Panobinostat and Sorafenib in Treating Patients With Liver Cancer That is Metastatic and/or Cannot Be Removed by Surgery

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Panobinostat and sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib may also stop the growth of liver cancer by blocking blood flow to the tumor. PURPOSE: This phase I trial is studying the side effects and best dose of panobinostat when given together with sorafenib in treating patients with liver cancer that is metastatic and/or cannot be removed by surgery.

Detailed Description
-----------------
OBJECTIVES: Primary Assess the safety and tolerability of panobinostat when combined with standard doses of sorafenib tosylate in patients with metastatic and/or unresectable hepatocellular carcinoma. Determine the maximum tolerated dose of panobinostat when combined with standard doses of sorafenib tosylate in these patients. Secondary Determine the response rate. Determine the progression-free survival. Determine the overall survival rate. OUTLINE: This is a dose escalation study of panobinostat. Patients receive panobinostat IV on days 1 and 8 and oral sorafenib tosylate twice daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed for 30 days.

Official Title
-----------------
Phase I Study of Combination of Sorafenib and LBH589 in Hepatocellular Carcinoma

Conditions
-----------------
Liver Cancer

Intervention / Treatment
-----------------
* Drug: panobinostat
* Drug: sorafenib tosylate


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically or cytologically confirmed hepatocellular carcinoma Metastatic and/or unresectable disease Child-Pugh score A or B PATIENT CHARACTERISTICS: ECOG performance status 0-2 Neutrophil count > 1500/mm³ Platelet count > 100,000/mm³ Hemoglobin ≥ 9 g/dL AST and ALT ≤ 2.5 times upper limit of normal (ULN) (≤ 5.0 times ULN if elevation due to disease involvement) Serum bilirubin ≤ 1.5 times ULN Serum creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 50 mL/min Total serum calcium (corrected for serum albumin) or ionized calcium ≥ lower limit of normal (LLN) Serum potassium ≥ LLN Serum sodium ≥ LLN Serum albumin ≥ LLN or 3 g/dL LVEF ≥ LLN as demonstrated by baseline MUGA or ECHO TSH and free T4 within normal limits (thyroid hormone replacement therapy allowed) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-method contraception (one being a barrier method) during and for 3 months after completion of study treatment INR < 1.5 or PT/PTT within normal limits No impaired cardiac function including any 1 of the following: QTc > 450 msec on screening ECG Congenital long QT syndrome History of sustained ventricular tachycardia 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 Myocardial infarction or unstable angina within the past 6 months Congestive heart failure (NYHA class III-IV) Right bundle branch block and left anterior hemiblock (bifascicular block) No uncontrolled hypertension No thrombolic or embolic events (e.g., cerebrovascular accident and transient ischemic attacks) within the past 6 months No pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within the past 4 weeks No other hemorrhage/bleeding event > CTCAE Grade 3 within the past 4 weeks No unresolved diarrhea > CTCAE grade 1 No other concurrent severe and/or uncontrolled medical conditions No other primary malignancy within the past 5 years except curatively treated carcinoma in situ of the cervix or basal cell or squamous cell carcinoma of the skin No serious non-healing wound, ulcer, or bone fracture No evidence or history of bleeding diathesis or coagulopathy No significant traumatic injury within the past 4 weeks No known or suspected allergy to sorafenib tosylate or any other study drug No condition that would impair a patient's ability to swallow whole pills No malabsorption problem No known human immunodeficiency virus (HIV) or hepatitis C positivity (baseline testing for HIV and hepatitis C is not required) No significant history of non-compliance to medical regimens PRIOR CONCURRENT THERAPY: No prior HDAC inhibitors, DAC inhibitors, HSP90 inhibitors, sorafenib tosylate, or valproic acid for the treatment of cancer More than 4 weeks since prior chemotherapy, investigational drugs, or major surgery and recovered More than 4 weeks since open biopsy More than 5 days since prior and no concurrent valproic acid for any medical condition No concurrent St. John's wort or rifampin No concurrent drugs with a risk of causing torsades de pointes No concurrent CYP3A4 inhibitors No concurrent radiotherapy No concurrent grapefruit, grapefruit juice, or Seville (sour) oranges No other concurrent investigational therapy No other concurrent anticancer agents Concurrent anticoagulation treatment with warfarin or heparin allowed

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: LBH589<br>This study utilizes a sequential dose-escalation design to define the MTD of LBH589 when combined with standard doses of sorafenib. | Drug: panobinostat<br>* Dose escalation: 7.5 mg/m2 day 1 and day 8 of 21 days cycle 10 mg/m2 day 1 and day 8 of 21 days cycle 15 mg/m2 day 1 and day 8 of 21 days cycle 20 mg/m2 day 1 and day 8 of 21 days cycle 30 mg/m2 day 1 and day 8 of 21 days cycle<br>Drug: sorafenib tosylate<br>* 400 mg PO BID<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Safety and Tolerability | •Primary objective of the phase I trial will be to assess the safety and tolerability and to determine the maximum tolerated dose (MTD) of LBH 589 when combined with standard doses of sorafenib in the treatment of hepatocellular carcinoma. | 6months to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Evaluate time to progression vs progression free survival | 6mo 1 year | 
| Overall survival | Overall survival (OS) will be measured from study entry until death from any cause. | until death | 
| Response as assessed by RECIST | To ensure comparability, baseline methods and on-study methods for response assessment must be performed using identical techniques. In addition, all subjects with evidence of objective tumor response (CR, PR or SD) should have the response confirmed with repeat assessments at least 21 days after the first documentation of response, resuming bimonthly (every 42 days) assessments thereafter. Objective tumor response will be assessed using the RECIST method. | every 42 days | 
| Adverse events and abnormal laboratory value severity as assessed by NCI CTCAE version 3.0 | Events should be documented and recorded at each visit. Subjects should be followed for adverse events for 30 days after the last protocol related assessment, or until drug-related toxicities have resolved, whichever is later. | weekly during treatment to 30 days after treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult primary hepatocellular carcinoma, advanced adult primary liver cancer, recurrent adult primary liver cancer, localized unresectable adult primary liver cancer