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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
160
Everolimus was supplied as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets
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).
Dana Farber Cancer Institute SC-2
Boston, Massachusetts, United States
Montefiore Medical Center MMC
The Bronx, New York, United States
Oregon Health & Science University Knight Cancer Institute
Portland, Oregon, United States
University of Texas/MD Anderson Cancer Center UT MD Anderson Cancer Ctr
Houston, Texas, United States
Novartis Investigative Site
Buenos Aires, Buenos Aires, Argentina
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.
Time frame: Once 80 PFS events had occurred aproximately after 24 months
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Once 80 PFS events had occurred
PFS and the Predictive Probability of Success in Phase III
105 PFS events expected after approximately 36 months
Time frame: 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.
Time frame: Once 80 PFS events had occurred
Summary of Pharmacokinetics (PK) for Everolimus for AUClast
Time frame: Cycle 2 Day 1
Summary of Pharmacokinetics (PK) for Everolimus for CL/F
Time frame: Cycle 2 Day 1
Summary of Pharmacokinetics (PK) for Everolimus for Cmax and Cmin
Time frame: Cycle 2 Day 1
Summary of Pharmacokinetics (PK) for Everolimus for Tmax
Time frame: Cycle 2 Day 1
Summary of Pasireotide Concentrations Following Intramuscular Injection of Pasireotide LAR 60mg
Time frame: Cycle 1 Day 21, Cycle 2 Day 29
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Novartis Investigative Site
Caba, Buenos Aires, Argentina
Novartis Investigative Site
St Leonards, New South Wales, Australia
Novartis Investigative Site
Herston, Queensland, Australia
Novartis Investigative Site
Brussels, Belgium
Novartis Investigative Site
Brussels, Belgium
...and 37 more locations