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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Progesterone Receptor-positive Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer

Intervention / Treatment
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* Drug: letrozole
* Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
* Procedure: therapeutic conventional surgery
* Procedure: breast biopsy
* Other: diagnostic laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: letrozole<br> <br> * Other names: LTZ;Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097<br> <br> * Other names: RO4929097;Procedure: therapeutic conventional surgery<br> <br> Procedure: breast biopsy<br> <br> * Other names: biopsy of breast;Other: diagnostic laboratory biomarker analysis<br> <br> Other: pharmacological study<br> <br> * Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | Baseline | 
| Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | 21 days | 
| Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | 42 days | 
| Measurement of NOTCH 1 and 4, activated NOTCH (ICN), Hey 1 and NOTCH ligands (DLL4 and Jagged 1) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | At time of surgery | 
| Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. For the analysis of the gene expression data, the overall false discovery rate (FDR), which is defined as the expected portion of false positives, will be controlled at 20% to generate a list of genes for further investigation. | Baseline | 
| Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. For the analysis of the gene expression data, the overall FDR, which is defined as the expected portion of false positives, will be controlled at 20% to generate a list of genes for further investigation. | 21 days | 
| Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. For the analysis of the gene expression data, the overall FDR, which is defined as the expected portion of false positives, will be controlled at 20% to generate a list of genes for further investigation. | 42 days | 
| Genomic analysis of RNA transcriptome, mirco-RNA transcriptome, and DNA methylation | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. For the analysis of the gene expression data, the overall FDR, which is defined as the expected portion of false positives, will be controlled at 20% to generate a list of genes for further investigation. | At time of surgery | 
| Measurement of cell proliferation (Ki-67) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | Baseline | 
| Measurement of cell proliferation (Ki-67) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | 21 days | 
| Measurement of cell proliferation (Ki-67) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | 42 days | 
| Measurement of cell proliferation (Ki-67) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | At time of surgery | 
| Measurement of appoptosis (TUNEL and activated caspase) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | Baseline | 
| Measurement of appoptosis (TUNEL and activated caspase) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | 21 days | 
| Measurement of appoptosis (TUNEL and activated caspase) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | 42 days | 
| Measurement of appoptosis (TUNEL and activated caspase) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | At time of surgery | 
| Measurement of angiogenesis (VEGF and CD31) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | Baseline | 
| Measurement of angiogenesis (VEGF and CD31) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | 21 days | 
| Measurement of angiogenesis (VEGF and CD31) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | 42 days | 
| Measurement of angiogenesis (VEGF and CD31) | All measurements are continuous. Descriptive statistics will be calculated to summarize change of each measurement from the baseline value. A two-sided Wilcoxon signed rank test will be used to compare each measurement at a specific time to the baseline value. | At time of surgery |