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

Case Comprehensive Cancer Center (Case CCC)

Status and phase

Terminated

Phase 1

Conditions

Liver Cancer

Treatments

Drug: panobinostat

Drug: sorafenib tosylate

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00873002

P30CA043703 (U.S. NIH Grant/Contract)

CLBH589BUS23T

CASE6208 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

3 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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