Sorafenib Dose Ramp-Up in Hepatocellular Carcinoma (HCC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01203787
Recruitment Status : Completed
First Posted : September 16, 2010
Results First Posted : February 11, 2015
Last Update Posted : March 5, 2015
Information provided by (Responsible Party):
University of Florida

Brief Summary:
Open-label study to evaluate the safety and tolerability of Sorafenib dose ramp-up (starting at a lower dose and then gradually increasing the dose) versus standard Sorafenib dosing in subjects with unresectable and/or metastatic hepatocellular carcinoma.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: Sorafenib Standard Dosing Regimen Drug: Sorafenib Ramp-Up Regimen Phase 4

Detailed Description:
This is an open-label study that investigates the impact of a dose ramp-up strategy for sorafenib in patients with HCC. Clinical trial and post-marketing data suggest that sorafenib dose reductions and discontinuations due to adverse events are common and limit the drug's effectiveness. It is our hypothesis that a dose escalation strategy for sorafenib will improve the tolerability and allow a greater percentage of patients to remain on drug. The primary end-point of the study is the total accumulated and median daily dose of sorafenib delivered at month 2 and 4.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multicenter, Randomized Pilot Study of the Effect of Sorafenib Dosing Schedule on Tolerability and Drug Delivery
Study Start Date : December 2010
Actual Primary Completion Date : January 2014
Actual Study Completion Date : March 2014

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: Sorafenib Standard Dosing Regimen
Sorafenib 400 mg (2 tablets of 200 mg) twice daily until end of treatment or week 24
Drug: Sorafenib Ramp-Up Regimen
200 mg daily, Day 0-Day 13 200 mg twice daily, Day 14-Day 20 600 mg daily, Day 21-Day 27 400 mg twice daily, Day 28 until end of treatment400 mg twice daily
Other Name: Nexavar (Bay43-9006)

Experimental: Sorafenib Ramp-Up Regimen
200 mg daily from Day 0-Day 13 200 mg twice daily from Day 14-Day 20 600 mg daily from Day 21-Day 27 400 mg twice daily beginning Day 28 until end of treatment or Week 24
Drug: Sorafenib Standard Dosing Regimen
Sorafenib 400 mg twice daily until wk 24 or end of treatment
Other Name: Nexavar(Bay43-9006)

Primary Outcome Measures :
  1. Total (Cumulative) Dose Delivery of Sorafenib [ Time Frame: 4 months-1/12/2010-1/27/14 ]
    This outcome measure table shows the median cumulative dose delivered to the subjects randomized to the standard dosing regimen (N=63) and ramp-up regimen (N=57) at 4 months of treatment.

  2. Cumulative Dose of Sorafenib [ Time Frame: 11/22/2010-1/27/14 ]
    Table below shows mean cumulative dose of sorafenib for each of the dosing regimens.

Secondary Outcome Measures :
  1. Safety and Efficacy of Sorafenib Dosing Regimens [ Time Frame: Baseline-End of Treatment (11/22/2010-3/10/2014) ]
    Safety of Sorafenib was assessed by the frequency and severity of adverse events according to NCI-CTCAE grading

  2. Safety of Dosing Regimens as Assessed by the Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE [ Time Frame: 11/22/2010-3/10/2014 ]
    The total number of CTCAE (Common Terminology Criteria) grade 4 adverse events was collected for each dosing regimen beginning at baseline until Week 24/Early Termination Visit.

  3. Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE [ Time Frame: 11/22/2010-3/10/2014 ]
    The total number of CTCAE (Common Terminology Criteria) grade 5 adverse events was collected for each dosing regimen beginning at baseline through 6 months of treatment.

  4. Number of Subjects With Dose Interruptions [ Time Frame: Baseline-End of Treatment (11/22/2010-3/10/2014) ]
  5. Number of Subjects With Dose Reductions [ Time Frame: 11/22/2010-3/10/2014 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • HCC must be unresectable and/or metastatic
  • CPT score <9 at the time of screening (that is all Child A and Child B with a score of 7 or 8)
  • Age 20-75 years
  • Signed informed consent
  • EGD for variceal screening performed as per standard of care prophylaxis with non-selective beta-blockers or ligation
  • ECOG Performance Status ≤ 2.
  • Adequate bone marrow, liver and renal function as assessed by the following:

    1. Hemoglobin > 8.5 g/dl
    2. Absolute neutrophil count (ANC) > 1,500/mm3
    3. Platelet count > 50,000/mm3
    4. Total bilirubin < 3 mg/dl
    5. ALT and AST ( < 5 x ULN)
    6. Creatinine < 1.5 times ULN
  • Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment
  • Women of childbearing potential and non-surgically sterile men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib.
  • Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
  • INR< 2.3. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.
  • Life expectancy of at least 24 weeks

Exclusion Criteria:

  • Absence of informed consent
  • Child-Pugh score >9
  • ECOG PS >2
  • Active alcohol dependence per PI discretion
  • History of organ or bone marrow transplant
  • Plans to relocate from the study center within the period of the trial
  • Pregnancy or breastfeeding
  • Contraindications to sorafenib

    1. Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
    2. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
    3. Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis.
    4. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
  • Known human immunodeficiency virus (HIV) infection
  • Active clinically serious infection > CTCAE Grade 2.
  • Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
  • Bleeding

    1. Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug.
    2. Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug.
    3. Evidence or history of bleeding diathesis or coagulopathy
  • Serious non-healing wound, ulcer, or bone fracture.
  • Major surgery, open biopsy or significant traumatic injury within 4 weeks prior to first study drug.
  • Use of St. John's Wort or rifampin (rifampicin).
  • Known or suspected allergy to sorafenib or any agent given in the course of this trial.
  • Any condition that impairs patient's ability to swallow whole pills.
  • Any malabsorption problem.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01203787

United States, Florida
University of Florida Hepatology
Gainesville, Florida, United States, 32610-0277
Mayo Clinic
Jacksonville, Florida, United States, 32224
Florida Hospital Transplant Center
Orlando, Florida, United States, 32804
Tampa General Hospital
Tampa, Florida, United States, 33606
United States, Illinois
Loyola University Medical Center
Maywood, Illinois, United States, 60153
United States, Michigan
Henry Ford Health System
Detroit, Michigan, United States, 48202
United States, Pennsylvania
Drexel University College of Medicine
Philadelphia, Pennsylvania, United States, 19107
United States, Texas
University of Texas Health Science Center Houston
Houston, Texas, United States, 77030
Brooke Army Medical Center
San Antonio, Texas, United States, 78234
Sponsors and Collaborators
University of Florida
Principal Investigator: David R Nelson, MD University of Florida

Responsible Party: University of Florida Identifier: NCT01203787     History of Changes
Other Study ID Numbers: ONC-2010-19
First Posted: September 16, 2010    Key Record Dates
Results First Posted: February 11, 2015
Last Update Posted: March 5, 2015
Last Verified: February 2015

Keywords provided by University of Florida:
Hepatocellular Carcinoma
Liver Cancer

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Growth Substances
Physiological Effects of Drugs