Sorafenib Dose Ramp-Up in Hepatocellular Carcinoma (HCC)

Phase 4

Completed

• Conditions: Hepatocellular Carcinoma
• Interventions: Drug: Sorafenib Ramp-Up Regimen; Drug: Sorafenib Standard Dosing Regimen

• Registration Number: NCT01203787
• Lead Sponsor: 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.

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 Timeline

• Study First Submitted: 2010-09-10
• Study First Submitted QC: 2010-09-15
• Study First Posted: 2010-09-16
• Study Start: 2010-12
• Primary Completion: 2014-01
• Study Completion: 2014-03
• Results First Submitted: 2015-01-27
• Results First Submitted QC: 2015-01-27
• Status Verified: 2015-02
• Results First Posted: 2015-02-11
• Last Update Submitted: 2015-02-13
• Last Update Posted: 2015-03-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 120

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sorafenib Standard Dosing Regimen	Sorafenib Ramp-Up Regimen	Sorafenib 400 mg (2 tablets of 200 mg) twice daily until end of treatment or week 24
Sorafenib Ramp-Up Regimen	Sorafenib Standard Dosing 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

Primary Outcome Measures

Name	Time	Method
Total (Cumulative) Dose Delivery of Sorafenib	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.
Cumulative Dose of Sorafenib	11/22/2010-1/27/14	Table below shows mean cumulative dose of sorafenib for each of the dosing regimens.

Secondary Outcome Measures

Name	Time	Method
Safety and Efficacy of Sorafenib Dosing Regimens	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
Safety of Dosing Regimens as Assessed by the Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE	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.
Frequency and Severity of Adverse Events According to National Cancer Institute- CTCAE	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.
Number of Subjects With Dose Interruptions	Baseline-End of Treatment (11/22/2010-3/10/2014)
Number of Subjects With Dose Reductions	11/22/2010-3/10/2014

Trial Locations

Locations (9)

University of Florida Hepatology; 🇺🇸 Gainesville, Florida, United States

Mayo Clinic; 🇺🇸 Jacksonville, Florida, United States

Florida Hospital Transplant Center; 🇺🇸 Orlando, Florida, United States

Loyola University Medical Center; 🇺🇸 Maywood, Illinois, United States

Henry Ford Health System; 🇺🇸 Detroit, Michigan, United States

Drexel University College of Medicine; 🇺🇸 Philadelphia, Pennsylvania, United States

Tampa General Hospital; 🇺🇸 Tampa, Florida, United States

University of Texas Health Science Center Houston; 🇺🇸 Houston, Texas, United States

Brooke Army Medical Center; 🇺🇸 San Antonio, Texas, United States