Clinical trial NCT00410124: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Renal Cell Carcinoma
Keywords: advanced kidney cancer
everolimus
kidney cancer
oral therapy
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2006-12-12
Enrollment: 416
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC
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.
Secondary outcomes:
measure: Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments
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)
measure: Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC
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
measure: Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC
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
measure: 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.
timeFrame: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date
measure: Time to Definitive Deterioration of the FKS-DRS Risk Score by at Least 2 Score Units Using Kaplan-Meier Method, by Treatment.
timeFrame: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date
measure: 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.
timeFrame: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date
measure: 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)
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.
measure: Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max)
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.
measure: Pharmacokinetics of RAD001: Area Under Curve (AUC) in a Dosing Interval From Time-zero to Time of the Last Quantifiable Concentration. (AUC 0-tlast)
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.
measure: Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast)
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.
measure: Pharmacokinetics of RAD001: Apparent Systemic Clearance From Blood Following Extravascular Administration (CL/F)
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.
measure: Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F)
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.
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Novartis Investigative Site
state: Arkansas
city: Duarte
country: United States
facility: Novartis Investigative Site
state: California
city: Sacramento
country: United States
facility: Novartis Investigative Site
state: California
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Santa Monica
country: United States
facility: Novartis Investigative Site
state: California
city: Ocoee
country: United States
facility: Novartis Investigative Site
state: Florida
city: Orlando
country: United States
facility: Novartis Investigative Site
state: Florida
city: Indianapolis
country: United States
facility: Novartis Investigative Site
state: Indiana
city: Indianapolis
country: United States
facility: Novartis Investigative Site
state: Indiana
city: Louisville
country: United States
facility: Novartis Investigative Site
state: Kentucky
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Detroit
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Minneapolis
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Columbia
country: United States
facility: Novartis Investigative Site
state: Missouri
city: St. Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Las Vegas
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Buffalo
country: United States
facility: Novartis Investigative Site
state: New York
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Chapel Hill
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Durham
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Raleigh
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Canton
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Portland
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Pittsburgh
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Bedford
country: United States
facility: Novartis Investigative Site
state: Texas
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
city: Tyler
country: United States
facility: Novartis Investigative Site
state: Texas
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Spokane
country: United States
facility: Novartis Investigative Site
state: Washington
city: Morgantown
country: United States
facility: Novartis Investigative Site
state: West Virginia
city: Camperdown
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Randwick
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: South Brisbane
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Woodville
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Heidelberg
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Hamilton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Bordeaux Cedex
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Lyon Cedex
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Saint-Herblain Cédex
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 3
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Frankfurt/M
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Kassel
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: München
country: Germany
facility: Novartis Investigative Site
city: Cremona
country: Italy
facility: Novartis Investigative Site
state: CR
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Pavia
country: Italy
facility: Novartis Investigative Site
state: PV
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Matsuyama
country: Japan
facility: Novartis Investigative Site
state: Ehime
city: Sapporo
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Sapporo
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Tsukuba
country: Japan
facility: Novartis Investigative Site
state: Ibaraki
city: Kurashiki
country: Japan
facility: Novartis Investigative Site
state: Okayama
city: OsakaSayama
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Sunto-gun
country: Japan
facility: Novartis Investigative Site
state: Shizuoka
city: Utsunomiya
country: Japan
facility: Novartis Investigative Site
state: Tochigi
city: Chuo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Akita
country: Japan
facility: Novartis Investigative Site
city: Chiba
country: Japan
facility: Novartis Investigative Site
city: Fukuoka
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Tokushima
country: Japan
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
city: Nijmegen
country: Netherlands
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Gdañsk
country: Poland
facility: Novartis Investigative Site
city: Lodz
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Stein A, Bellmunt J, Escudier B, Kim D, Stergiopoulos SG, Mietlowski W, Motzer RJ; RECORD-1 Trial Study Group. Survival prediction in everolimus-treated patients with metastatic renal cell carcinoma incorporating tumor burden response in the RECORD-1 trial. Eur Urol. 2013 Dec;64(6):994-1002. doi: 10.1016/j.eururo.2012.11.032. Epub 2012 Nov 21.
citation: Stein A, Wang W, Carter AA, Chiparus O, Hollaender N, Kim H, Motzer RJ, Sarr C. Dynamic tumor modeling of the dose-response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial. BMC Cancer. 2012 Jul 23;12:311. doi: 10.1186/1471-2407-12-311.
citation: Oudard S, Thiam R, Fournier LS, Medioni J, Lamuraglia M, Scotte F, Fabre E, Kim D, Kpamegan E, Panneerselvam A, Cuenod CA. Optimisation of the tumour response threshold in patients treated with everolimus for metastatic renal cell carcinoma: analysis of response and progression-free survival in the RECORD-1 study. Eur J Cancer. 2012 Jul;48(10):1512-8. doi: 10.1016/j.ejca.2012.01.027. Epub 2012 Feb 16.
citation: Porta C, Calvo E, Climent MA, Vaishampayan U, Osanto S, Ravaud A, Bracarda S, Hutson TE, Escudier B, Grunwald V, Kim D, Panneerselvam A, Anak O, Motzer RJ. Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial. Eur Urol. 2012 Apr;61(4):826-33. doi: 10.1016/j.eururo.2011.12.057. Epub 2012 Jan 5.
citation: Calvo E, Escudier B, Motzer RJ, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Ravaud A, Kim D, Panneerselvam A, Anak O, Figlin RA. Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. Eur J Cancer. 2012 Feb;48(3):333-9. doi: 10.1016/j.ejca.2011.11.027. Epub 2011 Dec 30.
citation: White DA, Camus P, Endo M, Escudier B, Calvo E, Akaza H, Uemura H, Kpamegan E, Kay A, Robson M, Ravaud A, Motzer RJ. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med. 2010 Aug 1;182(3):396-403. doi: 10.1164/rccm.200911-1720OC. Epub 2010 Mar 1.
citation: Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. doi: 10.1016/S0140-6736(08)61039-9. Epub 2008 Jul 22.