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