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A Phase I Study of Sorafenib and Vorinostat in Advanced Hepatocellular Carcinoma

Phase 1
18 Years
Open (Enrolling)
Liver Cancer

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Trial Information

A Phase I Study of Sorafenib and Vorinostat in Advanced Hepatocellular Carcinoma

Primary Objectives:

I. To determine doses for the combination of vorinostat with standard dose sorafenib (400 mg
twice daily) and reduced dose sorafenib (200 mg twice daily appropriate for phase II study
in HCC.

Secondary Objectives:

I. To evaluate the safety, tolerance, and toxicity of the combination of sorafenib and
vorinostat in patients with HCC.

II. To observe antitumor effects of the combination. III. To evaluate the feasibility of
circulating tumor cell analysis for tumor cell enumeration, and target protein expression on
HCC tumor cells.

Outline: This is a dose-escalation study of vorinostat. Patients receive sorafenib
tosylate orally (PO) twice daily (BID) continuously and vorinostat PO once daily (QD), for 5
days each week. Courses repeat every 4 weeks in the absence of disease progression or
unacceptable toxicity

Inclusion Criteria


- Diagnosis of hepatocellular carcinoma (HCC): The diagnosis of HCC may be based upon
pathological or clinical criteria (Clinical diagnosis requires a history of
cirrhosis, chronic hepatitis B infection, or non-alcoholic hepatosteatosis (NASH)
and, for imaging abnormalities 1 to 2 cm in diameter, classic enhancement by at least
two of three imaging techniques (computed tomography, Magnetic resonance imaging,
Ultrasound), or, for imaging abnormalities > 2cm, classic enhancement by at least one
imaging technique and an alpha-fetoprotein (AFP) > 200 ng/mL

- Performance status Eastern Cooperative Oncology Group (ECOG) equal or less than 2

- If cirrhosis, Child-Pugh classification A or B

- Total bilirubin =< 3.0 mg/dL

- Creatinine =< 1.5 x upper institutional limit

- prothrombin (PT)/international normalized ratio (INR) =< 1.7 (if not due to

- absolute neutrophil count (ANC) >= 1.5

- Platelets >= 60,000

- hemoglobin (Hgb) >= 8.5 (transfusion or erythropoietin-like substances not permitted)

- Any prior therapies such as surgery, chemoembolization, radiofrequency ablation, and
alcohol injection are allowed as long as toxicity from prior therapy is =< grade 1
(Prior sorafenib is allowed, and patients must be on a stable tolerable dose prior to
enrollment; if it is known that the patient tolerates standard dose sorafenib (400 mg
orally twice daily), then they will enroll in cohort A; if they tolerate reduced dose
sorafenib (200 mg orally twice daily), then they will enroll in cohort B;
participation in an additional research imaging study is permissible, imaging for
this study will be evaluated independently)

- Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) criteria or elevated AFP

- Ability to understand and willingness to sign a written informed consent (A signed
informed consent must be obtained prior to any study specific procedures)

- Women of childbearing potential must have a negative pregnancy test performed within
7 days prior to the start of treatment (Women of childbearing potential and men must
agree to use a medically accepted form of birth control for the duration of study
participation; Men must agree to use a medically accepted form of birth control for 4
months following completion of study treatment)


- Candidate for surgical resection, orthotopic liver transplantation

- Known central nervous system metastasis

- Any investigational agent within 4 weeks or 5 half-times, whichever is longer, of
first dose of study treatment

- Known or presumed intolerance of sorafenib or vorinostat

- Unable to swallow medication

- Suspected malabsorption

- Active illicit substance or alcohol abuse

- Contraindication to antiangiogenic agents, including: Pulmonary hemorrhage/bleeding
event >= Grade 2 within 4 weeks of first dose of study drug; Any other
hemorrhage/bleeding event >= Grade 3 within 4 weeks of first dose of study treatment;
serious non-healing wound, ulcer, or bone fracture.

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months

- Major cardiac dysfunction, such as uncontrolled angina, congestive heart failure with
New York Heart Association (NYHA) class III or higher, known left ventricular
ejection fraction less than 40%

- Systolic blood pressure > 160 mmHg or diastolic pressure > 90 mmHg despite optimal
medical management

- Significant lung disease (oxygen saturation less than 88% in room air)

- Serious uncontrolled infection; known human immunodeficiency virus
(HIV)-seropositivity requiring retroviral therapy, or diagnosis of acquired immune
deficiency syndrome (AIDS); diagnosis of chronic hepatitis B or C allowed

- Other condition(s) that in the opinion of the investigator might compromise the
objectives of the study

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the appropriate doses of vorinostat and sorafenib when given in combination to patients with hepatocellular carcinoma

Outcome Description:

Identify the maximum tolerated dose of the combination regimen of vorinostat and sorafenib to study further for efficacy of treatment for hepatocellular carcinoma

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Andrew S. Poklepovic, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Virginia Commonwealth University


United States: Institutional Review Board

Study ID:




Start Date:

August 2010

Completion Date:

December 2015

Related Keywords:

  • Liver Cancer
  • adult primary hepatocellular carcinoma
  • advanced adult primary liver cancer
  • recurrent adult primary liver cancer
  • Liver Neoplasms
  • Carcinoma, Hepatocellular



Hunter Holmes McGuire VA Medical CenterRichmond, Virginia  23249
Virginia Commonwealth UniversityRichmond, Virginia