Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Recurrent or Progressive Glioblastoma

PRIMARY OBJECTIVES:

I. 6-month progression-free survival (PFS6). (Group A) II. Efficiency of neurosphere
generation after pretreatment with RO4929097 (gamma-secretase/Notch signalling pathway
inhibitor RO4929097). (Group B)

SECONDARY OBJECTIVES:

I. Radiographic response rate. (Group A) II. Toxicities associated with this regimen. (Group
A) III. Overall survival. (Group A) IV. Expression levels of Notch pathway components and
downstream targets. (Group B) V. Tumor propagation. An extension of lifespan by 50% in tumor
bearing mice (mice bearing fresh tumor tissue). (Group B) VI. Patient event-free survival in
correlation with expression levels of Notch pathway components and downstream targets.

VII. 6-month progression-free survival (PFS6). VIII. Toxicities associated with this
regimen. IX. Overall survival.

OUTLINE: Patients are assigned to 1 of 2 treatment groups.

GROUP A: Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097
orally (PO) once daily (QD) on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

GROUP B (surgical resection indicated): Patients receive gamma-secretase/Notch signalling
pathway inhibitor RO4929097 PO QD on days -6 to -1. Patients undergo surgical resection on
day 0. Within 30 days after surgical resection, patients receive gamma-secretase/Notch
signalling pathway inhibitor RO4929097 as in Group A.

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

Inclusion Criteria:

- Patients must have histologically proven glioblastoma which is progressive or
recurrent following radiation therapy +/- chemotherapy

- Patients must have measurable contrast-enhancing progressive or recurrent
glioblastoma by magnetic resonance imaging (MRI) imaging within two weeks of starting
treatment; patient must be able to tolerate MRIs

- GROUP B PATIENTS ONLY: Patients must be eligible for surgical resection according to
the following criteria:

- Expectation that the surgeon can resect >= 50% of the Gd-enhancing tumor with
low risk of inducing neurological injury

- Absence of hematologic, cardiac or other medical contraindications to surgery

- Surgery must take place Monday-Thursday with the exception of patients being
treated at Cleveland Clinic/University Hospitals: these patients may undergo
surgery Monday-Friday

- Patients must have a tumor size >= 2.5 cm in diameter in two perpendicular
planes in order to enable correlative studies

- Paraffin embedded tissue must be available from initial surgical resection at
diagnosis (prior to any treatment)

- Patients may have an unlimited number of prior therapy regimens but no prior
gamma-secretase inhibitors

- Patients must have recovered from severe toxicity of prior therapy; the following
intervals from previous treatments are required to be eligible:

- 3 months from the completion of radiation

- 6 weeks from a nitrosourea chemotherapy

- 3 weeks from a non-nitrosourea chemotherapy

- 4 weeks from any investigational (not Food and Drug Administration
[FDA]-approved) agents

- 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., small
molecule targeted therapy, thalidomide, bevacizumab, etc.)

- Patients may not be on an enzyme-inducing anti-epileptic drug (EIAED); if previously
on an EIAED, patient must be off for at least 14 days prior to the first dose of
RO4929097

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be
able to care for himself/herself with occasional help from others)

- Hemoglobin >= 9 g/dL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 4.0 x institutional upper limit of normal

- Creatinine within institutional upper limit of normal OR

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

- Electrolytes - calcium, chloride, magnesium, potassium, phosphorus, sodium within
institutional normal limits

- Patients must be able to provide written informed consent

- Women of childbearing potential and men must use two forms of contraception (i.e.,
barrier contraception and one other method of contraception) starting 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

- PREGNANCY TESTING: 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 prior to treatment start and be required to agree to have the test
repeated within 24 hours prior to the first dose of RO4929097 (serum or urine);
a pregnancy test (serum or urine) will also be administered every 4 weeks
(within 24 hours prior to starting every cycle) if their menstrual cycles are
regular or every 2 weeks if their cycles are irregular while on study; 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 potential of RO4929097 to cause serious or
life-threatening birth defects

- 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

- Patients may not be breast-feeding

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or
bladder; patients with prior malignancies must be disease-free for >= five years

- Patients must have a Mini Mental State Exam score of >= 15

Exclusion Criteria:

- Patients with serious concurrent infection or medical illness, which would jeopardize
the ability of the patient to receive the treatment outlined in this protocol with
reasonable safety, are ineligible

- Patients with prior treatment with gamma-secretase inhibitors are ineligible

- Patients may not be receiving any other investigational agents

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to RO4929097 or other agents used in the study are
ineligible

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

- Patients with the following cardiovascular abnormalities are ineligible: baseline
QTcF > 450 msec (male) or QTcF > 470 msec (female)

- Patients with a requirement for antiarrhythmics or other medications known to prolong
QTc are ineligible

- Patients with a history of being serologically positive for hepatitis B or C, or who
have a history of cirrhosis are ineligible

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

- Patients with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, a history of torsades de pointes or other significant cardiac arrhythmias
other than chronic stable atrial fibrillation, or psychiatric illness/social
situations that would limit compliance with study requirements, are ineligible

- Pregnant women or those who are breastfeeding are ineligible

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- 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