RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed After Treatment With Sorafenib and/or Sunitinib (RECORD-1)

• ClinicalTrials.gov Identifier: NCT00410124
• Recruitment Status: Completed
• First Posted: December 12, 2006
• Results First Posted: January 15, 2013
• Last Update Posted: January 15, 2013
• 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: Metastatic Renal Cell Carcinoma
• Interventions: Drug: RAD001; Drug: Placebo
• Enrollment: 416

Participant Flow

Recruitment Details
Pre-assignment Details	Core period was terminated due to early achievements of efficacy targets and patients who were receiving study drug and patients receiving placebo in double blind phase had option to continue into the extension phase to receive open label RAD001.

Arm/Group Title	RAD001 +BSC	Placebo + BSC / RAD001
Arm/Group Description	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Period Title: Core Phase Double Blind (15 Months)
Started	277 [1]	139
Ongoing	13	4
Completed Double Blind Treatment	62	2
Completed	75 [2]	6 [3]
Not Completed	202	133
Reason Not Completed
Adverse Event	36	2
Abnormal Laboratory Value	1	0
Protocol Violation	2	1
Withdrawal by Subject	13	2
Lost to Follow-up	4	0
Administrative Problems	2	0
Death	7	4
Disease Progression	137	124
[1] Started indicates randomized (FAS) and treated; [2] Patients ongoing/completed double blind phase had option entering extension phase continuing RAD001.; [3] All patients ongoing/completed/not completed in core had option to enter extension taking RAD001.
Period Title: Extension Phase - Open Label (45 Months)
Started	67	111 [1]
Completed	0	0
Not Completed	67	111
Reason Not Completed
Adverse Event	7	19
Abnormal Laboratory Values	0	1
Abnormal Test Procedures	0	1
Withdrawal by Subject	1	1
Death	2	10
Disease Progression	56	78
Patient no longer required study drug	1	0
Final Primary Analysis	0	1
[1] Patients on placebo in core received RAD001 in extension phase.

Baseline Characteristics

Arm/Group Title		RAD001 +BSC	Placebo + BSC	Total
Arm/Group Description		The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Total of all reporting groups
Overall Number of Baseline Participants		277	139	416
Baseline Analysis Population Description		[Not Specified]
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	277 participants	139 participants	416 participants
<65 years		165	98	263
>=65 years		112	41	153
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	277 participants	139 participants	416 participants
	Female	61 22.0%	33 23.7%	94 22.6%
	Male	216 78.0%	106 76.3%	322 77.4%

Outcome Measures

1. Primary Outcome

Title	Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC
Description	Progression Free survival is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary statistical analysis of PFS was based on central radiological assessments using a one-sided stratified log-rank test. Radiological assessments: every 8 weeks (+/-1 week) during the first year and every 12 weeks (+/- 1 week) during the second year and thereafter and at the end of the study. Kaplan-Meier methodology was used to estimate the median PFS for each treatment group.
Time Frame	Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported between date of first patient randomized until 28Feb2008 cut of date.

Outcome Measure Data

Analysis Population Description

Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description:	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Overall Number of Participants Analyzed	277	139
Median (95% Confidence Interval); Unit of Measure: Months
	4.90; (3.98 to 5.52)	1.87; (1.84 to 1.94)

2. Secondary Outcome

Title	Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments
Description	Overall survival (OS) was defined as the time from date of randomization to date of death due to any cause. Kaplan-Meier methodology was used to estimate the median overall survival for each treatment group
Time Frame	Assessed every month up to 2 years after the last patient was randomized into the study from the date of randomization to the time of death. (Data cutoff was 15Nov2009)

Outcome Measure Data

Analysis Population Description

Full analysis set was performed on the intent-to-treat population which consisted of all randomized patients.

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description:	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Overall Number of Participants Analyzed	277	139
Median (95% Confidence Interval); Unit of Measure: Months
	13.57; (11.96 to 17.87)	13.01; (10.09 to 16.66)

3. Secondary Outcome

Title	Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC
Description	The Best Overall Response rate (BOR) is defined as the percentage of patients having achieved confirmed Complete Response + Partial Response. Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression. • Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression. Radiological assessments: every 8 weeks (+/-1 week) during the first year and every 12 weeks (+/- 1 week) during the second year and thereafter and at the end of the study.
Time Frame	Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported, between date of first patient randomized until 28Feb2008 cutoff date

Outcome Measure Data

Analysis Population Description

Full analysis set was performed on the intent-to-treat population which consisted of all randomized patients.

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description:	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Overall Number of Participants Analyzed	277	139
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of Participants
	1.8; (0.6 to 4.2)	0.0 [1]; (NA to NA)

[1]

Upper and lower limit cannot be measured.

4. Secondary Outcome

Title	Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC
Description	Duration of overall response (CR or PR) applies only to patients whose Best Overall Response (BOR) was Complete Response (CR) or Partial Response (PR). The start date is the date of first documented response (CR or PR) and the end date is the date of event defined as the first documented progression or death. Radiological assessments: every 8 weeks (+/-1 week) during the first year and every 12 weeks (+/- 1 week) during the second year and thereafter and at the end of the study.
Time Frame	Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported, between date of first patient randomized until 28Feb2008 cutoff date

Outcome Measure Data

Analysis Population Description

Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description:	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Overall Number of Participants Analyzed	5	0
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)

[1]

No duration of response result due to small number of responders.

5. Secondary Outcome

Title	Analysis of Time to Definitive Deterioration of the Global Health Status/QoL Scale(QL) Scores of the EORTC QLQ-30 Questionnaire by at Least 10 Percent Using Kaplan Meier Method, by Treatment.
Description	The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. Global health status / QoL scale (QL), consisting of 2 questions each scored from 1 (very poor) to 7 (excellent), and with possible scores ranging from 2 to 14. Higher score indicates better functioning. Definitive deterioration by at least 10% is defined as a decrease in score by at least 10% compared to baseline, with no increase above this threshold observed during the course of the study. A single measure reporting a decrease of at least 10% is considered definitive only if it is the last one available for the patient. Time to definitive deterioration is the number of days between the date of randomization and date of assessment at which definitive deterioration is seen.
Time Frame	Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

Outcome Measure Data

Analysis Population Description

Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description:	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Overall Number of Participants Analyzed	277	139
Median (95% Confidence Interval); Unit of Measure: months
	4.76; (3.71 to 6.47)	3.91 [1]; (2.79 to NA)

[1]

Upper limit was beyond the timeframe of the analysis.

6. Secondary Outcome

Title	Time to Definitive Deterioration of the FKS-DRS Risk Score by at Least 2 Score Units Using Kaplan-Meier Method, by Treatment.
Description	The Functional Assessment of Cancer Therapy - Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) is a set of items to assess symptoms experienced by patients with advanced kidney cancer. These symptoms include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. There were 4 response categories (1=Not at all, 2= A little, 3=Quite a bit, 4=Very much), sum of item responses can range from 0 to 36. "0"= severely symptomatic patient and the highest score is an asymptomatic patient. Definitive deterioration of the FKSI-DRS score was defined as a decrease by at least 2 units compared to baseline, with no later increase above this threshold observed during the study. A single measure reporting a decrease of at least 2 units was considered definitive only if it is the last one available for the patient. Time to definitive deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen.
Time Frame	Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

Outcome Measure Data

Analysis Population Description

Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description:	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Overall Number of Participants Analyzed	277	139
Median (95% Confidence Interval); Unit of Measure: months
	4.76; (3.75 to 7.39)	3.84; (2.04 to 4.57)

7. Secondary Outcome

Title	Time to Definitive Deterioration of the Physical Functioning Scale (PF)Score of the EORTC QLQ-C30 Questionnaire by at Least 10 Percent Using Kaplan_Meier Method, by Treatment.
Description	The EORTC QLQ-C30 contains 30 items. These include five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact). Physical Functioning (PF) sub-scale, consisting of 5 questions each scored from 1 (not at all) to 4 (very much), and with possible values ranging from 5 to 20. Definitive deterioration by at least 10% is defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study. A single measure reporting a decrease of at least 10% is considered definitive only if it is the last one available for the patient. Time to definitive deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen.
Time Frame	Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

Outcome Measure Data

Analysis Population Description

Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description:	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
Overall Number of Participants Analyzed	277	139
Median (95% Confidence Interval); Unit of Measure: months
	5.06; (3.78 to 7.39)	4.57 [1]; (2.79 to NA)

[1]

Upper limit could not be calculated.

8. Secondary Outcome

Title	Pharmacokinetics of RAD001:Peak Concentration in a Dosing Interval (C-max); Pre-dose Concentration at 24-h Time Point in Dosing Interval (C-min) and Average Concentration in a Dosing Interval =(C-avg)
Description	Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol. C-avg= Area under curve (AUC) in a dosing interval from time-zero to time of the last quantifiable concentration (AUC0-tlast)/ time of the last quantifiable concentration in a dosing interval (tlast)
Time Frame	At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day1, Cycle 1 Day 15 and at pre-dose from Cycle 2(day1) and all subsequent treatment cycles up until data cut-off 28 Feb 2008.

Outcome Measure Data

Analysis Population Description

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Arm/Group Title	Day 1	Day 15
Arm/Group Description:	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 1 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed. Troughs were collected for all patients on Day 1 of each treatment Cycle from month 2 until discontinuation from the study drug.	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.
Overall Number of Participants Analyzed	13	12
Mean (Standard Deviation); Unit of Measure: ng/mL
C-max	68.1 (29.8)	76.7 (39.3)
C-min	7.9 (3.4)	19.8 (12.3)
C-avg	19.0 (7.0)	30.4 (10.9)

9. Secondary Outcome

Title	Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max)
Description	Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.
Time Frame	At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose of From Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008.

Outcome Measure Data

Analysis Population Description

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Arm/Group Title	Day 1	Day 15
Arm/Group Description:	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 1 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed. Troughs were collected for all patients on Day 1 of each treatment Cycle from month 2 until discontinuation from the study drug.	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.
Overall Number of Participants Analyzed	13	12
Median (Full Range); Unit of Measure: h
	1.0; (1.0 to 2.0)	1.0; (1.0 to 5.0)

10. Secondary Outcome

Title	Pharmacokinetics of RAD001: Area Under Curve (AUC) in a Dosing Interval From Time-zero to Time of the Last Quantifiable Concentration. (AUC 0-tlast)
Description	Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.
Time Frame	At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008.

Outcome Measure Data

Analysis Population Description

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Arm/Group Title	Day 1	Day 15
Arm/Group Description:	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 1 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed. Troughs were collected for all patients on Day 1 of each treatment Cycle from month 2 until discontinuation from the study drug.	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.
Overall Number of Participants Analyzed	13	12
Mean (Standard Deviation); Unit of Measure: ng.h/mL
	455.0 (168.5)	729.1 (262.7)

11. Secondary Outcome

Title	Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast)
Description	Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.
Time Frame	At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008.

Outcome Measure Data

Analysis Population Description

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Arm/Group Title	Day 1	Day 15
Arm/Group Description:	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 1 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed. Troughs were collected for all patients on Day 1 of each treatment Cycle from month 2 until discontinuation from the study drug.	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.
Overall Number of Participants Analyzed	13	12
Median (Full Range); Unit of Measure: hour
	24.0; (24.0 to 24.0)	24.0; (24.0 to 24.0)

12. Secondary Outcome

Title	Pharmacokinetics of RAD001: Apparent Systemic Clearance From Blood Following Extravascular Administration (CL/F)
Description	Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.Apparent oral clearance of RAD001 (CL/F) was calculated using AUC in a dosing interval of 24 hours (AUC0-24hours) value on Day 15 as: CL/F = dose/ AUC0-τ
Time Frame	At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008.

Outcome Measure Data

Analysis Population Description

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Arm/Group Title	Day 15
Arm/Group Description:	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.
Overall Number of Participants Analyzed	12
Mean (Standard Deviation); Unit of Measure: L/hour
	15.4 (5.3)

13. Secondary Outcome

Title	Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F)
Description	Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.
Time Frame	At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008.

Outcome Measure Data

Analysis Population Description

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Arm/Group Title	Day 15
Arm/Group Description:	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.
Overall Number of Participants Analyzed	12
Mean (Standard Deviation); Unit of Measure: L/hour/m^2
	7.5 (2.3)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	The Safety population consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment. Patients were analyzed according to the treatment actually received.
Arm/Group Title	Randomized to RAD001+ BSC ( Blinded + Open Label)	Randomized to Placebo + BSC (Open Label)	Randomized to Placebo + BSC (Double Blind Only)
Arm/Group Description	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care.
All-Cause Mortality
	Randomized to RAD001+ BSC ( Blinded + Open Label)	Randomized to Placebo + BSC (Open Label)	Randomized to Placebo + BSC (Double Blind Only)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Randomized to RAD001+ BSC ( Blinded + Open Label)	Randomized to Placebo + BSC (Open Label)	Randomized to Placebo + BSC (Double Blind Only)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	135/274 (49.27%)	60/111 (54.05%)	17/26 (65.38%)
Blood and lymphatic system disorders
Anaemia † 1	13/274 (4.74%)	5/111 (4.50%)	0/26 (0.00%)
Bone marrow reticulin fibrosis † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Haemolysis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Thrombocytopenia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Cardiac disorders
Aortic valve incompetence † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Cardiac disorder † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Cardiac failure † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Cardiac failure congestive † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Left ventricular dysfunction † 1	1/274 (0.36%)	1/111 (0.90%)	0/26 (0.00%)
Myocardial infarction † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Myocardial ischaemia † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Pericardial effusion † 1	1/274 (0.36%)	1/111 (0.90%)	0/26 (0.00%)
Tachycardia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Endocrine disorders
Adrenal insufficiency † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Hypothyroidism † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Eye disorders
Eye pain † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Gastrointestinal disorders
Abdominal distension † 1	1/274 (0.36%)	0/111 (0.00%)	1/26 (3.85%)
Abdominal pain † 1	7/274 (2.55%)	1/111 (0.90%)	0/26 (0.00%)
Abdominal pain lower † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Ascites † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Constipation † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Diarrhoea † 1	2/274 (0.73%)	1/111 (0.90%)	0/26 (0.00%)
Dysphagia † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Faecaloma † 1	1/274 (0.36%)	0/111 (0.00%)	1/26 (3.85%)
Gastrointestinal haemorrhage † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Gastrointestinal sounds abnormal † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Haematochezia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Inguinal hernia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Intestinal obstruction † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Nausea † 1	3/274 (1.09%)	1/111 (0.90%)	0/26 (0.00%)
Pancreatitis acute † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Peritoneal effusion † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Peritonitis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Proctalgia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Small intestinal obstruction † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Stomatitis † 1	3/274 (1.09%)	0/111 (0.00%)	0/26 (0.00%)
Tongue oedema † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Vomiting † 1	4/274 (1.46%)	1/111 (0.90%)	0/26 (0.00%)
General disorders
Asthenia † 1	4/274 (1.46%)	1/111 (0.90%)	2/26 (7.69%)
Chest discomfort † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Chest pain † 1	4/274 (1.46%)	0/111 (0.00%)	0/26 (0.00%)
Disease progression † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Fatigue † 1	7/274 (2.55%)	0/111 (0.00%)	0/26 (0.00%)
General physical health deterioration † 1	3/274 (1.09%)	1/111 (0.90%)	2/26 (7.69%)
Generalised oedema † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Malaise † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Mucosal inflammation † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Non-cardiac chest pain † 1	4/274 (1.46%)	0/111 (0.00%)	0/26 (0.00%)
Oedema peripheral † 1	3/274 (1.09%)	1/111 (0.90%)	0/26 (0.00%)
Pain † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Performance status decreased † 1	1/274 (0.36%)	2/111 (1.80%)	0/26 (0.00%)
Pyrexia † 1	13/274 (4.74%)	5/111 (4.50%)	0/26 (0.00%)
Hepatobiliary disorders
Bile duct obstruction † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Biloma † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Cholangitis † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Cholangitis acute † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Cholecystitis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Cholelithiasis † 1	1/274 (0.36%)	2/111 (1.80%)	0/26 (0.00%)
Cholestasis † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Hepatic failure † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Hepatic steatosis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Hyperbilirubinaemia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Jaundice † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Liver disorder † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Immune system disorders
Hypersensitivity † 1	1/274 (0.36%)	1/111 (0.90%)	0/26 (0.00%)
Infections and infestations
Appendicitis † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Bronchitis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Bronchopulmonary aspergillosis † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Cellulitis † 1	0/274 (0.00%)	2/111 (1.80%)	0/26 (0.00%)
Enterococcal infection † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Escherichia infection † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Fungal infection † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Gastroenteritis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Incision site infection † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Klebsiella infection † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Klebsiella sepsis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Lung abscess † 1	1/274 (0.36%)	2/111 (1.80%)	0/26 (0.00%)
Lung infection † 1	4/274 (1.46%)	0/111 (0.00%)	0/26 (0.00%)
Pelvic abscess † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Pleural infection † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Pneumonia † 1	10/274 (3.65%)	1/111 (0.90%)	0/26 (0.00%)
Pneumonia bacterial † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Pneumonia viral † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Pyelonephritis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Rectal abscess † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Respiratory tract infection † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Salmonellosis † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Sepsis † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Septic shock † 1	3/274 (1.09%)	1/111 (0.90%)	0/26 (0.00%)
Sinusitis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Staphylococcal sepsis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Upper respiratory tract infection † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Viral infection † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Wound abscess † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Injury, poisoning and procedural complications
Cervical vertebral fracture † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Device dislocation † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Femur fracture † 1	1/274 (0.36%)	0/111 (0.00%)	1/26 (3.85%)
Fracture † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Humerus fracture † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Ilium fracture † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Lower limb fracture † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Medical device complication † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Post procedural bile leak † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Radiation skin injury † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Rib fracture † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Spinal fracture † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Stent occlusion † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Subdural haematoma † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Subdural haemorrhage † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Tracheal haemorrhage † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Wound dehiscence † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Investigations
Bile duct pressure increased † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Blood alkaline phosphatase increased † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Blood amylase increased † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Blood bilirubin increased † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Blood chloride decreased † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Blood creatine phosphokinase increased † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Blood creatinine increased † 1	4/274 (1.46%)	1/111 (0.90%)	0/26 (0.00%)
Blood urea increased † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Ejection fraction decreased † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Lipase increased † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Metabolism and nutrition disorders
Cachexia † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Cell death † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Decreased appetite † 1	3/274 (1.09%)	1/111 (0.90%)	0/26 (0.00%)
Dehydration † 1	9/274 (3.28%)	2/111 (1.80%)	1/26 (3.85%)
Diabetes mellitus † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Diabetes mellitus inadequate control † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Diabetic ketoacidosis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Hypercalcaemia † 1	3/274 (1.09%)	0/111 (0.00%)	2/26 (7.69%)
Hyperkalaemia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Hypomagnesaemia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Hyponatraemia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/274 (0.36%)	1/111 (0.90%)	0/26 (0.00%)
Back pain † 1	4/274 (1.46%)	1/111 (0.90%)	1/26 (3.85%)
Bone pain † 1	4/274 (1.46%)	0/111 (0.00%)	0/26 (0.00%)
Hypercreatinaemia † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Muscular weakness † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Musculoskeletal chest pain † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Osteonecrosis † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Pathological fracture † 1	2/274 (0.73%)	1/111 (0.90%)	1/26 (3.85%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Cancer pain † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Infected neoplasm † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Lung neoplasm † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Lymphangiosis carcinomatosa † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Metastases to bone † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Metastases to central nervous system † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Metastases to liver † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Metastases to lung † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Metastases to spine † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Pleura carcinoma † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Renal cancer metastatic † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Transitional cell carcinoma † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Tumour haemorrhage † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Tumour pain † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Nervous system disorders
Aphasia † 1	1/274 (0.36%)	0/111 (0.00%)	1/26 (3.85%)
Balance disorder † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Cerebral haemorrhage † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Coma † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Convulsion † 1	0/274 (0.00%)	1/111 (0.90%)	1/26 (3.85%)
Depressed level of consciousness † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Dizziness † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Encephalopathy † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Grand mal convulsion † 1	0/274 (0.00%)	1/111 (0.90%)	1/26 (3.85%)
Headache † 1	2/274 (0.73%)	0/111 (0.00%)	1/26 (3.85%)
Hemiplegia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Lethargy † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Loss of consciousness † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Paraesthesia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Spinal cord compression † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Status epilepticus † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Tremor † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Trigeminal neuralgia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Psychiatric disorders
Agitation † 1	0/274 (0.00%)	1/111 (0.90%)	1/26 (3.85%)
Confusional state † 1	2/274 (0.73%)	0/111 (0.00%)	1/26 (3.85%)
Delirium † 1	1/274 (0.36%)	1/111 (0.90%)	0/26 (0.00%)
Depression † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Hallucination † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Intentional self-injury † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Mental status changes † 1	2/274 (0.73%)	1/111 (0.90%)	0/26 (0.00%)
Psychotic disorder † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Suicide attempt † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Renal and urinary disorders
Haematuria † 1	2/274 (0.73%)	1/111 (0.90%)	1/26 (3.85%)
Hydronephrosis † 1	0/274 (0.00%)	2/111 (1.80%)	0/26 (0.00%)
Renal failure † 1	5/274 (1.82%)	4/111 (3.60%)	0/26 (0.00%)
Renal failure acute † 1	3/274 (1.09%)	3/111 (2.70%)	1/26 (3.85%)
Renal impairment † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Ureteric dilatation † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Ureteric obstruction † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Ureteric stenosis † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Urinary retention † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Reproductive system and breast disorders
Pelvic pain † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	3/274 (1.09%)	0/111 (0.00%)	0/26 (0.00%)
Asphyxia † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Atelectasis † 1	2/274 (0.73%)	0/111 (0.00%)	0/26 (0.00%)
Cough † 1	4/274 (1.46%)	1/111 (0.90%)	0/26 (0.00%)
Dyspnoea † 1	25/274 (9.12%)	11/111 (9.91%)	1/26 (3.85%)
Dyspnoea exertional † 1	1/274 (0.36%)	1/111 (0.90%)	0/26 (0.00%)
Haemoptysis † 1	3/274 (1.09%)	1/111 (0.90%)	0/26 (0.00%)
Hydrothorax † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Hypoxia † 1	2/274 (0.73%)	1/111 (0.90%)	0/26 (0.00%)
Interstitial lung disease † 1	6/274 (2.19%)	3/111 (2.70%)	0/26 (0.00%)
Lung disorder † 1	3/274 (1.09%)	2/111 (1.80%)	0/26 (0.00%)
Lung infiltration † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Pleural effusion † 1	11/274 (4.01%)	8/111 (7.21%)	0/26 (0.00%)
Pleuritic pain † 1	0/274 (0.00%)	2/111 (1.80%)	0/26 (0.00%)
Pneumonitis † 1	11/274 (4.01%)	2/111 (1.80%)	0/26 (0.00%)
Pulmonary alveolar haemorrhage † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Pulmonary embolism † 1	2/274 (0.73%)	2/111 (1.80%)	0/26 (0.00%)
Pulmonary infarction † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Pulmonary toxicity † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Respiratory distress † 1	0/274 (0.00%)	1/111 (0.90%)	0/26 (0.00%)
Respiratory failure † 1	2/274 (0.73%)	3/111 (2.70%)	1/26 (3.85%)
Skin and subcutaneous tissue disorders
Night sweats † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Pruritus † 1	1/274 (0.36%)	1/111 (0.90%)	0/26 (0.00%)
Vascular disorders
Circulatory collapse † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Deep vein thrombosis † 1	1/274 (0.36%)	1/111 (0.90%)	0/26 (0.00%)
Haematoma † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
Shock † 1	1/274 (0.36%)	0/111 (0.00%)	0/26 (0.00%)
Thrombosis † 1	0/274 (0.00%)	0/111 (0.00%)	1/26 (3.85%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Randomized to RAD001+ BSC ( Blinded + Open Label)	Randomized to Placebo + BSC (Open Label)	Randomized to Placebo + BSC (Double Blind Only)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	261/274 (95.26%)	106/111 (95.50%)	23/26 (88.46%)
Blood and lymphatic system disorders
Anaemia † 1	108/274 (39.42%)	42/111 (37.84%)	4/26 (15.38%)
Lymphopenia † 1	29/274 (10.58%)	7/111 (6.31%)	0/26 (0.00%)
Thrombocytopenia † 1	19/274 (6.93%)	8/111 (7.21%)	0/26 (0.00%)
Ear and labyrinth disorders
Ear pain † 1	3/274 (1.09%)	6/111 (5.41%)	0/26 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	31/274 (11.31%)	10/111 (9.01%)	1/26 (3.85%)
Abdominal pain upper † 1	20/274 (7.30%)	6/111 (5.41%)	1/26 (3.85%)
Aphthous stomatitis † 1	26/274 (9.49%)	13/111 (11.71%)	0/26 (0.00%)
Constipation † 1	60/274 (21.90%)	25/111 (22.52%)	5/26 (19.23%)
Diarrhoea † 1	90/274 (32.85%)	28/111 (25.23%)	2/26 (7.69%)
Dry mouth † 1	22/274 (8.03%)	5/111 (4.50%)	4/26 (15.38%)
Haemorrhoids † 1	17/274 (6.20%)	1/111 (0.90%)	0/26 (0.00%)
Nausea † 1	78/274 (28.47%)	27/111 (24.32%)	5/26 (19.23%)
Stomatitis † 1	106/274 (38.69%)	33/111 (29.73%)	3/26 (11.54%)
Vomiting † 1	63/274 (22.99%)	19/111 (17.12%)	3/26 (11.54%)
General disorders
Asthenia † 1	96/274 (35.04%)	31/111 (27.93%)	9/26 (34.62%)
Fatigue † 1	86/274 (31.39%)	40/111 (36.04%)	8/26 (30.77%)
General physical health deterioration † 1	6/274 (2.19%)	3/111 (2.70%)	2/26 (7.69%)
Mucosal inflammation † 1	53/274 (19.34%)	26/111 (23.42%)	0/26 (0.00%)
Non-cardiac chest pain † 1	12/274 (4.38%)	8/111 (7.21%)	0/26 (0.00%)
Oedema peripheral † 1	79/274 (28.83%)	25/111 (22.52%)	5/26 (19.23%)
Pyrexia † 1	55/274 (20.07%)	24/111 (21.62%)	1/26 (3.85%)
Infections and infestations
Bronchitis † 1	17/274 (6.20%)	6/111 (5.41%)	1/26 (3.85%)
Nasopharyngitis † 1	20/274 (7.30%)	8/111 (7.21%)	1/26 (3.85%)
Urinary tract infection † 1	14/274 (5.11%)	5/111 (4.50%)	0/26 (0.00%)
Investigations
Blood alkaline phosphatase increased † 1	11/274 (4.01%)	6/111 (5.41%)	0/26 (0.00%)
Blood creatinine increased † 1	29/274 (10.58%)	3/111 (2.70%)	0/26 (0.00%)
Gamma-glutamyltransferase increased † 1	20/274 (7.30%)	7/111 (6.31%)	0/26 (0.00%)
Weight decreased † 1	27/274 (9.85%)	19/111 (17.12%)	2/26 (7.69%)
Metabolism and nutrition disorders
Decreased appetite † 1	82/274 (29.93%)	24/111 (21.62%)	6/26 (23.08%)
Dehydration † 1	9/274 (3.28%)	5/111 (4.50%)	2/26 (7.69%)
Hypercalcaemia † 1	10/274 (3.65%)	4/111 (3.60%)	3/26 (11.54%)
Hypercholesterolaemia † 1	60/274 (21.90%)	21/111 (18.92%)	0/26 (0.00%)
Hyperglycaemia † 1	36/274 (13.14%)	15/111 (13.51%)	2/26 (7.69%)
Hypertriglyceridaemia † 1	45/274 (16.42%)	17/111 (15.32%)	0/26 (0.00%)
Hypophosphataemia † 1	18/274 (6.57%)	4/111 (3.60%)	0/26 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	39/274 (14.23%)	20/111 (18.02%)	1/26 (3.85%)
Back pain † 1	39/274 (14.23%)	13/111 (11.71%)	2/26 (7.69%)
Bone pain † 1	11/274 (4.01%)	9/111 (8.11%)	1/26 (3.85%)
Musculoskeletal chest pain † 1	14/274 (5.11%)	3/111 (2.70%)	0/26 (0.00%)
Musculoskeletal pain † 1	10/274 (3.65%)	8/111 (7.21%)	1/26 (3.85%)
Myalgia † 1	7/274 (2.55%)	8/111 (7.21%)	0/26 (0.00%)
Pain in extremity † 1	34/274 (12.41%)	17/111 (15.32%)	3/26 (11.54%)
Nervous system disorders
Dizziness † 1	19/274 (6.93%)	3/111 (2.70%)	3/26 (11.54%)
Dysgeusia † 1	32/274 (11.68%)	14/111 (12.61%)	1/26 (3.85%)
Headache † 1	53/274 (19.34%)	14/111 (12.61%)	2/26 (7.69%)
Paraesthesia † 1	12/274 (4.38%)	1/111 (0.90%)	2/26 (7.69%)
Psychiatric disorders
Anxiety † 1	14/274 (5.11%)	3/111 (2.70%)	2/26 (7.69%)
Insomnia † 1	30/274 (10.95%)	11/111 (9.91%)	2/26 (7.69%)
Renal and urinary disorders
Dysuria † 1	5/274 (1.82%)	6/111 (5.41%)	0/26 (0.00%)
Haematuria † 1	4/274 (1.46%)	0/111 (0.00%)	2/26 (7.69%)
Nocturia † 1	10/274 (3.65%)	8/111 (7.21%)	1/26 (3.85%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	96/274 (35.04%)	30/111 (27.03%)	4/26 (15.38%)
Dyspnoea † 1	59/274 (21.53%)	28/111 (25.23%)	3/26 (11.54%)
Dyspnoea exertional † 1	17/274 (6.20%)	8/111 (7.21%)	1/26 (3.85%)
Epistaxis † 1	51/274 (18.61%)	12/111 (10.81%)	0/26 (0.00%)
Oropharyngeal pain † 1	10/274 (3.65%)	6/111 (5.41%)	0/26 (0.00%)
Pleural effusion † 1	13/274 (4.74%)	8/111 (7.21%)	0/26 (0.00%)
Pneumonitis † 1	18/274 (6.57%)	4/111 (3.60%)	0/26 (0.00%)
Skin and subcutaneous tissue disorders
Dry skin † 1	38/274 (13.87%)	14/111 (12.61%)	3/26 (11.54%)
Erythema † 1	15/274 (5.47%)	2/111 (1.80%)	0/26 (0.00%)
Nail disorder † 1	20/274 (7.30%)	7/111 (6.31%)	0/26 (0.00%)
Onychoclasis † 1	16/274 (5.84%)	2/111 (1.80%)	0/26 (0.00%)
Pruritus † 1	43/274 (15.69%)	12/111 (10.81%)	2/26 (7.69%)
Rash † 1	83/274 (30.29%)	29/111 (26.13%)	1/26 (3.85%)
Vascular disorders
Hypertension † 1	14/274 (5.11%)	7/111 (6.31%)	0/26 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA

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.

Principal Investigators are NOT employed by the organization sponsoring the study. Other disclosure agreement that restricts the right of the PI 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 pooled data (i.e.,data from all sites) in clinical trial.

Results Point of Contact

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

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

Stein A, Bellmunt J, Escudier B, Kim D, Stergiopoulos SG, Mietlowski W, Motzer RJ; RECORD-1 Trial Study Group. Survival prediction in everolimus-treated patients with metastatic renal cell carcinoma incorporating tumor burden response in the RECORD-1 trial. Eur Urol. 2013 Dec;64(6):994-1002. doi: 10.1016/j.eururo.2012.11.032. Epub 2012 Nov 21.

Stein A, Wang W, Carter AA, Chiparus O, Hollaender N, Kim H, Motzer RJ, Sarr C. Dynamic tumor modeling of the dose-response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial. BMC Cancer. 2012 Jul 23;12:311. doi: 10.1186/1471-2407-12-311.

Oudard S, Thiam R, Fournier LS, Medioni J, Lamuraglia M, Scotte F, Fabre E, Kim D, Kpamegan E, Panneerselvam A, Cuenod CA. Optimisation of the tumour response threshold in patients treated with everolimus for metastatic renal cell carcinoma: analysis of response and progression-free survival in the RECORD-1 study. Eur J Cancer. 2012 Jul;48(10):1512-8. doi: 10.1016/j.ejca.2012.01.027. Epub 2012 Feb 16.

Porta C, Calvo E, Climent MA, Vaishampayan U, Osanto S, Ravaud A, Bracarda S, Hutson TE, Escudier B, Grunwald V, Kim D, Panneerselvam A, Anak O, Motzer RJ. Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial. Eur Urol. 2012 Apr;61(4):826-33. doi: 10.1016/j.eururo.2011.12.057. Epub 2012 Jan 5.

Calvo E, Escudier B, Motzer RJ, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Ravaud A, Kim D, Panneerselvam A, Anak O, Figlin RA. Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. Eur J Cancer. 2012 Feb;48(3):333-9. doi: 10.1016/j.ejca.2011.11.027. Epub 2011 Dec 30.

White DA, Camus P, Endo M, Escudier B, Calvo E, Akaza H, Uemura H, Kpamegan E, Kay A, Robson M, Ravaud A, Motzer RJ. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med. 2010 Aug 1;182(3):396-403. doi: 10.1164/rccm.200911-1720OC. Epub 2010 Mar 1.

Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. doi: 10.1016/S0140-6736(08)61039-9. Epub 2008 Jul 22.

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT00410124
• Other Study ID Numbers: CRAD001C2240; 2006-002070-21 ( EudraCT Number )
• First Submitted: December 11, 2006
• First Posted: December 12, 2006
• Results First Submitted: October 23, 2012
• Results First Posted: January 15, 2013
• Last Update Posted: January 15, 2013