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

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