Safety and Efficacy Studies of Panobinostat and Bicalutamide in Patients With Recurrent Prostate Cancer After Castration

The preclinical data indicate that Panobinostat restores the sensitivity of
androgen-independent cells to bicalutamide (Casodex®) and the combination has synergistic
inhibitory activity. Here, we hypothesize that treatment of castration-resistant patients
with Panobinostat will enhance the response to the second line hormone therapy with
bicalutamide (Casodex®). In the proposed phase I study, the maximum tolerated dose of
tri-weekly, intermittent oral Panobinostat at three different dose levels (60, 90, 120
mg/week) in combination with Casodex (50mg PO) will be determined; The following phase II
study will evaluated the efficacies of 9-month treatments of the selected
Panobinostat-Casodex combination and also a lower dose of Panobinostat. We expect that
Casodex-Panobinostat combination treatment of castration-resistant patients will prevent
biochemical and/or metastatic disease progression of these patients compared to historical
controls in the same time period.

Inclusion Criteria:

- Male patients aged ≥ 18 years old

- Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed

- Patients must meet laboratory criteria

- Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional
normal.

- ECOG Performance Status of ≤ 2

- Documented history of adenocarcinoma of the prostate.

- Patients must have evidence of disease progression while receiving androgen
suppression therapy by orchiectomy or other primary hormonal therapy including, but
not limited to (LHRH agonist therapy (e.g., leuprolide or goserelin) or LHRH
antagonist (e.g. aberelix). Note: patients who have not undergone bilateral
orchiectomy must continue LHRH therapy while on protocol

- Testosterone must be < 50 ng/dl confirmed within 4 weeks prior to registration for
patients on LHRH therapy

- Patients must have evidence of disease progression with either one or both of the
conditions listed:

- Biochemical progression only

- Metastases on bone scan

- Patients may have received one chemotherapy, investigational agent or immunotherapy in
the neoadjuvant, adjuvant setting or during initial LHRH therapy with new evidence of
disease progression after discontinuation of therapy for ≥ 2 weeks.

- Patients must have received one or more prior second line hormone therapy for
progression while on LHRH treatment or orchiectomy.

- Patients treated with one first line chemotherapy combination for hormone refractory
progression ≥ 4 weeks prior to registration who have evidence of disease progression
and had only one second line hormone therapy and did not experience PSA response to
bicalutamide (Casodex®) withdrawal.

Exclusion Criteria:

- Prior treatment with an HDAC inhibitor

- Impaired cardiac function including any one of the following:

- Screening ECG with a QTc > 450 msec confirmed by central laboratory prior to
enrollment to the study

- Patients with congenital long QT syndrome

- History of sustained ventricular tachycardia

- Any history of ventricular fibrillation or torsades de pointes

- Bradycardia defined as heart rate < 50 beats per minute. Patients with a
pacemaker and heart rate ≥ 50 beats per minute are eligible.

- Patients with a myocardial infarction or unstable angina within 6 months of study
entry

- Congestive heart failure (NY Heart Association class III or IV)

- Right bundle branch block in conjunction with left anterior hemi-block
(bifasicular block)

- Uncontrolled hypertension

- Concomitant use of drugs with a risk of causing torsades de pointes

- Concomitant use of CYP3A4 inhibitors

- Patients with unresolved diarrhea greater than CTCAE grade 1

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral LBH589

- Other concurrent severe and/or uncontrolled medical conditions

- Patients who have received chemotherapy, any investigational drug or undergone major
surgery < 4 weeks prior to starting study drug or who have not recovered from side
effects of such therapy.

- Concomitant use of any anti-cancer therapy or radiation therapy.

- Male patients whose sexual partners are WOCBP not using effective birth control

- Patients with a history of another primary malignancy within the last 2 years that was
not curatively treated, excluding basal or squamous cell carcinoma of the skin

- Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C;
baseline testing for HIV and hepatitis C is not required

- Patients with any significant history of non-compliance to medical regimens or with
inability to grant a reliable informed consent

- Patients previously treated with bicalutamide (Casodex®) who experienced a PSA
withdrawal response in the washout period as described in Inclusion #11 will not be
eligible

- Concurrent use of estrogens or estrogen like substances (i.e. PC-SPES, Saw Palmetto,
or other herbal product which may contain phytoestrogens) is not allowed. Prior use of
these agents will need to be discontinued at least 4 weeks prior to enrollment, for
the above.

- Radiotherapy within the 4 weeks prior to registration

- Inadequate bone marrow function measured 28 days prior to registration

- No serious concurrent medical illness or active infection that would jeopardize the
ability of the patient to receive therapy as outlined in the protocol with reasonable
safety.

- Liver metastasis.

- The use of bisphosphonates in the absence of metastasis will not be allowed. Patients
on bisphosphonates for more than 4 weeks for asymptomatic bone metastasis and with
continued evidence of PSA progression may continue on bisphosphonates every 4 weeks.

- Hydronephrosis with impaired renal function.

- Active spinal cord compression.