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

Study Overview
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Brief Summary
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This study will define the safety and efficacy of Everolimus (RAD001) administered daily in patients with glioblastoma multiforme (GBM)

Detailed Description
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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.

Official Title
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A Phase II Trial of RAD001 in Patients With Recurrent Glioblastoma Multiforme

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Everolimus
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: No Surgery (Everolimus 10 mg)<br>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. | Drug: Everolimus<br>* Tablets taken once a day with a full glass of water.<br>* Other names: RAD001;|
| Experimental: Everolimus 10 mg + Surgery<br>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. | Drug: Everolimus<br>* Tablets taken once a day with a full glass of water.<br>* Other names: RAD001;Procedure: Surgery<br>* Salvage surgical resection<br>|
| Experimental: Everolimus 5 mg + Surgery<br>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. | Drug: Everolimus<br>* Tablets taken once a day with a full glass of water.<br>* Other names: RAD001;Procedure: Surgery<br>* Salvage surgical resection<br>|
| Active Comparator: Everolimus 0 mg + Surgery<br>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. | Drug: Everolimus<br>* Tablets taken once a day with a full glass of water.<br>* Other names: RAD001;Procedure: Surgery<br>* Salvage surgical resection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Day 7-9 (during salvage surgery) | 
| 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. | First day of treatment to study discontinuation (up to 60 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgery Group: Blood and Brain Tissue Levels of Everolimus (RAD001) |  | Baseline and Day 7-9 (Blood samples were collected one day prior to surgery and tissue samples were collected during surgery.) | 
| 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. | After surgery (within 96 hours), Weeks 4 and 8 and then every 8 weeks after restarting treatment until study discontinuation (Up to 28 weeks) | 
| 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. | After surgery, week 4, week 8 and every 8 weeks thereafter | 
| 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. | First day of treatment to study discontinuation (up to 60 weeks) | 
| 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. | First day of treatment to study discontinuation (Up to 28 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma Multiforme, GBM, RAD001, RAD