Panobinostat and Letrozole in Treating Patients With Metastatic Breast Cancer

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.

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