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

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

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.

Study Overview

• Status: Terminated
• Conditions: Stage II Breast Cancer; Stage IIIA Breast Cancer; Estrogen Receptor-positive Breast Cancer; Progesterone Receptor-positive Breast Cancer; HER2-negative Breast Cancer
• Intervention / Treatment: Other: pharmacological study; Procedure: therapeutic conventional surgery; Other: diagnostic laboratory biomarker analysis; Drug: letrozole; Procedure: breast biopsy; Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097

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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama At Birmingham
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee-Womens Hospital of UPMC
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Other: pharmacological study; Other Names: pharmacological studies; Procedure: therapeutic conventional surgery; Other: diagnostic laboratory biomarker analysis; Drug: letrozole; Other Names: CGS 20267; Femara; LTZ; Procedure: breast biopsy; Other Names: biopsy of breast; Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Other Names: RO4929097; R4733

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Shannon Puhalla, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: September 23, 2010
• First Submitted That Met QC Criteria: September 23, 2010
• First Posted (Estimate): September 24, 2010

Study Record Updates

• Last Update Posted (Estimate): September 30, 2013
• Last Update Submitted That Met QC Criteria: September 27, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole; R04929097
• Other Study ID Numbers: NCI-2011-02487 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U01CA099168 (U.S. NIH Grant/Contract); UPCI-09-080; CDR0000683397; UPCI 09-080 (Other Identifier: University of Pittsburgh Cancer Institute); 8554 (Other Identifier: CTEP)