Trial Outcomes & Findings for 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 (NCT NCT00410124)

Last Updated: 2013-01-15

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

416 participants

Primary outcome timeframe

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.

Results posted on

2013-01-15

Participant Flow

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.

Participant milestones

Participant milestones
Measure	RAD001 +BSC 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.	Placebo + BSC / RAD001 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.
Core Phase Double Blind (15 Months) STARTED	277	139
Core Phase Double Blind (15 Months) Ongoing	13	4
Core Phase Double Blind (15 Months) Completed Double Blind Treatment	62	2
Core Phase Double Blind (15 Months) COMPLETED	75	6
Core Phase Double Blind (15 Months) NOT COMPLETED	202	133
Extension Phase - Open Label (45 Months) STARTED	67	111
Extension Phase - Open Label (45 Months) COMPLETED	0	0
Extension Phase - Open Label (45 Months) NOT COMPLETED	67	111

Reasons for withdrawal

Reasons for withdrawal
Measure	RAD001 +BSC 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.	Placebo + BSC / RAD001 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.
Core Phase Double Blind (15 Months) Adverse Event	36	2
Core Phase Double Blind (15 Months) Abnormal Laboratory Value	1	0
Core Phase Double Blind (15 Months) Protocol Violation	2	1
Core Phase Double Blind (15 Months) Withdrawal by Subject	13	2
Core Phase Double Blind (15 Months) Lost to Follow-up	4	0
Core Phase Double Blind (15 Months) Administrative Problems	2	0
Core Phase Double Blind (15 Months) Death	7	4
Core Phase Double Blind (15 Months) Disease Progression	137	124
Extension Phase - Open Label (45 Months) Adverse Event	7	19
Extension Phase - Open Label (45 Months) Abnormal Laboratory Values	0	1
Extension Phase - Open Label (45 Months) Abnormal Test Procedures	0	1
Extension Phase - Open Label (45 Months) Withdrawal by Subject	1	1
Extension Phase - Open Label (45 Months) Death	2	10
Extension Phase - Open Label (45 Months) Disease Progression	56	78
Extension Phase - Open Label (45 Months) Patient no longer required study drug	1	0
Extension Phase - Open Label (45 Months) Final Primary Analysis	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	RAD001 +BSC n=277 Participants 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.	Placebo + BSC n=139 Participants 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 n=416 Participants Total of all reporting groups
Age, Customized <65 years	165 participants n=99 Participants	98 participants n=107 Participants	263 participants n=206 Participants
Age, Customized >=65 years	112 participants n=99 Participants	41 participants n=107 Participants	153 participants n=206 Participants
Sex: Female, Male Female	61 Participants n=99 Participants	33 Participants n=107 Participants	94 Participants n=206 Participants
Sex: Female, Male Male	216 Participants n=99 Participants	106 Participants n=107 Participants	322 Participants n=206 Participants

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=277 Participants 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.	Placebo + BSC n=139 Participants 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.
Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC	4.90 Months Interval 3.98 to 5.52	1.87 Months Interval 1.84 to 1.94

SECONDARY outcome

Timeframe: 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)

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

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

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=277 Participants 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.	Placebo + BSC n=139 Participants 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 Survival (OS) Assessed by the Monthly Overall Survival Assessments	13.57 Months Interval 11.96 to 17.87	13.01 Months Interval 10.09 to 16.66

SECONDARY outcome

Timeframe: 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

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

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.

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=277 Participants 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.	Placebo + BSC n=139 Participants 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.
Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC	1.8 Percentage of Participants Interval 0.6 to 4.2	0.0 Percentage of Participants Upper and lower limit cannot be measured.

SECONDARY outcome

Timeframe: 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

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

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.

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=5 Participants 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.	Placebo + BSC 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.
Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC	NA months No duration of response result due to small number of responders.	—

SECONDARY outcome

Timeframe: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

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

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.

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=277 Participants 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.	Placebo + BSC n=139 Participants 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.
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.	4.76 months 95% Confidence Interval 3.71 • Interval 3.71 to 6.47	3.91 months 95% Confidence Interval 23.486 • Interval 2.79 to Upper limit was beyond the timeframe of the analysis.

SECONDARY outcome

Timeframe: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

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

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.

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=277 Participants 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.	Placebo + BSC n=139 Participants 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.
Time to Definitive Deterioration of the FKS-DRS Risk Score by at Least 2 Score Units Using Kaplan-Meier Method, by Treatment.	4.76 months Interval 3.75 to 7.39	3.84 months Interval 2.04 to 4.57

SECONDARY outcome

Timeframe: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

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

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.

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=277 Participants 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.	Placebo + BSC n=139 Participants 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.
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.	5.06 months Interval 3.78 to 7.39	4.57 months Interval 2.79 to Upper limit could not be calculated.

SECONDARY outcome

Timeframe: 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.

Population: 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.

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)

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=13 Participants 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.	Placebo + BSC n=12 Participants 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.
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) C-max	68.1 ng/mL Standard Deviation 29.8	76.7 ng/mL Standard Deviation 39.3
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) C-min	7.9 ng/mL Standard Deviation 3.4	19.8 ng/mL Standard Deviation 12.3
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) C-avg	19.0 ng/mL Standard Deviation 7.0	30.4 ng/mL Standard Deviation 10.9

SECONDARY outcome

Timeframe: 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.

Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=13 Participants 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.	Placebo + BSC n=12 Participants 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.
Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max)	1.0 h Interval 1.0 to 2.0	1.0 h Interval 1.0 to 5.0

SECONDARY outcome

Timeframe: 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.

Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=13 Participants 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.	Placebo + BSC n=12 Participants 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.
Pharmacokinetics of RAD001: Area Under Curve (AUC) in a Dosing Interval From Time-zero to Time of the Last Quantifiable Concentration. (AUC 0-tlast)	455.0 ng.h/mL Standard Deviation 168.5	729.1 ng.h/mL Standard Deviation 262.7

SECONDARY outcome

Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=13 Participants 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.	Placebo + BSC n=12 Participants 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.
Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast)	24.0 hour Interval 24.0 to 24.0	24.0 hour Interval 24.0 to 24.0

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=12 Participants 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.	Placebo + BSC 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.
Pharmacokinetics of RAD001: Apparent Systemic Clearance From Blood Following Extravascular Administration (CL/F)	15.4 L/hour Standard Deviation 5.3	—

SECONDARY outcome

Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.

Outcome measures

Outcome measures
Measure	RAD001 +BSC n=12 Participants 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.	Placebo + BSC 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.
Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F)	7.5 L/hour/m^2 Standard Deviation 2.3	—

Adverse Events

Randomized to RAD001+ BSC ( Blinded + Open Label)

Serious events: 135 serious events

Other events: 261 other events

Deaths: 0 deaths

Randomized to Placebo + BSC (Open Label)

Serious events: 60 serious events

Other events: 106 other events

Deaths: 0 deaths

Randomized to Placebo + BSC (Double Blind Only)

Serious events: 17 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER