Study of Panobinostat Monotherapy in Women With HER2-negative Locally Recurrent or Metastatic Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Panobinostat
Intervention description: Hard gelatine capsule - 5mg and 20mg
Intervention MeSH terms: Panobinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 54.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of the study is to assess the benefit of oral panobinostat monotherapy given to
      women with HER2-negative 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 (14 days)
             prior to registration

          -  Histologically or cytologically confirmed breast cancer with locally recurrent or
             radiological evidence of metastatic disease. Locally recurrent disease must not be
             amenable to resection with curative intent.

          -  Measurable disease per RECIST (Response Evaluation Criteria in Solid Tumor) guidelines

          -  HER2-negative patients by local laboratory testing (IHC 0 or 1+ staining, IHC 2+
             staining but in situ hybridization negative, or in situ hybridization negative).

          -  ER and PgR testing from a local laboratory is required prior to patient registration

          -  For Arm I: at least two lines of prior endocrine therapy (in adjuvant and/or
             metastatic settings) are required. Up to two prior cytotoxic chemotherapies are
             allowed in the metastatic setting (prior adjuvant and neoadjuvant chemotherapy is
             allowed).

          -  For Arm II: up to 2 prior cytotoxic chemotherapy regimens for treatment of metastatic
             or locally recurrent breast cancer are allowed.

          -  Complete radiological tumor measurement within 4 weeks (28 days) prior to
             registration:

               -  Chest: CT scan with intravenous contrast if the contrast is not medically
                  contraindicated or MRI

               -  Abdomen: CT scan with intravenous or oral contrast if the contrast is not
                  medically contraindicated or MRI

               -  Brain: CT scan or MRI

               -  Bone: Whole body Bone Scintigraphy

          -  Patients must meet the following laboratory criteria within 2 weeks (14 days) prior to
             registration:

          -  Hematology

          -  Neutrophil count of > 1200/mm3

          -  Platelet count of > 100,000/mm3

          -  Hemoglobin ≥ 90 g/L

          -  Biochemistry

          -  AST/SGOT and 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, and calcium within normal limits for
             the institution

          -  Serum albumin ≥ LLN or 30g/L

          -  Clinically euthyroid function (TSH and free T4). (Patients are permitted to receive
             thyroid hormone supplements to treat underlying hypothyroidism).

          -  LVEF assessment (2-D echocardiogram or MUGA scan) performed within 6 weeks prior to
             registration, showing a LVEF value > 50%

          -  Electrocardiogram performed within 1 week prior to registration (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 registration and agree to appropriate method of pregnancy
             prevention.

          -  Patient should have an archival tumor sample available for confirmation of HER2,
             Estrogen and Progesterone status by the central lab.

        Exclusion Criteria:

          -  Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer

          -  Patients who need valproic acid for any other medical condition during the study or
             within 5 days prior to first panobinostat treatment

          -  Patients who have received prior systemic anti-cancer therapy (cytotoxic chemotherapy,
             endocrine therapy, targeted therapy, monoclonal antibody or biologic therapy) or
             investigational agent within the last 4 weeks prior to registration (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 registration; 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 registration

          -  Patients with unresolved diarrhea ≥CTCAE 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 obligate use of a 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
             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 MI within 6 months of registration

          -  Congestive Heart Failure (New York Heart Association functional classification III-IV)

          -  History of unexplained syncope

          -  Other clinically significant heart disease (e.g. cardiomyopathy, cardiac artery
             disease, uncontrolled hypertension, or history of poor compliance with an
             antihypertensive regimen)

          -  Family history of long QT syndrome, unexplained syncope or unexplained sudden death

          -  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 biphosphonates unless if initiated prior to study entry (at least 4 weeks
             before patient registration)

          -  Pregnant (i.e., positive beta-human chorionic gonadotropin test) or breast feeding
             patient

          -  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 30 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