A Phase Ib Neoadjuvant Study of the Gamma Secretase Inhibitor (RO4929097) in Combination With the Aromatase Inhibitor Letrozole in Post-Menopausal Women With Stage II/III Hormone Receptor-Positive 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