RO4929097 And Exemestane in Treating Pre- and Postmenopausal Patients With Advanced or Metastatic Breast Cancer

Inclusion Criteria:

• Diagnosis of breast cancer

  • Locally advanced or metastatic disease for which curative measures are not effective

    • Relapsed disease with (or within 6 months of discontinuation of) an adjuvant nonsteroidal aromatase inhibitor or tamoxifen
    • Progressive disease during treatment with first- or second-line hormonal therapy that could include a nonsteroidal aromatase inhibitor, tamoxifen, or fulvestrant

  • Recurrent disease

    • No locally recurrent resectable disease

  • Histologically confirmed estrogen receptor-positive (ER+) by IHC

    • Must have ≥ 5% strong staining for ER+ or ≥ 10% weak staining
• Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques OR as ≥ 10 mm by spiral CT scan
• No HER2/neu-positive disease
• No known brain metastases
• Pre- or postmenopausal status
• ECOG performance status 0-1
• Life expectancy ≥ 6 months
• WBC ≥ 3,500/mm^3
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 2 mg/dL
• AST and ALT ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Able to swallow and retain oral medication
• Negative pregnancy test
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for ≥ 12 months after completion of study therapy
• More than 5 years since other invasive cancer except basal or squamous cell cancer of the skin or cervical carcinoma in situ
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 or other agents used in the study
• No history of torsades de pointes
• No malabsorption syndrome or other condition that would interfere with intestinal absorption (e.g., ulcerative colitis)
• Not serologically positive for hepatitis B or C, have a history of liver disease, other forms of hepatitis, or cirrhosis
• No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia

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

  • Ongoing or active infection requiring parenteral antibiotics
  • Impairment of lung function (e.g., chronic obstructive pulmonary disease or lung conditions requiring oxygen therapy)
  • Symptomatic congestive heart failure (NYHA class III-IV heart disease)
  • Unstable angina pectoris, angioplasty, stenting, and or myocardial infarction within the past 6 months
  • Uncontrolled hypertension (systolic BP > 180 mm Hg or diastolic BP > 100 mm Hg on 2 consecutive measurements separated by a 1-week period) despite adequate medical support
  • Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, torsades de pointes, ventricular tachycardia that is symptomatic, or requiring treatment)
  • A requirement for antiarrthymics or other medications known to prolong QTC
  • Uncontrolled diabetes (hyperosmolar state, ketoacidosis, etc.)
  • Psychiatric illness and/or social situations that would limit compliance with study requirements
• No baseline QTcF > 450 msec (male) or > 470 msec (female)
• See Disease Characteristics
• Fully recovered from all previous adverse events
• No prior exemestane for metastatic or recurrent breast cancer, or within the past 6 months in the adjuvant setting
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
• At least 2 weeks since prior radiotherapy
• At least 2 weeks since prior and no other concurrent investigational agents
• No prior exposure to γ-secretase inhibitors
• No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
• No other concurrent CYP3A4 substrates, inducers, or inhibitors
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent anticancer agents or therapies, including chemotherapy, radiotherapy, surgery, immunotherapy, hormonal therapy, or biologic therapy
• No concurrent medications or food that may interfere with the metabolism of gamma-secretase inhibitor RO4929097, including ketoconazole and grapefruit juice
• No concurrent antiarrhythmics or other medications known to prolong QTc