Everolimus and Octreotide in Patients With Advanced Carcinoid Tumor

Study Overview
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Brief Summary
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The purpose of this study was to evaluate whether everolimus 10 mg / day added to treatment with depot octreotide prolongs progression free survival compared to treatment with octreotide alone in patients with advanced carcinoid tumor.

Official Title
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A Randomized, Double-blind Placebo-controlled, Multicenter Phase III Study in Patients With Advanced Carcinoid Tumor Receiving Octreotide Depot and Everolimus 10 mg/Day or Octreotide Depot and Placebo

Conditions
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Carcinoid Tumor, Malignant Carcinoid Syndrome

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


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Advanced (unresectable or metastatic) carcinoid tumor Confirmed low-grade or intermediate-grade neuroendocrine carcinoma Documented progression of disease within 12 months prior to randomization. Measurable disease determined by triphasic computer tomography (CT) scan or magnetic resonance imaging (MRI). Exclusion criteria: Poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoma, or small cell carcinoma. Hepatic artery embolization within the last 6 months or cryoablation of hepatic metastasis within 2 months of enrollment. Previous treatment with mammalian target of rapamycin (mTOR) inhibitors (sirolimus, temsirolimus, everolimus) Intolerance or hypersensitivity to octreotide, everolimus, or other rapamycins. Severe or uncontrolled medical conditions Chronic treatment with corticosteroids or other immunosuppressive agent. Other primary cancer within 3 years. 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Octreotide+ Everolimus<br>Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1. | Drug: Octreotide<br>* Octreotide 30 mg intramuscularly (i.m.) every 28 days.<br>* Other names: Sandostatin LAR® Depot;Drug: Everolimus<br>* A 10-mg oral daily dosing regimen (two 5-mg tablets) of everolimus.<br>* Other names: RAD001;|
| Placebo Comparator: Octreotide+ Placebo<br>Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1. | Drug: Octreotide<br>* Octreotide 30 mg intramuscularly (i.m.) every 28 days.<br>* Other names: Sandostatin LAR® Depot;Drug: Placebo<br>* A 10-mg oral daily dosing regimen (two 5-mg tablets) of matching placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review | Progression free survival (PFS) is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary analysis of PFS was based on the independent central adjudicated assessment using Kaplan-Meier method. | Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST) | The best overall response rate is defined as the percentage of patients having achieved confirmed Complete Response + Partial Response. Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression. • Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression. | Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 | 
| Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline 5-hydroxyindoleacetic Acid (5-HIAA) Level | 5-HIAA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of 5-HIAA in urine were defined as 'High' if they exceeded the median value, and 'Low' if they were lower than or equal to the median. | If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 | 
| Overall Survival Using Kaplan-Meier Methodology | Overall survival was defined as the time from the date of randomization to the date of death from any cause. If a patient was not known to have died, survival was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the median overall survival for each treatment group. | Months 12, 24, 36, 48 | 
| Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Double-Blind Phase) | AEs 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. SAEs 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. | From first day of treatment up to 28 days after last day of treatment in double blind | 
| Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs) (Open Label Phase) | AEs 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. SAEs 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. | From first day of treatment up to 28 days after last day of treatment in double blind | 
| Progression Free Survival (PFS) as Per Adjudicated Central Review by Baseline Chromogranin A (CgA) | Serum CgA levels in urine are frequently elevated in patients with advanced carcinoid tumors. Baseline levels of serum CgA were characterized relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be 'Elevated'; otherwise considered as Non-elevated. | If elevated at baseline, evaluated every cycle visit (28 days/cycle) reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Carcinoid, Tumor, Neuroendocrine, Carcinoma, Everolimus, Octreotide