RO4929097, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Malignant Glioma

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose/recommended phase II dose of RO4929097 in
combination with temozolomide and radiotherapy in patients with glioblastoma or malignant
gliomas.

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of RO4929097 when given in combination with temozolomide
(correlative study C1).

II. To evaluate brain and tumor penetration of RO4929097 when given in recommended phase II
single agent schedule and when given at the maximum tolerated dose (MTD) for the combination
with radiotherapy and temozolomide (correlative study C2).

TERTIARY OBJECTIVES:

I. To evaluate pharmacodynamic effects of RO4929097 in the resected specimens, and
comparison with specimens obtained from untreated patients.

II. Effects of RO4929097 on the cancer stem cell population (correlative study C4).

III. Effects of RO4929097 on angiogenesis (correlative study C5). IV. To evaluate the
combined effects of RO4929097, radiation and temozolomide in explants established from
patients' tumor specimens (correlative study C6).

V. To evaluate the effects of RO4929097 on magnetic resonance imaging (MRI) parameters
(correlative study C7), including dynamic contrast enhanced (DCE) MRI perfusion, diffusion
weighted imaging and volumetric analysis.

VI. Preliminary evaluation of efficacy of this treatment regimen: 6 month (6m) and median
progression-free and overall survival, and response rates.

VII. To evaluate potential biomarkers of gamma-secretase and Notch inhibition activity
(correlative study C8).

OUTLINE: This is a dose-escalation study of gamma-secretase/Notch signalling pathway
inhibitor RO4929097. Patients are assigned to 1 of 2 treatment arms.

PRE-SURGERY TREATMENT: Patients receive gamma-secretase/Notch signalling pathway inhibitor
RO4929097 orally (PO) once daily (QD) on days 1-7 of week 1 and day 1 of week 2.

SURGERY: Patients undergo surgery 2-3 hours after administration of gamma-secretase/Notch
signalling pathway inhibitor RO4929097 on day 1 of week 2.

TREATMENT CONCURRENT WITH RADIOTHERAPY: Beginning 3-4 weeks after surgery, patients undergo
conventional focal (intensity-modulated radiation therapy [IMRT] or 3-D conformal)
radiotherapy 5 days a week for approximately 6 weeks. Patients also receive
gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO QD for approximately 10
weeks beginning the day of radiotherapy and temozolomide PO QD for approximately 6 weeks
beginning the day before radiotherapy.

ADJUVANT TREATMENT FOLLOWING RADIOTHERAPY: Approximately 4 weeks after completion of
radiotherapy, patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097
PO QD on days 1-28 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for
12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months.

Inclusion Criteria:

- Patients must have newly diagnosed glioblastoma, anaplastic astrocytoma, gliosarcoma
or other malignant gliomas with the exception of pure anaplastic oligodendroglioma;
note: patients with presumed malignant glioma based on radiographic assessment may be
enrolled onto Arm A of the study without histological confirmation provided they meet
the following additional eligibility criteria:

- The MRI of the brain shows typical findings of a malignant glioma or
glioblastoma (single ring-enhancing mass with necrotic portions)

- To exclude brain abscess, diffusion-weighted MRI must show absence of restricted
diffusion corresponding to the necrotic center of the lesion

- To confirm the diagnosis of neoplastic disease, MR perfusion must show that the
lesion has increased perfusion

- To exclude pilocytic astrocytoma, the patient's age must be over 25

- To exclude brain metastasis, a computed tomography (CT) of the chest, abdomen
and pelvis must demonstrate absence of other malignancy

- The principal investigator must review MRI and CT findings and agree with
diagnosis of presumed malignant glioma

- Note: If after the on-protocol surgery the patient is found not to meet
histological criteria described (diagnosis of glioblastoma, anaplastic
astrocytoma, gliosarcoma or other malignant gliomas with the exception of
pure anaplastic oligodendroglioma), the patient will be removed from the
study and replaced

- ARM A ONLY: Patients must have an indication for additional debulking surgery as part
of their initial treatment

- Life expectancy of greater than 2 months

- Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%)

- Hemoglobin >= 9 g/dL

- Leukocytes > 3,000/mcL

- Absolute neutrophil count > 1,500/mcL

- Platelets > 100,000/mcL

- Total bilirubin < 1.5 X institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance > 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Women of childbearing potential and men must use two forms of contraception (i.e.,
barrier contraception and one other method of contraception) at least 4 weeks prior
to study entry, for the duration of study participation, and for at least 12 months
post-treatment; should a woman become pregnant or suspect she is pregnant while she
or her partner are participating in this study and for 12 months after study
participation, the patient should inform the treating physician immediately

- Women of childbearing potential are required to have a negative serum pregnancy test
(with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours
prior to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or
urine) will be administered every 4 weeks if their menstrual cycles are regular or
every 2 weeks if their cycles are irregular while on study within the 24-hour period
prior to the administration of RO4929097; a positive urine test must be confirmed by
a serum pregnancy test; prior to dispensing RO4929097, the investigator must confirm
and document the patient's use of two contraceptive methods, dates of negative
pregnancy test, and confirm the patient's understanding of the teratogenic potential
of RO4929097

- Female patients of childbearing potential are defined as follows:

- Patients with regular menses

- Patients, after menarche with amenorrhea, irregular cycles, or using a
contraceptive method that precludes withdrawal bleeding

- Women who have had tubal ligation

- Female patients may be considered to NOT be of childbearing potential for the
following reasons:

- The patient has undergone total abdominal hysterectomy with bilateral
salpingo-oophorectomy or bilateral oophorectomy

- The patient is medically confirmed to be menopausal (no menstrual period) for 24
consecutive months

- Pre-pubertal females; the parent or guardian of young female patients who have
not yet started menstruation should verify that menstruation has not begun. If a
young female patient reaches menarche during the study, then she is to be
considered as a woman of childbearing potential from that time forward

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

Exclusion Criteria:

- Prior chemotherapy, radiotherapy, biological or experimental therapy for glioma

- Prior history of radiotherapy to the brain, head or neck

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to RO4929097 or other agents used in the study

- Patients taking medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible

- Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of
CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097
concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore,
patients who are taking concurrent medications that are strong inducers/inhibitors or
substrates of CYP3A4 should be switched to alternative medications to minimize any
potential risk; if such patients cannot be switched to alternative medications, they
will be ineligible to participate in this study

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption; patients must be able to swallow tablets

- Patients with known history of hepatitis B or C, or who have a history of liver
disease, other forms of hepatitis or cirrhosis are ineligible; (hepatitis B and C
serology should be obtained as part of pre-treatment evaluation but are not required
for eligibility)

- Patients with uncontrolled electrolyte abnormalities including hypocalcemia,
hypomagnesemia, hyponatremia, hypophosphatemia, and hypokalemia defined as less than
the lower limit of normal for the institution, despite adequate electrolyte
supplementation are excluded from this study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, history of
torsades de pointes or other significant cardiac arrhythmias, or psychiatric
illness/social situations that would limit compliance with study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with RO4929097 or temozolomide; these potential risks may also
apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated

- A corrected QT (QTc) > 450 msec in males and a QTc > 470 msec in females

- Patients who have not recovered to < Common Terminology Criteria for Adverse Events
(CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate
in this study

- ARM A ONLY: Patients with contraindication to a brain surgical procedure

- A requirement for antiarrhythmics or other medications known to prolong QTc