Clinical trial NCT00903175: Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients With Metastatic Renal Cell Carcinoma
Official title: An Open-label, Multicenter Phase II Study to Compare the Efficacy and Safety of RAD001 as First-line Followed by Second-line Sunitinib Versus Sunitinib as First-line Followed by Second-line RAD001 in the Treatment of Patients With Metastatic Renal Cell Carcinoma.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Renal Cell Carcinoma
Keywords: RAD001
everolimus
sunitinib
renal cell carcinoma
kidney cancer
metastatic renal cell cancer
advanced kidney cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-05-18
Enrollment: 471
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study assessed the efficacy and safety of first-line RAD001 followed by second-line sunitinib versus the opposite sequence: first-line sunitinib followed by second-line RAD001 for the treatment of patients with MRCC.


Eligibility criteria: Inclusion Criteria:

1. Patients with advanced renal cell carcinoma.
2. Patients with at least one measurable lesion.
3. Patients with a Karnofsky Performance Status ≥70%.
4. Adequate bone marrow function.
5. Adequate liver function.
6. Adequate renal function.
7. Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN)
8. Women of childbearing potential must have had a negative serum pregnancy test within 14 days prior to the administration of the study medication. Adequate contraception must be used while on study.

Exclusion Criteria:

1. Less than 4 weeks post-major surgery
2. Patients who had radiation therapy within 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed within 2 weeks prior to study treatment start).
3. Patients in need for major surgical procedure during the course of the study
4. Patients with a serious non-healing wound, ulcer, or bone fracture
5. Patients with a history of seizure(s) not controlled with standard medical therapy
6. Patients who have received prior systemic treatment for their metastatic RCC
7. Patients who have previously received systemic mTOR inhibitors (sirolimus, temsirolimus, everolimus) or VEGF inhibitors. Note: History of adjuvant immunotherapy, vaccines or adjuvant sorafenib following localized surgical nephrectomy is acceptable.
8. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins or to its excipients
9. Patients with a known hypersensitivity to sunitinib or its excipients
10. History or clinical evidence of central nervous system (CNS) metastases. Note: Subjects who have previously-treated CNS metastases (surgery plus or minus radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible:

    * Are asymptomatic and,
    * have had no evidence of active CNS metastases for ≥ 6 months prior to enrollment and,
    * have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC)
11. Clinically significant gastrointestinal abnormalities including, but not limited to:

    * Malabsorption syndrome
    * Major resection of the stomach or small bowel that could affect the absorption of study drug
    * Active peptic ulcer disease
    * Inflammatory bowel disease
    * Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation
    * History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
12. Poorly controlled hypertension \[defined as systolic blood pressure (SBP) of ≥160mmHg or diastolic blood pressure (DBP) of ≥ 95mmHg\]
13. Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent
14. Patients with a known history of HIV seropositivity.
15. Patients with active bleeding.
16. Patients who have any severe and/or uncontrolled medical conditions or other conditions within the past 12 months that could affect their participation in the study such as:

    * Cardiac angioplasty or stenting, unstable angina pectoris, symptomatic peripheral vascular disease, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction ≤ 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia, cerebrovascular accidents ≤ 6 months before study treatment start.
    * Prolongation of corrected QT interval (QTc) \> 500 milliseconds (msecs).
    * Severally impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 0\^2 saturation that is 88% or less at rest on room air.
    * Poorly controlled diabetes as defined by fasting serum glucose \>2.0 x ULN.
    * Any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study.
    * Liver disease such as chronic active hepatitis or chronic persistent hepatitis.
17. History of cerebrovascular accident (CVA) including transient ischemic attack (TIA).
18. History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.
19. Patients who have a history of another primary malignancy and off treatment for ≤ 3 years
20. Female patients of child-bearing potential who are not using adequate birth control methods, or who are pregnant or breast feeding.
21. Patients who are using other investigational agents or who had received investigational drugs ≤ 2 weeks prior to study treatment start.
22. Patients unwilling or unable to comply with the protocol.

Primary outcomes:
measure: Progression Free Survival First-Line (PFS 1-L)
timeFrame: based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months
Secondary outcomes:
measure: Progression-free Survival Combined (PFS-C)
timeFrame: based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to about 56 months
measure: Overall Survival (OS)
timeFrame: Every 2 months from randomization up to 3 years after last patient randomized
measure: Overall Response Rate (ORR) - First -Line (1-L)
timeFrame: based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months
measure: Duration of Response (DoR) - First-Line (1-L)
timeFrame: based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months
measure: Time to Definitive Deterioration of the FKSI-DRS Risk Score by at Least 3 Score Units by First-line Drug
timeFrame: <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months
measure: Time to Definitive Deterioration of the FKSI-DRS Risk Score by at Least 3 Score Units by First and Second-line Drugs Combined
timeFrame: <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months
measure: Time to Definitive Deterioration of the Physical Functioning (PF) Scale of the EORTC QLQ-C30 - by First-Line (1L) Drug
timeFrame: <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months
measure: Time to Definitive Deterioration of the Physical Functioning Scale of the EORTC QLQ-C30 - by First and Second-Line Drugs Combined
timeFrame: <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months
measure: Time to Definitive Deterioration of the Global Health Status/QoL Scores of the EORTC QLQ-C30 by First-Line Drug
timeFrame: <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months
measure: Time to Definitive Deterioration of the Global Health Status/QoL Scores of the EORTC QLQ-C30 by First and Second-Line Drugs Combined
timeFrame: <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months
measure: Time to Definitive Deterioration of the Fatigue Scale of the EORTC QLQ-C30 by First-Line Drug
timeFrame: <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months
measure: Time to Definitive Deterioration of the Fatigue Scale of the EORTC QLQ-C30 by First and Second-Line Drugs Combined
timeFrame: <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham/ Kirklin Clinic Comprehensive CancerCenter (1)
state: Alabama
city: Mobile
country: United States
facility: University of South Alabama / Mitchell Cancer Institute Dept. of Mitchell Cancer Inst.
state: Alabama
city: Fayetteville
country: United States
facility: Highlands Oncology Group HighlandsOncGrp-Bentonville(2)
state: Arkansas
city: La Jolla
country: United States
facility: University of California San Diego - Moores Cancer Center Dept of Moores Cancer Ctr (5)
state: California
city: Los Angeles
country: United States
facility: University of California at Los Angeles Dept. of UCLA (3)
state: California
city: Aurora
country: United States
facility: University of Colorado Dept. of Anschutz Cancer (2)
state: Colorado
city: Norwalk
country: United States
facility: Norwalk Hospital Norwlak SC
state: Connecticut
city: Washington
country: United States
facility: Georgetown University/Lombardi Cancer Center Dept.of Lombardi Cancer Ctr (2
state: District of Columbia
city: Boca Raton
country: United States
facility: Lynn Cancer Institute
state: Florida
city: Miami
country: United States
facility: University of Miami SC
state: Florida
city: Orlando
country: United States
facility: MD Anderson Cancer Center - Orlando Dept.ofMDACC-Orlando
state: Florida
city: Athens
country: United States
facility: University Cancer & Blood Center, LLC Dept of NE GCC (2)
state: Georgia
city: Augusta
country: United States
facility: Georgia Health Sciences University Dept. of MCG
state: Georgia
city: Savannah
country: United States
facility: Summit Cancer Care
state: Georgia
city: Chicago
country: United States
facility: NorthwesternUniv.Med.School/Robert H. Lurie Comp.Cancer Ctr Dept.ofNorthwesternMemHospital
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center /Cardinal Bernardin Cancer Cardinal Bernardin Cancer (3)
state: Illinois
city: Metairie
country: United States
facility: Crescent City Research Consortium, LLC SC
state: Louisiana
city: Baltimore
country: United States
facility: VA Maryland Health Care Dept.of GreenbaumCancerCent(7)
state: Maryland
city: Baltimore
country: United States
facility: Weinberg Cancer Institute at Franklin Square Hospital
state: Maryland
city: Billings
country: United States
facility: Billings Clinic Dept of Billings Clinic(2)
state: Montana
city: Hackensack
country: United States
facility: Hackensack University Medical Center DeptofHackensackUniv.MedCtr.
state: New Jersey
city: Voorhees
country: United States
facility: Cooper Cancer Center
state: New Jersey
city: Lake Success
country: United States
facility: Clinical Research Alliance
state: New York
city: NY
country: United States
facility: Memorial Sloan Kettering Cancer Center Dept. of MSKCC
state: New York
city: Syracuse
country: United States
facility: SUNY - Upstate Medical University Div. of Hematology-Oncology
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Dept. of LinbergerCancerCtr(3)
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute Oncology
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center Duke
state: North Carolina
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center Dept of OHSC
state: Oklahoma
city: Bethlehem
country: United States
facility: St. Luke's Hospital and Health Network St Luke's Hospital (2)
state: Pennsylvania
city: Memphis
country: United States
facility: The West Clinic Dept. of the West Clinic
state: Tennessee
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD(2)
state: Texas
city: Tyler
country: United States
facility: East Texas Medical Center Cancer Institute
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists Dept.of Utah Cancer Spec. (3)
state: Utah
city: Milwaukee
country: United States
facility: Aurora Advanced Healthcare SC
state: Wisconsin
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: La Plata
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Tucuman
country: Argentina
facility: Novartis Investigative Site
city: Woodville
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Victoria
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Greenfield Park
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Saskatoon
country: Canada
facility: Novartis Investigative Site
state: Saskatchewan
city: Herlev
country: Denmark
facility: Novartis Investigative Site
city: Angers cedex 02
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Vandoeuvre-Les-Nancy Cede
country: France
facility: Novartis Investigative Site
city: Aschaffenburg
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Weiden
country: Germany
facility: Novartis Investigative Site
city: Hongkong
country: Hong Kong
facility: Novartis Investigative Site
city: Shatin, New Territories
country: Hong Kong
facility: Novartis Investigative Site
city: Arezzo
country: Italy
facility: Novartis Investigative Site
state: AR
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Daejeon
country: Korea, Republic of
facility: Novartis Investigative Site
city: Chihuahua
country: Mexico
facility: Novartis Investigative Site
city: Den Haag
country: Netherlands
facility: Novartis Investigative Site
city: Maastricht
country: Netherlands
facility: Novartis Investigative Site
city: Jesus Maria
country: Peru
facility: Novartis Investigative Site
state: Lima
city: Elche
country: Spain
facility: Novartis Investigative Site
state: Alicante
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sabadell
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Lleida
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan, ROC
city: Niaosong Township
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Bristol
country: United Kingdom
facility: Novartis Investigative Site
state: Avon
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Voss MH, Chen D, Reising A, Marker M, Shi J, Xu J, Ostrovnaya I, Seshan VE, Redzematovic A, Chen YB, Patel P, Han X, Hsieh JJ, Hakimi AA, Motzer RJ. PTEN Expression, Not Mutation Status in TSC1, TSC2, or mTOR, Correlates with the Outcome on Everolimus in Patients with Renal Cell Carcinoma Treated on the Randomized RECORD-3 Trial. Clin Cancer Res. 2019 Jan 15;25(2):506-514. doi: 10.1158/1078-0432.CCR-18-1833. Epub 2018 Oct 16.
citation: Knox JJ, Barrios CH, Kim TM, Cosgriff T, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page RD, Beck JT, Cheung F, Yadav S, Patel P, Geoffrois L, Niolat J, Berkowitz N, Marker M, Chen D, Motzer RJ. Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC. Ann Oncol. 2017 Jun 1;28(6):1339-1345. doi: 10.1093/annonc/mdx075.
citation: Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung FY, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014 Sep 1;32(25):2765-72. doi: 10.1200/JCO.2013.54.6911. Epub 2014 Jul 21.