Study of Panobinostat Monotherapy in Women With HER2-negative Locally Recurrent or Metastatic Breast Cancer

This was a phase II, open label, multi-centre, two-arm, two-stage design, international
study of oral panobinostat in women with HER2-negative locally recurrent or metastatic
breast cancer.

In the first stage of the trial, 21 evaluable patients HR+ (ER+ and/or PgR+), HER2-negative,
were to be treated (Arm I); if less than 3 responses were observed, that arm would be
stopped and the treatment in this patient population would be declared as ineffective. In
the other arm, 27 evaluable patients HR- (ER- and PgR-), HER2-negative, were to be treated
(Arm II); if less than 2 responses were observed, that arm would be stopped and the
treatment in this patient population would be declared as ineffective.

Given these protocol conditions, the study was stopped in Arm II due to low recruitment as
there was insufficient data available to draw conclusions regarding efficacy in that arm. It
should also be noted that only one response was observed in this group.. In Arm I, among the
25 evaluable patients, the study did not achieve the required number of tumor responses to
allow enrolment to continue.

As such the protocol was amended to stop enrolment and remove analysis of the initially
planned secondary objectives (Progression Free Survival and Overall Survival) considering
the small study sample size. The patients already included were given the option to continue
in the study until they reached their planned end-of-study visit.

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