Sorafenib and LBH589 in Hepatocellular Carcinoma (HCC)

Sponsor

University of Erlangen-Nürnberg Medical School (Other)

Overall Status

Terminated

CT.gov ID

NCT00823290

Collaborator

(none)

Enrollment

Location

Actual Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Drug: Sorafenib + LBH589	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

2 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Trial of Sorafenib and LBH589 in the Treatment of Advanced HCC

Actual Study Start Date :

Jan 1, 2009

Actual Primary Completion Date :

Dec 1, 2010

Actual Study Completion Date :

Dec 1, 2010

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of LBH589 [1 year]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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