RO4929097 And Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer

Inclusion Criteria:

• Must meet 1 of the following criteria:

  • Histologically or cytologically confirmed breast or other cancer, such as lung cancer, melanoma, etc., with newly diagnosed metastatic disease to the brain (phase I)

    • Patients who have available systemic therapeutic options with a demonstrated survival benefit will not be eligible

  • Histologically or cytologically confirmed breast cancer with newly diagnosed metastatic disease to the brain

    • Estrogen receptor-negative disease (phase II)
• Patients with newly diagnosed brain metastases who have received therapeutic regimens with well-characterized, delayed toxicity (e.g., hematologic toxicity observed following carmustine or mitomycin C) will not receive experimental therapy until the patient has adequately recovered from all drug-related toxicities
• Measurable disease in the brain, defined as >= 1 lesion that can be accurately measured in >= 2 dimensions (longest diameter and its longest perpendicular diameter to be recorded)
• Tumor HER2/neu status positive or negative
• No leptomeningeal metastases
• Menopausal status not specified

• Karnofsky performance status (PS) 70-100%

  • Recursive Partitioning Analysis (RPA) class I or II
  • A small feasibility cohort of 10 RPA class III (Karnofsky PS < 70%) allowed, however they will not be included in the efficacy analysis
• WBC >= 3,000/mm^3
• ANC >= 1,000/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 9 g/dL
• Total bilirubin normal
• AST (SGOT) =< 2.5 times upper limit of normal (ULN)
• ALT (SGPT) =< 2.5 times ULN
• Creatinine normal OR creatinine clearance >= 60 mL/min
• Fertile patients must use 2 forms of effective contraception (i.e., barrier contraception and one other method of contraception) for the duration of study and for >= 12 months after treatment
• Negative pregnancy test
• Not pregnant or nursing
• Able to swallow pills
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097
• No malabsorption syndrome or other condition that would interfere with intestinal absorption
• Not known to be serologically positive for hepatitis A, B, or C, or have a history of liver disease, other forms of hepatitis, or cirrhosis
• No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia despite adequate electrolyte supplementation
• No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, and hypokalemia

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

  • Ongoing or active infection
  • Symptomatic congestive heart failure (NYHA class III or IV)
  • Unstable angina pectoris
  • A history of torsades de pointes or other significant cardiac arrhythmias
  • Stable atrial fibrillation
  • Psychiatric illness and/or social situations that would limit compliance with study requirements
• Baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
• No requirement for antiarrhythmics or other medications known to prolong QTc

• The use of oral or intravenous corticosteroids is allowed as needed for symptomatic management of cerebral edema

  • Typical doses of dexamethasone include 4 mg, up to four times daily, administered either orally or intravenously

• Any type or number of prior therapies allowed

  • No prior therapy with Notch inhibitors
  • No prior cranial radiation
  • Therapy-naive patients allowed
• At least 14 days since any prior experimental therapy, chemotherapy, or radiotherapy and recovered to < grade 2 toxicities
• No other concurrent investigational agents
• No concurrent combination antiretroviral therapy in HIV-positive patients
• No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
• No concurrent medications that are generally accepted by the QTdrugs.org Advisory Board to carry a risk for Torsades de Pointes, including antiemetics
• No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4
• No concurrent medications or food that may interfere with the metabolism of gamma-secretase inhibitor RO4929097, including ketoconazole and grapefruit juice
• No other concurrent anticancer agents or therapies