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
Overview
- Phase
- Phase 1
- Intervention
- letrozole
- Conditions
- Estrogen Receptor-positive Breast Cancer
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 28
- Locations
- 3
- Primary Endpoint
- 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
- Status
- Terminated
- Last Updated
- 12 years ago
Overview
Brief Summary
This phase I trial is studying the side effects and best dose of RO4929097 when given together with letrozole in treating post-menopausal women with stage II or stage III breast cancer. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving RO4929097 together with letrozole may be an effective treatment for breast cancer.
Detailed Description
PRIMARY OBJECTIVES: 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. SECONDARY OBJECTIVES: 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 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.
Investigators
Eligibility Criteria
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
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I
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.
Intervention: letrozole
Arm I
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.
Intervention: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Arm I
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.
Intervention: therapeutic conventional surgery
Arm I
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.
Intervention: breast biopsy
Arm I
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.
Intervention: diagnostic laboratory biomarker analysis
Arm I
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.
Intervention: pharmacological study
Outcomes
Primary Outcomes
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
Time Frame: 21 days
Secondary Outcomes
- Measurement of cell proliferation (Ki-67)(At time of surgery)
- Measurement of appoptosis (TUNEL and activated caspase)(At time of surgery)
- Measurement of angiogenesis (VEGF and CD31)(At time of surgery)
- Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1)(At time of surgery)
- Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation(At time of surgery)