Everolimus After (Chemo)Embolization for Liver Metastases From Digestive Endocrine Tumors

Study Overview
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Brief Summary
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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%

Official Title
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Everolimus as Treatment After Embolization or Chemoembolization for Liver Metastases From Digestive Endocrine Tumors

Conditions
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Neuroendocrine Tumors, Hepatic Metastases, Metastases

Intervention / Treatment
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* Drug: Everolimus
* Device: embolization
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: embolization or chemoembolization plus everolimus<br>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). | Drug: Everolimus<br>* 10 mg per day of everolimus during 24 months or until progression disease<br>Device: embolization<br>* 2 sessions embolization with spheric particles<br>* Other names: spheric particules of 100 to 500 µm;Drug: Doxorubicin<br>* 2 sessions chemoembolization with 10 mg of lipiodol with 100 mg of doxorubicine<br>* Other names: Chemoembolization;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 months | 
| 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. | 24 months | 
| Toxicities treatment | the toxicities recorded at each monthly visit, described using -CTCAE version 4.0; grade 3 and 4 toxicities will be reviewed; | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, neuroendocrine tumors, gastrointestinal tract, metastases, liver, hepatic