Efficacy and Safety of Everolimus (RAD001) Compared to Placebo in Patients With Advanced Neuroendocrine Tumors

Study Overview
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Brief Summary
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The purpose of this study was to evaluate progression free survival in those participants assigned everolimus 10 mg/day plus Best Supportive Care versus those assigned to placebo plus Best Supportive Care in Advanced Neuroendocrine Tumors of pancreatic origin.

Official Title
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A Randomized Double-blind Phase III Study of RAD001 10 mg/d Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Pancreatic Neuroendocrine Tumor (NET)

Conditions
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Advanced Neuroendocrine Tumors of Pancreatic Origin

Intervention / Treatment
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* Drug: Everolimus
* Drug: Everolimus Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients must have advanced (unresectable or metastatic) biopsy-proven pancreatic NET Measurable disease by radiologic assessment Adequate blood work Performance Status 0-2 : Ability to be out of bed most of the time Adult male or female patients ≥ 18 years of age Women of childbearing potential must have a negative serum pregnancy test Written informed consent from patients must be obtained in accordance to local guidelines Exclusion criteria: Patients with severe kind of (poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma) cancer are not eligible Other chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to starting this trial Hepatic artery procedure called embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation/ radiofrequency ablation of hepatic metastasis within 2 months of enrollment Prior therapy with the same kind of medication (mTOR inhibitors: sirolimus, temsirolimus, everolimus). Uncontrolled diabetes mellitus Patients who have any severe and/or uncontrolled medical conditions such as: Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent Patients with a known history of HIV seropositivity No other prior or concurrent cancer at the time enrolling to this trial Other protocol defined inclusion/ exclusion criteria applied

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus 10 mg/day<br>Participants received 10 mg per day of Everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1). | Drug: Everolimus<br>* A 10-mg dose of everolimus was given by continuous oral daily dosing of two 5-mg tablets.<br>* Other names: RAD001;|
| Placebo Comparator: Placebo<br>Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1). | Drug: Everolimus Placebo<br>* a 10-mg dose of matching placebo to Everolimus was given by continuous oral daily dosing of two 5-mg tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression Free Survival (PFS) Based as Per Investigator Using Kaplan-Meier Methodology | Progression of disease is defined as the time from study start to the date of first documented progression of disease or death due to any cause. Progression of disease is defined by RECIST criteria: Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions. | Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response Rate ( CR {Complete Response} OR PR {Partial Response}) | Objective Response defined by RECIST criteria: Partial response (PR) must have ≥ 30% decrease in the sum of the longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks . Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions | Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010 | 
| Overall Survival | Overall survival (OS) was defined as the time from date of randomization to the date of death due to any cause. Analyses were performed using all deaths in the FAS population regardless of whether they were observed during the double-blind treatment period, the open-label treatment period, the post-treatment evaluations, or the survival follow-up period. | Baseline, to death- no time limit | 
| Progression Free Survival According to Ki-67 Levels Categorized as: Less Than or Equal to 2%, > 2% to Less Than or Equal to 5% and > 5% | The level of Ki 67 expression for evaluable tumor samples were analyzed towards progression free survival (PFS) as per local investigator assessment. The Ki-67 protein is a cellular marker for proliferation. It is strictly associated with cell proliferation. During interphase, the Ki-67 antigen can be exclusively detected within the cell nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. Baseline Ki 67 levels were categorized as: less than or equal to 2%, > 2% to less than or equal to 5% and > 5%. | Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010 | 
| Progression Free Survival According to Chromogramin A Tumor Marker (CgA) Baseline Level and According to CgA Early Response | Baseline levels of serum CgA SE were characterized towards progression free survival (PFS) as per local investigator assessment, relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be 'Elevated' otherwise considered as Non-elevated. An 'early response' (applicable to only those patients with elevated levels at baseline) was defined as a decrease of greater than or equal to 30% from baseline to Cycle 2 Day 1 or normalization by Cycle 2 Day 1. CgA is widely expressed in well-differentiated pancreatic NET. CgA is present in the secretory granules of neuroendocrine cells. Pancreatic NET patients often present with elevated circulating levels of CgA in their blood. Baseline levels of these biomarkers are considered as prognostic factors. | Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010 | 
| Progression Free Survival According to Neuron Specific Enolase Tumor Marker (NSE) Baseline Level and According to NSE Early Response | Baseline levels of serum NSE were characterized towards PFS as per local investigator assessment, relative to the upper limited of normal (ULN). NSE levels exceeding ULN were considered to be 'Elevated' otherwise considered as Non-elevated. An 'early response' (applicable to only those patients with elevated levels at baseline) was defined as a decrease of greater than or equal to 30% from baseline to Cycle 2 Day 1 or normalization by Cycle 2 Day 1. NSE is widely expressed in well-differentiated pancreatic NET. NSE is usually expressed in the cytoplasm. Pancreatic NET patients often present with elevated circulating levels of NSE in their blood. Baseline levels of these biomarkers are considered as prognostic factors. | Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010 | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) | Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. | on or after the start of double-blind study medication until no later than 28 days after double-blind study medication discontinuation | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) (Open-label Period) | Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. | on or after the start of open-label study medication until no later than 28 days after open-label study medication discontinuation | 
| Evaluation of Pharmacokinetics (PK) Parameter: AUC0-t Last | The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. This PK parameter is area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t last). | Day 1 of every cycle (28 days/cycle) throughout the study | 
| Evaluation of Pharmacokinetics (PK) Parameters: Cmax, Cmin | The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. The PK parameter: maximum (peak) drug concentration (Cmax) and minimum (trough) drug concentration (Cmin). | Day 1 of every cycle (28 days/cycle) throughout the study | 
| Evaluation of Pharmacokinetics (PK) Parameter: CL/F | The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. The PK parameter clearance of distribution expressed as a function of bioavailability (CL/F). | Day 1 of every cycle (28 days/cycle) throughout the study | 
| Evaluation of Pharmacokinetics (PK) Parameter: Tmax -Time to Maximum (Peak) Drug Concentration | The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. Values for tmax where summarized in median (range). | Day 1 of every cycle (28 days/cycle) throughout the study | 
| Analysis of Time to Definitive Deterioration of WHO Performance Status Using Kaplan-Meier | Time to definitive worsening is defined as a definitive increase in performance status from a baseline of 0 or 1 to WHO >= 2, or from a baseline value of 2 to WHO >= 3. If no earlier deterioration, patients were censored at the end of follow-up or at the start of further antineoplastic therapy. Rates of patients with no deterioration at 3 and 6 months were computed using Kaplan-meier method. Grade 0: Able to carry out all activity without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory & able to do light work; Grade 2: Ambulatory & capable of all self-care but unable to carry out any work. Up & about more than 50% of waking hours; Grade 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled & cannot carry on any self-care; totally confined to bed or chair. | 3 months, 6 months | 
| Plasma Angiogenesis Marker: Basic Fibroblast Growth Factor (bFGF) | This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules. | Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 | 
| Plasma Angiogenesis Marker: Placental Growth Factor (PLGF) | This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules. | Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 | 
| Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1) | This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules. | Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 | 
| Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2) | This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules. | Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 | 
| Plasma Angiogenesis Marker: Vascular Endothelial Growth Factor (VEGF) | This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules. | Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase III, Advanced Neuroendocrine Tumor in adults, RAD001, NET, everolimus, mTOr, islet cell, neuroendocrine