Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma

OBJECTIVES:

- To determine the maximum tolerated dose (MTD) of everolimus in combination with
temozolomide and 3D-conformal radiotherapy or intensity-modulated radiotherapy (IMRT)
followed by adjuvant temozolomide with or without everolimus in patients with newly
diagnosed glioblastoma. (Mayo Clinic Rochester [MCR] AND Mayo Clinic Jacksonville [MCJ]
patients only) (Phase I)

- To assess and describe the adverse events of everolimus in combination with temozolomide
and 3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without
everolimus in patients with newly diagnosed glioblastoma. (MCR and MCJ patients only)
(Phase I)

- To assess treatment effectiveness of everolimus in combination with temozolomide and
3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without
everolimus, until progression, in patients with newly diagnosed glioblastoma. (all North
Central Cancer Treatment Group [NCCTG] patients) (Phase II)

- To characterize the toxicities of everolimus in combination with temozolomide and
3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without
everolimus in patients with newly diagnosed glioblastoma. (all NCCTG patients) (Phase
II)

- Evaluate whether suppression of fludeoxyglucose F18 (18FDG) uptake in tumor and normal
brain can be used to determine a biologically effective dose for efficient penetration
of everolimus through the blood-brain barrier. (MCR and MCJ patients only) (Phase I)

- Correlate everolimus levels with 18FDG uptake suppression in tumor and normal brain.
(MCR and MCJ patients only) (Phase I)

- Assess the relationship between efficacy endpoints (i.e., survival, progression-free
survival, and response) and changes in 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) uptake
for patients treated at MCR. (all NCCTG patients) (Phase II)

- Assess the relationship between efficacy endpoints (i.e., survival, progression-free
survival, and response), and phospho-Akt, PTEN status, and MGMT expression and promoter
methylation status. (all NCCTG patients) (Phase II)

- Assess the relationship between efficacy endpoints (i.e., survival, progression-free
survival, and response) and baseline gene expression signatures from paraffin embedded
pre-treatment tumor samples. (all NCCTG patients) (Phase II)

- Correlate gene expression between paraffin and frozen samples. (all NCCTG patients)
(Phase II)

- Evaluate potential mechanisms of therapy resistance in recurrent tumor samples obtained
at the time of surgery for recurrent disease. (Phase I and II)

OUTLINE: This is a multicenter, phase I dose-escalation study of everolimus followed by a
phase II study.

- Phase I (Mayo Clinic Rochester [MCR] AND Mayo Clinic Jacksonville [MCJ] ONLY):

- Concurrent therapy (courses 1 and 2): Patients receive oral everolimus once weekly
in weeks 1-7 or 1-8 and oral temozolomide once daily in weeks 2-7 or 3-8. Patients
also undergo radiotherapy 5 days a week in either weeks 2-7 or 3-8. Four to six
weeks later, patients proceed to adjuvant therapy. This rest period is defined as
course 2.

- Adjuvant therapy with everolimus and temozolomide (courses 3-8): Patients receive
oral everolimus on days 1, 8, 15, and 22 and oral temozolomide on days 1-5.
Treatment repeats every 28 days for 6 courses in the absence of disease progression
or unacceptable toxicity.

- Adjuvant therapy with everolimus alone (courses 9 and all subsequent courses):
Patients receive oral everolimus on days 1, 8, 15, and 22. Treatment repeats every
28 days in the absence of disease progression our unacceptable toxicity.

- Phase II (Open to MCR center ONLY) (All North Central Cancer Treatment Group [NCCTG]
centers closed to accrual as of 02/17/11):

- Concurrent therapy (courses 1 and 2): Patients receive oral everolimus and oral
temozolomide and 3D-conformal radiotherapy or IMRT as in phase I. Patients will
undergo a 4-6 week rest period in course 2 and then proceed to adjuvant therapy.

- Adjuvant therapy with everolimus and temozolomide (courses 3-8): Patients receive
oral everolimus and oral temozolomide as in phase I.

- Adjuvant therapy with everolimus alone (courses 9 and all subsequent courses):
Patients receive oral everolimus as in phase I.

All patients undergo fludeoxyglucose (FDG)- or fluorothymidine-labeled PET/CT scans at
baseline and periodically during treatment.

Patients undergo blood sample collection periodically for pharmacological studies. Samples
are analyzed for everolimus blood levels and correlated with 18FDG uptake suppression in
tumor and normal brain via LC-MSMS. Previously collected tumor tissue are analyzed for
protein biomarkers including PTEN gene expression levels via fluorescence in situ
hybridization (FISH) and immunohistochemistry (IHC) and phosphorylation on Ser473 and Ser308
of Akt and MGMT expression and promoter methylation via IHC. Samples are also analyzed for
DNA sequencing. Some samples are banked for future studies.

After completion of study treatment, patients are followed every 2 months for 1 year, every 3
months for 1 year, and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 138 patients (24 patients in phase I and 114 patients in phase
II) will be accrued for this study.

DISEASE CHARACTERISTICS:

- Histologically confirmed diagnosis of 1 of the following:

- Glioblastoma multiforme (grade 4 astrocytoma)

- Other grade 4 astrocytoma variants (e.g., giant cell)

- No grade 4 oligodendrogliomas or oligoastrocytomas

- Gliosarcoma

- Newly diagnosed disease

- Measurable disease ≥ 1 cm³ (phase I patients only)

- Some patients may be registered on protocol NCCTG-947252

- No oligodendrogliomas or oligoastrocytomas

PATIENT CHARACTERISTICS:

Inclusion criteria:

- ECOG performance status 0-2

- ANC ≥ 1,500/μL

- Hemoglobin ≥ 9.0 g/dL

- Platelet count ≥ 100,000/μL

- Total bilirubin ≤ 2.5 x institutional upper limit of normal (ULN)

- Serum total cholesterol < 350 mg/dL

- Serum total triglycerides < 400 mg/dL

- AST ≤ 2.5 x ULN

- Creatinine ≤ 1.5 x ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 60 days after
completion of study therapy

- Must be willing to undergo 2 mandatory research PET or PET/CT scans (all MCR and MCJ
patients in phase I and MCR only patients in phase II)

- Must be willing to abstain from eating or drinking grapefruit or grapefruit juice
during study treatment

- Must be willing to follow a diet low in fat and cholesterol while taking everolimus

- Must be willing to have imaging scans submitted for central review

- Ability to understand and willingness to sign a written informed consent

Exclusion criteria:

- Other active cancers requiring therapy to control disease or prior cancer diagnoses
which pose a greater than 30% risk of death within the next 2 years

- Gastrointestinal tract disease resulting in an inability to take oral medication or a
requirement for IV alimentation, prior surgical procedures affecting absorption, or
active uncontrolled peptic ulcer disease

- Uncontrolled intercurrent illness including, but not limited to, any of the following:

- Ongoing, uncontrolled, or active (acute or chronic) infection or disorder

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Severely impaired lung function

- Uncontrolled diabetes (fasting serum glucose > 2 x ULN) OR diabetes that would
interfere with the performance of the FDG-PET/CT or FDG-PET scans

- Liver disease (e.g., cirrhosis, chronic active hepatitis, chronic persistent
hepatitis, or history of hepatitis B)

- Known HIV positivity

- Positive hepatitis B antigen (HBsAg) or hepatitis C serology (HCV) tests

- Any history of allergy or intolerance to dacarbazine (DTIC)

- Significant traumatic injury within the past 21 days

- Severe allergy to sulfa medications

- Inability to tolerate levofloxacin with dapsone or pentamidine (inhaled or IV)

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

- At least 1 week, but no more than 6 weeks since prior surgical resection or biopsy

- Must comply with antibiotic prophylaxis with either trimethoprim/sulfamethoxazole
(daily or 3 times per week), oral dapsone (daily) combined with daily levofloxacin, or
monthly pentamidine (inhaled or IV) combined with daily levofloxacin

Exclusion criteria:

- Prior chemotherapy for any brain tumor

- Prior temozolomide or mTOR inhibitor therapies

- Any prior cranial radiotherapy

- Planned immunization with attenuated live vaccines ≤ 7 days prior to and during study
period

- At least 21 days since prior major surgery (excluding neurosurgical biopsy, resection
of brain tumor, or treatment of immediate post-neurosurgical complication [e.g.,
intracranial hematoma])

- Concurrent or prior treatment for this cancer with any other investigational agents

- Concurrent enzyme-inducing anticonvulsants (EIACs) or other strong inducers of CYP3A4
(i.e., carbamazepine, phenytoin, phenobarbital/primidone, rifabutin, rifampin, or St.
John's wort)

- Concurrent therapeutic doses of warfarin

- Low molecular weight heparin is allowed

- Concurrent systematic leukocyte growth factors (e.g., G-CSF or GM-CSF), except for the
treatment of severe neutropenia

- Concurrent drugs or substances known to inhibit or induce CYP3A

- Other concurrent chronic treatment with immunosuppressive agents except dexamethasone

- Other concurrent anticancer agents

- Concurrent live vaccines