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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multicenter Phase III Study to Compare the Safety and Efficacy of RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed on VEGF Receptor Tyrosine Kinase Inhibitor

Conditions
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Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Drug: RAD001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RAD001 +BSC<br>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. | Drug: RAD001<br>* The dose of RAD001 was 10 mg/day. Patients were instructed to take two tablets (5 mg each) by mouth every day.<br>* Other names: Everolimus;|
| Placebo Comparator: Placebo (plus BSC)<br>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. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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) | 
| 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 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 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 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 | 
| 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. | Baseline and every 28 days under treatment and at discontinuation from RAD001 until 28Feb2008 cutoff date | 
| 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. | Baseline and every 28 days under treatment and at discontinuation from RAD001 until 28Feb2008 cutoff date | 
| 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. | Baseline and every 28 days under treatment and at discontinuation from RAD001 until 28Feb2008 cutoff date | 
| 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) | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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 | 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. | 
| 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced kidney cancer, everolimus, kidney cancer, oral therapy