Efficacy and Safety of Everolimus (RAD001) Compared to Placebo in Patients With Advanced Neuroendocrine Tumors (RADIANT-3)

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)

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.

Study Overview

• Status: Completed
• Conditions: Advanced Neuroendocrine Tumors of Pancreatic Origin
• Intervention / Treatment: Drug: Everolimus; Drug: Everolimus Placebo

• Study Type: Interventional
• Enrollment (Actual): 410
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1200
    • Novartis Investigative Site
  • Bruxelles, Belgium, 1070
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Brazil
  • CE
    • Fortaleza, CE, Brazil, 60430-370
      • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Novartis Investigative Site
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Novartis Investigative Site
  • Ontario
    • London, Ontario, Canada, N6A 4L6
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H3A 1A1
      • Novartis Investigative Site
• France
  • Besancon Cedex, France, 25030
    • Novartis Investigative Site
  • Clichy, France, 92110
    • Novartis Investigative Site
  • Dijon, France, 21079
    • Novartis Investigative Site
  • Lille Cedex, France, 59020
    • Novartis Investigative Site
  • Lyon, France, 69437
    • Novartis Investigative Site
  • Marseille cedex 05, France, 13385
    • Novartis Investigative Site
  • Montpellier Cedex 5, France, 34298
    • Novartis Investigative Site
  • Paris, France, 75015
    • Novartis Investigative Site
  • Paris Cedex 13, France, 75651
    • Novartis Investigative Site
  • Reims, France, 51092
    • Novartis Investigative Site
  • Strasbourg, France, 67098
    • Novartis Investigative Site
  • Toulouse Cedex 4, France, 31054
    • Novartis Investigative Site
  • Villejuif Cedex, France, 94805
    • Novartis Investigative Site
• Germany
  • Bad Berka, Germany, 99438
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Marburg, Germany, 35033
    • Novartis Investigative Site
  • München, Germany, 81377
    • Novartis Investigative Site
• Greece
  • Athens, Greece, GR-115 22
    • Novartis Investigative Site
  • GR
    • Athens, GR, Greece, 115 27
      • Novartis Investigative Site
• Italy
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41100
      • Novartis Investigative Site
  • PI
    • Pisa, PI, Italy, 56124
      • Novartis Investigative Site
• Japan
  • Chiba
    • Kashiwa, Chiba, Japan
      • Novartis Investigative Site
  • Fukuoka
    • Fukuoka-city, Fukuoka, Japan, 812-8582
      • Novartis Investigative Site
  • Tokyo
    • Chuo-ku, Tokyo, Japan
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 738-736
    • Novartis Investigative Site
  • Korea
    • Seoul, Korea, Korea, Republic of, 120-752
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 110 744
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 135-710
      • Novartis Investigative Site
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
• Slovakia
  • Slovak Republic
    • Martin, Slovak Republic, Slovakia, 036 59
      • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
  • Cataluña
    • Hospitalet de LLobregat, Cataluña, Spain, 08907
      • Novartis Investigative Site
• Sweden
  • Uppsala, Sweden, SE-751 85
    • Novartis Investigative Site
• Switzerland
  • Zurich, Switzerland, 8091
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Novartis Investigative Site
  • Lin-Ko, Taiwan, 33305
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taiwan, ROC
    • Taipei, Taiwan, ROC, Taiwan, 112
      • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Songkla, Thailand, 90110
    • Novartis Investigative Site
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Novartis Investigative Site
  • London, United Kingdom, EC1A 7BE
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
  • Greater Manchester
    • Withington, Greater Manchester, United Kingdom, M20 4BX
      • Novartis Investigative Site
• United States
  • Alabama
    • Mobile, Alabama, United States, 36688
      • University of South Alabama / Mitchell Cancer Institute Deptof Mitchell Cancer Inst(2)
  • California
    • Anaheim, California, United States, 92801
      • Pacific Cancer Medical Center, Inc.
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center SC-2
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles UCLA (3)
    • San Francisco, California, United States, 94143-0128
      • University of California San Francisco Dept. of UCSF Comp. Cancer
  • Colorado
    • Denver, Colorado, United States
      • Kaiser Permanente Northwest Franklin Medical Offices
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute Malignant Hematology Clinic
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Goshen Center for Cancer Dept. of Indiana Univ. Cancer
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Medical Center Dept. of Iowa Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville / James Graham Brown Cancer Center SC
  • Louisiana
    • New Orleans, Louisiana, United States, 70115
      • LSU HEALTH SCIENCES CENTER/ LSU SCHOOL OF MEDICINE Dept. of Neuroendocrine Clinic
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center BMC
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute Dept.of KarmanosCancerInst (4)
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • New Hampshire
    • Littleton, New Hampshire, United States, 03561
      • Littleton Regional Hospital Dept. of Hematology/Oncology
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center- New York Presbyterian Dept. of Columbia Med. Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Levine Cancer Institute
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State Comprehensive Cancer Center/James Cancer Hospital Dept. of OHSU Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University Dept. of OHSU (3)
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States
      • St. Luke's Hospital and Health Network St. Luke's Cancer Network
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center Hillman Cancer Center
  • Texas
    • Fort Worth, Texas, United States, 76104
      • The Center for Cancer and Blood Disorders
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Dept of MD Anderson CancerCent

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Everolimus 10 mg/day; Participants received 10 mg per day of Everolimus plus best supportive care. Patients received their first dose of everolimus at Visit 2 (Cycle 1 Day 1).	Drug: Everolimus; A 10-mg dose of everolimus was given by continuous oral daily dosing of two 5-mg tablets.; Other Names: RAD001
Placebo Comparator: Placebo; Participants received matching placebo to everolimus daily plus best supportive care. Patients received their first dose of matching placebo at Visit 2 (Cycle 1 Day 1).	Drug: Everolimus Placebo; a 10-mg dose of matching placebo to Everolimus was given by continuous oral daily dosing of two 5-mg tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Progression Free Survival (PFS) Based as Per Investigator Using Kaplan-Meier Methodology	Progression of disease is defined as the time from study start to the date of first documented progression of disease or death due to any cause. Progression of disease is defined by RECIST criteria: Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions.	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Objective Response Rate ( CR {Complete Response} OR PR {Partial Response})	Objective Response defined by RECIST criteria: Partial response (PR) must have ≥ 30% decrease in the sum of the longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks . Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions	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
Overall Survival	Overall survival (OS) was defined as the time from date of randomization to the date of death due to any cause. Analyses were performed using all deaths in the FAS population regardless of whether they were observed during the double-blind treatment period, the open-label treatment period, the post-treatment evaluations, or the survival follow-up period.	Baseline, to death- no time limit
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%	The level of Ki 67 expression for evaluable tumor samples were analyzed towards progression free survival (PFS) as per local investigator assessment. The Ki-67 protein is a cellular marker for proliferation. It is strictly associated with cell proliferation. During interphase, the Ki-67 antigen can be exclusively detected within the cell nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. Baseline Ki 67 levels were categorized as: less than or equal to 2%, > 2% to less than or equal to 5% and > 5%.	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
Progression Free Survival According to Chromogramin A Tumor Marker (CgA) Baseline Level and According to CgA Early Response	Baseline levels of serum CgA SE were characterized towards progression free survival (PFS) as per local investigator assessment, relative to the upper limited of normal (ULN). CgA levels exceeding 2 x ULN were considered to be 'Elevated' otherwise considered as "Non-elevated". An 'early response' (applicable to only those patients with elevated levels at baseline) was defined as a decrease of greater than or equal to 30% from baseline to Cycle 2 Day 1 or normalization by Cycle 2 Day 1. CgA is widely expressed in well-differentiated pancreatic NET. CgA is present in the secretory granules of neuroendocrine cells. Pancreatic NET patients often present with elevated circulating levels of CgA in their blood. Baseline levels of these biomarkers are considered as prognostic factors.	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
Progression Free Survival According to Neuron Specific Enolase Tumor Marker (NSE) Baseline Level and According to NSE Early Response	Baseline levels of serum NSE were characterized towards PFS as per local investigator assessment, relative to the upper limited of normal (ULN). NSE levels exceeding ULN were considered to be 'Elevated' otherwise considered as "Non-elevated". An 'early response' (applicable to only those patients with elevated levels at baseline) was defined as a decrease of greater than or equal to 30% from baseline to Cycle 2 Day 1 or normalization by Cycle 2 Day 1. NSE is widely expressed in well-differentiated pancreatic NET. NSE is usually expressed in the cytoplasm. Pancreatic NET patients often present with elevated circulating levels of NSE in their blood. Baseline levels of these biomarkers are considered as prognostic factors.	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
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs)	Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.	on or after the start of double-blind study medication until no later than 28 days after double-blind study medication discontinuation
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) (Open-label Period)	Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.	on or after the start of open-label study medication until no later than 28 days after open-label study medication discontinuation
Evaluation of Pharmacokinetics (PK) Parameter: AUC0-t Last	The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. This PK parameter is area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t last).	Day 1 of every cycle (28 days/cycle) throughout the study
Evaluation of Pharmacokinetics (PK) Parameters: Cmax, Cmin	The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. The PK parameter: maximum (peak) drug concentration (Cmax) and minimum (trough) drug concentration (Cmin).	Day 1 of every cycle (28 days/cycle) throughout the study
Evaluation of Pharmacokinetics (PK) Parameter: CL/F	The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. The PK parameter clearance of distribution expressed as a function of bioavailability (CL/F).	Day 1 of every cycle (28 days/cycle) throughout the study
Evaluation of Pharmacokinetics (PK) Parameter: Tmax -Time to Maximum (Peak) Drug Concentration	The PK parameters for a full PK profile at steady-state were determined in blood using non compartmental methods. Values for tmax where summarized in median (range).	Day 1 of every cycle (28 days/cycle) throughout the study
Analysis of Time to Definitive Deterioration of WHO Performance Status Using Kaplan-Meier	Time to definitive worsening is defined as a definitive increase in performance status from a baseline of 0 or 1 to WHO >= 2, or from a baseline value of 2 to WHO >= 3. If no earlier deterioration, patients were censored at the end of follow-up or at the start of further antineoplastic therapy. Rates of patients with no deterioration at 3 and 6 months were computed using Kaplan-meier method. Grade 0: Able to carry out all activity without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory & able to do light work; Grade 2: Ambulatory & capable of all self-care but unable to carry out any work. Up & about more than 50% of waking hours; Grade 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled & cannot carry on any self-care; totally confined to bed or chair.	3 months, 6 months
Plasma Angiogenesis Marker: Basic Fibroblast Growth Factor (bFGF)	This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
Plasma Angiogenesis Marker: Placental Growth Factor (PLGF)	This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1)	This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2)	This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1
Plasma Angiogenesis Marker: Vascular Endothelial Growth Factor (VEGF)	This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Visit NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: July 31, 2007
• First Submitted That Met QC Criteria: July 31, 2007
• First Posted (Estimate): August 1, 2007

Study Record Updates

• Last Update Posted (Estimate): July 1, 2015
• Last Update Submitted That Met QC Criteria: June 4, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Phase III; everolimus; NET; RAD001; neuroendocrine; islet cell; Advanced Neuroendocrine Tumor in adults; mTOr
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: CRAD001C2324; 2006-006819-75 (EudraCT Number)