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
I. 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.
II. To assess the safety of this regimen in these patients.
I. To evaluate the pharmacokinetics of this regimen, taking into consideration the induction
of CYP3A4, in these patients.
II. To characterize the pharmacodynamic effects of letrozole prior to and during
administration of RO4929097 with attention to suppression of estradiol and estrone levels.
III. 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.
IV. 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
OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor
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.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD defined as the dose level at which no more than 1 of 6 patients experience a DLT, and the dose below that at which at least 2/6 patients have DLT according to NCI CTCAE version 4.0
University of Pittsburgh
United States: Food and Drug Administration
|University of Pittsburgh||Pittsburgh, Pennsylvania 15261|
|University of Alabama at Birmingham||Birmingham, Alabama 35294-3300|
|Magee-Womens Hospital - University of Pittsburgh Medical Center||Pittsburgh, Pennsylvania 15213|