RO4929097 and Letrozole in Treating Post-Menopausal Women With Hormone Receptor-Positive Stage II or Stage III Breast Cancer

Inclusion Criteria:

• Pathologically confirmed invasive breast cancer

  • Stage II or III disease (T2-T3, N0-2)

    • No N3, T4 disease

  • Estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+)

    • H score ≥ 10 or positivity ≥ 10%
  • HER2 negative as determined by IHC (1 or 2+) or FISH (< 2.0+)
• Bilateral disease allowed as long as all tumors are ER+ and ≥ 1 is T2-T3

• Patient must have disease that is palpable on physical exam and able to be imaged via breast ultrasound

  • Defined as ≥ 1 T2 tumor > 2 cm
  • Multifocal disease allowed provided that ≥ 1 of the tumors is > 2 cm
• No metastatic disease by CT scans of the chest, abdomen, and pelvis, a PET/CT bone scan, or nuclear medicine bone scan
• No inflammatory breast cancer or presence of breast tumor cells in the dermal lymphatics of the breast

• Post-menopausal meeting 1 of the following criteria:

  • Bilateral oophorectomy
  • Age ≥ 50 years and amenorrheic for > 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression (spontaneous amenorrhea)
• ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)
• Life expectancy > 3 months
• ANC ≥ 1,000/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9 g/dL
• Total bilirubin normal
• AST and ALT ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Baseline QTcF ≤ 470 msec
• 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 malabsorption syndrome or other condition that would interfere with intestinal absorption
• Able to swallow tablets
• Not 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 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 arrhythmia other than chronic, stable atrial fibrillation
  • Psychiatric illness and/or social situations that would limit compliance with study requirements
• Recovered to < grade 2 CTCAE toxicities related to prior therapy

• No prior chemotherapy, hormonal therapy, radiotherapy, or biological therapy for breast cancer

  • Prior treatment for non-melanoma skin cancer or carcinoma in situ of the cervix allowed
  • No prior hormone therapy for ductal carcinoma in situ (DCIS)
• No other concurrent investigational agents
• No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)

• No concurrent medications that are strong inducers and/or inhibitors or substrates of CYP3A4

  • Switching to alternative medications allowed
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent antiarrhythmics or other medications known to prolong QTc
• No other concurrent anticancer agents or therapies
• No concurrent grapefruit juice