Glioblastoma Multiforme
Conditions
Keywords
Glioblastoma Multiforme, GBM, RAD001, RAD
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.
Interventions
DRUGEverolimus
Tablets taken once a day with a full glass of water.
PROCEDURESurgery
Salvage surgical resection
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Surgery Group: Percentage Change From the Baseline in S6 Kinase Levels | Baseline and Day 7-9 (during salvage surgery) | 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 | First day of treatment to study discontinuation (up to 60 weeks) | 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
| Measure | Time frame | Description |
|---|---|---|
| Surgery Group: Biomarkers Phosphatase and Tensin Homolog (PTEN) and Epidermal Growth Factor Receptor (EGFR) | After surgery, week 4, week 8 and every 8 weeks thereafter | 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. |
| 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: Number of Participants With Adverse Events | First day of treatment to study discontinuation (Up to 28 weeks) | 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. |
| No Surgery Group: Progression Free Survival | First day of treatment to study discontinuation (up to 60 weeks) | 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: Progression-free Survival | After surgery (within 96 hours), Weeks 4 and 8 and then every 8 weeks after restarting treatment until study discontinuation (Up to 28 weeks) | 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. |
Countries
United States
Participant flow
Pre-assignment details
Eligible participants were separated into 2 Groups: Group 1 (Surgery Group) patients were scheduled for salvage surgery and randomly assigned to one of 3 pre-surgery treatment groups: 0, 5 or 10 mg/day Everolimus for 7 days. Group 2 (No Surgery Group) patients were not scheduled for salvage surgery and received 10 mg/day Everolimus.
Participants by arm
| Arm | Count |
|---|---|
| No Surgery (Everolimus 10 mg) 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. | 24 |
| Everolimus 10 mg + Surgery 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. | 6 |
| Everolimus 5 mg + Surgery 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. | 5 |
| Everolimus 0 mg + Surgery 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. | 6 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative | 1 | 1 | 0 | 0 |
| Overall Study | Adverse Event | 1 | 1 | 2 | 3 |
| Overall Study | Death | 2 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Study drug no longer required | 0 | 1 | 0 | 0 |
| Overall Study | Unsatisfactory therapeutic effect | 18 | 3 | 3 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | No Surgery (Everolimus 10 mg) | Everolimus 10 mg + Surgery | Everolimus 5 mg + Surgery | Everolimus 0 mg + Surgery | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 1 Participants | 0 Participants | 1 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 5 Participants | 5 Participants | 5 Participants | 29 Participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 0 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Male | 19 Participants | 2 Participants | 5 Participants | 2 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 5 / 5 | 6 / 6 | 20 / 24 |
| serious Total, serious adverse events | 1 / 6 | 1 / 5 | 2 / 6 | 6 / 24 |
Outcome results
Primary
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.
Time frame: First day of treatment to study discontinuation (up to 60 weeks)
Population: No Surgery Group participants from the Intent-to-treat (ITT) population who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus 10 mg + Surgery | No Surgery Group: Best Overall Tumor Response | Complete response | 0 Participants |
| Everolimus 10 mg + Surgery | No Surgery Group: Best Overall Tumor Response | Stable disease | 3 Participants |
| Everolimus 10 mg + Surgery | No Surgery Group: Best Overall Tumor Response | Partial response | 0 Participants |
| Everolimus 10 mg + Surgery | No Surgery Group: Best Overall Tumor Response | Progressive disease | 7 Participants |
| Everolimus 10 mg + Surgery | No Surgery Group: Best Overall Tumor Response | Complete response + Partial response | 0 Participants |
| Everolimus 5 mg + Surgery | No Surgery Group: Best Overall Tumor Response | Progressive disease | 6 Participants |
| Everolimus 5 mg + Surgery | No Surgery Group: Best Overall Tumor Response | Complete response + Partial response | 0 Participants |
| Everolimus 5 mg + Surgery | No Surgery Group: Best Overall Tumor Response | Complete response | 0 Participants |
| Everolimus 5 mg + Surgery | No Surgery Group: Best Overall Tumor Response | Partial response | 0 Participants |
| Everolimus 5 mg + Surgery | No Surgery Group: Best Overall Tumor Response | Stable disease | 6 Participants |
Primary
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.
Time frame: Baseline and Day 7-9 (during salvage surgery)
Population: Study was terminated due to slow enrollment.
Secondary
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.
Time frame: First day of treatment to study discontinuation (up to 60 weeks)
Population: No Surgery Group participants from the Intent-to-treat (ITT) population who received at least one dose of study medication.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus 10 mg + Surgery | No Surgery Group: Progression Free Survival | 4.14 Weeks |
| Everolimus 5 mg + Surgery | No Surgery Group: Progression Free Survival | 4.14 Weeks |
| Everolimus 0 mg + Surgery | No Surgery Group: Progression Free Survival | 4.14 Weeks |
Secondary
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.
Time frame: After surgery, week 4, week 8 and every 8 weeks thereafter
Population: Study was terminated due to slow enrollment.
Secondary
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.)
Population: Study was terminated due to slow enrollment.
Secondary
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.
Time frame: First day of treatment to study discontinuation (Up to 28 weeks)
Population: Surgery Group participants from the Safety population who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Endocrine disorders | 1 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Eye disorders | 1 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Investigations | 3 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Metabolism and nutrition disorders | 6 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Immune system disorders | 1 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Injury, poisoning, and procedural complications | 5 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Neoplasms benign, malignant and unspecified | 0 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Vascular disorders | 2 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Musculoskeletal and connective tissue disorders | 1 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Cardiac disorders | 0 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Renal and urinary disorders | 0 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Respiratory, thoracic and mediastinal disorders | 0 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Blood and lymphatic system disorders | 4 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Surgical and medical procedures | 1 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Reproductive system and breast disorders | 0 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Infections and infestations | 4 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | General disorders & administration site conditions | 4 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Gastrointestinal disorders | 5 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Psychiatric disorders | 5 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Nervous system disorders | 4 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Ear and labyrinth disorders | 2 Participants |
| Everolimus 10 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Skin and subcutaneous tissue disorders | 4 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Ear and labyrinth disorders | 0 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Gastrointestinal disorders | 5 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Nervous system disorders | 5 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | General disorders & administration site conditions | 4 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Metabolism and nutrition disorders | 4 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Blood and lymphatic system disorders | 2 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Infections and infestations | 2 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Psychiatric disorders | 3 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Skin and subcutaneous tissue disorders | 2 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Investigations | 1 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Injury, poisoning, and procedural complications | 3 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Musculoskeletal and connective tissue disorders | 1 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Respiratory, thoracic and mediastinal disorders | 2 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Renal and urinary disorders | 1 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Vascular disorders | 1 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Immune system disorders | 1 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Eye disorders | 1 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Reproductive system and breast disorders | 1 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Cardiac disorders | 0 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Endocrine disorders | 0 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Surgical and medical procedures | 0 Participants |
| Everolimus 5 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Neoplasms benign, malignant and unspecified | 0 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Immune system disorders | 1 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Skin and subcutaneous tissue disorders | 2 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Nervous system disorders | 5 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Eye disorders | 0 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Psychiatric disorders | 2 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Infections and infestations | 3 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Ear and labyrinth disorders | 0 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Blood and lymphatic system disorders | 5 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Neoplasms benign, malignant and unspecified | 0 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Reproductive system and breast disorders | 0 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Metabolism and nutrition disorders | 3 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Surgical and medical procedures | 0 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Cardiac disorders | 1 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Respiratory, thoracic and mediastinal disorders | 2 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Musculoskeletal and connective tissue disorders | 2 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | General disorders & administration site conditions | 5 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Renal and urinary disorders | 2 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Injury, poisoning, and procedural complications | 0 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Gastrointestinal disorders | 3 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Vascular disorders | 2 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Investigations | 1 Participants |
| Everolimus 0 mg + Surgery | Surgery Group: Number of Participants With Adverse Events | Endocrine disorders | 0 Participants |
Secondary
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.
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)
Population: Results for the Surgery Group only include patients with residual tumor following salvage surgery.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus 10 mg + Surgery | Surgery Group: Progression-free Survival | 25.9 Weeks |
| Everolimus 5 mg + Surgery | Surgery Group: Progression-free Survival | 9.1 Weeks |
| Everolimus 0 mg + Surgery | Surgery Group: Progression-free Survival | NA Weeks |
| Total | Surgery Group: Progression-free Survival | 14.9 Weeks |