Efficacy and Safety of Everolimus (RAD001) Compared to Placebo in Patients With Advanced Neuroendocrine Tumors (RADIANT-3)

• ClinicalTrials.gov Identifier: NCT00510068
• Recruitment Status: Completed
• First Posted: August 1, 2007
• Results First Posted: December 15, 2011
• Last Update Posted: July 1, 2015
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Advanced Neuroendocrine Tumors of Pancreatic Origin
• Interventions: Drug: Everolimus; Drug: Everolimus Placebo
• Enrollment: 410

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Period Title: Double-blind Period
Started	207	203
Safety Population	204	203
Completed	0	0
Not Completed	207	203
Reason Not Completed
Disease progression	98	169
Final primary analysis	52	18
Adverse Event	37	7
Withdrawal by Subject	8	6
Death	4	3
Abnormal test result (s)	1	0
Lost to Follow-up	1	0
Protocol Violation	6	0
Period Title: Open-label Period
Started	225 [1]	0
Completed	0	0
Not Completed	225	0
Reason Not Completed
Disease Progression	124	0
Adverse Event	46	0
Withdrawal by Subject	21	0
Administrative problems	17	0
Death	7	0
New cancer therapy	7	0
Protocol Violation	2	0
Abnormal laboratory value (s)	1	0
[1] 172 patients switched over from placebo & 53 who were initially randomized to Everolimus arm.

Baseline Characteristics

Arm/Group Title		Everolimus 10 mg/Day	Placebo	Total
Arm/Group Description		Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).	Total of all reporting groups
Overall Number of Baseline Participants		207	203	410
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	207 participants	203 participants	410 participants
		57.1 (12.2)	56.2 (11.4)	56.6 (11.8)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	207 participants	203 participants	410 participants
<65 years		146	153	299
>=65 years		61	50	111
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	207 participants	203 participants	410 participants
	Female	97 46.9%	86 42.4%	183 44.6%
	Male	110 53.1%	117 57.6%	227 55.4%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	207 participants	203 participants	410 participants
Caucasian		156	166	322
Asian		40	34	74
Black		9	2	11
Other		2	1	3

Outcome Measures

1. Primary Outcome

Title	Time to Progression Free Survival (PFS) Based as Per Investigator Using Kaplan-Meier Methodology
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Median (95% Confidence Interval); Unit of Measure: Months
	11.04; (8.41 to 13.86)	4.60; (3.06 to 5.39)

2. Secondary Outcome

Title	Percentage of Participants With Objective Response Rate ( CR {Complete Response} OR PR {Partial Response})
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	4.8; (2.3 to 8.7)	2.0; (0.5 to 5.0)

3. Secondary Outcome

Title	Overall Survival
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all randomized patients.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Median (95% Confidence Interval); Unit of Measure: Months
	44.02; (35.61 to 51.75)	37.68; (29.14 to 45.77)

4. Secondary Outcome

Title	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%
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Median (95% Confidence Interval); Unit of Measure: Months
Ki67 <=2% (n: 7, 17)	12.52; (3.42 to 14.75)	3.68; (2.86 to 5.52)
2% <Ki67 <=5% (n: 24, 13)	10.94; (5.55 to 16.59)	8.48; (3.78 to 13.83)
Ki67 >5% (n: 20, 22)	7.69 [1]; (5.59 to NA)	3.15; (2.79 to 5.55)

[1]

Upper boundary of the 95% (Confidence Interval (CI) was not computable

5. Secondary Outcome

Title	Progression Free Survival According to Chromogramin A Tumor Marker (CgA) Baseline Level and According to CgA Early Response
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Median (95% Confidence Interval); Unit of Measure: Months
CgA Levels at baseline: CgA <= 2x ULN (n:121, 97)	11.17; (8.54 to 16.49)	4.90; (2.99 to 5.55)
CgA levels at baseline: CgA > 2x ULN (n:84, 103)	8.54; (7.69 to 13.80)	4.34; (2.86 to 5.39)
Early CgA response: Response (n: 48, 22)	8.54; (7.56 to 14.00)	5.70; (3.19 to 8.54)
Early CgA response: Non-Response (n:40, 82)	11.14 [1]; (6.90 to NA)	3.19; (2.83 to 5.36)

[1]

Upper boundary of the 95% Confidence Interval (CI) was not be computable

6. Secondary Outcome

Title	Progression Free Survival According to Neuron Specific Enolase Tumor Marker (NSE) Baseline Level and According to NSE Early Response
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Median (95% Confidence Interval); Unit of Measure: Months
NSE Levels at baseline: <= ULN (n: 155, 138)	13.86; (10.81 to 18.10)	5.36; (3.78 to 5.55)
NSE levels at baseline: > ULN (n: 48, 56)	8.11; (4.24 to 11.17)	2.83; (2.60 to 3.06)
Early NSE response: Response (n: 24, 16)	8.11; (4.24 to 11.40)	3.06; (2.23 to 5.36)
Early NSE response: Non-Response (n:16, 27)	3.79; (2.60 to 13.80)	2.58; (1.84 to 2.83)

7. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs)
Description	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

Outcome Measure Data

Analysis Population Description

The Safety Set consists of all patients who received any study drug and had at least one post-baseline safety assessment.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	204	203
Measure Type: Number; Unit of Measure: Participants
Adverse events (AEs)	203	198
Death	111	23
Serious Adverse Events	84	52

8. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) (Open-label Period)
Description	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

Outcome Measure Data

Analysis Population Description

The open-label set was used to summarize the safety analyses performed on data collected in the open-label period of the study: the open-label set included only patients who received at least one dose of open-label everolimus 10 mg and had at least one safety assessment during the open-label period of the study.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	225	0
Measure Type: Number; Unit of Measure: Participants
Adverse events (AEs)	221
Death	122
Serious Adverse Events	108

9. Secondary Outcome

Title	Evaluation of Pharmacokinetics (PK) Parameter: AUC0-t Last
Description	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

Outcome Measure Data

Analysis Population Description

The Safety Set consisted of all patients who received any study drug and had at least one postbaseline safety assessment.

Arm/Group Title	Everolimus 10 mg/Day	Everolimus 5 mg/Day
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received 5 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	7	1
Mean (Standard Deviation); Unit of Measure: ng.h/mL
	594 (313)	481 [1] (NA)

[1]

Summary statistics were only produced if the sample size for the dose group in the respective cycle is 3 or more.

10. Secondary Outcome

Title	Evaluation of Pharmacokinetics (PK) Parameters: Cmax, Cmin
Description	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

Outcome Measure Data

Analysis Population Description

The Safety Set consisted of all patients who received any study drug and had at least one postbaseline safety assessment.

Arm/Group Title	Everolimus 10 mg/Day	Everolimus 5 mg/Day
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received 5 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	7	1
Mean (Standard Deviation); Unit of Measure: ng/mL
Cmax	62.4 (18.5)	27.4 [1] (NA)
Cmin	9.80 (4.95)	12.2 [1] (NA)

[1]

Summary statistics will only be produced if the sample size for the dose group in the respective cycle is 3 or more.

11. Secondary Outcome

Title	Evaluation of Pharmacokinetics (PK) Parameter: CL/F
Description	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

Outcome Measure Data

Analysis Population Description

The Safety Set consisted of all patients who received any study drug and had at least one postbaseline safety assessment.

Arm/Group Title	Everolimus 10 mg/Day	Everolimus 5 mg/Day
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received 5 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	7	1
Mean (Standard Deviation); Unit of Measure: L/h
	20.2 (7.7)	10.7 [1] (NA)

[1]

Summary statistics were only produced if the sample size for the dose group in the respective cycle is 3 or more.

12. Secondary Outcome

Title	Evaluation of Pharmacokinetics (PK) Parameter: Tmax -Time to Maximum (Peak) Drug Concentration
Description	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

Outcome Measure Data

Analysis Population Description

The Safety Set consisted of all patients who received any study drug and had at least one postbaseline safety assessment.

Arm/Group Title	Everolimus 10 mg/Day	Everolimus 5 mg/Day
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received 5 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	7	1
Median (Full Range); Unit of Measure: h
	1.17; (0.5 to 24.0)	3.0 [1]; (NA to NA)

[1]

Summary statistics were only produced if the sample size for the dose group in the respective cycle is 3 or more.

13. Secondary Outcome

Title	Analysis of Time to Definitive Deterioration of WHO Performance Status Using Kaplan-Meier
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Measure Type: Number; Unit of Measure: % of participants with no deterioration
Month 3	94.4	91.8
Month 6	90.6	86.3

14. Secondary Outcome

Title	Plasma Angiogenesis Marker: Basic Fibroblast Growth Factor (bFGF)
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Mean (Standard Deviation); Unit of Measure: pg/mL
Baseline (n:198, 195)	52.59 (101.659)	51.49 (78.049)
Cycle 2 Day 1 (n: 185, 184)	38.43 (51.809)	58.33 (72.938)
Cycle 3 Day 1 (n: 185, 174)	51.97 (89.064)	59.08 (72.495)
Cycle 4 Day 1 (n: 171, 159)	51.28 (82.139)	54.58 (75.350)

15. Secondary Outcome

Title	Plasma Angiogenesis Marker: Placental Growth Factor (PLGF)
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Mean (Standard Deviation); Unit of Measure: pg/mL
Baseline (n:198, 195)	45.82 (282.084)	32.92 (52.586)
Cycle 2 Day 1 (n: 185, 184)	25.78 (33.420)	35.38 (57.135)
Cycle 3 Day 1 (n: 185, 174)	26.55 (28.839)	33.84 (65.361)
Cycle 4 Day 1 (n: 171, 159)	25.69 (18.312)	35.47 (67.314)

16. Secondary Outcome

Title	Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1)
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Mean (Standard Deviation); Unit of Measure: pg/mL
Baseline (n:198, 195)	264.18 (272.190)	256.69 (187.866)
Cycle 2 Day 1 (n: 185, 184)	307.46 (808.316)	299.03 (541.933)
Cycle 3 Day 1 (n: 185, 174)	263.81 (187.329)	253.37 (250.841)
Cycle 4 Day 1 (n: 171, 159)	258.03 (223.980)	242.17 (163.561)

17. Secondary Outcome

Title	Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2)
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Mean (Standard Deviation); Unit of Measure: pg/mL
Baseline (n:197, 193)	30061.30 (8607.379)	31299.61 (9091.460)
Cycle 2 Day 1 (n: 185, 183)	22691.18 (6793.409)	30223.21 (8447.992)
Cycle 3 Day 1 (n: 185, 173)	22021.23 (6393.414)	29264.67 (8408.405)
Cycle 4 Day 1 (n: 172, 158)	21218.17 (6249.977)	28308.58 (8477.049)

18. Secondary Outcome

Title	Plasma Angiogenesis Marker: Vascular Endothelial Growth Factor (VEGF)
Description	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all patients who were randomized.

Arm/Group Title	Everolimus 10 mg/Day	Placebo
Arm/Group Description:	Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).
Overall Number of Participants Analyzed	207	203
Mean (Standard Deviation); Unit of Measure: pg/mL
Baseline (n:198, 195)	265.09 (283.123)	326.16 (323.891)
Cycle 2 Day 1 (n: 185, 184)	243.03 (183.010)	326.78 (377.752)
Cycle 3 Day 1 (n: 185, 174)	280.18 (268.582)	292.27 (286.154)
Cycle 4 Day 1 (n: 171, 159)	283.51 (326.634)	319.60 (325.409)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Everolimus 10mg/Day	Placebo	Open Label - Everolimus 10mg
Arm/Group Description	Afinitor DB: Participants received 10 mg per day of everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).	Afinitor OL (for data collected in the open-label period of the study): The open-label set included only patients who received at least one dose of open-label everolimus 10 mg and had at least one safety assessment during the open-label period of the study.
All-Cause Mortality
	Everolimus 10mg/Day	Placebo	Open Label - Everolimus 10mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Everolimus 10mg/Day	Placebo	Open Label - Everolimus 10mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	84/204 (41.18%)	52/203 (25.62%)	108/225 (48.00%)
Blood and lymphatic system disorders
Anaemia † 1	7/204 (3.43%)	3/203 (1.48%)	3/225 (1.33%)
Febrile neutropenia † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Lymphadenopathy † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Microcytic anaemia † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Neutropenia † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Thrombocytopenia † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Angina pectoris † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Atrial flutter † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Cardiac arrest † 1	2/204 (0.98%)	0/203 (0.00%)	1/225 (0.44%)
Cardiac failure † 1	2/204 (0.98%)	1/203 (0.49%)	0/225 (0.00%)
Cardiac failure congestive † 1	2/204 (0.98%)	0/203 (0.00%)	1/225 (0.44%)
Cardio-respiratory arrest † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Coronary artery stenosis † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Left ventricular dysfunction † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Myocardial infarction † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Myocarditis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Palpitations † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Pericardial effusion † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Right ventricular dysfunction † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Right ventricular failure † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Supraventricular tachycardia † 1	0/204 (0.00%)	0/203 (0.00%)	3/225 (1.33%)
Tricuspid valve incompetence † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Congenital, familial and genetic disorders
Branchial cyst † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Ear and labyrinth disorders
Deafness † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Endocrine disorders
Adrenal insufficiency † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Hypercalcaemia of malignancy † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Eye disorders
Cataract † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Macular fibrosis † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Ophthalmoplegia † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Gastrointestinal disorders
Abdominal discomfort † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Abdominal distension † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Abdominal hernia † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Abdominal hernia obstructive † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Abdominal pain † 1	6/204 (2.94%)	5/203 (2.46%)	13/225 (5.78%)
Abdominal pain upper † 1	2/204 (0.98%)	2/203 (0.99%)	3/225 (1.33%)
Abdominal rigidity † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Ascites † 1	3/204 (1.47%)	0/203 (0.00%)	0/225 (0.00%)
Colitis † 1	2/204 (0.98%)	0/203 (0.00%)	0/225 (0.00%)
Colitis ischaemic † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Diarrhoea † 1	5/204 (2.45%)	2/203 (0.99%)	3/225 (1.33%)
Duodenal stenosis † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Dyspepsia † 1	0/204 (0.00%)	1/203 (0.49%)	1/225 (0.44%)
Enterocolitis † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Gastritis † 1	0/204 (0.00%)	0/203 (0.00%)	2/225 (0.89%)
Gastritis erosive † 1	1/204 (0.49%)	1/203 (0.49%)	0/225 (0.00%)
Gastrointestinal haemorrhage † 1	1/204 (0.49%)	2/203 (0.99%)	5/225 (2.22%)
Gastrooesophageal reflux disease † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Haematemesis † 1	1/204 (0.49%)	1/203 (0.49%)	0/225 (0.00%)
Ileus † 1	1/204 (0.49%)	1/203 (0.49%)	1/225 (0.44%)
Ileus paralytic † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Intestinal dilatation † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Melaena † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Nausea † 1	3/204 (1.47%)	4/203 (1.97%)	7/225 (3.11%)
Oesophageal haemorrhage † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Oesophageal stenosis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Oesophageal varices haemorrhage † 1	1/204 (0.49%)	1/203 (0.49%)	1/225 (0.44%)
Pancreatitis † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Pancreatitis acute † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Peptic ulcer haemorrhage † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Rectal haemorrhage † 1	0/204 (0.00%)	2/203 (0.99%)	1/225 (0.44%)
Small intestinal haemorrhage † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Small intestinal obstruction † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Stomatitis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Subileus † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Swollen tongue † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Tongue oedema † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Upper gastrointestinal haemorrhage † 1	2/204 (0.98%)	1/203 (0.49%)	1/225 (0.44%)
Vomiting † 1	2/204 (0.98%)	4/203 (1.97%)	10/225 (4.44%)
General disorders
Asthenia † 1	5/204 (2.45%)	2/203 (0.99%)	6/225 (2.67%)
Chest pain † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Chills † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Death † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Device occlusion † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Fatigue † 1	0/204 (0.00%)	2/203 (0.99%)	1/225 (0.44%)
General physical health deterioration † 1	1/204 (0.49%)	1/203 (0.49%)	3/225 (1.33%)
Generalised oedema † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Influenza like illness † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Malaise † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Multi-organ failure † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Non-cardiac chest pain † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Oedema † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Oedema peripheral † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Performance status decreased † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Pyrexia † 1	8/204 (3.92%)	3/203 (1.48%)	8/225 (3.56%)
Sudden death † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Thrombosis in device † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Hepatobiliary disorders
Bile duct obstruction † 1	0/204 (0.00%)	1/203 (0.49%)	2/225 (0.89%)
Bile duct stenosis † 1	0/204 (0.00%)	1/203 (0.49%)	1/225 (0.44%)
Cholangitis † 1	2/204 (0.98%)	0/203 (0.00%)	5/225 (2.22%)
Cholangitis acute † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Cholecystitis acute † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Cholecystitis chronic † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Cholelithiasis † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Cholestasis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Hepatic failure † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Hepatic necrosis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Hepatotoxicity † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Hyperbilirubinaemia † 1	1/204 (0.49%)	1/203 (0.49%)	1/225 (0.44%)
Jaundice † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Jaundice cholestatic † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Immune system disorders
Anaphylactic reaction † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Anaphylactic shock † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Drug hypersensitivity † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Infections and infestations
Arthritis bacterial † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Atypical pneumonia † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Bacteraemia † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Bacterial infection † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Biliary tract infection † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Campylobacter infection † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Cellulitis † 1	0/204 (0.00%)	0/203 (0.00%)	3/225 (1.33%)
Cholecystitis infective † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Clostridium difficile infection † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Cystitis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Diverticulitis † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Enterococcal bacteraemia † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Escherichia sepsis † 1	2/204 (0.98%)	0/203 (0.00%)	0/225 (0.00%)
Escherichia urinary tract infection † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Gastroenteritis † 1	2/204 (0.98%)	2/203 (0.99%)	2/225 (0.89%)
Gastroenteritis viral † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Infection † 1	3/204 (1.47%)	0/203 (0.00%)	1/225 (0.44%)
Liver abscess † 1	1/204 (0.49%)	0/203 (0.00%)	2/225 (0.89%)
Lobar pneumonia † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Lung infection † 1	0/204 (0.00%)	0/203 (0.00%)	2/225 (0.89%)
Perihepatic abscess † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Pilonidal cyst † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Pneumonia † 1	3/204 (1.47%)	2/203 (0.99%)	10/225 (4.44%)
Pneumonia mycoplasmal † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Post procedural infection † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Pulmonary tuberculosis † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Sepsis † 1	0/204 (0.00%)	1/203 (0.49%)	1/225 (0.44%)
Septic shock † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Sinusitis † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Staphylococcal sepsis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Streptococcal sepsis † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Subcutaneous abscess † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Tonsillitis † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Urinary tract infection † 1	0/204 (0.00%)	0/203 (0.00%)	2/225 (0.89%)
Viral infection † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Wound infection staphylococcal † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Injury, poisoning and procedural complications
Femoral neck fracture † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Foot fracture † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Hip fracture † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Incisional hernia † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Intentional overdose † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Overdose † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Patella fracture † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Procedural pain † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Rib fracture † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Wound complication † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Wound secretion † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Investigations
Alanine aminotransferase increased † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Ammonia increased † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Aspartate aminotransferase increased † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Blood bilirubin increased † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Blood creatinine increased † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Blood potassium decreased † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
C-reactive protein increased † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Haemoglobin decreased † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Weight decreased † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	2/204 (0.98%)	0/203 (0.00%)	3/225 (1.33%)
Dehydration † 1	5/204 (2.45%)	2/203 (0.99%)	2/225 (0.89%)
Diabetes mellitus † 1	1/204 (0.49%)	1/203 (0.49%)	3/225 (1.33%)
Diabetes mellitus inadequate control † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Diabetic ketoacidosis † 1	0/204 (0.00%)	0/203 (0.00%)	2/225 (0.89%)
Electrolyte imbalance † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Fluid overload † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Gout † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Hypercalcaemia † 1	2/204 (0.98%)	3/203 (1.48%)	0/225 (0.00%)
Hyperglycaemia † 1	2/204 (0.98%)	2/203 (0.99%)	3/225 (1.33%)
Hyperkalaemia † 1	1/204 (0.49%)	1/203 (0.49%)	0/225 (0.00%)
Hypoglycaemia † 1	0/204 (0.00%)	1/203 (0.49%)	4/225 (1.78%)
Hypokalaemia † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Hyponatraemia † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Hypophagia † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Hypophosphataemia † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Ketoacidosis † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Metabolic acidosis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Polydipsia † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/204 (0.00%)	1/203 (0.49%)	1/225 (0.44%)
Back pain † 1	1/204 (0.49%)	2/203 (0.99%)	2/225 (0.89%)
Bone pain † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Flank pain † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Neck pain † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Pain in extremity † 1	0/204 (0.00%)	2/203 (0.99%)	0/225 (0.00%)
Polyarthritis † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Rhabdomyolysis † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Spinal osteoarthritis † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Spinal pain † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Cancer pain † 1	0/204 (0.00%)	2/203 (0.99%)	0/225 (0.00%)
Gastrinoma † 1	0/204 (0.00%)	0/203 (0.00%)	2/225 (0.89%)
Malignant melanoma † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Neuroendocrine tumour † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Pancreatic neuroendocrine tumour metastatic † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Nervous system disorders
Ataxia † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Cerebrovascular accident † 1	1/204 (0.49%)	0/203 (0.00%)	3/225 (1.33%)
Depressed level of consciousness † 1	0/204 (0.00%)	2/203 (0.99%)	1/225 (0.44%)
Dizziness † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Epiduritis † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Hepatic encephalopathy † 1	1/204 (0.49%)	0/203 (0.00%)	2/225 (0.89%)
Hypoglycaemic coma † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Loss of consciousness † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Memory impairment † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Mental impairment † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Sciatica † 1	1/204 (0.49%)	1/203 (0.49%)	0/225 (0.00%)
Syncope † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Tremor † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Unresponsive to stimuli † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Psychiatric disorders
Confusional state † 1	3/204 (1.47%)	3/203 (1.48%)	2/225 (0.89%)
Listless † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Mental status changes † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Renal and urinary disorders
Calculus urinary † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Haematuria † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Nephrolithiasis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Pollakiuria † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Polyuria † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Pyelocaliectasis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Renal colic † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Renal failure † 1	3/204 (1.47%)	1/203 (0.49%)	1/225 (0.44%)
Renal failure acute † 1	2/204 (0.98%)	3/203 (1.48%)	4/225 (1.78%)
Renal impairment † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Renal tubular necrosis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome † 1	1/204 (0.49%)	0/203 (0.00%)	1/225 (0.44%)
Bronchial hyperreactivity † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Cough † 1	2/204 (0.98%)	1/203 (0.49%)	1/225 (0.44%)
Dyspnoea † 1	6/204 (2.94%)	2/203 (0.99%)	2/225 (0.89%)
Haemoptysis † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Hypoxia † 1	1/204 (0.49%)	1/203 (0.49%)	0/225 (0.00%)
Interstitial lung disease † 1	3/204 (1.47%)	0/203 (0.00%)	1/225 (0.44%)
Lung infiltration † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Nasal obstruction † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Pleural effusion † 1	2/204 (0.98%)	1/203 (0.49%)	1/225 (0.44%)
Pleurisy † 1	0/204 (0.00%)	1/203 (0.49%)	1/225 (0.44%)
Pneumonitis † 1	7/204 (3.43%)	0/203 (0.00%)	2/225 (0.89%)
Pneumothorax † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Pulmonary congestion † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Pulmonary embolism † 1	5/204 (2.45%)	1/203 (0.49%)	1/225 (0.44%)
Pulmonary hypertension † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Pulmonary oedema † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Respiratory failure † 1	2/204 (0.98%)	1/203 (0.49%)	2/225 (0.89%)
Skin and subcutaneous tissue disorders
Rash † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Stasis dermatitis † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Vascular disorders
Aneurysm ruptured † 1	0/204 (0.00%)	0/203 (0.00%)	1/225 (0.44%)
Hypertensive crisis † 1	0/204 (0.00%)	1/203 (0.49%)	0/225 (0.00%)
Hypotension † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
Venous thrombosis † 1	1/204 (0.49%)	0/203 (0.00%)	0/225 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, 16.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Everolimus 10mg/Day	Placebo	Open Label - Everolimus 10mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	201/204 (98.53%)	190/203 (93.60%)	218/225 (96.89%)
Blood and lymphatic system disorders
Anaemia † 1	48/204 (23.53%)	18/203 (8.87%)	55/225 (24.44%)
Leukopenia † 1	12/204 (5.88%)	4/203 (1.97%)	9/225 (4.00%)
Lymphopenia † 1	15/204 (7.35%)	6/203 (2.96%)	10/225 (4.44%)
Neutropenia † 1	14/204 (6.86%)	4/203 (1.97%)	24/225 (10.67%)
Thrombocytopenia † 1	29/204 (14.22%)	2/203 (0.99%)	20/225 (8.89%)
Gastrointestinal disorders
Abdominal distension † 1	18/204 (8.82%)	14/203 (6.90%)	19/225 (8.44%)
Abdominal pain † 1	47/204 (23.04%)	48/203 (23.65%)	55/225 (24.44%)
Abdominal pain upper † 1	30/204 (14.71%)	15/203 (7.39%)	29/225 (12.89%)
Aphthous stomatitis † 1	25/204 (12.25%)	8/203 (3.94%)	22/225 (9.78%)
Ascites † 1	13/204 (6.37%)	4/203 (1.97%)	7/225 (3.11%)
Constipation † 1	30/204 (14.71%)	26/203 (12.81%)	32/225 (14.22%)
Diarrhoea † 1	97/204 (47.55%)	47/203 (23.15%)	96/225 (42.67%)
Dry mouth † 1	23/204 (11.27%)	9/203 (4.43%)	8/225 (3.56%)
Dyspepsia † 1	13/204 (6.37%)	13/203 (6.40%)	8/225 (3.56%)
Flatulence † 1	10/204 (4.90%)	8/203 (3.94%)	14/225 (6.22%)
Gastrooesophageal reflux disease † 1	5/204 (2.45%)	6/203 (2.96%)	13/225 (5.78%)
Haemorrhoids † 1	6/204 (2.94%)	4/203 (1.97%)	17/225 (7.56%)
Mouth ulceration † 1	14/204 (6.86%)	4/203 (1.97%)	15/225 (6.67%)
Nausea † 1	66/204 (32.35%)	64/203 (31.53%)	80/225 (35.56%)
Stomatitis † 1	110/204 (53.92%)	27/203 (13.30%)	105/225 (46.67%)
Toothache † 1	11/204 (5.39%)	5/203 (2.46%)	10/225 (4.44%)
Vomiting † 1	61/204 (29.90%)	41/203 (20.20%)	70/225 (31.11%)
General disorders
Asthenia † 1	35/204 (17.16%)	40/203 (19.70%)	41/225 (18.22%)
Chills † 1	11/204 (5.39%)	1/203 (0.49%)	14/225 (6.22%)
Fatigue † 1	91/204 (44.61%)	53/203 (26.11%)	73/225 (32.44%)
Influenza like illness † 1	9/204 (4.41%)	3/203 (1.48%)	16/225 (7.11%)
Oedema peripheral † 1	76/204 (37.25%)	23/203 (11.33%)	66/225 (29.33%)
Pyrexia † 1	56/204 (27.45%)	23/203 (11.33%)	57/225 (25.33%)
Infections and infestations
Bronchitis † 1	4/204 (1.96%)	3/203 (1.48%)	15/225 (6.67%)
Influenza † 1	6/204 (2.94%)	7/203 (3.45%)	12/225 (5.33%)
Nasopharyngitis † 1	33/204 (16.18%)	14/203 (6.90%)	38/225 (16.89%)
Pneumonia † 1	11/204 (5.39%)	0/203 (0.00%)	13/225 (5.78%)
Sinusitis † 1	14/204 (6.86%)	4/203 (1.97%)	17/225 (7.56%)
Upper respiratory tract infection † 1	16/204 (7.84%)	7/203 (3.45%)	28/225 (12.44%)
Urinary tract infection † 1	23/204 (11.27%)	11/203 (5.42%)	23/225 (10.22%)
Investigations
Alanine aminotransferase increased † 1	10/204 (4.90%)	9/203 (4.43%)	17/225 (7.56%)
Aspartate aminotransferase increased † 1	12/204 (5.88%)	11/203 (5.42%)	28/225 (12.44%)
Blood alkaline phosphatase increased † 1	12/204 (5.88%)	11/203 (5.42%)	25/225 (11.11%)
Blood creatinine increased † 1	10/204 (4.90%)	4/203 (1.97%)	15/225 (6.67%)
Haemoglobin decreased † 1	15/204 (7.35%)	2/203 (0.99%)	16/225 (7.11%)
Weight decreased † 1	58/204 (28.43%)	24/203 (11.82%)	72/225 (32.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	59/204 (28.92%)	37/203 (18.23%)	64/225 (28.44%)
Dehydration † 1	10/204 (4.90%)	7/203 (3.45%)	22/225 (9.78%)
Diabetes mellitus † 1	20/204 (9.80%)	0/203 (0.00%)	21/225 (9.33%)
Hypercholesterolaemia † 1	26/204 (12.75%)	2/203 (0.99%)	16/225 (7.11%)
Hyperglycaemia † 1	40/204 (19.61%)	21/203 (10.34%)	58/225 (25.78%)
Hyperlipidaemia † 1	16/204 (7.84%)	2/203 (0.99%)	10/225 (4.44%)
Hypoglycaemia † 1	11/204 (5.39%)	7/203 (3.45%)	10/225 (4.44%)
Hypokalaemia † 1	17/204 (8.33%)	5/203 (2.46%)	11/225 (4.89%)
Hypophosphataemia † 1	20/204 (9.80%)	3/203 (1.48%)	21/225 (9.33%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	31/204 (15.20%)	14/203 (6.90%)	34/225 (15.11%)
Back pain † 1	31/204 (15.20%)	22/203 (10.84%)	40/225 (17.78%)
Muscle spasms † 1	21/204 (10.29%)	8/203 (3.94%)	15/225 (6.67%)
Musculoskeletal chest pain † 1	12/204 (5.88%)	4/203 (1.97%)	15/225 (6.67%)
Musculoskeletal pain † 1	12/204 (5.88%)	9/203 (4.43%)	17/225 (7.56%)
Myalgia † 1	15/204 (7.35%)	14/203 (6.90%)	17/225 (7.56%)
Pain in extremity † 1	29/204 (14.22%)	10/203 (4.93%)	22/225 (9.78%)
Nervous system disorders
Dizziness † 1	24/204 (11.76%)	16/203 (7.88%)	18/225 (8.00%)
Dysgeusia † 1	38/204 (18.63%)	11/203 (5.42%)	46/225 (20.44%)
Headache † 1	62/204 (30.39%)	30/203 (14.78%)	52/225 (23.11%)
Psychiatric disorders
Depression † 1	14/204 (6.86%)	3/203 (1.48%)	18/225 (8.00%)
Insomnia † 1	28/204 (13.73%)	17/203 (8.37%)	27/225 (12.00%)
Renal and urinary disorders
Proteinuria † 1	10/204 (4.90%)	2/203 (0.99%)	13/225 (5.78%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	45/204 (22.06%)	21/203 (10.34%)	54/225 (24.00%)
Dyspnoea † 1	33/204 (16.18%)	13/203 (6.40%)	34/225 (15.11%)
Epistaxis † 1	44/204 (21.57%)	3/203 (1.48%)	38/225 (16.89%)
Oropharyngeal pain † 1	23/204 (11.27%)	12/203 (5.91%)	29/225 (12.89%)
Pleural effusion † 1	12/204 (5.88%)	2/203 (0.99%)	6/225 (2.67%)
Pneumonitis † 1	21/204 (10.29%)	0/203 (0.00%)	17/225 (7.56%)
Skin and subcutaneous tissue disorders
Acne † 1	13/204 (6.37%)	5/203 (2.46%)	15/225 (6.67%)
Alopecia † 1	8/204 (3.92%)	9/203 (4.43%)	12/225 (5.33%)
Dermatitis acneiform † 1	9/204 (4.41%)	2/203 (0.99%)	13/225 (5.78%)
Dry skin † 1	26/204 (12.75%)	12/203 (5.91%)	28/225 (12.44%)
Erythema † 1	11/204 (5.39%)	3/203 (1.48%)	4/225 (1.78%)
Nail disorder † 1	28/204 (13.73%)	2/203 (0.99%)	26/225 (11.56%)
Onychoclasis † 1	14/204 (6.86%)	2/203 (0.99%)	12/225 (5.33%)
Pruritus † 1	40/204 (19.61%)	26/203 (12.81%)	42/225 (18.67%)
Rash † 1	107/204 (52.45%)	32/203 (15.76%)	90/225 (40.00%)
Vascular disorders
Flushing † 1	4/204 (1.96%)	6/203 (2.96%)	12/225 (5.33%)
Hypertension † 1	24/204 (11.76%)	9/203 (4.43%)	29/225 (12.89%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, 16.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Chan DL, Yao JC, Carnaghi C, Buzzoni R, Herbst F, Ridolfi A, Strosberg J, Kulke MH, Pavel M, Singh S. Markers of Systemic Inflammation in Neuroendocrine Tumors: A Pooled Analysis of the RADIANT-3 and RADIANT-4 Studies. Pancreas. 2021 Feb 1;50(2):130-137. doi: 10.1097/MPA.0000000000001745.

Yao JC, Voi M, Lincy J, Pavel M. Reply to V. Amoroso et al. J Clin Oncol. 2017 May 1;35(13):1488-1489. doi: 10.1200/JCO.2017.71.3875. Epub 2017 Jan 23. No abstract available.

Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, He W, Chen D, Capdevila J, de Vries EGE, Tomassetti P, Hobday T, Pommier R, Oberg K. Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study. J Clin Oncol. 2016 Nov 10;34(32):3906-3913. doi: 10.1200/JCO.2016.68.0702. Epub 2016 Sep 30.

Lombard-Bohas C, Yao JC, Hobday T, Van Cutsem E, Wolin EM, Panneerselvam A, Stergiopoulos S, Shah MH, Capdevila J, Pommier R. Impact of prior chemotherapy use on the efficacy of everolimus in patients with advanced pancreatic neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-3 trial. Pancreas. 2015 Mar;44(2):181-9. doi: 10.1097/MPA.0000000000000262.

Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. doi: 10.1056/NEJMoa1009290.

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT00510068
• Other Study ID Numbers: CRAD001C2324; 2006-006819-75 ( EudraCT Number )
• First Submitted: July 31, 2007
• First Posted: August 1, 2007
• Results First Submitted: November 11, 2011
• Results First Posted: December 15, 2011
• Last Update Posted: July 1, 2015