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

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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.

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Time to Progression Free Survival (PFS) Based as Per Investigator Using Kaplan-Meier Methodology [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]. Median, Months (95% Confidence Interval). Everolimus 10 mg/Day (n=207): 11.04 (8.41 to 13.86); Placebo (n=203): 4.60 (3.06 to 5.39).

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Percentage of Participants With Objective Response Rate ( CR {Complete Response} OR PR {Partial Response}) [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, Percentage of participants (95% Confidence Interval). Everolimus 10 mg/Day (n=207): 4.8 (2.3 to 8.7); Placebo (n=203): 2.0 (0.5 to 5.0).

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Overall Survival [Baseline, to death- no time limit]. Median, Months (95% Confidence Interval). Everolimus 10 mg/Day (n=207): 44.02 (35.61 to 51.75); Placebo (n=203): 37.68 (29.14 to 45.77).

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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% [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]. Median, Months (95% Confidence Interval). Ki67 <=2% (n: 7, 17): Everolimus 10 mg/Day (n=207): 12.52 (3.42 to 14.75); Placebo (n=203): 3.68 (2.86 to 5.52). 2% <Ki67 <=5% (n: 24, 13): Everolimus 10 mg/Day (n=207): 10.94 (5.55 to 16.59); Placebo (n=203): 8.48 (3.78 to 13.83). Ki67 >5% (n: 20, 22): Everolimus 10 mg/Day (n=207): 7.69 (5.59 to NA) [Upper boundary of the 95% (Confidence Interval (CI) was not computable]; Placebo (n=203): 3.15 (2.79 to 5.55).

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Progression Free Survival According to Chromogramin A Tumor Marker (CgA) Baseline Level and According to CgA Early Response [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]. Median, Months (95% Confidence Interval). CgA Levels at baseline: CgA <= 2x ULN (n:121, 97): Everolimus 10 mg/Day (n=207): 11.17 (8.54 to 16.49); Placebo (n=203): 4.90 (2.99 to 5.55). CgA levels at baseline: CgA > 2x ULN (n:84, 103): Everolimus 10 mg/Day (n=207): 8.54 (7.69 to 13.80); Placebo (n=203): 4.34 (2.86 to 5.39). Early CgA response: Response (n: 48, 22): Everolimus 10 mg/Day (n=207): 8.54 (7.56 to 14.00); Placebo (n=203): 5.70 (3.19 to 8.54). Early CgA response: Non-Response (n:40, 82): Everolimus 10 mg/Day (n=207): 11.14 (6.90 to NA) [Upper boundary of the 95% Confidence Interval (CI) was not be computable]; Placebo (n=203): 3.19 (2.83 to 5.36).

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Progression Free Survival According to Neuron Specific Enolase Tumor Marker (NSE) Baseline Level and According to NSE Early Response [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]. Median, Months (95% Confidence Interval). NSE Levels at baseline: <= ULN (n: 155, 138): Everolimus 10 mg/Day (n=207): 13.86 (10.81 to 18.10); Placebo (n=203): 5.36 (3.78 to 5.55). NSE levels at baseline: > ULN (n: 48, 56): Everolimus 10 mg/Day (n=207): 8.11 (4.24 to 11.17); Placebo (n=203): 2.83 (2.60 to 3.06). Early NSE response: Response (n: 24, 16): Everolimus 10 mg/Day (n=207): 8.11 (4.24 to 11.40); Placebo (n=203): 3.06 (2.23 to 5.36). Early NSE response: Non-Response (n:16, 27): Everolimus 10 mg/Day (n=207): 3.79 (2.60 to 13.80); Placebo (n=203): 2.58 (1.84 to 2.83).

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Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) [on or after the start of double-blind study medication until no later than 28 days after double-blind study medication discontinuation]. Number, Participants. Adverse events (AEs): Everolimus 10 mg/Day (n=204): 203; Placebo (n=203): 198. Death: Everolimus 10 mg/Day (n=204): 111; Placebo (n=203): 23. Serious Adverse Events: Everolimus 10 mg/Day (n=204): 84; Placebo (n=203): 52.

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Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) (Open-label Period) [on or after the start of open-label study medication until no later than 28 days after open-label study medication discontinuation]. Number, Participants. Adverse events (AEs): Everolimus 10 mg/Day (n=225): 221. Death: Everolimus 10 mg/Day (n=225): 122. Serious Adverse Events: Everolimus 10 mg/Day (n=225): 108.

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Evaluation of Pharmacokinetics (PK) Parameter: AUC0-t Last [Day 1 of every cycle (28 days/cycle) throughout the study]. Mean, ng.h/mL (Standard Deviation). Everolimus 10 mg/Day (n=7): 594 (313); Everolimus 5 mg/Day (n=1): 481 (NA) [Summary statistics were only produced if the sample size for the dose group in the respective cycle is 3 or more.].

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Evaluation of Pharmacokinetics (PK) Parameters: Cmax, Cmin [Day 1 of every cycle (28 days/cycle) throughout the study]. Mean, ng/mL (Standard Deviation). Cmax: Everolimus 10 mg/Day (n=7): 62.4 (18.5); Everolimus 5 mg/Day (n=1): 27.4 (NA) [Summary statistics will only be produced if the sample size for the dose group in the respective cycle is 3 or more.]. Cmin: Everolimus 10 mg/Day (n=7): 9.80 (4.95); Everolimus 5 mg/Day (n=1): 12.2 (NA) [Summary statistics will only be produced if the sample size for the dose group in the respective cycle is 3 or more.].

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Evaluation of Pharmacokinetics (PK) Parameter: CL/F [Day 1 of every cycle (28 days/cycle) throughout the study]. Mean, L/h (Standard Deviation). Everolimus 10 mg/Day (n=7): 20.2 (7.7); Everolimus 5 mg/Day (n=1): 10.7 (NA) [Summary statistics were only produced if the sample size for the dose group in the respective cycle is 3 or more.].

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Evaluation of Pharmacokinetics (PK) Parameter: Tmax -Time to Maximum (Peak) Drug Concentration [Day 1 of every cycle (28 days/cycle) throughout the study]. Median, h (Full Range). Everolimus 10 mg/Day (n=7): 1.17 (0.5 to 24.0); Everolimus 5 mg/Day (n=1): 3.0 (NA to NA) [Summary statistics were only produced if the sample size for the dose group in the respective cycle is 3 or more.].

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Analysis of Time to Definitive Deterioration of WHO Performance Status Using Kaplan-Meier [3 months, 6 months]. Number, % of participants with no deterioration. Month 3: Everolimus 10 mg/Day (n=207): 94.4 (90.0 to 96.8); Placebo (n=203): 91.8 (86.8 to 95.0). Month 6: Everolimus 10 mg/Day (n=207): 90.6 (85.2 to 94.0); Placebo (n=203): 86.3 (79.3 to 91.0).

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Plasma Angiogenesis Marker: Basic Fibroblast Growth Factor (bFGF) [Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]. Mean, pg/mL (Standard Deviation). Baseline (n:198, 195): Everolimus 10 mg/Day (n=207): 52.59 (101.659); Placebo (n=203): 51.49 (78.049). Cycle 2 Day 1 (n: 185, 184): Everolimus 10 mg/Day (n=207): 38.43 (51.809); Placebo (n=203): 58.33 (72.938). Cycle 3 Day 1 (n: 185, 174): Everolimus 10 mg/Day (n=207): 51.97 (89.064); Placebo (n=203): 59.08 (72.495). Cycle 4 Day 1 (n: 171, 159): Everolimus 10 mg/Day (n=207): 51.28 (82.139); Placebo (n=203): 54.58 (75.350).

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Plasma Angiogenesis Marker: Placental Growth Factor (PLGF) [Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]. Mean, pg/mL (Standard Deviation). Baseline (n:198, 195): Everolimus 10 mg/Day (n=207): 45.82 (282.084); Placebo (n=203): 32.92 (52.586). Cycle 2 Day 1 (n: 185, 184): Everolimus 10 mg/Day (n=207): 25.78 (33.420); Placebo (n=203): 35.38 (57.135). Cycle 3 Day 1 (n: 185, 174): Everolimus 10 mg/Day (n=207): 26.55 (28.839); Placebo (n=203): 33.84 (65.361). Cycle 4 Day 1 (n: 171, 159): Everolimus 10 mg/Day (n=207): 25.69 (18.312); Placebo (n=203): 35.47 (67.314).

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Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1) [Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]. Mean, pg/mL (Standard Deviation). Baseline (n:198, 195): Everolimus 10 mg/Day (n=207): 264.18 (272.190); Placebo (n=203): 256.69 (187.866). Cycle 2 Day 1 (n: 185, 184): Everolimus 10 mg/Day (n=207): 307.46 (808.316); Placebo (n=203): 299.03 (541.933). Cycle 3 Day 1 (n: 185, 174): Everolimus 10 mg/Day (n=207): 263.81 (187.329); Placebo (n=203): 253.37 (250.841). Cycle 4 Day 1 (n: 171, 159): Everolimus 10 mg/Day (n=207): 258.03 (223.980); Placebo (n=203): 242.17 (163.561).

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Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2) [Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]. Mean, pg/mL (Standard Deviation). Baseline (n:197, 193): Everolimus 10 mg/Day (n=207): 30061.30 (8607.379); Placebo (n=203): 31299.61 (9091.460). Cycle 2 Day 1 (n: 185, 183): Everolimus 10 mg/Day (n=207): 22691.18 (6793.409); Placebo (n=203): 30223.21 (8447.992). Cycle 3 Day 1 (n: 185, 173): Everolimus 10 mg/Day (n=207): 22021.23 (6393.414); Placebo (n=203): 29264.67 (8408.405). Cycle 4 Day 1 (n: 172, 158): Everolimus 10 mg/Day (n=207): 21218.17 (6249.977); Placebo (n=203): 28308.58 (8477.049).

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Plasma Angiogenesis Marker: Vascular Endothelial Growth Factor (VEGF) [Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1]. Mean, pg/mL (Standard Deviation). Baseline (n:198, 195): Everolimus 10 mg/Day (n=207): 265.09 (283.123); Placebo (n=203): 326.16 (323.891). Cycle 2 Day 1 (n: 185, 184): Everolimus 10 mg/Day (n=207): 243.03 (183.010); Placebo (n=203): 326.78 (377.752). Cycle 3 Day 1 (n: 185, 174): Everolimus 10 mg/Day (n=207): 280.18 (268.582); Placebo (n=203): 292.27 (286.154). Cycle 4 Day 1 (n: 171, 159): Everolimus 10 mg/Day (n=207): 283.51 (326.634); Placebo (n=203): 319.60 (325.409).