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

• ClinicalTrials.gov Identifier: NCT00510068
• Recruitment Status: Completed
• First Posted: August 1, 2007
• Results First Posted: December 15, 2011
• Last Update Posted: July 1, 2015
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: July 31, 2007
• First Posted Date: August 1, 2007
• Results First Submitted Date: November 11, 2011
• Results First Posted Date: December 15, 2011
• Last Update Posted Date: July 1, 2015
• Study Start Date: July 2007
• Actual Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2012)

Time to Progression Free Survival (PFS) Based as Per Investigator Using Kaplan-Meier Methodology [ Time Frame: 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 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.

• Original Primary Outcome Measures (submitted: July 31, 2007): • Assess the clinical activity of everolimus plus best supportive care as defined by progression free survival, per Response Evaluation Criteria In Solid Tumors (RECIST) criteria, in patients with advanced Neuroendocrine Tumors.

Current Secondary Outcome Measures (submitted: June 4, 2015)

• Percentage of Participants With Objective Response Rate ( CR {Complete Response} OR PR {Partial Response}) [ Time Frame: 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 ]
  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
• Overall Survival [ Time Frame: Baseline, to death- no time limit ]
  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.
• 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% [ Time Frame: 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 ]
  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%.
• Progression Free Survival According to Chromogramin A Tumor Marker (CgA) Baseline Level and According to CgA Early Response [ Time Frame: 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 ]
  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.
• Progression Free Survival According to Neuron Specific Enolase Tumor Marker (NSE) Baseline Level and According to NSE Early Response [ Time Frame: 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 ]
  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.
• Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) [ Time Frame: on or after the start of double-blind study medication until no later than 28 days after double-blind study medication discontinuation ]
  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.
• Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) (Open-label Period) [ Time Frame: on or after the start of open-label study medication until no later than 28 days after open-label study medication discontinuation ]
  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.
• Evaluation of Pharmacokinetics (PK) Parameter: AUC0-t Last [ Time Frame: Day 1 of every cycle (28 days/cycle) throughout the study ]
  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).
• Evaluation of Pharmacokinetics (PK) Parameters: Cmax, Cmin [ Time Frame: Day 1 of every cycle (28 days/cycle) throughout the study ]
  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).
• Evaluation of Pharmacokinetics (PK) Parameter: CL/F [ Time Frame: Day 1 of every cycle (28 days/cycle) throughout the study ]
  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).
• Evaluation of Pharmacokinetics (PK) Parameter: Tmax -Time to Maximum (Peak) Drug Concentration [ Time Frame: Day 1 of every cycle (28 days/cycle) throughout the study ]
  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).
• Analysis of Time to Definitive Deterioration of WHO Performance Status Using Kaplan-Meier [ Time Frame: 3 months, 6 months ]
  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.
• Plasma Angiogenesis Marker: Basic Fibroblast Growth Factor (bFGF) [ Time Frame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 ]
  This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.
• Plasma Angiogenesis Marker: Placental Growth Factor (PLGF) [ Time Frame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 ]
  This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.
• Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 1 (sVEGFR1) [ Time Frame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 ]
  This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.
• Plasma Angiogenesis Marker: Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2) [ Time Frame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 ]
  This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.
• Plasma Angiogenesis Marker: Vascular Endothelial Growth Factor (VEGF) [ Time Frame: Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 ]
  This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.

• Original Secondary Outcome Measures (submitted: July 31, 2007): To evaluate the effect of everolimus on other tumor endpoints: objective response rate (Complete Response [CR] and Partial Response [PR]), response duration To compare overall survival (OS) between the study arms
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Advanced Neuroendocrine Tumors of Pancreatic Origin

Intervention

• Drug: Everolimus
  A 10-mg dose of everolimus was given by continuous oral daily dosing of two 5-mg tablets.
  Other Name: RAD001
• Drug: Everolimus Placebo
  a 10-mg dose of matching placebo to Everolimus was given by continuous oral daily dosing of two 5-mg tablets.

Study Arms

• 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).
  Intervention: Drug: Everolimus
• 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).
  Intervention: Drug: Everolimus Placebo

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 30, 2009): 410
• Original Estimated Enrollment (submitted: July 31, 2007): 392
• Actual Study Completion Date: March 2014
• Actual Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Brazil, Canada, France, Germany, Greece, Italy, Japan, Korea, Republic of, Netherlands, Slovakia, Spain, Sweden, Switzerland, Taiwan, Thailand, United Kingdom, United States

Administrative Information

• NCT Number: NCT00510068
• Other Study ID Numbers: CRAD001C2324; 2006-006819-75 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Not Provided
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Novartis
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: June 2015