Trial Information

Phase I/II Evaluation of Everolimus (RAD001), Radiation and Temozolomide (TMZ) Followed by Adjuvant Temozolomide and Everolimus in 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 Center 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.