Study of Panobinostat Monotherapy in Women With v-ERB-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) Positive Locally Recurrent or Metastatic Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Panobinostat - LBH589; Panobinostat - LBH589
Intervention description: Solution for infusion - 25mg/5ml; Hard gelatine capsules - 5mg and 20 mg
Intervention MeSH terms: Panobinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of the study is to assess the benefit of panobinostat monotherapy given either
      orally or i.v. to women with HER2-positive locally recurrent or metastatic breast cancer
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent obtained prior to any study-related procedures

          -  Women ≥ 18 years old

          -  Patients with an ECOG performance status of ≤ 2 assessed within 2 weeks prior to
             randomization

          -  Histologically or cytologically confirmed invasive breast carcinoma with locally
             recurrent or radiological evidence of metastatic disease. Locally recurrent disease
             must not be amenable to resection with curative intent.

          -  Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST)
             guidelines

          -  HER2-positive breast cancer patients by local laboratory testing

          -  Prior trastuzumab-containing regimen (in neoadjuvant and/or adjuvant and/or metastatic
             settings) regardless of whether trastuzumab was given as monotherapy or in combination
             with chemotherapy. Any number of prior trastuzumab regimens is acceptable. Additional
             treatment with lapatinib after or before trastuzumab treatment is permitted, but not
             mandatory.

          -  Radiological evidence of relapse or disease progression while on trastuzumab (or
             lapatinib) or within 12 months of the last dose of adjuvant trastuzumab.

          -  Complete radiology and tumor assessment within 4 weeks prior to randomization:

               -  Chest: Computed Tomography(CT) scan with intravenous contrast if the contrast is
                  not medically contraindicated or Magnetic Resonance Imaging(MRI)

               -  Abdomen: CT scan with intravenous and oral contrast if the contrast is not
                  medically contraindicated or MRI

               -  Brain: CT scan or MRI

               -  Bone: Whole body Bone Scintigraphy

          -  Up to 2 prior cytotoxic chemotherapy regimens, in addition to neo-adjuvant and
             adjuvant, for treatment of metastatic or locally recurrent breast cancer (including
             those cytotoxic chemotherapy treatments in combination with trastuzumab and/or
             lapatinib)

          -  Patients must meet the following laboratory criteria within 2 weeks (14 days) prior to
             randomization:

          -  Hematology

          -  Neutrophil count of > 1200/mm3

          -  Platelet count of > 100,000/mm3

          -  Hemoglobin ≥ 90 g/L

          -  Biochemistry

          -  Aspartate aminotransferase/glutamic oxaloacetic transaminase (AST/SGOT) and alanine
             aminotransferase/glutamic pyruvic transaminase(ALT/SGPT) ≤ 2.5 x upper limit of normal
             (ULN) or ≤ 5.0 x ULN if the transaminase elevation is due to disease involvement

          -  Serum bilirubin ≤ 1.5 x ULN

          -  Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 mL/min

          -  Serum potassium, sodium, magnesium, phosphorus, total calcium (corrected for serum
             albumin) or ionized calcium within normal limits for the institution

          -  Serum albumin ≥ Lower Limit of Normal(LLN) or 30g/L

          -  Clinically euthyroid function (thyroid-stimulating hormone (TSH) and free T4).
             (Patients are permitted to receive thyroid hormone supplements to treat underlying
             hypothyroidism).

          -  Left Ventricular Ejection Fraction(LVEF) assessment (2-D echocardiogram or Multiple
             Uptake Gated Acquisition Scan(MUGA) scan) performed within 6 weeks prior to
             randomization, showing a LVEF value > 50%

          -  Electrocardiogram performed within 1 week prior to randomization (details about
             findings on the Electrocardiogram that are not acceptable for participating in the
             study are reported in the Exclusion criteria section)

          -  Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
             within 7 days prior to randomization and agree to appropriate method of pregnancy
             prevention

        Exclusion Criteria:

          -  Prior Histone Deacetylase(HDAC),Deacetylase(DAC), Heat Shock Protein 90 (HSP90)
             inhibitors or valproic acid for the treatment of cancer

          -  Patients who will need valproic acid for any medical condition during the study or
             within 5 days prior to first panobinostat treatment

          -  Patients who have received prior chemotherapy or investigational agent within the last
             4 weeks prior to randomization (6 weeks for nitrosoureas and mitomycin; 2 weeks for
             capecitabine)

          -  Patients who have received prior radiotherapy to ≥ 25% of the bone marrow within the
             last 4 weeks prior to randomization; local radiotherapy is allowed however all
             recently irradiated lesions should not be included in the measurable disease
             assessment

          -  Patients who have received prior investigational agents within the last 4 weeks prior
             to randomization

          -  Patients with unresolved diarrhea ≥CTCAE (National Cancer Institute Common Terminology
             Criteria for Adverse Events) grade 1

          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of oral panobinostat

          -  History of cardiac dysfunction including any one of the following:

          -  Complete left bundle branch block or necessity for a permanent cardiac pacemaker or
             congenital long QT syndrome or history or presence of ventricular tachyarrhythmias or
             clinically significant resting bradycardia (<50 beats per minute) or QTcF > 450 msec
             on screening electrocardiogram(ECG) or right bundle branch block and left anterior
             hemiblock (bifascicular block)

          -  Presence of unstable atrial fibrillation (ventricular response rate >100 bpm).
             Patients with stable atrial fibrillation are allowed in the study provided they do not
             meet the other cardiac exclusion criteria

          -  Previous history angina pectoris or acute myocardial infarction(MI) within 6 months of
             randomization

          -  Congestive heart failure (New York Heart Association functional classification III-IV)

          -  Other clinically significant heart disease (e.g. cardiomyopathy, cardiac artery
             disease, uncontrolled hypertension, or history of poor compliance with an
             antihypertensive regimen)

          -  Acute or chronic liver or renal disease

          -  Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
             diabetes mellitus, active untreated or uncontrolled infection, chronic obstructive or
             chronic restrictive pulmonary disease including dyspnoea at rest from any cause) that
             could cause unacceptable safety risks or compromise compliance with the protocol

          -  Concomitant use of drugs with a risk of causing torsades de pointes where such
             treatments cannot be discontinued or switched to a different medication prior to
             starting study drug

          -  Brain metastases, unless patient randomized on study at least 90 days from completion
             of brain radiotherapy and / or surgery without radiologic or functional evidence of
             progressive brain metastases, and off corticosteroids above the dose of 7.5 mg
             prednisone or equivalent; No concurrent radiotherapy for brain metastasis is allowed

          -  Clinically significant third space fluid accumulation

          -  Concurrent bisphosphonates unless if initiated prior to study entry (at least 4 weeks
             before study randomization)

          -  Pregnant (i.e., positive beta-human chorionic gonadotropin test) or breast feeding

          -  Unable to swallow oral medications

          -  Not willing to use a double barrier method of non-hormonal birth control.
             Contraception must be used during the study and for 90 days after last dose of study
             treatment.

          -  Patients with any significant history of non-compliance to medical regimens or with
             inability to grant a reliable informed consent