Sorafenib Dose Ramp-Up in Hepatocellular Carcinoma (HCC)

Study Overview
=================
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.

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

Conditions
-----------------
Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Drug: Sorafenib Standard Dosing Regimen
* Drug: Sorafenib Ramp-Up Regimen


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sorafenib Standard Dosing Regimen<br>Sorafenib 400 mg (2 tablets of 200 mg) twice daily until end of treatment or week 24 | Drug: Sorafenib Ramp-Up Regimen<br>* 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<br>* Other names: Nexavar (Bay43-9006);|
| Experimental: Sorafenib Ramp-Up Regimen<br>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<br>* Sorafenib 400 mg twice daily until wk 24 or end of treatment<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatocellular Carcinoma, HCC, Liver Cancer