Panobinostat and Letrozole in Treating Patients With Metastatic Breast Cancer

Study Overview
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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.

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.

Official Title
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Phase I/II Study of Panobinostat (LBH589) and Letrozole in Patients With Triple Negative Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: letrozole
* Drug: panobinostat
* Genetic: RNA analysis
* Genetic: microarray analysis
* Genetic: reverse transcriptase-polymerase chain reaction
* Other: enzyme-linked immunosorbent assay
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: panobinostat (LBH589) and letrozole<br>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. | Drug: letrozole<br> <br> Drug: panobinostat<br> <br> Genetic: RNA analysis<br> <br> Genetic: microarray analysis<br> <br> Genetic: reverse transcriptase-polymerase chain reaction<br> <br> Other: enzyme-linked immunosorbent assay<br> <br> Other: immunohistochemistry staining method<br> <br> Other: laboratory biomarker analysis<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated Dose (Phase I) | MTD is defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6> new patients). If dose-limiting toxicity (DLT) is not seen in any of the 3 patients, 3 new patients will be accrued and treated at the next higher dose level. If DLT are seen in 2 or 3 of 3 patients treated at a given dose level, then the next 3 patients will be treated at the next lower dose level, if only 3 patients were enrolled and treated at this lower dose level. The number of DLT's will be reported here. | Up to 2.5 months | 
| Response Rate (Phase II) | A confirmed response is defined to be a CR or PR (as determined by RECIST (version 1.1 criteria) noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Response will be evaluated using all cycles of treatment. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable for response. A CR is defined as: All of the following must be true: Disappearance of all non-nodal target lesions Each target lymph node must have reduction in short axis to <1.0 cm A PR is defined as: At least a 30% decrease in the sum of the longest diameters of the non-nodal target lesions and the short axes of the target lymph nodes taking as reference the BSD (Section 11.41) | from baseline up to 5 years post-registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Time (Phase II) | Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier | from baseline up to 5 years post-registration | 
| Time-to-disease Progression (Phase II) | Time-to-disease progression (TTP) is defined as the time from registration to documentation of disease progression. If a patient dies without a documentation of disease progression, the patient will be considered to have had tumor progression at the time of their death unless there is sufficient documented evidence to conclude no progression occurred prior to death. The distribution of TTP will be estimated using the method of Kaplan-Meier. Progression is defined as at least one of the following: At least one new malignant lesion or a lymph node whose short axis has increased to >1.5 cm At least a 20% increase in the sum of diameters of target lesions taking as reference the MSD. In addition, the sum must also demonstrate an absolute increase of at least 0.5 cm | from baseline up to 6 months | 
| Progression-free Survival (Phase II) | Progression-free survival (PFS) is defined as the time from registration to progression or death due to any cause. PFS at 6 months will be estimated. The distribution of PFS will be estimated using the method of Kaplan-Meier. | from baseline up to 6 months | 
| Duration of Response (Phase II) | Duration of response is defined for all evaluable patients who have achieved a confirmed response as the date at which the patient's objective status is first noted to be a CR or PR to the earliest date progression is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier. | from baseline up to 5 years post-registration | 
| Clinical Benefit Rate | Clinical benefit rate will be estimated by the total number of patients with an objective status of CR, PR, or SD for duration of at least 6 months divided by the total number of evaluable patients. All evaluable patients will be used for this analysis. Exact binomial 95% confidence intervals for the true clinical benefit rate will be calculated. | from baseline up to 6 months | 
| Time to Treatment Failure | Time to treatment failure (TTF) is defined as the time from the date of registration to the date at which the patient is removed from treatment due to progression, unacceptable adverse events, or refusal. The distribution of TTF will be estimated using the method of Kaplan-Meier | from baseline up to 5 years post-registration | 
| Confirmed Response Rate (Phase I) | A confirmed response is defined to be a CR or PR (as determined by RECIST criteria) noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Response will be evaluated using all cycles of treatment. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable for response. The number of confirmed responses will be reported here. | from baseline up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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male breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, HER2-negative breast cancer, HER2-positive breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, triple-negative breast cancer, recurrent breast cancer, stage IV breast cancer