Hepatic Metastases, Metastases, Neuroendocrine Tumors
Conditions
Keywords
cancer, neuroendocrine tumors, gastrointestinal tract, metastases, liver, hepatic
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%
Interventions
DRUGEverolimus
10 mg per day of everolimus during 24 months or until progression disease
DEVICEembolization
2 sessions embolization with spheric particles
DRUGDoxorubicin
2 sessions chemoembolization with 10 mg of lipiodol with 100 mg of doxorubicine
Sponsors
Federation Francophone de Cancerologie Digestive
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Hepatic Progression Free Survival at 24 Months | Up to 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. Progression-free survival rate (PFS) (based on the investigator) 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
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (Hepatic or Not) | From randomization until the date of first progression (clinical or radiological) or death from any cause whichever came first, assessed up to 3 years | Progression-free survival rate was 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 news for alive patients |
| Overall Survival | From randomization until death or last news for alive patients | Overall survival was 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. |
Countries
France
Participant flow
Recruitment details
Between 28th December 2012 and 16t March 2016, 74 patients were included by 19 french centers. Actual start date was actulaized in the protocol section.
Pre-assignment details
Before enrollement, standard examinations (biological, clinical) were done. In terms of imaging, abdominal and thoracic computed tomography scan or MRI were also done.
Participants by arm
| Arm | Count |
|---|---|
| Embolization or Chemoembolization Plus Everolimus 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).
Everolimus: 10 mg per day of everolimus during 24 months or until progression disease
embolization: 2 sessions embolization with spheric particles
Doxorubicin: 2 sessions chemoembolization with 10 mg of lipiodol with 100 mg of doxorubicine | 74 |
| Total | 74 |
Baseline characteristics
| Characteristic | Embolization or Chemoembolization Plus Everolimus |
|---|---|
| Age, Continuous | 65.4 years STANDARD_DEVIATION 8.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 74 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment France | 74 participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 32 / 74 |
| other Total, other adverse events | 67 / 74 |
| serious Total, serious adverse events | 35 / 74 |
Outcome results
Primary
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. Progression-free survival rate (PFS) (based on the investigator) 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: Up to 24 months
Population: The analysis population for the primary endpoint was defined as the population of evaluable patients. A patient was considered evaluable if he or she hadreceived at least one dose of everolimus and at least one image on treatment.~A patient who died (from any cause after treatment) or progressed to liver disease before 24 months was evaluable and considered a failure for the primary endpoint.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Embolization or Chemoembolization Plus Everolimus | Rate of Hepatic Progression Free Survival at 24 Months | Patients with hepatic progression or DCD at 24 months | 47 Participants |
| Embolization or Chemoembolization Plus Everolimus | Rate of Hepatic Progression Free Survival at 24 Months | Patients alive without hepatic progression at 24 months | 20 Participants |
Secondary
Overall Survival
Overall survival was 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: From randomization until death or last news for alive patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Embolization or Chemoembolization Plus Everolimus | Overall Survival | 51.0 Months |
Secondary
Progression-free Survival (Hepatic or Not)
Progression-free survival rate was 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 news for alive patients
Time frame: From randomization until the date of first progression (clinical or radiological) or death from any cause whichever came first, assessed up to 3 years
Population: All patients included in the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Embolization or Chemoembolization Plus Everolimus | Progression-free Survival (Hepatic or Not) | 16.9 months |