Sorafenib and LBH589 in Hepatocellular Carcinoma (HCC)

The recruitment status of this study is unknown because the information has not been verified recently.
Verified January 2009 by University of Erlangen-Nürnberg Medical School.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
University of Erlangen-Nürnberg Medical School
ClinicalTrials.gov Identifier:
NCT00823290
First received: January 14, 2009
Last updated: January 11, 2010
Last verified: January 2009
  Purpose

Histone deacetylase inhibitors (HDACi) like LBH589 have recently been established as novel potent anti-cancer agents for solid and hematologic malignancies. Several pre-clinical reports have shown a good anti-tumoral activity of different HDACi on human or murine HCC models. These compounds, e.g. Trichostatin A, SAHA, MS-275 and others, have been shown to induce apoptosis in HCC cells and to inhibit growth of HCC by inhibiting proliferation and tumor-related angiogenesis in vivo. Furthermore, HDACi sensitize HCC in a synergistic manner to other forms of cytotoxic stimulation, e.g. by conventional chemotherapeutic drugs or TRAIL-mediated apoptosis. It has also been shown that the combination of HDACi with various kinase inhibitors like sorafenib, erlotinib or others, promotes the anti-tumor efficacy of single agents.

Based on the investigators' own previous experiences with different HDACi and LBH589 in preclinical HCC models, a strong anti-proliferative and pro-apoptotic as well as an anti-angiogenic effect will be expected by combining LBH589 with an existing sorafenib treatment. It is assumed that this combination will prolong overall survival and time-to-progression with lowered adverse effects in HCC patients.


Condition Intervention Phase
Hepatocellular Carcinoma
Drug: Sorafenib + LBH589
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of Sorafenib and LBH589 in the Treatment of Advanced HCC

Resource links provided by NLM:


Further study details as provided by University of Erlangen-Nürnberg Medical School:

Primary Outcome Measures:
  • Maximum tolerated dose of LBH589 [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Safety, tolerability and adverse events (based on CTCAE 3.0) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Reduction of lesion size (radiologically assessed according to RECIST) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Laboratory abnormalities (CTC grade 3 or grade 4 toxicities) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 18
Study Start Date: January 2009
Estimated Study Completion Date: December 2010
Estimated Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Sorafenib + LBH589
    Sorafenib standard regimen + oral LBH589
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • male or female patients > 18 years of age
  • patients who have a life expectancy of at least 12 weeks
  • patients with advanced hepatocellular carcinoma
  • patients with have histologically or radiologically confirmed HCC; documentation of original biopsy for diagnosis is acceptable if tumor tissue is unavailable
  • at least one tumor lesion that can be accurately measured in at least one dimension according to RECIST and which has not been treated with local therapy (hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection); the scans should be approximately 2 weeks old to be used as baseline scan
  • patients who received Sorafenib 2 x 400 mg a day between 4 to 6 weeks without dose reduction due to dose limiting toxicities
  • at least a period of 4 weeks prior to baseline scan after completion of a local therapy such as surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation
  • patients who have an ECOG PS of 0, 1 or 2 respectively Karnofsky Performance Status > 70%
  • cirrhotic status of Child-Pugh-class A or B (max. 7 points); Child-Pugh status should be calculated based on clinical findings and laboratory results during the screening period
  • no signs of decompensated liver cirrhosis
  • white blood cells > 3,000/mm³
  • neutrophils > 1,500/mm³
  • platelets > 100,000/mm³
  • bilirubin > 3x upper limit of normal (ULN)
  • AST and ALT > 3x ULN
  • creatinine normal
  • PTT < 1.5x ULN
  • fasting serum cholesterol < 350 mg/dL
  • triglycerides < 300 mg/dL
  • proteinuria < 1g in 24 h
  • no history of allergic reactions to compounds similar to Panobinostat or Sorafenib
  • no prior thromboembolic disease
  • no history of hematemesis or hemoptysis
  • no other uncontrolled illness
  • women of childbearing potential must have had a negative serum or urine pregnancy test 48 hours prior to the administration of the first study treatment
  • patients who give a written informed consent obtained according to local guidelines
  • no other concurrent investigational drugs or anticancer agents
  • no concurrent traditional Chinese or herbal medicine (e.g. sho-saiko-to, silymarine)

Exclusion Criteria:

  • patients currently receiving chemotherapy, immunotherapy or radio-therapy or who have received these within 4 weeks of study entry
  • patients who do not tolerate therapy with Sorafenib 2 x 400 mg a day
  • prior use of systemic investigational agents for HCC
  • previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors and any cancer curatively treated > 3 years prior to entry is permitted;
  • chronic treatment with steroids or another immunosuppressive agent
  • a known history of HIV seropositivity
  • renal failure requiring hemo- or peritoneal dialysis
  • history of cardiac disease: congestive heart failure (> New York Heart Association class 2), active coronary artery disease, cardiac arrhythmias requiring anti- arrhythmic therapy other than beta blockers or digoxin, uncontrolled hypertension; myocardial infarction more than 6 month prior to study entry is permitted
  • active clinically serious infections (> grade 2 National Cancer Institute-Common Terminology Criteria for Adverse Events - CTCAE - version 3.0)
  • known carcinomatous meningitis or uncontrolled brain disease
  • patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry or on oral anti-vitamin K medication (except low dose coumarin)
  • history of organ allograft
  • uncontrolled diabetes
  • impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption LBH589 or Sorafenib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
  • patients who have not recovered from surgery
  • female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods; if barrier contraceptives are being used, these must be continued throughout the trial by both sexes
  • patients who are using other investigational agents or who had received investigational drugs > 4 weeks prior to study inclusion
  • history of noncompliance to medical regimens
  • patients unwilling to or unable to comply with the protocol
  • substance abuse, medical, psychological or social conditions that may interfere with the patients participation in the study or evaluation of the study results
  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: NCT00823290

Contacts
Contact: Matthias Ocker, MD +49-6421-58 ext 68931 Matthias.Ocker@staff.uni-marburg.de
Contact: Susanne Gahr, MD +49-9131-85 ext 35000 susanne.gahr@uk-erlangen.de

Locations
Germany
Department of Medicine 1, University Hospital Erlangen Recruiting
Erlangen, Germany, 91054
Contact: Matthias Ocker, MD    +49-6421-58 ext 68931    Matthias.Ocker@staff.uni-marburg.de   
Contact: Susanne Gahr, MD    +49-9131-85 ext 35000    susanne.gahr@uk-erlangen.de   
Principal Investigator: Deike Strobel, MD         
Sponsors and Collaborators
University of Erlangen-Nürnberg
  More Information

No publications provided

Responsible Party: PD Dr. Matthias Ocker, University Hospital Erlangen
ClinicalTrials.gov Identifier: NCT00823290     History of Changes
Other Study ID Numbers: CLBH589BDE02
Study First Received: January 14, 2009
Last Updated: January 11, 2010
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University of Erlangen-Nürnberg Medical School:
HCC
sorafenib
HDAC
LBH589
Panobinostat

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

ClinicalTrials.gov processed this record on September 18, 2014