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

A Randomized Phase II, Open-label Multicenter Trial of Panobinostat Monotherapy in Women With HER2 Positive Locally Recurrent or Metastatic Breast Cancer

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

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