Phase 1 Trial of RO4929097 in Combination With Standard Radiotherapy and Temozolomide for Newly Diagnosed Malignant Glioma: A Pharmacokinetic and Pharmacodynamic Study

Inclusion Criteria:

- Newly diagnosed glioblastoma, including any of the following subtypes:

- Glioblastoma

- Anaplastic astrocytoma

- Gliosarcoma

- Other malignant gliomas

- No pure anaplastic oligodendroglioma

- Patients with presumed malignant glioma based on radiographic assessment may be
enrolled onto the protocol without histological confirmation provided they meet the
following additional eligibility criteria:

- 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 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

- If after the on-protocol surgery the patient is found not to meet histological
criteria, the patient will be removed from the study and replaced

- Underwent prior stereotactic biopsy or incomplete surgical resection

- Indication for additional debulking surgery

- No contraindication to a brain surgical procedure

- Patients who are not candidates for surgical resection may be allowed (except
brain surgery)

- ECOG performance status 0-1 (Karnofsky 70-100%)

- Life expectancy > 2 months

- Leukocytes > 3,000/mm^3

- ANC > 1,500/mm^3

- Platelet count > 100,000/mm^3

- Hemoglobin ≥ 9 g/dL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT < 2.5 times ULN

- Creatinine normal OR creatinine clearance > 60 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use two forms of effective contraception for 4 weeks before,
during, and 12 months after completion of study therapy

- Able to swallow tablets

- QTc ≤ 450 msec in males and a QTc ≤ 470 msec in females

- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to gamma-secretase inhibitor RO4929097 or other agents used in
this study

- No malabsorption syndrome or other condition that would interfere with intestinal
absorption

- No known history of hepatitis B or C or history of liver disease or other forms of
hepatitis or cirrhosis

- No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia,
hyponatremia, hypophosphatemia, or hypokalemia defined as less than the lower limit
of normal for the institution, despite adequate electrolyte supplementation

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- History of torsades de pointes or other significant cardiac arrhythmias

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

- No requirement for antiarrhythmics or other medications known to prolong QTc

- No concurrent medications or food that may interfere with the metabolism of RO4929097
including ketoconazole and grapefruit

- Must be recovered to < grade 2 toxicities related to prior therapy

- No prior chemotherapy, radiotherapy, biological, or experimental therapy for glioma

- No prior radiotherapy to the brain, head, or neck

- No combination antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No concurrent medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)

- Patients on concurrent medications that are strong inducers and/or inhibitors of
CYP3A4 should switched to alternative medications to minimize any potential risk

- No concurrent hypofractionated radiotherapy or radiosurgery