Efficacy of Everolimus Alone or in Combination With Pasireotide LAR in Advanced PNET

Study Overview
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Brief Summary
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This study will estimate the treatment effect of everolimus in combination with pasireotide LAR relative to everolimus alone on progression-free survival (PFS) in patients with advanced progressive PNET. A planned primary analysis was completed with data cut of 02-Apr-2014. The study did not meet its primary objective, which was based on progression-free survival (PFS) as per local radiology assessment and was prematurely terminated with the last patient last visit on 19-Feb-2015. However, it is important to note that the data did not reveal any new safety concerns. It was decided to stop the study and this decision was shared with the study sites on 31-Jul-2014.

Official Title
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A Randomized, Open-label Phase II Multicenter Study Evaluating the Efficacy of Oral Everolimus Alone or in Combination With Pasireotide LAR i.m. in Advanced Progressive Pancreatic Neuroendocrine Tumors (PNET) - The COOPERATE-2 Study

Conditions
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Islet Cell Tumor

Intervention / Treatment
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* Drug: Everolimus
* Drug: Pasireotide LAR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced histologically confirmed well differentiated pancreatic neuroendocrine tumor Progressive disease within the last 12 months Measurable disease per RECIST Version 1.0 determined by multiphase MRI or triphasic CT Exclusion Criteria: Patients currently requiring somatostatin analog treatment Prior therapy with mTOR inhibitors or pasireotide Patients with more than 2 prior systemic treatment regimens Previous cytotoxic chemotherapy, targeted therapy, somatostatin analogs, or biotherapy within the last 4 weeks Other protocol-defined inclusion/exclusion criteria may apply

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paseriotide LAR + Everolimus<br>everolimus 10 mg once daily po in combination with pasireotide LAR 60 mg every 28 days (q28d) im | Drug: Everolimus<br>* Everolimus was supplied as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets<br>* Other names: RAD001;Drug: Pasireotide LAR<br>* Pasireotide LAR intra-muscular depot injections were supplied as a powder in vials containing 20 mg and 40 mg with ampoules containing 2 mL of vehicle (for reconstitution).<br>* Other names: SOM230 LAR;|
| Experimental: Everolimus<br>everolimus 10 mg once daily po alone | Drug: Everolimus<br>* Everolimus was supplied as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets<br>* Other names: RAD001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Per Local Radiological Review | PFS per RECIST 1.0. (Response Evaluation Criteria in Solid Tumors). PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause. | Once 80 PFS events had occurred aproximately after 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability Profile of Everolimus Alone or in Combination With Pasireotide LAR | Consisted of monitoring and recording the rate, type, severity, and causal relationship of adverse events (AEs) and serious AEs (SAEs) to treatment. The safety analysis was based mainly on the frequency of AEs or SAEs and on the number of laboratory values that fell outside of pre-determined range. | Once 80 PFS events had occurred | 
| Objective Response Rate (ORR) as Per Radiology Review | Objective response was determined by the local radiologist according to the RECIST Version 1.0. ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR). This is also referred to as Overall response rate. CR: Disappearance of all nontarget lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameter of all target lesions recorded at or after baseline. | Once 80 PFS events had occurred | 
| Duration of Response (DoR) | 80 PFS are expected after approximately 24 months. Kaplan Meier was initially planned to be used to depict duration of response by treatment group and by stratum. Later based on the mode of action of everolimus and pasireotide and based on study experience, only a low number of objective responses per RECIST were expected. Therefore, protocol was amended to only list duration of response, and confirmed responses were flagged in the listing. Hence, statistical analyses were not planned and such data are not available for the following table. | Once 80 PFS events had occurred | 
| Overall Survival (OS) Using Kaplan Meier Method | Overall survival was defined as the time from date of randomization/start of treatment to date of death due to any cause. If a patient is not known to have died, survival was to be censored at the date of last contact. | Once 80 PFS events had occurred | 
| PFS and the Predictive Probability of Success in Phase III | 105 PFS events expected after approximately 36 months | Once 105 PFS events had occurred occurred | 
| Disease Control Rate (DCR) as Per Radiology Review | Disease control rate is the percentage of patients with a best overall response of CR or PR or stable disease (SD) determined by the local radiologist according to the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) Version 1.0. CR: Disappearance of all nontarget lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameter of all target lesions recorded at or after baseline. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD). PD: Any progression ≤ 18 weeks after randomization (and not qualifying for CR, PR or stable disease SD. | Once 80 PFS events had occurred | 
| Summary of Pharmacokinetics (PK) for Everolimus for AUClast |  | Cycle 2 Day 1 | 
| Summary of Pharmacokinetics (PK) for Everolimus for CL/F |  | Cycle 2 Day 1 | 
| Summary of Pharmacokinetics (PK) for Everolimus for Cmax and Cmin |  | Cycle 2 Day 1 | 
| Summary of Pharmacokinetics (PK) for Everolimus for Tmax |  | Cycle 2 Day 1 | 
| Summary of Pasireotide Concentrations Following Intramuscular Injection of Pasireotide LAR 60mg |  | Cycle 1 Day 21, Cycle 2 Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic, Neuroendocrine tumors, PNET, Pasireotide, Everolimus, Advanced progressive pancreatic neuroendocrine tumor