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Panobinostat and Letrozole in...

Panobinostat and Letrozole in Treating Patients With Metastatic Breast Cancer

Last Updated: 2017-06-27

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

28 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-09-30

Study Completion Date

2013-09-03

Brief Summary

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RATIONALE: Panobinostat 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 lowering the amount of estrogen the body makes. Giving panobinostat together with letrozole may be an effective treatment for breast cancer.

PURPOSE: This phase I/II trial is studying the side effects and best dose of panobinostat when given together with letrozole and to see how well it works in treating patients with metastatic breast cancer.

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Detailed Description

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OBJECTIVES:

Primary Objectives

* To determine the maximum-tolerated dose of panobinostat in combination with letrozole in patients with metastatic breast cancer. (Phase I)
* To determine the safety of this regimen in these patients. (Phase I)
* To assess the confirmed response rate and safety profile of this regimen in patients with triple-negative disease. (Phase II)

Secondary Objectives

* To assess the therapeutic effects of this regimen in these patients. (Phase I)
* To examine the duration of response, clinical benefit rate, and time to treatment failure in patients treated with this regimen. (Phase II)
* To examine the time to progression, progression-free survival, and overall survival of patients treated with this regimen. (Phase II)
* To examine the estrogen, progesterone, and HER2 status of tumor at primary compared to metastatic tissue, and possibly after treatment. (exploratory)
* To bank paraffin-embedded tissue blocks/slides and blood products for future studies. (exploratory)
* To determine expression levels of biomarkers of treatment response (i.e., ER, PR, aromatase, NFkappaB, Ki67, and Caspase 3) in accessible tumors pre- and post-therapy via immunohistochemistry. (exploratory)
* To determine whether ELISA for KLK11 in serum can be used as marker of activity of letrozole and LBH589. (exploratory) The Phase I portion of this study closed and the Phase II portion of the study opened as per NCCTG Addendum 6, effective January 23, 2012.

OUTLINE: This is a multicenter, phase I dose-escalation study of panobinostat followed by a phase II study. (The Phase I portion of this study closed and the Phase II portion of the study opened as per NCCTG Addendum 6, effective January 23, 2012.)

Patients receive oral panobinostat once daily on days 1, 3, and 5 in weeks 1-4 and oral letrozole once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Tumor tissue and blood samples are collected and banked for future biomarker and other analysis. Samples are also analyzed for biomarkers utilizing immunohistochemistry, microarray, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA).

After completion of study therapy, patients are followed up every 3-6 months for up to 5 years.

Conditions

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Breast Cancer

Study Design

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Allocation Method

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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panobinostat (LBH589) and letrozole

Each patient will receive panobinostat (LBH589) and letrozole. Patients will be administered LBH589 PO, 3 days per week for a total of 4 weeks. Patients will also be administered letrozole 2.5 mg PO Days 1-28 every 4 weeks. There are two phases of the study. The first phase determines the maximum tolerated dose for LBH589 in combination with letrozole. The second phase is to assess and confirm the response rate and safety profile of LBH589 in combination with letrozole.

Group Type EXPERIMENTAL

letrozole

Intervention Type DRUG

panobinostat

Intervention Type DRUG

RNA analysis

Intervention Type GENETIC

microarray analysis

Intervention Type GENETIC

reverse transcriptase-polymerase chain reaction

Intervention Type GENETIC

enzyme-linked immunosorbent assay

Intervention Type OTHER

immunohistochemistry staining method

Intervention Type OTHER

laboratory biomarker analysis

Intervention Type OTHER

Interventions

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letrozole

Intervention Type DRUG

panobinostat

Intervention Type DRUG

RNA analysis

Intervention Type GENETIC

microarray analysis

Intervention Type GENETIC

reverse transcriptase-polymerase chain reaction

Intervention Type GENETIC

enzyme-linked immunosorbent assay

Intervention Type OTHER

immunohistochemistry staining method

Intervention Type OTHER

laboratory biomarker analysis

Intervention Type OTHER

Eligibility Criteria

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Inclusion Criteria

DISEASE CHARACTERISTICS:

* Histologically confirmed breast cancer

* Metastatic disease amenable to biopsy
* Unresected tumor with no intention to undergo resection during study
* Archival tissue from the primary diagnosis or fresh biopsy from metastatic cancer site required
* Measurable or non-measurable disease for phase I study (The Phase I portion of this study closed and the Phase II portion of the study opened as per NCCTG Addendum 6, effective January 23, 2012.)

* Measurable disease only for phase II study
* Available tumor estrogen (ER), progesterone (PR), and HER2 status from metastatic site tested by IHC or FISH OR results from the original tumor diagnosis

* Any ER, PR, or HER2 level (positive or negative) acceptable (phase I)
* Triple-negative disease only (phase II)

* ER and PR negative defined as ≤ 1% by IHC
* HER2 negative

* Patients with triple-negative breast cancer allowed provided there is clinical or radiographic evidence of tumor progression in the adjuvant or metastatic setting
* No patients whose disease can be treated with known standard therapy that is potentially curative or definitely capable of extending life expectancy
* No known CNS metastasis
* Hormone-receptor status:

* ER and PR positive or negative (phase I)
* ER and PR negative (phase II)

PATIENT CHARACTERISTICS:

* ECOG performance status 0-1 (phase I) or 0-2 (phase II)
* Postmenopausal defined by 1 of the following:

* ≥ 60 years of age
* ≥ 45 years of age with last menstrual period ≥ 12 months prior and estradiol and follicle-stimulating hormone levels in postmenopausal range
* Bilateral oophorectomy
* Life expectancy ≥ 12 weeks
* ANC ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Total bilirubin normal
* ALT and AST ≤ 3 times upper limit of normal (ULN) (≤ 5 times ULN if due to liver metastasis)
* Serum creatinine ≤ 1.5 times ULN
* TSH normal (thyroid hormone supplements allowed for patients with hypothyroidism)
* Not pregnant or nursing
* Fertile patients must use effective contraception
* Willing to return to Mayo Clinic or NCCTG institution (phase II) for follow-up
* Willing to provide blood samples for correlative research purposes
* No uncontrolled or intercurrent illness including, but not limited to, any of the following:

* Ongoing or active infection
* Symptomatic congestive heart failure
* Unstable angina pectoris
* Cardiac arrhythmia
* Psychiatric illness and/or social situations that would limit compliance with study requirements
* No NYHA class III or IV cardiovascular disease
* No known seizure disorder
* No co-morbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
* No immunocompromised patients, including patients known to be HIV positive

* Immunocompromised patients due to the use of corticosteroids allowed
* No malignancy within the past 5 years except for nonmelanoma skin cancer or carcinoma in situ of the cervix
* No history of myocardial infarction ≤ 6 months
* No congenital long QT syndrome or QTcF\>450 msec, including:

* Complete left bundle block or use of a permanent cardiac pacemaker, history or presence of ventricular tachyarrhythmias, clinically significant resting bradycardia (\<50 beats per minute)
* Right bundle branch block + left anterior hemiblock (bifascicular block)
* No congestive heart failure requiring use of maintenance therapy for life-threatening ventricular arrhythmias

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* More than 4 weeks since prior chemotherapy or radiotherapy and fully recovered

* No radiotherapy to \> 25 % of bone marrow
* Prior treatments allowed (phase II):

* 0 or 1 prior chemotherapy regimens for breast cancer
* ≤ 2 prior aromatase-inhibitor regimens (including letrozole)
* Not currently receiving treatment in a different clinical study in which investigational procedures are performed or investigational therapies are administered
* No other concurrent investigational agent for the primary neoplasm
* No concurrent CYP3A4 inhibitors or inducers

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Winston Tan, MD, FACP

Role: STUDY_CHAIR

Mayo Clinic

Locations

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Mayo Clinic Scottsdale

Scottsdale, Arizona, United States

Site Status

Contra Costa Regional Medical Center

Martinez, California, United States

Site Status

El Camino Hospital Cancer Center

Mountain View, California, United States

Site Status

Bay Area Breast Surgeons, Incorporated

Oakland, California, United States

Site Status

CCOP - Bay Area Tumor Institute

Oakland, California, United States

Site Status

Larry G Strieff MD Medical Corporation

Oakland, California, United States

Site Status

Tom K Lee, Incorporated

Oakland, California, United States

Site Status

Pismo Beach, California, United States

Site Status

Doctors Medical Center - San Pablo Campus

San Pablo, California, United States

Site Status

Aurora Presbyterian Hospital

Aurora, Colorado, United States

Site Status

Boulder Community Hospital

Boulder, Colorado, United States

Site Status

Penrose Cancer Center at Penrose Hospital

Colorado Springs, Colorado, United States

Site Status

St. Anthony Central Hospital

Denver, Colorado, United States

Site Status

Porter Adventist Hospital

Denver, Colorado, United States

Site Status

Presbyterian - St. Luke's Medical Center

Denver, Colorado, United States

Site Status

St. Joseph Hospital

Denver, Colorado, United States

Site Status

Rose Medical Center

Denver, Colorado, United States

Site Status

Swedish Medical Center

Englewood, Colorado, United States

Site Status

Poudre Valley Hospital

Fort Collins, Colorado, United States

Site Status

Front Range Cancer Specialists

Fort Collins, Colorado, United States

Site Status

North Colorado Medical Center

Greeley, Colorado, United States

Site Status

Sky Ridge Medical Center

Lone Tree, Colorado, United States

Site Status

Hope Cancer Care Center at Longmont United Hospital

Longmont, Colorado, United States

Site Status

McKee Medical Center

Loveland, Colorado, United States

Site Status

St. Mary - Corwin Regional Medical Center

Pueblo, Colorado, United States

Site Status

North Suburban Medical Center

Thornton, Colorado, United States

Site Status

Exempla Lutheran Medical Center

Wheat Ridge, Colorado, United States

Site Status

Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center

Hartford, Connecticut, United States

Site Status

Florida Hospital Memorial Medical Center

Daytona Beach, Florida, United States

Site Status

Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital

Fort Lauderdale, Florida, United States

Site Status

Memorial Cancer Institute at Memorial Regional Hospital

Hollywood, Florida, United States

Site Status

Mayo Clinic - Jacksonville

Jacksonville, Florida, United States

Site Status

Ella Milbank Foshay Cancer Center at Jupiter Medical Center

Jupiter, Florida, United States

Site Status

CCOP - Mount Sinai Medical Center

Miami Beach, Florida, United States

Site Status