Sorafenib and LBH589 in Hepatocellular Carcinoma (HCC)

NCT00823290 | Terminated Phase 1

• 1 other identifier: CLBH589BDE02
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hepatocellular Carcinoma

Keywords

HCC; sorafenib; HDAC; LBH589; Panobinostat

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose of LBH589

  1 year

Secondary Outcomes (3)

• Safety, tolerability and adverse events (based on CTCAE 3.0)

  1 year

• Reduction of lesion size (radiologically assessed according to RECIST)

  1 year

• Laboratory abnormalities (CTC grade 3 or grade 4 toxicities)

  1 year

Interventions

Sorafenib + LBH589 DRUG

Sorafenib standard regimen + oral LBH589

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Erlangen-Nürnberg Medical School: lead

Study Sites (1)

Department of Medicine 1, University Hospital Erlangen

Erlangen, 91054, Germany

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Sorafenib; Panobinostat

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Hydroxamic Acids; Hydroxylamines; Amines; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: January 14, 2009
• First Posted: January 15, 2009
• Study Start: January 1, 2009
• Primary Completion: December 1, 2010
• Study Completion: December 1, 2010
• Last Updated: December 14, 2020

Record last verified: 2020-12

Locations

DE (1)