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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
410
A 10-mg dose of everolimus was given by continuous oral daily dosing of two 5-mg tablets.
a 10-mg dose of matching placebo to Everolimus was given by continuous oral daily dosing of two 5-mg tablets.
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 frame: 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
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 frame: 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.
Time frame: Baseline, to death- no time limit
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University of South Alabama / Mitchell Cancer Institute Deptof Mitchell Cancer Inst(2)
Mobile, Alabama, United States
Pacific Cancer Medical Center, Inc.
Anaheim, California, United States
Cedars Sinai Medical Center SC-2
Los Angeles, California, United States
University of California at Los Angeles UCLA (3)
Los Angeles, California, United States
University of California San Francisco Dept. of UCSF Comp. Cancer
San Francisco, California, United States
Kaiser Permanente Northwest Franklin Medical Offices
Denver, Colorado, United States
H. Lee Moffitt Cancer Center & Research Institute Malignant Hematology Clinic
Tampa, Florida, United States
Indiana University Health Goshen Center for Cancer Dept. of Indiana Univ. Cancer
Indianapolis, Indiana, United States
University of Iowa Medical Center Dept. of Iowa Medical Center
Iowa City, Iowa, United States
University of Louisville / James Graham Brown Cancer Center SC
Louisville, Kentucky, United States
...and 72 more locations
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 frame: 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 frame: 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 frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1