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Study of Everolimus (RAD001) in Patients With Recurrent Glioblastoma Multiforme (GBM)

Primary Purpose

Glioblastoma Multiforme

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Everolimus
Surgery
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme focused on measuring Glioblastoma Multiforme, GBM, RAD001, RAD

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age 18 years of age or older
  • Histologically confirmed Glioblastoma Multiforme (GBM)
  • Radiographic evidence of disease progression
  • Patients must have evaluable contrast enhancing tumor
  • Availability of paraffin blocks or unstained pathology slides for biomarker studies
  • Karnofsky Performance Status of greater than or equal to 60%

Exclusion Criteria:

  • Prior treatment with Mammalian target of rapamycin (mTOR) inhibitor
  • History of another malignancy within 3 years
  • Cardiac pacemaker
  • Ferromagnetic metal implants other than those approves as safe for use in Magnetic resonance imaging (MRI) scanners
  • Claustrophobia
  • Obesity
  • Unstable systemic diseases
  • Elevated cholesterol or triglycerides
  • Radiation therapy or cytotoxic chemotherapy <=4 weeks prior to study enrollment. Patient must have recovered from the toxic effects of a prior chemotherapy.
  • Patients must be off all enzyme inducing anticonvulsants for at least 2 week before study enrollment can occur
  • Need for increasing dose of steroids. Patients on a stable or tapering dose of steroids >=7 days were permitted.

Sites / Locations

  • UCLA
  • Northwestern University
  • Massachusetts General Hospital
  • Beth Israel Deaconess Medical Center
  • Dana Farber Cancer Institute
  • Duke University - Preston Robert Tisch Brain Tumor Center
  • University of Cincinnati
  • Seattle Cancer Care Alliance

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Active Comparator

Arm Label

No Surgery (Everolimus 10 mg)

Everolimus 10 mg + Surgery

Everolimus 5 mg + Surgery

Everolimus 0 mg + Surgery

Arm Description

Participants with recurrent Glioblastoma Multiforme (GBM) not scheduled to undergo salvage surgical resection, received a daily oral dose of 10 mg Everolimus (RAD001) until evidence of disease progression or toxicity.

Participants scheduled to undergo salvage surgical resection received a daily oral dose of 10 mg Everolimus for 7 days prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity.

Participants scheduled to undergo salvage surgical resection received a daily oral dose of 5 mg Everolimus for 7 days prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity.

Participants scheduled to undergo salvage surgical resection received no treatment with Everolimus prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity.

Outcomes

Primary Outcome Measures

Surgery Group: Percentage Change From the Baseline in S6 Kinase Levels
In the Surgery Group, the primary efficacy assessment was inhibition of Mammalian target of rapamycin (mTOR) as defined as ≥75% S6 phosphorylation. The occurrence of S6 phosphorylation was determined by phosphor-S6 immunohistochemical staining. Tumor cells from the initial surgical resection and from the salvage resection were used for assessments.
No Surgery Group: Best Overall Tumor Response
The best overall tumor response is reported for participants with 1 previous relapse and participants with ≥2 previous relapses according to the following categories: Complete Response, Partial Response, Stable Disease and Progressive Disease. Gadolinium chelate-enhanced Magnetic Resonance Imaging (MRI) was used for tumor analysis. The objective assessment of tumor response was evaluated at each site by the designated pathologist based on the Neuro-Oncology criteria for Tumor Response for Central Nervous System (CNS) tumors.

Secondary Outcome Measures

Surgery Group: Blood and Brain Tissue Levels of Everolimus (RAD001)
Surgery Group: Progression-free Survival
Progression-free survival (PFS) was assessed using Gadolinium chelate-enhanced Magnetic Resonance Imaging (MRI) and based on the Neuro-Oncology Criteria for Tumor Response for CNS tumors. PFS was measured from the first day of treatment after surgery to disease progression or death and is derived using the Kaplan-Meier method.
Surgery Group: Biomarkers Phosphatase and Tensin Homolog (PTEN) and Epidermal Growth Factor Receptor (EGFR)
The secondary efficacy assessment was to evaluate the role of PTEN and EGFR pathway status on phosphor-S6. Tumor cells from the initial surgical resection and from the salvage resection were used for assessments. Immunohistochemistry and Fluorescence in-situ hybridization (FISH) were used to assess PTEN and EGFR pathway status. Study was terminated due to slow enrollment. Analysis was not possible due to insufficient sample size.
No Surgery Group: Progression Free Survival
Progression-free survival (PFS) was assessed using Gadolinium chelate-enhanced Magnetic Resonance Imaging (MRI) and based on the Neuro-Oncology Criteria for Tumor Response for CNS tumors. PFS is reported for participants with 1 previous relapse and participants with ≥2 previous relapses. PFS was measured from the first day of treatment to disease progression or death and is derived using the Kaplan-Meier method.
Surgery Group: Number of Participants With Adverse Events
The number of participants with any adverse event by System Organ Class. Additional information about Adverse Events can be found in the Adverse Event Section.

Full Information

First Posted
August 10, 2007
Last Updated
September 20, 2011
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00515086
Brief Title
Study of Everolimus (RAD001) in Patients With Recurrent Glioblastoma Multiforme (GBM)
Official Title
A Phase II Trial of RAD001 in Patients With Recurrent Glioblastoma Multiforme
Study Type
Interventional

2. Study Status

Record Verification Date
September 2011
Overall Recruitment Status
Terminated
Why Stopped
Early termination due to slow enrollment and protocol-defined stopping rule.
Study Start Date
August 2007 (undefined)
Primary Completion Date
August 2009 (Actual)
Study Completion Date
August 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

5. Study Description

Brief Summary
This study will define the safety and efficacy of Everolimus (RAD001) administered daily in patients with glioblastoma multiforme (GBM)
Detailed Description
This was a multicenter, open label, randomized study of RAD001 dosed daily in patients with recurrent GBM. The study was conducted with 2 parallel groups of patients. Group 1 was designed to study the biological effects of RAD001 in patients scheduled to undergo salvage surgical resection, and Group 2 was to enroll patients who were not scheduled for surgery. Patients in Group 1 were randomly assigned to one of three pre-surgery treatment groups (0, 5 or 10 mg/day RAD001 for 7 days). All patients in Group 2 were to receive a fixed daily dose of 10 mg/day oral RAD001.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma Multiforme
Keywords
Glioblastoma Multiforme, GBM, RAD001, RAD

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
41 (Actual)

8. Arms, Groups, and Interventions

Arm Title
No Surgery (Everolimus 10 mg)
Arm Type
Experimental
Arm Description
Participants with recurrent Glioblastoma Multiforme (GBM) not scheduled to undergo salvage surgical resection, received a daily oral dose of 10 mg Everolimus (RAD001) until evidence of disease progression or toxicity.
Arm Title
Everolimus 10 mg + Surgery
Arm Type
Experimental
Arm Description
Participants scheduled to undergo salvage surgical resection received a daily oral dose of 10 mg Everolimus for 7 days prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity.
Arm Title
Everolimus 5 mg + Surgery
Arm Type
Experimental
Arm Description
Participants scheduled to undergo salvage surgical resection received a daily oral dose of 5 mg Everolimus for 7 days prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity.
Arm Title
Everolimus 0 mg + Surgery
Arm Type
Active Comparator
Arm Description
Participants scheduled to undergo salvage surgical resection received no treatment with Everolimus prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity.
Intervention Type
Drug
Intervention Name(s)
Everolimus
Other Intervention Name(s)
RAD001
Intervention Description
Tablets taken once a day with a full glass of water.
Intervention Type
Procedure
Intervention Name(s)
Surgery
Intervention Description
Salvage surgical resection
Primary Outcome Measure Information:
Title
Surgery Group: Percentage Change From the Baseline in S6 Kinase Levels
Description
In the Surgery Group, the primary efficacy assessment was inhibition of Mammalian target of rapamycin (mTOR) as defined as ≥75% S6 phosphorylation. The occurrence of S6 phosphorylation was determined by phosphor-S6 immunohistochemical staining. Tumor cells from the initial surgical resection and from the salvage resection were used for assessments.
Time Frame
Baseline and Day 7-9 (during salvage surgery)
Title
No Surgery Group: Best Overall Tumor Response
Description
The best overall tumor response is reported for participants with 1 previous relapse and participants with ≥2 previous relapses according to the following categories: Complete Response, Partial Response, Stable Disease and Progressive Disease. Gadolinium chelate-enhanced Magnetic Resonance Imaging (MRI) was used for tumor analysis. The objective assessment of tumor response was evaluated at each site by the designated pathologist based on the Neuro-Oncology criteria for Tumor Response for Central Nervous System (CNS) tumors.
Time Frame
First day of treatment to study discontinuation (up to 60 weeks)
Secondary Outcome Measure Information:
Title
Surgery Group: Blood and Brain Tissue Levels of Everolimus (RAD001)
Time Frame
Baseline and Day 7-9 (Blood samples were collected one day prior to surgery and tissue samples were collected during surgery.)
Title
Surgery Group: Progression-free Survival
Description
Progression-free survival (PFS) was assessed using Gadolinium chelate-enhanced Magnetic Resonance Imaging (MRI) and based on the Neuro-Oncology Criteria for Tumor Response for CNS tumors. PFS was measured from the first day of treatment after surgery to disease progression or death and is derived using the Kaplan-Meier method.
Time Frame
After surgery (within 96 hours), Weeks 4 and 8 and then every 8 weeks after restarting treatment until study discontinuation (Up to 28 weeks)
Title
Surgery Group: Biomarkers Phosphatase and Tensin Homolog (PTEN) and Epidermal Growth Factor Receptor (EGFR)
Description
The secondary efficacy assessment was to evaluate the role of PTEN and EGFR pathway status on phosphor-S6. Tumor cells from the initial surgical resection and from the salvage resection were used for assessments. Immunohistochemistry and Fluorescence in-situ hybridization (FISH) were used to assess PTEN and EGFR pathway status. Study was terminated due to slow enrollment. Analysis was not possible due to insufficient sample size.
Time Frame
After surgery, week 4, week 8 and every 8 weeks thereafter
Title
No Surgery Group: Progression Free Survival
Description
Progression-free survival (PFS) was assessed using Gadolinium chelate-enhanced Magnetic Resonance Imaging (MRI) and based on the Neuro-Oncology Criteria for Tumor Response for CNS tumors. PFS is reported for participants with 1 previous relapse and participants with ≥2 previous relapses. PFS was measured from the first day of treatment to disease progression or death and is derived using the Kaplan-Meier method.
Time Frame
First day of treatment to study discontinuation (up to 60 weeks)
Title
Surgery Group: Number of Participants With Adverse Events
Description
The number of participants with any adverse event by System Organ Class. Additional information about Adverse Events can be found in the Adverse Event Section.
Time Frame
First day of treatment to study discontinuation (Up to 28 weeks)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18 years of age or older Histologically confirmed Glioblastoma Multiforme (GBM) Radiographic evidence of disease progression Patients must have evaluable contrast enhancing tumor Availability of paraffin blocks or unstained pathology slides for biomarker studies Karnofsky Performance Status of greater than or equal to 60% Exclusion Criteria: Prior treatment with Mammalian target of rapamycin (mTOR) inhibitor History of another malignancy within 3 years Cardiac pacemaker Ferromagnetic metal implants other than those approves as safe for use in Magnetic resonance imaging (MRI) scanners Claustrophobia Obesity Unstable systemic diseases Elevated cholesterol or triglycerides Radiation therapy or cytotoxic chemotherapy <=4 weeks prior to study enrollment. Patient must have recovered from the toxic effects of a prior chemotherapy. Patients must be off all enzyme inducing anticonvulsants for at least 2 week before study enrollment can occur Need for increasing dose of steroids. Patients on a stable or tapering dose of steroids >=7 days were permitted.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
UCLA
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Duke University - Preston Robert Tisch Brain Tumor Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Facility Name
Seattle Cancer Care Alliance
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Study of Everolimus (RAD001) in Patients With Recurrent Glioblastoma Multiforme (GBM)

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