Metastatic Renal Cell Carcinoma
Conditions
Keywords
advanced kidney cancer, everolimus, kidney cancer, oral therapy
Brief summary
To assess whether daily treatment with RAD001 could slow the growth and spread of metastatic carcinoma of the kidney. The safety of RAD001 was also to be studied in this trial.
Interventions
DRUGRAD001
The dose of RAD001 was 10 mg/day. Patients were instructed to take two tablets (5 mg each) by mouth every day.
DRUGPlacebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Patients with metastatic carcinoma and with histological or cytological confirmation of clear cell RCC (tissue from the original diagnosis of renal cell cancer is acceptable). * The date of progression on sunitinib and/or sorafenib must be within 6 months. * Patients may have received one or both agents * Prior therapy with cytokines (i.e., IL-2, Interferon) and/or VEGF-ligand inhibitors (i.e., bevacizumab) are permitted. * Prior vaccine therapy in the adjuvant setting is permitted. * Patients with at least one measurable lesion at baseline as per the Response evaluation criteria in solid tumors (RECIST) criteria, either on physical exam or as determined by Computer Tomography (CT) Scan or Magnetic Resonance Imaging (MRI). * Patients with a Karnofsky Performance Status ≥70%. * Adequate bone marrow, liver and renal function. * Patients with a life expectancy ≥ 3 months. * Women of childbearing potential must have had a negative serum or urine pregnancy test 48 hours prior to the administration of the first study treatment. * Patients who give a written informed consent obtained according to local guidelines
Exclusion criteria
* Patients currently receiving chemotherapy, immunotherapy, or radio-therapy or who have received these within 4 weeks of study entry * Patients who have previously received mTOR inhibitors. * Patients with a known hypersensitivity to RAD001 or other rapamycins (sirolimus, temsirolimus) or to its excipients. * Patients with untreated CNS metastases or who are neurologically unstable despite treatment of the CNS metastases. (Patients with treated CNS metastases, who are neurologically stable off of corticosteroids, are eligible to enter study). * Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent * Patients with a known history of HIV seropositivity. * Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low dose coumadin) * Patients who have any severe and/or uncontrolled medical conditions * Patients who have a history of another primary malignancy ≤ 3 years, with the exception of non-melanoma skin cancer, and carcinoma in situ of uterine cervix * Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. * Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to randomization * Patients unwilling to or unable to comply with the protocol Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC | 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 | 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. |
| Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC | 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 | 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. |
| 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. | Baseline and every 28 days under treatment and at discontinuation from RAD001 until 28Feb2008 cutoff date | 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 to Definitive Deterioration of the FKS-DRS Risk Score by at Least 2 Score Units Using Kaplan-Meier Method, by Treatment. | Baseline and every 28 days under treatment and at discontinuation from RAD001 until 28Feb2008 cutoff date | 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 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. | Baseline and every 28 days under treatment and at discontinuation from RAD001 until 28Feb2008 cutoff date | 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. |
| Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments | 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) | 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 |
| Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max) | 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. |
| Pharmacokinetics of RAD001: Area Under Curve (AUC) in a Dosing Interval From Time-zero to Time of the Last Quantifiable Concentration. (AUC 0-tlast) | 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. |
| Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast) | 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. |
| Pharmacokinetics of RAD001: Apparent Systemic Clearance From Blood Following Extravascular Administration (CL/F) | 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.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 |
| Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F) | 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. |
| 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) | 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. | 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) |
Countries
Australia, Canada, France, Germany, Italy, Japan, Netherlands, Poland, Spain, United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| 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, 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. | 277 |
| Placebo + BSC 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. | 139 |
| Total | 416 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Phase Double Blind (15 Months) | Abnormal Laboratory Value | 1 | 0 |
| Core Phase Double Blind (15 Months) | Administrative Problems | 2 | 0 |
| Core Phase Double Blind (15 Months) | Adverse Event | 36 | 2 |
| Core Phase Double Blind (15 Months) | Death | 7 | 4 |
| Core Phase Double Blind (15 Months) | Disease Progression | 137 | 124 |
| Core Phase Double Blind (15 Months) | Lost to Follow-up | 4 | 0 |
| Core Phase Double Blind (15 Months) | Protocol Violation | 2 | 1 |
| Core Phase Double Blind (15 Months) | Withdrawal by Subject | 13 | 2 |
| 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) | Adverse Event | 7 | 19 |
| 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) | Final Primary Analysis | 0 | 1 |
| Extension Phase - Open Label (45 Months) | Patient no longer required study drug | 1 | 0 |
| Extension Phase - Open Label (45 Months) | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | RAD001 +BSC | Placebo + BSC | Total |
|---|---|---|---|
| Age, Customized <65 years | 165 participants | 98 participants | 263 participants |
| Age, Customized >=65 years | 112 participants | 41 participants | 153 participants |
| Sex: Female, Male Female | 61 Participants | 33 Participants | 94 Participants |
| Sex: Female, Male Male | 216 Participants | 106 Participants | 322 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 261 / 274 | 106 / 111 | 23 / 26 |
| serious Total, serious adverse events | 135 / 274 | 60 / 111 | 17 / 26 |
Outcome results
Primary
Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC
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.
Population: Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RAD001 +BSC | 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 |
| Placebo + BSC | Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC | 1.87 Months |
Secondary
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.
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
Population: Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| RAD001 +BSC | 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 |
| Placebo + BSC | 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. | 3.91 months | 95% Confidence Interval 23.486 |
Secondary
Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC
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
Population: Full analysis set was performed on the intent-to-treat population which consisted of all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAD001 +BSC | Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC | 1.8 Percentage of Participants |
| Placebo + BSC | Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC | 0.0 Percentage of Participants |
Secondary
Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC
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
Population: Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RAD001 +BSC | Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC | NA months |
Secondary
Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments
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)
Population: Full analysis set was performed on the intent-to-treat population which consisted of all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RAD001 +BSC | Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments | 13.57 Months |
| Placebo + BSC | Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments | 13.01 Months |
Secondary
Pharmacokinetics of RAD001: Apparent Systemic Clearance From Blood Following Extravascular Administration (CL/F)
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.
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RAD001 +BSC | Pharmacokinetics of RAD001: Apparent Systemic Clearance From Blood Following Extravascular Administration (CL/F) | 15.4 L/hour | Standard Deviation 5.3 |
Secondary
Pharmacokinetics of RAD001: Area Under Curve (AUC) in a Dosing Interval From Time-zero to Time of the Last Quantifiable Concentration. (AUC 0-tlast)
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.
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RAD001 +BSC | 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 |
| Placebo + BSC | Pharmacokinetics of RAD001: Area Under Curve (AUC) in a Dosing Interval From Time-zero to Time of the Last Quantifiable Concentration. (AUC 0-tlast) | 729.1 ng.h/mL | Standard Deviation 262.7 |
Secondary
Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F)
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.
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RAD001 +BSC | Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F) | 7.5 L/hour/m^2 | Standard Deviation 2.3 |
Secondary
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)
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.
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RAD001 +BSC | 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 |
| RAD001 +BSC | 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 |
| RAD001 +BSC | 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 |
| Placebo + BSC | 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 | 76.7 ng/mL | Standard Deviation 39.3 |
| Placebo + BSC | 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 | 19.8 ng/mL | Standard Deviation 12.3 |
| Placebo + BSC | 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 | 30.4 ng/mL | Standard Deviation 10.9 |
Secondary
Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max)
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.
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RAD001 +BSC | Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max) | 1.0 h |
| Placebo + BSC | Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max) | 1.0 h |
Secondary
Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast)
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.
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RAD001 +BSC | Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast) | 24.0 hour |
| Placebo + BSC | Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast) | 24.0 hour |
Secondary
Time to Definitive Deterioration of the FKS-DRS Risk Score by at Least 2 Score Units Using Kaplan-Meier Method, by Treatment.
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
Population: Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RAD001 +BSC | 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 |
| Placebo + BSC | Time to Definitive Deterioration of the FKS-DRS Risk Score by at Least 2 Score Units Using Kaplan-Meier Method, by Treatment. | 3.84 months |
Secondary
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.
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
Population: Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RAD001 +BSC | 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 |
| Placebo + BSC | 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. | 4.57 months |