Sorafenib and Vorinostat in Treating Patients With Advanced Liver Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2015 by Virginia Commonwealth University
Sponsor:
Collaborator:
Massey Cancer Center
Information provided by (Responsible Party):
Virginia Commonwealth University
ClinicalTrials.gov Identifier:
NCT01075113
First received: February 19, 2010
Last updated: December 18, 2015
Last verified: December 2015
  Purpose
This phase I trial is studying the side effects and best dose of vorinostat when given together with sorafenib tosylate in treating patients with advanced liver cancer. Sorafenib tosylate and vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor.

Condition Intervention Phase
Liver Cancer
Drug: sorafenib tosylate
Drug: vorinostat
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Sorafenib and Vorinostat in Advanced Hepatocellular Carcinoma

Resource links provided by NLM:


Further study details as provided by Virginia Commonwealth University:

Primary Outcome Measures:
  • Determine the appropriate Doses for the combination of sorafenib tosylate and vorinostat appropriate for phase II study in hepatocellular carcinoma (HCC). [ Time Frame: Up to 4 years ] [ Designated as safety issue: Yes ]
    Identify the maximum tolerated dose of the combination regimen of vorinostat and sorafenib to study further for efficacy of treatment for hepatocellular carcinoma


Secondary Outcome Measures:
  • Adverse events will be characterized in terms of nature, severity, attribution, onset and resolution according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: Yes ]
    Safety, tolerance, and toxicity of the combination of sorafenib tosylate and vorinostat in patients with HCC. Observe toxicities experienced by patients treated in cohorts of escalating doses of the drug combination.

  • Anti-tumor effects of the combination of sorafenib tosylate and vorinostat [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Tumor masses will be evaluated for response according to the RECIST Criteria. Summarized using descriptive statistics for each cohort, along with their corresponding 95% confidence intervals.


Estimated Enrollment: 40
Study Start Date: August 2010
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A
Sorafenib + Vorinostat. Patients receive sorafenib tosylate PO BID continuously and vorinostat PO QD, for 5 days each week. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohort A has only one dose level: sorafenib 400 mg orally twice a day with vorinostat 300 mg orally, which has been found to be the RP2D in patients with solid tumors in a recent study by Dasari et al [23]. Cohort A was modified to include 2 dose levels: Dose level A1 (sorafenib 400 mg orally twice a day and vorinostat 200 mg orally once a day) and dose level A-1 (sorafenib 400 mg orally twice a day with vorinostat 100 mg orally once a day). The starting dose upon reopening after approval of this version will be dose level A-1a. Dose level A1 will only be used if dose level A-1a is not tolerable.
Drug: sorafenib tosylate
Given orally
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Experimental: Arm B CLOSED
Reduced Dose 200mg Sorafenib + Vorinostat. Patients receive sorafenib tosylate PO BID continuously and vorinostat PO QD, for 5 days each week. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohort B has 2 dose levels starting at the second dose level (sorafenib 200 mg orally twice a day with vorinostat 400 mg orally). Cohort B has been closed. Cohort B was intended to evaluate the possibility of dose intensification of vorinostat when patients were unable to tolerate standard dose sorafenib, and required dose-reduced sorafenib. The patients accrued to date in Cohort B were unable to tolerate therapy, and it has been determined that dose intensification of vorinostat is not possible, despite reducing the dose of sorafenib.
Drug: sorafenib tosylate
Given orally
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza

Detailed Description:

Outline: This is a dose-escalation study of vorinostat. The purpose of this research study is to test the safety and effectiveness of a combination of two cancer drugs, sorafenib (Nexavar) and vorinostat (Zolinza), in advanced liver cancer (hepatocellular carcinoma). Advanced means that the cancer has spread too far to consider surgery. Approximately 19 people will take part in this study.

After enrollment of 6 patients at sorafenib 400 mg orally twice a day and vorinostat 300 mg orally, as recommended by Dasari et al [23], only 2 of the 6 patients were evaluable for DLT (no DLTs). The other 4 patients were not evaluable for DLT because of required dose modifications. Because of this dose modification need, Cohort A has been modified to include 2 dose levels: Dose level A-1a (sorafenib 400 mg orally twice a day and vorinostat 200 mg orally once a day) and dose level A1 (sorafenib 400 mg orally twice a day with vorinostat 100 mg orally once a day). The starting dose upon reopening after approval of this version will be dose level A-1a. Dose level A1 will only be used if dose level A-1a is not tolerable.

  Eligibility

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

Inclusion

  • Diagnosis of hepatocellular carcinoma (HCC) by
  • biopsy-proven pathologic diagnosis or by clinical criteria as defined below:
  • Clinical Criteria to be met if patient has a history of cirrhosis or chronic hepatitis B infection:
  • Imaging abnormalities > 1 cm in size with classic enhancement by MRI or triple-phase CT scan
  • AFP of any value
  • Clinical criteria to be met if patient has no history of cirrhosis or chronic hepatitis B infection:
  • Imaging abnormalities > 1 cm in size with classic enhancement by MRI or triple-phase CT scan
  • And AFP > 20 mg/dL
  • Adult ≥ 18 years.
  • Performance status Eastern Cooperative Oncology Group (ECOG) equal or less than 1
  • If cirrhosis, Child-Pugh classification A or B
  • Total bilirubin =< 3.0 mg/dL
  • Creatinine =< 1.5 x upper limit of normal (ULN) for the laboratory
  • International Normalized Ratio (INR) =< 1.7 (if not due to anticoagulants)
  • absolute neutrophil count (ANC) >= 1,500/mm3
  • Platelets >=80,000/mm3
  • hemoglobin (Hgb) >= 8.5 g/dL (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 (Update - Version 9, 9/8/15: Cohort B is closed). Participation in an additional research imaging study is permissible; imaging for this study will be evaluated independently.
  • Measurable or evaluable disease by RECIST criteria (v 1.1) mRECIST, 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 2 weeks 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 and for 4 months following completion of study treatment.

Exclusion

  • Candidate for surgical resection, orthotopic liver transplantation
  • Known central nervous system metastasis
  • Any investigational agent within 4 weeks of first dose of study treatment
  • Known or presumed intolerance of sorafenib or vorinostat
  • Unable to swallow medication
  • Suspected malabsorption
  • Active 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. Hepatic portal vein thrombus is not considered an exclusion criterion, as this is a common finding in patients with advanced liver cancer and progressive disease. This does not confer increased risk for deep venous thrombosis, and is not treated with anticoagulation.
  • 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
  • Medical, psychological, or social conditions that, in the opinion of the investigator, may increase the patient's risk or interfere with the patient's participation in the study or hinder 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: NCT01075113

Contacts
Contact: Andrew S. Poklepovic, MD 804-628-2321 andrew.poklepovic@vcuhealth.org
Contact: MCC Early-Phase Clinical Trials Program Solid Tumor Investigator-Initiated Trials (SIIT) 804-628-9238 masseysiit@vcu.edu

Locations
United States, Virginia
Hunter Holmes McGuire VA Medical Center Active, not recruiting
Richmond, Virginia, United States, 23249
Virginia Commonwealth University Recruiting
Richmond, Virginia, United States, 23298
Contact: Andrew Poklepovic, MD    804-628-2321    andrew.poklepovic@vcuhealth.org   
Contact: Mary B Tombes, NP    804-628-1357    masseysiit@vcu.edu   
Principal Investigator: Andrew Poklepovic, MD         
Sponsors and Collaborators
Virginia Commonwealth University
Massey Cancer Center
Investigators
Principal Investigator: Andrew S. Poklepovic, MD Virginia Commonwealth University
  More Information

Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT01075113     History of Changes
Other Study ID Numbers: MCC-12122  NCI-2010-00185 
Study First Received: February 19, 2010
Last Updated: December 18, 2015
Health Authority: United States: Institutional Review Board

Keywords provided by Virginia Commonwealth University:
adult primary hepatocellular carcinoma
advanced adult primary liver cancer
recurrent adult primary liver cancer

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Liver Neoplasms
Adenocarcinoma
Carcinoma
Digestive System Diseases
Digestive System Neoplasms
Liver Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Niacinamide
Sorafenib
Vorinostat
Antineoplastic Agents
Enzyme Inhibitors
Growth Substances
Histone Deacetylase Inhibitors
Micronutrients
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Therapeutic Uses
Vitamin B Complex
Vitamins

ClinicalTrials.gov processed this record on April 27, 2016