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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 416
- 试验地点
- 1
- 主要终点
- Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: RAD001 (Drug)
Placebo (plus 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.
干预措施: Placebo (Drug)
结局指标
主要结局
Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC
时间窗: 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.
次要结局
- 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))
- 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)
- 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)
- 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)
- 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)
- 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)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)