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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00510068
First received: July 31, 2007
Last updated: June 4, 2015
Last verified: June 2015
  Purpose

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.


Condition Intervention Phase
Advanced Neuroendocrine Tumors of Pancreatic Origin
Drug: Everolimus
Drug: Everolimus Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    This biomarker is related to angiogenesis pathway, was analyzed to determine the effects of everolimus on plasma antiangiogenic molecules.


Enrollment: 410
Study Start Date: July 2007
Study Completion Date: March 2014
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00510068

  Show 82 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Additional Information:
No publications provided by Novartis

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00510068     History of Changes
Other Study ID Numbers: CRAD001C2324, 2006-006819-75
Study First Received: July 31, 2007
Results First Received: November 11, 2011
Last Updated: June 4, 2015
Health Authority: United States: Food and Drug Administration
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Brazil: Associação Fundo de Incentivo à Pesquisa
Canada: Health Canada
France: Agence Nationale de Sécurité du Médicament et des produits de santé
Germany: Federal Institute for Drugs and Medical Devices
Greece: Ministry of Health and Welfare
Italy: The Italian Medicines Agency
Japan: Pharmaceuticals and Medical Devices Agency
South Korea: Korea Food and Drug Administration (KFDA)
Netherlands: Medical Ethics Review Committee (METC)
Slovakia: State Institute for Drug Control
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Sweden: Medical Products Agency
Switzerland: Swissmedic
Taiwan: Center for Drug Evaluation
Thailand: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Novartis:
Phase III
Advanced Neuroendocrine Tumor in adults
RAD001
NET
everolimus
mTOr
islet cell
neuroendocrine

Additional relevant MeSH terms:
Apudoma
Carcinoid Tumor
Neuroendocrine Tumors
Adenocarcinoma
Adenoma
Carcinoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Everolimus
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on June 30, 2015