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Sorafenib Dose Ramp-Up in Hepatocellular Carcinoma (HCC)

Primary Purpose

Hepatocellular Carcinoma

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Sorafenib Standard Dosing Regimen
Sorafenib Ramp-Up Regimen
Sponsored by
University of Florida
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring Hepatocellular Carcinoma, HCC, Liver Cancer

Eligibility Criteria

20 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Florida Hepatology
  • Mayo Clinic
  • Florida Hospital Transplant Center
  • Tampa General Hospital
  • Loyola University Medical Center
  • Henry Ford Health System
  • Drexel University College of Medicine
  • University of Texas Health Science Center Houston
  • Brooke Army Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Sorafenib Standard Dosing Regimen

Sorafenib Ramp-Up Regimen

Arm Description

Sorafenib 400 mg (2 tablets of 200 mg) twice daily until end of treatment or week 24

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

Outcomes

Primary Outcome Measures

Total (Cumulative) Dose Delivery of Sorafenib
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.
Cumulative Dose of Sorafenib
Table below shows mean cumulative dose of sorafenib for each of the dosing regimens.

Secondary Outcome Measures

Safety and Efficacy of Sorafenib Dosing Regimens
Safety of Sorafenib was assessed by the frequency and severity of adverse events according to NCI-CTCAE grading
Safety of Dosing Regimens as Assessed by the Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE
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.
Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE
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.
Number of Subjects With Dose Interruptions
Number of Subjects With Dose Reductions

Full Information

First Posted
September 10, 2010
Last Updated
February 13, 2015
Sponsor
University of Florida
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1. Study Identification

Unique Protocol Identification Number
NCT01203787
Brief Title
Sorafenib Dose Ramp-Up in Hepatocellular Carcinoma (HCC)
Official Title
Multicenter, Randomized Pilot Study of the Effect of Sorafenib Dosing Schedule on Tolerability and Drug Delivery
Study Type
Interventional

2. Study Status

Record Verification Date
February 2015
Overall Recruitment Status
Completed
Study Start Date
December 2010 (undefined)
Primary Completion Date
January 2014 (Actual)
Study Completion Date
March 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Florida

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma
Keywords
Hepatocellular Carcinoma, HCC, Liver Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
120 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sorafenib Standard Dosing Regimen
Arm Type
Active Comparator
Arm Description
Sorafenib 400 mg (2 tablets of 200 mg) twice daily until end of treatment or week 24
Arm Title
Sorafenib Ramp-Up Regimen
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Sorafenib Standard Dosing Regimen
Other Intervention Name(s)
Nexavar(Bay43-9006)
Intervention Description
Sorafenib 400 mg twice daily until wk 24 or end of treatment
Intervention Type
Drug
Intervention Name(s)
Sorafenib Ramp-Up Regimen
Other Intervention Name(s)
Nexavar (Bay43-9006)
Intervention Description
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
Primary Outcome Measure Information:
Title
Total (Cumulative) Dose Delivery of Sorafenib
Description
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.
Time Frame
4 months-1/12/2010-1/27/14
Title
Cumulative Dose of Sorafenib
Description
Table below shows mean cumulative dose of sorafenib for each of the dosing regimens.
Time Frame
11/22/2010-1/27/14
Secondary Outcome Measure Information:
Title
Safety and Efficacy of Sorafenib Dosing Regimens
Description
Safety of Sorafenib was assessed by the frequency and severity of adverse events according to NCI-CTCAE grading
Time Frame
Baseline-End of Treatment (11/22/2010-3/10/2014)
Title
Safety of Dosing Regimens as Assessed by the Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE
Description
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.
Time Frame
11/22/2010-3/10/2014
Title
Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE
Description
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.
Time Frame
11/22/2010-3/10/2014
Title
Number of Subjects With Dose Interruptions
Time Frame
Baseline-End of Treatment (11/22/2010-3/10/2014)
Title
Number of Subjects With Dose Reductions
Time Frame
11/22/2010-3/10/2014

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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: Hemoglobin > 8.5 g/dl Absolute neutrophil count (ANC) > 1,500/mm3 Platelet count > 50,000/mm3 Total bilirubin < 3 mg/dl ALT and AST ( < 5 x ULN) 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 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. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis. 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 Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug. Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David R Nelson, MD
Organizational Affiliation
University of Florida
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Florida Hepatology
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610-0277
Country
United States
Facility Name
Mayo Clinic
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
Florida Hospital Transplant Center
City
Orlando
State/Province
Florida
ZIP/Postal Code
32804
Country
United States
Facility Name
Tampa General Hospital
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Facility Name
Loyola University Medical Center
City
Maywood
State/Province
Illinois
ZIP/Postal Code
60153
Country
United States
Facility Name
Henry Ford Health System
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Drexel University College of Medicine
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
University of Texas Health Science Center Houston
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Brooke Army Medical Center
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78234
Country
United States

12. IPD Sharing Statement

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Sorafenib Dose Ramp-Up in Hepatocellular Carcinoma (HCC)

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