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

Phase I/II Randomized Trial of LBH589 (Panobinostat) at Two Dose Levels Combined With Bicalutamide (Casodex) in Men With Castration-resistant Prostate Cancer

This trial is designed to investigate the safety, dosing schedule, and efficacy of the combination treatment of Panobinostat (a histone deacetylase inhibitor) and hormone therapy for recurrent prostate cancer. This trial is at its Phase II stage. As of July 23, 2013 Arm B was closed to accrual, all the remaining slots in accrual will be allocated to Arm A.

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.