Clinical trial NCT00510068: Efficacy and Safety of Everolimus (RAD001) Compared to Placebo in Patients With Advanced Neuroendocrine Tumors
Official title: A Randomized Double-blind Phase III Study of RAD001 10 mg/d Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Pancreatic Neuroendocrine Tumor (NET)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Advanced Neuroendocrine Tumors of Pancreatic Origin
Keywords: Phase III
Advanced Neuroendocrine Tumor in adults
RAD001
NET
everolimus
mTOr
islet cell
neuroendocrine
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2007-08-01
Enrollment: 410
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: The purpose of this study was to evaluate progression free survival in those participants assigned everolimus 10 mg/day plus Best Supportive Care versus those assigned to placebo plus Best Supportive Care in Advanced Neuroendocrine Tumors of pancreatic origin.


Eligibility criteria: Inclusion criteria:

1. Patients must have advanced (unresectable or metastatic) biopsy-proven pancreatic NET
2. Measurable disease by radiologic assessment
3. Adequate blood work
4. Performance Status 0-2 : Ability to be out of bed most of the time
5. Adult male or female patients ≥ 18 years of age
6. Women of childbearing potential must have a negative serum pregnancy test
7. Written informed consent from patients must be obtained in accordance to local guidelines

Exclusion criteria:

1. Patients with severe kind of (poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma) cancer are not eligible
2. Other chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to starting this trial
3. Hepatic artery procedure called embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation/ radiofrequency ablation of hepatic metastasis within 2 months of enrollment
4. Prior therapy with the same kind of medication (mTOR inhibitors: sirolimus, temsirolimus, everolimus).
5. Uncontrolled diabetes mellitus Patients who have any severe and/or uncontrolled medical conditions such as:
6. Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent
7. Patients with a known history of HIV seropositivity
8. No other prior or concurrent cancer at the time enrolling to this trial

Other protocol defined inclusion/ exclusion criteria applied

Primary outcomes:
measure: Time to Progression Free Survival (PFS) Based as Per Investigator Using Kaplan-Meier Methodology
timeFrame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010
Secondary outcomes:
measure: Percentage of Participants With Objective Response Rate ( CR {Complete Response} OR PR {Partial Response})
timeFrame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010
measure: Overall Survival
timeFrame: Baseline, to death- no time limit
measure: Progression Free Survival According to Ki-67 Levels Categorized as: Less Than or Equal to 2%, > 2% to Less Than or Equal to 5% and > 5%
timeFrame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010
measure: Progression Free Survival According to Chromogramin A Tumor Marker (CgA) Baseline Level and According to CgA Early Response
timeFrame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010
measure: Progression Free Survival According to Neuron Specific Enolase Tumor Marker (NSE) Baseline Level and According to NSE Early Response
timeFrame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 17 August 2007, until cut-off date 28 February 2010
measure: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs)
timeFrame: on or after the start of double-blind study medication until no later than 28 days after double-blind study medication discontinuation
measure: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) (Open-label Period)
timeFrame: on or after the start of open-label study medication until no later than 28 days after open-label study medication discontinuation
measure: Evaluation of Pharmacokinetics (PK) Parameter: AUC0-t Last
timeFrame: Day 1 of every cycle (28 days/cycle) throughout the study
measure: Evaluation of Pharmacokinetics (PK) Parameters: Cmax, Cmin
timeFrame: Day 1 of every cycle (28 days/cycle) throughout the study
measure: Evaluation of Pharmacokinetics (PK) Parameter: CL/F
timeFrame: Day 1 of every cycle (28 days/cycle) throughout the study
measure: Evaluation of Pharmacokinetics (PK) Parameter: Tmax -Time to Maximum (Peak) Drug Concentration
timeFrame: Day 1 of every cycle (28 days/cycle) throughout the study
measure: Analysis of Time to Definitive Deterioration of WHO Performance Status Using Kaplan-Meier
timeFrame: 3 months, 6 months
measure: Plasma Angiogenesis Marker: Basic Fibroblast Growth Factor (bFGF)
timeFrame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
measure: Plasma Angiogenesis Marker: Placental Growth Factor (PLGF)
timeFrame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
measure: Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1)
timeFrame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
measure: Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2)
timeFrame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
measure: Plasma Angiogenesis Marker: Vascular Endothelial Growth Factor (VEGF)
timeFrame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama / Mitchell Cancer Institute Deptof Mitchell Cancer Inst(2)
state: Alabama
city: Anaheim
country: United States
facility: Pacific Cancer Medical Center, Inc.
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center SC-2
state: California
city: Los Angeles
country: United States
facility: University of California at Los Angeles UCLA (3)
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Dept. of UCSF Comp. Cancer
state: California
city: Denver
country: United States
facility: Kaiser Permanente Northwest Franklin Medical Offices
state: Colorado
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute Malignant Hematology Clinic
state: Florida
city: Indianapolis
country: United States
facility: Indiana University Health Goshen Center for Cancer Dept. of Indiana Univ. Cancer
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Medical Center Dept. of Iowa Medical Center
state: Iowa
city: Louisville
country: United States
facility: University of Louisville / James Graham Brown Cancer Center SC
state: Kentucky
city: New Orleans
country: United States
facility: LSU HEALTH SCIENCES CENTER/ LSU SCHOOL OF MEDICINE Dept. of Neuroendocrine Clinic
state: Louisiana
city: Boston
country: United States
facility: Boston Medical Center BMC
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute Dept.of KarmanosCancerInst (4)
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Littleton
country: United States
facility: Littleton Regional Hospital Dept. of Hematology/Oncology
state: New Hampshire
city: New York
country: United States
facility: Columbia University Medical Center- New York Presbyterian Dept. of Columbia Med. Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Columbus
country: United States
facility: Ohio State Comprehensive Cancer Center/James Cancer Hospital Dept. of OHSU Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University Dept. of OHSU (3)
state: Oregon
city: Bethlehem
country: United States
facility: St. Luke's Hospital and Health Network St. Luke's Cancer Network
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center Hillman Cancer Center
state: Pennsylvania
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders
state: Texas
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center Dept of MD Anderson CancerCent
state: Texas
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Fortaleza
country: Brazil
facility: Novartis Investigative Site
state: CE
city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Besancon Cedex
country: France
facility: Novartis Investigative Site
city: Clichy
country: France
facility: Novartis Investigative Site
city: Dijon
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Marseille cedex 05
country: France
facility: Novartis Investigative Site
city: Montpellier Cedex 5
country: France
facility: Novartis Investigative Site
city: Paris Cedex 13
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Reims
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 4
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Bad Berka
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Marburg
country: Germany
facility: Novartis Investigative Site
city: München
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Fukuoka-city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Chuo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
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: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Martin
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Cataluña
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Zurich
country: Switzerland
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan, ROC
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: Lin-Ko
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Songkla
country: Thailand
facility: Novartis Investigative Site
city: Withington
country: United Kingdom
facility: Novartis Investigative Site
state: Greater Manchester
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Chan DL, Yao JC, Carnaghi C, Buzzoni R, Herbst F, Ridolfi A, Strosberg J, Kulke MH, Pavel M, Singh S. Markers of Systemic Inflammation in Neuroendocrine Tumors: A Pooled Analysis of the RADIANT-3 and RADIANT-4 Studies. Pancreas. 2021 Feb 1;50(2):130-137. doi: 10.1097/MPA.0000000000001745.
citation: Yao JC, Voi M, Lincy J, Pavel M. Reply to V. Amoroso et al. J Clin Oncol. 2017 May 1;35(13):1488-1489. doi: 10.1200/JCO.2017.71.3875. Epub 2017 Jan 23. No abstract available.
citation: Yao JC, Pavel M, Lombard-Bohas C, Van Cutsem E, Voi M, Brandt U, He W, Chen D, Capdevila J, de Vries EGE, Tomassetti P, Hobday T, Pommier R, Oberg K. Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study. J Clin Oncol. 2016 Nov 10;34(32):3906-3913. doi: 10.1200/JCO.2016.68.0702. Epub 2016 Sep 30.
citation: Lombard-Bohas C, Yao JC, Hobday T, Van Cutsem E, Wolin EM, Panneerselvam A, Stergiopoulos S, Shah MH, Capdevila J, Pommier R. Impact of prior chemotherapy use on the efficacy of everolimus in patients with advanced pancreatic neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-3 trial. Pancreas. 2015 Mar;44(2):181-9. doi: 10.1097/MPA.0000000000000262.
citation: Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. doi: 10.1056/NEJMoa1009290.