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

Phase I Study of Combination of Sorafenib and LBH589 in Hepatocellular Carcinoma

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.

Study Overview

• Status: Terminated
• Conditions: Liver Cancer
• Intervention / Treatment: Drug: panobinostat; Drug: sorafenib tosylate

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: LBH589; This study utilizes a sequential dose-escalation design to define the MTD of LBH589 when combined with standard doses of sorafenib.	Drug: panobinostat; 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; Drug: sorafenib tosylate; 400 mg PO BID

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

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Richard Kim, MD, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• Clinical trial summary from the National Cancer Institute's PDQ® database

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: March 31, 2009
• First Submitted That Met QC Criteria: March 31, 2009
• First Posted (Estimate): April 1, 2009

Study Record Updates

• Last Update Posted (Estimate): March 20, 2012
• Last Update Submitted That Met QC Criteria: March 16, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: advanced adult primary liver cancer; recurrent adult primary liver cancer; localized unresectable adult primary liver cancer; adult primary hepatocellular carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Histone Deacetylase Inhibitors; Sorafenib; Panobinostat
• Other Study ID Numbers: CASE6208 (Other Identifier: Case Comprehensive Cancer Center); P30CA043703 (U.S. NIH Grant/Contract); CLBH589BUS23T