Sorafenib Dose Ramp-Up in Hepatocellular Carcinoma (HCC)

Multicenter, Randomized Pilot Study of the Effect of Sorafenib Dosing Schedule on Tolerability and Drug Delivery

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.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Sorafenib Ramp-Up Regimen; Drug: Sorafenib Standard Dosing Regimen

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
• Enrollment (Actual): 120
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: Nexavar(Bay43-9006)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	4 months-1/12/2010-1/27/14
Cumulative Dose of Sorafenib	Table below shows mean cumulative dose of sorafenib for each of the dosing regimens.	11/22/2010-1/27/14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Baseline-End of Treatment (11/22/2010-3/10/2014)
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.	11/22/2010-3/10/2014
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.	11/22/2010-3/10/2014
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

Collaborators and Investigators

• Sponsor: University of Florida
• Investigators: Principal Investigator: David R Nelson, MD, University of Florida

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: September 10, 2010
• First Submitted That Met QC Criteria: September 15, 2010
• First Posted (Estimate): September 16, 2010

Study Record Updates

• Last Update Posted (Estimate): March 5, 2015
• Last Update Submitted That Met QC Criteria: February 13, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Keywords: Hepatocellular Carcinoma; HCC; Liver Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: ONC-2010-19