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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00515086
• Collaborator: (none)
• Enrollment: 41
• Locations: 8
• Arms: 4
• Duration (Months): 24
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme	Drug: Everolimus; Procedure: Surgery	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of RAD001 in Patients With Recurrent Glioblastoma Multiforme
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Everolimus; Tablets taken once a day with a full glass of water.; Other Names: RAD001
Experimental: 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.	Drug: Everolimus; Tablets taken once a day with a full glass of water.; Other Names: RAD001 ; Procedure: Surgery; Salvage surgical resection
Experimental: 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.	Drug: Everolimus; Tablets taken once a day with a full glass of water.; Other Names: RAD001 ; Procedure: Surgery; Salvage surgical resection
Active Comparator: 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.	Drug: Everolimus; Tablets taken once a day with a full glass of water.; Other Names: RAD001 ; Procedure: Surgery; Salvage surgical resection

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.)]

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA	Los Angeles	California	United States	90095
2	Northwestern University	Chicago	Illinois	United States	60611
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
5	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
6	Duke University - Preston Robert Tisch Brain Tumor Center	Durham	North Carolina	United States	27710
7	University of Cincinnati	Cincinnati	Ohio	United States	45219
8	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00515086
• Other Study ID Numbers: CRAD001C2410
• First Posted: Aug 13, 2007
• Last Update Posted: Sep 22, 2011
• Last Verified: Sep 1, 2011

• Keywords provided by Novartis Pharmaceuticals: Glioblastoma Multiforme, GBM, RAD001, RAD
• Additional relevant MeSH terms: Glioblastoma; Everolimus

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	No Surgery (Everolimus 10 mg)	Everolimus 10 mg + Surgery	Everolimus 5 mg + Surgery	Everolimus 0 mg + Surgery
Arm/Group 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.
Period Title: Overall Study
STARTED	24	6	5	6
COMPLETED	0	0	0	0
NOT COMPLETED	24	6	5	6

Baseline Characteristics

Arm/Group Title	No Surgery (Everolimus 10 mg)	Everolimus 10 mg + Surgery	Everolimus 5 mg + Surgery	Everolimus 0 mg + Surgery	Total
Arm/Group 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.	Total of all reporting groups
Overall Participants	24	6	5	6	41
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 58.3%	5 83.3%	5 100%	5 83.3%	29 70.7%
>=65 years	10 41.7%	1 16.7%	0 0%	1 16.7%	12 29.3%
Sex: Female, Male (Count of Participants)
Female	5 20.8%	4 66.7%	0 0%	4 66.7%	13 31.7%
Male	19 79.2%	2 33.3%	5 100%	2 33.3%	28 68.3%

Outcome Measures

1. Primary Outcome

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)

Outcome Measure Data

Analysis Population Description

Study was terminated due to slow enrollment.

Arm/Group Title	Everolimus 10 mg + Surgery	Everolimus 5 mg + Surgery	Everolimus 0 mg + Surgery
Arm/Group 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.	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.
Measure Participants	0	0	0

2. Primary Outcome

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)

Outcome Measure Data

Analysis Population Description

No Surgery Group participants from the Intent-to-treat (ITT) population who received at least one dose of study medication.

Arm/Group Title	No Surgery (1 Previous Relapse)	No Surgery ( ≥ 2 Previous Relapses)
Arm/Group Description	Participants with recurrent Glioblastoma Multiforme (GBM) with 1 previous relapse 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 with recurrent Glioblastoma Multiforme with ≥ 2 previous relapses not scheduled to undergo salvage surgical resection, received a daily oral dose of 10 mg Everolimus until evidence of disease progression or toxicity.
Measure Participants	12	12
Complete response + Partial response	0 0%	0 0%
Complete response	0 0%	0 0%
Partial response	0 0%	0 0%
Stable disease	3 12.5%	6 100%
Progressive disease	7 29.2%	6 100%

3. Secondary Outcome

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.)

Outcome Measure Data

Analysis Population Description

Study was terminated due to slow enrollment.

Arm/Group Title	Everolimus 10 mg + Surgery	Everolimus 5 mg + Surgery	Everolimus 0 mg + Surgery
Arm/Group 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.	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.
Measure Participants	0	0	0

4. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Results for the Surgery Group only include patients with residual tumor following salvage surgery.

Arm/Group Title	Everolimus 10 mg + Surgery	Everolimus 5 mg + Surgery	Everolimus 0 mg + Surgery	Total
Arm/Group 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.	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.	All the participants scheduled to undergo salvage surgical resection from three pre-surgery treatment groups (i.e 0, 5 or 10 mg/day (once daily) everolimus X 7 days).
Measure Participants	6	4	6	16
Median (95% Confidence Interval) [Weeks]	25.9	9.1	NA	14.9

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Study was terminated due to slow enrollment.

Arm/Group Title	Everolimus 10 mg + Surgery	Everolimus 5mg + Surgery	Everolimus 0 mg + Surgery
Arm/Group Description	Participants scheduled to undergo salvage surgical resection, received a daily oral dose of 10 mg Everolimus (RAD001) 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.
Measure Participants	0	0	0

6. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

No Surgery Group participants from the Intent-to-treat (ITT) population who received at least one dose of study medication.

Arm/Group Title	No Surgery (1 Previous Relapse)	No Surgery ( ≥ 2 Previous Relapses)	Total : No Surgery
Arm/Group Description	Participants with recurrent Glioblastoma Multiforme (GBM) with 1 previous relapse 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 with recurrent Glioblastoma Multiforme (GBM) with ≥ 2 previous relapses not scheduled to undergo salvage surgical resection, received a daily oral dose of 10 mg Everolimus until evidence of disease progression or toxicity.	Total participants enrolled with recurrent glioblastoma multiforme (GBM) who were not scheduled to undergo a planned salvage surgical resection. All participants in this arm were to receive a fixed daily dose of 10 mg/day oral everolimus.
Measure Participants	12	12	24
Median (95% Confidence Interval) [Weeks]	4.14	4.14	4.14

7. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Surgery Group participants from the Safety population who received at least one dose of study medication.

Arm/Group Title	Everolimus 10 mg + Surgery	Everolimus 5 mg + Surgery	Everolimus 0 mg + Surgery
Arm/Group Description	Participants scheduled to undergo salvage surgical resection, received a daily oral dose of 10 mg Everolimus (RAD001) 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.
Measure Participants	6	5	6
Gastrointestinal disorders	5 20.8%	5 83.3%	3 60%
Nervous system disorders	4 16.7%	5 83.3%	5 100%
General disorders & administration site conditions	4 16.7%	4 66.7%	5 100%
Metabolism and nutrition disorders	6 25%	4 66.7%	3 60%
Blood and lymphatic system disorders	4 16.7%	2 33.3%	5 100%
Infections and infestations	4 16.7%	2 33.3%	3 60%
Psychiatric disorders	5 20.8%	3 50%	2 40%
Skin and subcutaneous tissue disorders	4 16.7%	2 33.3%	2 40%
Investigations	3 12.5%	1 16.7%	1 20%
Injury, poisoning, and procedural complications	5 20.8%	3 50%	0 0%
Musculoskeletal and connective tissue disorders	1 4.2%	1 16.7%	2 40%
Respiratory, thoracic and mediastinal disorders	0 0%	2 33.3%	2 40%
Renal and urinary disorders	0 0%	1 16.7%	2 40%
Vascular disorders	2 8.3%	1 16.7%	2 40%
Immune system disorders	1 4.2%	1 16.7%	1 20%
Eye disorders	1 4.2%	1 16.7%	0 0%
Ear and labyrinth disorders	2 8.3%	0 0%	0 0%
Reproductive system and breast disorders	0 0%	1 16.7%	0 0%
Cardiac disorders	0 0%	0 0%	1 20%
Endocrine disorders	1 4.2%	0 0%	0 0%
Surgical and medical procedures	1 4.2%	0 0%	0 0%
Neoplasms benign, malignant and unspecified	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	Everolimus 10 mg + Surgery		Everolimus 5 mg + Surgery		Everolimus 0 mg + Surgery		No Surgery (Everolimus 10 mg)
Arm/Group 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.		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.		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.
All Cause Mortality
	Everolimus 10 mg + Surgery		Everolimus 5 mg + Surgery		Everolimus 0 mg + Surgery		No Surgery (Everolimus 10 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Everolimus 10 mg + Surgery		Everolimus 5 mg + Surgery		Everolimus 0 mg + Surgery		No Surgery (Everolimus 10 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		1/5 (20%)		2/6 (33.3%)		6/24 (25%)
Cardiac disorders
Myocardial infarction	0/6 (0%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
General disorders
Gait Disturbance	0/6 (0%)		0/5 (0%)		0/6 (0%)		2/24 (8.3%)
Pyrexia	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Infections and infestations
Bacterial Diarrhoea	0/6 (0%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Meningitis	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Perirectal Abscess	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Pneumocystis Jiroveci Pneumonia	0/6 (0%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Wound infection Staphylococcal	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Metabolism and nutrition disorders
Hypercholesterolaemia	0/6 (0%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Hypertriglyceridaemia	0/6 (0%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Musculoskeletal and connective tissue disorders
Muscular Weakness	0/6 (0%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Nervous system disorders
Convulsion	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Lethargy	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Neuropathy Peripheral	0/6 (0%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Pneumocephalus	0/6 (0%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
intracranial Hypotension	0/6 (0%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Pulmonary Oedema	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Everolimus 10 mg + Surgery		Everolimus 5 mg + Surgery		Everolimus 0 mg + Surgery		No Surgery (Everolimus 10 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		5/5 (100%)		6/6 (100%)		20/24 (83.3%)
Blood and lymphatic system disorders
Anaemia	3/6 (50%)		0/5 (0%)		2/6 (33.3%)		1/24 (4.2%)
Leukopenia	2/6 (33.3%)		0/5 (0%)		3/6 (50%)		6/24 (25%)
Lymph Node Pain	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Lymphopenia	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		3/24 (12.5%)
Neutropenia	2/6 (33.3%)		1/5 (20%)		2/6 (33.3%)		4/24 (16.7%)
Thrombocytopenia	3/6 (50%)		1/5 (20%)		2/6 (33.3%)		3/24 (12.5%)
Cardiac disorders
Tachycardia	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Ear and labyrinth disorders
Ear Discomfort	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Hypoacusis	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Tinnitus	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Endocrine disorders
Cushingoid	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Eye disorders
Vision Blurred	1/6 (16.7%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Gastrointestinal disorders
Aphthous Stomatitis	0/6 (0%)		1/5 (20%)		0/6 (0%)		1/24 (4.2%)
Constipation	3/6 (50%)		4/5 (80%)		1/6 (16.7%)		2/24 (8.3%)
Diarrhoea	1/6 (16.7%)		1/5 (20%)		0/6 (0%)		4/24 (16.7%)
Dysphagia	0/6 (0%)		1/5 (20%)		0/6 (0%)		1/24 (4.2%)
Frequent Bowel Movements	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Haemorrhoids	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Lip Pain	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Nausea	1/6 (16.7%)		0/5 (0%)		1/6 (16.7%)		2/24 (8.3%)
Stomatitis	0/6 (0%)		1/5 (20%)		0/6 (0%)		3/24 (12.5%)
Toothache	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
General disorders
Facial Pain	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Fatigue	3/6 (50%)		2/5 (40%)		2/6 (33.3%)		8/24 (33.3%)
Irritability	0/6 (0%)		0/5 (0%)		0/6 (0%)		2/24 (8.3%)
Localised Oedema	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Mucosal inflammation	2/6 (33.3%)		1/5 (20%)		3/6 (50%)		1/24 (4.2%)
Oedema Peripheral	2/6 (33.3%)		0/5 (0%)		1/6 (16.7%)		2/24 (8.3%)
Pain	0/6 (0%)		2/5 (40%)		0/6 (0%)		1/24 (4.2%)
Pyrexia	0/6 (0%)		0/5 (0%)		0/6 (0%)		2/24 (8.3%)
Immune system disorders
Drug Hypersensitivity	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Seasonal Allergy	0/6 (0%)		1/5 (20%)		1/6 (16.7%)		1/24 (4.2%)
Infections and infestations
Fungal Skin infection	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Gastroenteritis Viral	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Herpes Zoster Oticus	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Oral Candidiasis	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Oral Herpes	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Paronychia	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Pneumonia	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Respiratory Tract infection	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Sinusitis	1/6 (16.7%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Upper Respiratory Tract infection	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		1/24 (4.2%)
Urinary Tract infection	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		3/24 (12.5%)
Injury, poisoning and procedural complications
Contusion	0/6 (0%)		0/5 (0%)		0/6 (0%)		3/24 (12.5%)
Endotracheal intubation Complication	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Fall	0/6 (0%)		0/5 (0%)		0/6 (0%)		2/24 (8.3%)
Procedural Pain	4/6 (66.7%)		2/5 (40%)		0/6 (0%)		0/24 (0%)
Radiation Necrosis	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
incision Site Pain	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Investigations
Alanine Aminotransferase increased	2/6 (33.3%)		1/5 (20%)		1/6 (16.7%)		2/24 (8.3%)
Aspartate Aminotransferase increased	2/6 (33.3%)		0/5 (0%)		0/6 (0%)		2/24 (8.3%)
Blood Albumin Decreased	0/6 (0%)		0/5 (0%)		0/6 (0%)		2/24 (8.3%)
Blood Alkaline Phosphatase increased	1/6 (16.7%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Blood Bicarbonate Decreased	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Blood Cholesterol increased	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		4/24 (16.7%)
Blood Triglycerides increased	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		4/24 (16.7%)
Gamma-Glutamyltransferase increased	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Haemoglobin Decreased	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Heart Rate increased	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Low Density Lipoprotein increased	0/6 (0%)		0/5 (0%)		0/6 (0%)		3/24 (12.5%)
Oxygen Saturation Decreased	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Platelet Count Decreased	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		3/24 (12.5%)
Weight Decreased	0/6 (0%)		0/5 (0%)		0/6 (0%)		3/24 (12.5%)
Weight increased	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Metabolism and nutrition disorders
Anorexia	0/6 (0%)		1/5 (20%)		1/6 (16.7%)		2/24 (8.3%)
Decreased Appetite	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		2/24 (8.3%)
Hypercholesterolaemia	1/6 (16.7%)		0/5 (0%)		1/6 (16.7%)		4/24 (16.7%)
Hyperglycaemia	6/6 (100%)		2/5 (40%)		2/6 (33.3%)		5/24 (20.8%)
Hyperkalaemia	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Hyperlipidaemia	1/6 (16.7%)		1/5 (20%)		1/6 (16.7%)		1/24 (4.2%)
Hypertriglyceridaemia	1/6 (16.7%)		2/5 (40%)		1/6 (16.7%)		3/24 (12.5%)
Hypoalbuminaemia	1/6 (16.7%)		1/5 (20%)		2/6 (33.3%)		2/24 (8.3%)
Hypocalcaemia	2/6 (33.3%)		0/5 (0%)		1/6 (16.7%)		3/24 (12.5%)
Hypokalaemia	2/6 (33.3%)		0/5 (0%)		2/6 (33.3%)		1/24 (4.2%)
Hypomagnesaemia	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Hyponatraemia	1/6 (16.7%)		0/5 (0%)		1/6 (16.7%)		3/24 (12.5%)
Hypophosphataemia	2/6 (33.3%)		0/5 (0%)		2/6 (33.3%)		2/24 (8.3%)
Hypoproteinaemia	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)		1/5 (20%)		1/6 (16.7%)		1/24 (4.2%)
Muscular Weakness	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		2/24 (8.3%)
Musculoskeletal Pain	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Pain in Extremity	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		2/24 (8.3%)
Pain in Jaw	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Nervous system disorders
Amnesia	1/6 (16.7%)		0/5 (0%)		2/6 (33.3%)		0/24 (0%)
Aphasia	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Ataxia	3/6 (50%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Brain Oedema	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Cognitive Disorder	2/6 (33.3%)		1/5 (20%)		0/6 (0%)		1/24 (4.2%)
Depressed Level of Consciousness	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Dizziness	2/6 (33.3%)		1/5 (20%)		0/6 (0%)		1/24 (4.2%)
Facial Palsy	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Headache	1/6 (16.7%)		2/5 (40%)		1/6 (16.7%)		4/24 (16.7%)
Hemianopia	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Hemiparesis	0/6 (0%)		1/5 (20%)		0/6 (0%)		1/24 (4.2%)
Hypogeusia	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Memory Impairment	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
Mental Impairment	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Paraesthesia	0/6 (0%)		2/5 (40%)		0/6 (0%)		0/24 (0%)
Peripheral Motor Neuropathy	3/6 (50%)		1/5 (20%)		1/6 (16.7%)		0/24 (0%)
Peripheral Sensory Neuropathy	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Sinus Headache	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Somnolence	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Speech Disorder	2/6 (33.3%)		0/5 (0%)		1/6 (16.7%)		2/24 (8.3%)
Visual Field Defect	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Psychiatric disorders
Anxiety	2/6 (33.3%)		1/5 (20%)		0/6 (0%)		2/24 (8.3%)
Confusional State	1/6 (16.7%)		1/5 (20%)		1/6 (16.7%)		1/24 (4.2%)
Depression	2/6 (33.3%)		1/5 (20%)		0/6 (0%)		1/24 (4.2%)
Hallucination	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
insomnia	2/6 (33.3%)		1/5 (20%)		1/6 (16.7%)		3/24 (12.5%)
Renal and urinary disorders
Pollakiuria	0/6 (0%)		1/5 (20%)		0/6 (0%)		1/24 (4.2%)
Urinary incontinence	0/6 (0%)		0/5 (0%)		0/6 (0%)		2/24 (8.3%)
incontinence	0/6 (0%)		0/5 (0%)		2/6 (33.3%)		1/24 (4.2%)
Reproductive system and breast disorders
Sexual Dysfunction	0/6 (0%)		1/5 (20%)		0/6 (0%)		1/24 (4.2%)
Respiratory, thoracic and mediastinal disorders
Allergic Cough	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		0/24 (0%)
Aspiration	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Cough	0/6 (0%)		1/5 (20%)		1/6 (16.7%)		1/24 (4.2%)
Dyspnoea	0/6 (0%)		0/5 (0%)		1/6 (16.7%)		1/24 (4.2%)
Pneumothorax	0/6 (0%)		1/5 (20%)		0/6 (0%)		0/24 (0%)
Skin and subcutaneous tissue disorders
Pain of Skin	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Pruritus	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Rash	1/6 (16.7%)		1/5 (20%)		0/6 (0%)		2/24 (8.3%)
Rash Erythematous	0/6 (0%)		1/5 (20%)		0/6 (0%)		1/24 (4.2%)
Rash Maculo-Papular	0/6 (0%)		0/5 (0%)		2/6 (33.3%)		1/24 (4.2%)
Rash Papular	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		1/24 (4.2%)
increased Tendency To Bruise	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Surgical and medical procedures
Tooth Extraction	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Vascular disorders
Deep Vein Thrombosis	0/6 (0%)		0/5 (0%)		2/6 (33.3%)		0/24 (0%)
Haematoma	1/6 (16.7%)		0/5 (0%)		0/6 (0%)		0/24 (0%)
Hypertension	1/6 (16.7%)		1/5 (20%)		0/6 (0%)		0/24 (0%)

Limitations/Caveats

Due to the early termination of this study, the analysis of some of the planned objectives is not included in this clinical study report.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial; or the publication of the trial results in their entirety.