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

OBJECTIVES:

Primary

- To establish the maximum-tolerated dose and the recommended phase II dose of
gamma-secretase inhibitor RO4929097 (RO4929097) in combination with letrozole in
post-menopausal women with hormone receptor-positive stage II or III breast cancer.

- To assess the safety of this regimen in these patients.

Secondary

- To evaluate the pharmacokinetics of this regimen, taking into consideration the
induction of CYP3A4, in these patients.

- To characterize the pharmacodynamic effects of letrozole prior to and during
administration of RO4929097 with attention to suppression of estradiol and estrone
levels.

- To describe the pharmacodynamic effects of letrozole with or without RO4929097 on the
NOTCH pathway, proliferation, angiogenesis, stromal cell infiltration/pathways, and
comprehensive genomic analysis in tumor tissue of these patients.

- To describe the response, including clinical complete or partial objective response,
pathological complete response, and attainment of pathologic stage 0 or I status in
these patients.

OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor RO4929097
(RO4929097).

Patients receive oral letrozole once daily on days 1-21. Beginning in course 2, patients
also receive oral RO4929097 on days 1-3, 8-10, and 15-18. Treatment repeats every 21 days
for 6 courses in the absence of disease progression or unacceptable toxicity.

Beginning 1 week after completion of neoadjuvant therapy, patients undergo surgery or tumor
biopsy. Patients continue to receive oral letrozole once daily during surgery and for an
additional 4 weeks.

Blood and tumor tissue samples are collected at baseline and periodically during study for
pharmacokinetics, pharmacodynamics, and correlative studies.

After completion of study therapy, patients are followed up for 1 month and then every 6
months for 5 years.