Everolimus in Treating Patients With Recurrent Low-Grade Glioma

Phase 2

Completed

Conditions: Adult Subependymal Giant Cell Astrocytoma
Adult Diffuse Astrocytoma
Adult Mixed Glioma
Adult Oligodendroglioma
Recurrent Adult Brain Neoplasm

Interventions: Drug: Everolimus
Other: Archival Tissue Analysis

Registration Number: NCT00823459

Lead Sponsor: Susan Chang

Brief Summary: This phase II trial studies how well everolimus works in treating patients with recurrent low-grade glioma. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor.

Detailed Description: PRIMARY OBJECTIVES:

1. To determine progression-free survival at 6 months associated with use of RAD001 (everolimus) in patients initially diagnosed with low-grade glioma who undergo biopsy or subtotal resection at the time of recurrence with pathologic evidence of recurrent low-grade glioma (LGG).

SECONDARY OBJECTIVES:

1. To further delineate the safety profile of RAD001 in patients with recurrent LGG.

2. To assess overall survival (OS) in patients treated with RAD001.

3. To assess the objective response rate (ORR) in patients treated with RAD001.

4. To assess the correlation of protein kinase B (PKB)/Akt and phosphatase and tensin homolog (PTEN) expression with response, progression status by 6 months, and OS in patients treated with RAD001.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 58

Inclusion Criteria

Patients must have a Karnofsky performance status of >= 60
Patients must have a life expectancy > 8 weeks
All patients must sign an informed consent document indicating that they are aware of the investigational nature of this study
Patients must sign an authorization for the release of their protected health information
Patients must have a magnetic resonance imaging (MRI) scan performed within 14 days prior to initial protocol treatment
Patients must be registered in the University of California at San Francisco (UCSF) Neuro-Oncology database prior to treatment with study drug
Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
Platelets >= 100 x 10^9/L
Hemoglobin (Hb) > 9 g/dL
Serum bilirubin =< 1.5 x upper limit of normal (ULN)
International normalized ratio (INR) < 1.5 (anticoagulation is allowed if target INR =< 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight [LMW] heparin for > 2 weeks at the time of registration)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
Serum creatinine =< 1.5 x ULN
Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN; NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
Patients must have histologically proven intracranial low-grade glioma at initial diagnosis; low-grade gliomas include: astrocytoma, oligodendroglioma and mixed oligoastrocytoma; pilocytic astrocytomas are excluded
Patients must have unequivocal evidence for tumor recurrence or progression by histology as determined by review of pathology by an attending neuro-pathologist at UCSF
If most recent histology shows progression to high grade glioma, patients must have had prior radiotherapy in order to be eligible
Paraffin-embedded sections of tissue acquired from surgery at the time of suspected recurrence must be available for analysis
Patients must have evidence for tumor recurrence or progression by MRI as determined by radiographic review of images by an attending neuro-oncologist or neuro-radiologist at UCSF
If the steroid dose is increased between the date of the MRI and registration on the trial, a new baseline MRI is required; this MRI must be performed after >= 5 days on a stable dose of steroids
An MRI must be used throughout the period of protocol treatment for tumor measurement
Patients must have evaluable disease
Patients may have had treatment (including radiotherapy) for any number of relapses prior to this recurrence
Patients must be at least 4 weeks from the completion of any radiation therapy
Patients must be less than 4 months from the surgical procedure for this recurrence
Patients must have recovered from the toxic effects of prior therapy:
- 4 weeks from any investigational agent
- 4 weeks from prior cytotoxic therapy (except 6 weeks from nitrosoureas, 3 weeks from procarbazine, 3 weeks from vincristine)
- 3 weeks for non-cytotoxic or biologic agents e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, tarceva, etc; note a 3-week washout is required for prior treatment with bevacizumab

Exclusion Criteria

Patients who have not recovered from the side effects of a major surgery or significant traumatic injury or patients that may require major surgery during the course of the study
Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent; topical or inhaled corticosteroids, and treatment with low dose Decadron (=< 3 mg daily) are allowed
Other than surgery, patients may not have therapy for this recurrence (including radiation); supportive care such as steroids or anti-epileptics does not constitute treatment of recurrence
Patients must not have any significant medical illnesses that in the investigator?s opinion cannot be adequately controlled with appropriate therapy or would compromise the patient?s ability to tolerate this therapy
Patients with a history of any other cancer (except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible
Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period; close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus; examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Gu?rin (BCG), yellow fever, varicella and TY21a typhoid vaccines
Uncontrolled brain or all leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
- Symptomatic congestive heart failure of New York heart Association Class III or IV
- Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
- Severely impaired lung function
- Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN (Note: Optimal glycemic control should be achieved before starting trial therapy)
- Active (acute or chronic) or uncontrolled severe infections
- Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C)
A Hepatitis B/C blood test must be done at screening for all patients; patients who test positive for Hepatitis C antibodies and the Hepatitis B antigen are ineligible
A known history of human immunodeficiency virus (HIV) seropositivity
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
Impaired lung function: O2 saturation 88% or less at rest on room air by pulse oximetry; if O2 saturation is =< 88% at rest, further pulmonary function tests (PFTs) should be ordered to confirm normal pulmonary function and eligibility
Patients with an active, bleeding diathesis
Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods; adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug, by both sexes (women of childbearing potential [WOCBP] must have a negative urine or serum pregnancy test within 7 days prior to administration of RAD001)
Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment
Patients who have received prior treatment with an mammalian target of rapamycin (mTOR) inhibitor (e.g., sirolimus, temsirolimus, everolimus)
Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (e.g., sirolimus, temsirolimus) or to its excipients
History of noncompliance to medical regimens
Patients unwilling to or unable to comply with the protocol

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single-Arm Everolimus	Everolimus	Single-arm study with patients receiving Everolimus orally once daily dosing of 10 mg continuously from Day 1 of study until progression of disease or unacceptable toxicity. In addition archival tissue will be analysed for markers of P13K/mTOR pathway activation.
Single-Arm Everolimus	Archival Tissue Analysis	Single-arm study with patients receiving Everolimus orally once daily dosing of 10 mg continuously from Day 1 of study until progression of disease or unacceptable toxicity. In addition archival tissue will be analysed for markers of P13K/mTOR pathway activation.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival at 6 Months.	At 6 months after treatment start	Number of patients alive without progressive disease at 6 months. Assessment of progression was defined by RANO as a 25% increase in the sum of all the products of measurable lesions, clear worsening of any evaluable disease or any new lesion

Secondary Outcome Measures

Name	Time	Method
RAD001 Safety Profile in Patients With Recurrent LLG	13 months	Grade 4-5 treatment related adverse events as defined by CTCAE 3.0
Objective Response Rate (ORR) in Patients Treated With RAD001.	12 months	Objective response is defined as complete or partial response as defined by RANO criteria as determined by MRI and steroid requirement. Complete response was defined by disappearance of all measurable disease with minimal or no steroids; a partial response was defined as 50% in sum of all products in perpendicular diameters of all measurable lesions with no new lesions on stable or decreasing steroids.
Overall Survival (OS) in Patients Treated With RAD001.	Time from registration till death, an average of 5 years	Number of years from the day the patient started treatment until the date of death, an average of 5 years.
To Assess the Correlation of Activation of the PI3K/mTOR Pathway With Survival	5 years	Survival of patients with p-S6 staining of \>19% (activated pathway)