Panobinostat and Letrozole in Treating Patients With Metastatic Breast Cancer

Alliance for Clinical Trials in Oncology

Status and phase

Completed

Phase 2

Phase 1

Conditions

Breast Cancer

Treatments

Drug: letrozole

Other: laboratory biomarker analysis

Other: enzyme-linked immunosorbent assay

Genetic: microarray analysis

Genetic: RNA analysis

Other: immunohistochemistry staining method

Drug: panobinostat

Genetic: reverse transcriptase-polymerase chain reaction

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01105312

NCCTG-N093B

NCI-2011-02035 (Registry Identifier)

CDR0000669300 (Registry Identifier)

Details and patient eligibility

About

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.

Full description

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.

Enrollment

28 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

28 participants in 1 patient group

panobinostat (LBH589) and letrozole

Experimental group

Description:

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.

Treatment: