Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare the antitumor activity of everolimus plus best supportive care versus placebo plus best supportive care in patients with progressive nonfunctional neuroendocrine tumor (NET) of gastrointestinal (GI) or lung origin without a history of, or current symptoms of carcinoid syndrome.

Detailed Description
-----------------
This was a prospective, multi-center, randomized, double-blind, parallel-group, placebo-controlled, two-arm Phase III study comparing the efficacy and safety of everolimus 10 mg daily to placebo in patients with advanced NET of GI or lung origin without a history of, or current symptoms of carcinoid syndrome. After assessment of eligibility, participants qualifying for the study were randomized in a 2:1 ratio to receive either everolimus or matching placebo. Participants received daily oral doses of 10 mg everolimus or matching placebo as study drug. In both arms, the study drug was combined with best supportive care and treatment cycles were defined as 28 days. Participants were treated until disease progression as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0, intolerable toxicity, death, lost to follow-up or consent withdrawal. Regardless of the reason for study drug discontinuation, participants had a safety follow-up visit scheduled 30 days after the last dose of the study drug. Per data monitoring committee recommendation, all participants on treatment with placebo were allowed to crossover to open-label treatment with everolimus. This change was implemented through protocol amendment 3 (issued on 06-May-2016) after which remaining participants entered into open-label phase of the study.

Official Title
-----------------
A Randomized, Double-blind, Multicenter, Phase III Study of Everolimus (RAD001) Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced NET of GI or Lung Origin

Conditions
-----------------
Advanced NET of GI Origin, Advanced NET of Lung Origin, Neuroendocrine Tumors

Intervention / Treatment
-----------------
* Drug: Everolimus
* Drug: Placebo
* Other: Best suportive care (BSC)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically confirmed, well differentiated (G1 or G2), advanced (unresectable or metastatic), neuroendocrine tumor of GI or lung origin No history of and no active symptoms related to carcinoid syndrome In addition to treatment-naive patients, patients previously treated with SSA, Interferon (IFN), one prior line of chemotherapy, and/or PRRT were allowed into the study. Pretreated patients had to have progressed on or after the last treatment Radiological documented disease progression within 6 months prior to randomization Measurable disease WHO performance status ≤1 Adequate bone marrow, liver and renal function Exclusion Criteria: Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, pancreatic islet cell carcinoma, insulinoma, glucagonoma, gastrinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma Patients with pancreatic NET or NET of origins other than GI or Lung Patients with history of or active symptoms of carcinoid syndrome (e.g. flushing, diarrhea) Patients with more than one line of prior chemotherapy Prior targeted therapy Hepatic intra-arterial embolization within the last 6 months. Cryoablation or radiofrequency ablation of hepatic metastases within 2 months of randomization Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus) Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus) Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy Patients who had any severe and/or uncontrolled medical conditions such as: unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to randomization, serious uncontrolled cardiac arrhythmia active or uncontrolled severe infection liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA) Chronic treatment with corticosteroids or other immunosuppressive agents Known history of HIV seropositivity Pregnant or nursing (lactating) women Other protocol-defined inclusion/exclusion criteria might apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus + BSC<br>Participants received everolimus 10 mg once daily plus best supportive care (BSC) throughout the study | Drug: Everolimus<br>* Participants were treated with everolimus 10 mg (two 5 mg tablets) once daily orally taken<br>* Other names: RAD001;Other: Best suportive care (BSC)<br>* Best supportive care includes all care provided to participants deemed necessary by the treating physician, such as but not restricted to anti-diarrheals and analgesics. The optimal care of the patient is based on the treating physician's best medical judgment.<br>|
| Placebo Comparator: Placebo + BSC<br>Participants received matching placebo once daily plus best supportive care (BSC) during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period. | Drug: Placebo<br>* Participants were treated with two tablets of matching placebo once daily orally taken.<br>Other: Best suportive care (BSC)<br>* Best supportive care includes all care provided to participants deemed necessary by the treating physician, such as but not restricted to anti-diarrheals and analgesics. The optimal care of the patient is based on the treating physician's best medical judgment.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment | PFS is defined as the time from randomization to the date of the first documented tumor progression or death from any cause, whichever comes first. Progression was defined using modified RECIST 1.0 and as per central radiology assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Progression was assessed by cat scan (CT) and/or magnetic resonance imaging (MRI). For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. The percentage event-free probability estimate is the estimated probability that a patient will remain event-free in PFS up to the specified time point. | From date of randomization to progression or death, whichever comes first, assessed up to 27 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from the date of randomization to date of death due to any cause. If a death had not been observed by the date of analysis cut-off, then OS was censored at the date of last contact. All participants randomized to placebo arm who crossed over to everolimus were censored. | From date of randomization to date of death, assessed up to approximately 8 years | 
| Overall Response Rate (ORR) as Per Modified RECIST 1.0 According to Central Evaluation | ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), according to central evaluation and as per modified RECIST 1.0. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. | From randomization until end of treatment, assessed up to approximately 2.5 years | 
| Disease Control Rate (DCR) Based on Modified RECIST 1.0 and as Per Central Radiology Assessment | DCR is defined as the proportion of subjects with best overall response of CR or PR or stable disease based on modified RECIST 1.0 and as per central radiology assessment. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. | From randomization until end of treatment, assessed up to approximately 2.5 years | 
| Time to Definitive Deterioration in Functional Assessment of Cancer Therapy - General (FACT-G) Questionnaire Total Score | FACT-G is a self-assessed health-related quality of life questionnaire. The questionnaire is comprised of 27 questions examining physical, social/family, emotional, and functional well-being. Participants responded to the items on a five-point scale, ranging from 0: Not at all to 4: Very much. The total score ranges from 0 to 108, with higher scores indicating a better patient-reported outcome/quality of life. Definitive deterioration is defined as a decrease in the total score by at least 7 points compared to baseline with no further improvement. Death was considered as worsening of the FACT-G total score if it occurred close to the last available assessment, where close was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment. | From randomization to definitive deterioration of FACT-G total score, assessed up to approximately 3 years | 
| Change From Baseline in Chromogranin A (CgA) Levels | CgA is a potential biomarker for tumor response. Blood samples were collected for assessment of CgA levels. Change from Baseline at a particular visit was calculated as the CgA level at that visit minus Baseline. | From baseline (every 4 weeks) up to 116 weeks | 
| Change From Baseline in Neuron Specific Enolase (NSE) Levels | NSE is a potential biomarker for tumor response. Blood samples were collected for assessment of NSE levels. Change from Baseline at a particular visit was calculated as the NSE level at that visit minus Baseline. | From baseline (every 4 weeks) up to Week 116 | 
| Time to Definitive Deterioration in World Health Organization (WHO) Performance Status (PS) Change | WHO PS is a scale rated from 0 (fully active) to 5 (death) by a healthcare professional to assess the overall status of a patient: a lower score represents a higher ability to perform daily tasks. Deterioration is defined as an increase of at least one point compared to baseline. Deterioration is considered definitive if no improvements in the WHO PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. Death was considered as worsening of the WHO PS if it occurred close to the last available assessment, where close was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment. | From randomization to definitive deterioration of WHO performance status, assessed up to approximately 3 years | 
| Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29 | A pre-dose blood sample at day 29 was collected to determine the exposure of everolimus at the steady-state pre-dose concentration (Cmin). Cmin is provided for participants randomized to everolimus+BSC who received 10mg of everolimus daily and also for participants randomized to everolimus+BSC who received 5mg of everolimus daily which was required for a number of participants in the study experiencing adverse events requiring dose modifications | Pre-dose at Day 29. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neuroendocrine tumor, NET, progressive, advanced, gastrointestinal, GI or lung origin, nonfunctional, everolimus, Advanced NET of GI origin, Advanced NET of lung origin