital Européen Georges Pompidou
City
Paris
Country
France
Facility Name
Hôpital Robert Debré
City
Reims
Country
France
Facility Name
CHU
City
Rouen
Country
France
Facility Name
Hôpital Rangueil
City
Toulouse
Country
France
Facility Name
Hôpital Trousseau
City
Tours
Country
France
Facility Name
Institut Gustave Roussy
City
Villejuif
Country
France
12. IPD Sharing Statement
Citations:
PubMed Identifier
31678771
Citation
Walter T, Lepage C, Coriat R, Barbier E, Cadiot G, Caroli-Bosc FX, Aparicio T, Bouhier-Leporrier K, Hentic-Dhome O, Gay F, Dupont-Gossart AC, Duluc M, Lepere C, Lecomte T, Smith D, Petorin C, Di-Fiore F, Ghiringhelli F, Legoux JL, Guimbaud R, Baudin E, Lombard-Bohas C, de Baere T; FFCD 1104 investigators/investigators. Everolimus after hepatic arterial embolisation therapy of metastases from gastrointestinal neuroendocrine tumours: The FFCD 1104-EVACEL-GTE phase II study. Eur J Cancer. 2019 Dec;123:92-100. doi: 10.1016/j.ejca.2019.09.021. Epub 2019 Oct 31.
Results Reference
result
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Everolimus After (Chemo)Embolization for Liver Metastases From Digestive Endocrine Tumors
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