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

This study has been terminated.
(Dose Limiting Toxicity)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00873002
First received: March 31, 2009
Last updated: March 16, 2012
Last verified: March 2012
  Purpose

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.


Condition Intervention Phase
Liver Cancer
Drug: panobinostat
Drug: sorafenib tosylate
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of Combination of Sorafenib and LBH589 in Hepatocellular Carcinoma

Resource links provided by NLM:


Further study details as provided by Case Comprehensive Cancer Center:

Primary Outcome Measures:
  • Assessment of Safety and Tolerability [ Time Frame: 6months to 1 year ] [ Designated as safety issue: Yes ]
    •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.


Secondary Outcome Measures:
  • Progression-free survival [ Time Frame: 6mo 1 year ] [ Designated as safety issue: No ]
    Evaluate time to progression vs progression free survival

  • Overall survival [ Time Frame: until death ] [ Designated as safety issue: No ]
    Overall survival (OS) will be measured from study entry until death from any cause.

  • Response as assessed by RECIST [ Time Frame: every 42 days ] [ Designated as safety issue: No ]
    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.

  • Adverse events and abnormal laboratory value severity as assessed by NCI CTCAE version 3.0 [ Time Frame: weekly during treatment to 30 days after treatment ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 3
Study Start Date: March 2009
Study Completion Date: June 2010
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00873002

Locations
United States, Ohio
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44195
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Principal Investigator: Richard Kim, MD Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00873002     History of Changes
Other Study ID Numbers: CASE6208, P30CA043703, CASE6208, CLBH589BUS23T
Study First Received: March 31, 2009
Last Updated: March 16, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Case Comprehensive Cancer Center:
adult primary hepatocellular carcinoma
advanced adult primary liver cancer
recurrent adult primary liver cancer
localized unresectable adult primary liver cancer

Additional relevant MeSH terms:
Liver Neoplasms
Carcinoma, Hepatocellular
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Liver Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Sorafenib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 20, 2014