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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

TERMINATED

Clinical Phase

PHASE1

Total Enrollment

28 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-11-30

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

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

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

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.

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

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

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

Review each arm or cohort in the study, along with the interventions and objectives associated with them.

Arm I

CGS 20267 Femara LTZ R4733 RO4929097 biopsy of breast pharmacological studies

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

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

Minimum Eligible Age

18 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Responsible Party

Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.

Responsibility Role SPONSOR

Principal Investigators

Learn about the lead researchers overseeing the trial and their institutional affiliations.

Shannon Puhalla

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

Explore where the study is taking place and check the recruitment status at each participating site.

University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status

Magee-Womens Hospital of UPMC

Pittsburgh, Pennsylvania, United States

Site Status

University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, United States

Site Status

Countries

Review the countries where the study has at least one active or historical site.

United States