Effectiveness and Safety Study of TACE Plus Oral Sorafenib for Unresectable HCC

Study Overview
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Brief Summary
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The purpose of this study is to determine if TACE plus Sorafenib will improve outcome in patients with advanced hepatocellular carcinoma (HCC) not amenable to surgery.

Detailed Description
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The proposed study will make an important contribution to understanding not only the safety and efficacy of sorafenib in addition to TACE in patients diagnosed with unresectable HCC, but this will also be the first clinical trial with sorafenib to assess the effects of this novel therapy on HRQL. Understanding the effects of sorafenib on HRQL is critical in the treatment of HCC secondary to the modest benefits in survival that have been reported with conventional therapies. Our team has one of the largest experiences in evaluating HRQL in patients diagnosed with unresectable hepatocellular carcinoma. We have previously reported on alternative methods of evaluating HRQL, solutions for missing data in clinical trials as well as tested statistical and clinically meaningful differences, within and between treatment groups, in clinical trials with patients diagnosed with hepatobiliary carcinoma.

Official Title
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Phase II Trial of Transcatheter Arterial Chemoembolization (TACE) Plus Oral Sorafenib (BAY 43-9006, Nexavar®) for Unresectable Hepatocellular Carcinoma (HCC)

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Sorafenib
* Drug: TACE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with HCC seen at UPMC will be enrolled in this study if they meet the following eligibility criteria: Adults patients (≥ 18 years of age) with a diagnosis of HCC which is not amenable to surgical resection or local ablative therapy Histological confirmed HCC or clinical/laboratory diagnosis of HCC or nodules larger than 2 cm with typical vascular features or AFP > 200 Patient must have quantifiable disease limited to the liver Patients must have at least one tumor lesion that meets both of the following criteria: The lesion can be accurately measured in at least one dimension according to RECIST criteria The lesion has not been previously treated with surgery, radiation therapy, radiofrequency ablation, percutaneous ethanol or acetic acid injection, or cryoablation. ECOG performance status (PS) <2 No prior targeted antiangiogenic therapy. Metronomic chemotherapies are allowed. At least 4 weeks since prior systemic chemotherapy At least 4 weeks since prior TACE At least 4 weeks since prior interferon Not pregnant No significant baseline liver dysfunction. Cirrhotic status of Child-Pugh class A only No significant renal impairment (creatinine clearance < 30 mL/minute) or patients on dialysis No current infections requiring antibiotic therapy Not on anticoagulation or suffering from a known bleeding disorder No unstable coronary artery disease or recent MI The following laboratory parameters: Platelet count ≥ 60,000/µL Hemoglobin ≥ 8.5 g/dL Total bilirubin ≤ 1.5 mg/dL ASL and AST ≤ 5 x upper limit of normal Serum creatinine ≤ 1.5 x upper limit of normal INR ≤ 1.5 or a Pt/PTT within normal limits Absolute neutrophil count (ANC) > 1,500/mm3 Ability to understand the protocol and to agree to and sign a written informed consent document Exclusion Criteria: Previous or concurrent cancer that is distinct in primary site or histology from HCC except cervical carcinoma in situ, treated basal-cell carcinoma of the skin, superficial bladder tumors (Ta, Tis & T1), and any cancer curatively treated > 3 years prior to entry is permitted Renal failure requiring hemo- or peritoneal dialysis Child-Pugh B & C hepatic impairment History of cardiac disease: > NY Heart Association (NYHA) class 2 congestive heart failure, active coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, and uncontrolled hypertension. Myocardial infarction more than 6 months prior to study entry is permitted. Active clinically serious infections (> CTCAEv3 grade 2) Known history of HIV Known central nervous system tumors including metastatic brain disease History of organ allograft Substance abuse (current), psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results. Known or suspected allergy to the investigational agents or any agent given in association with this trial. Patients unable to swallow oral medications. Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of the study drug. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg, despite optimal medical management Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months 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 Serious non-healing wound, ulcer, or bone fracture Excluded therapies and medications, previous and concomitant: Prior use of Raf-kinase inhibitors (RKI), VEGF inhibitors, MEK inhibitors, or farnesyl transferase inhibitors Major surgery within 6 weeks of start of study drug Radiotherapy during study or within 3 weeks prior to start of study drug. Use of biologic response modifiers such as granulocyte colony-stimulating factor (G-CSF) within 3 weeks prior to study entry. Autologous bone marrow transplant or stem cell rescue within four months of study drug initiation Concomitant treatment with rifampin or St. John's wort.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tace and Sorafenib<br>Patients with unresectable HCC will be treated with TACE in combination with oral sorafenib administration. TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin. Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment. | Drug: Sorafenib<br>* Oral sorafenib (400 mg BID) will start the next day after the first TACE treatment until unacceptable toxicity occurs, or until study termination.<br>* Other names: Nexavar;Drug: TACE<br>* TACE will be accomplished with gelatin microspheres (Embospheres) following delivery of 125 mg/m2 of cisplatin.<br>* Other names: Transarterial Chemoembolization;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Progression-free Survival in This Patient Population Treated With the Proposed Combination Treatment Modality | Progression free survival (PFS) is calculated as the time interval between the date on which a patient first received protocol treatment and the documented date of disease progression or death. For a surviving and progression-free patient, PFS is censored by the last follow-up date when that patient is documented to be progression free. Progression is defined using RECIST v1.0, as a 20% increase in the sum of the longest diameter of target lesions, or a measureable increase in a non-target lesion, or the appearance of new lesions. | Up to 24 months (from initial treatment through 12 months follow-up) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the Overall Survival in Patients Treated With This Combination Regimen | Overall survival (OS) is calculated as the time interval between the date on which a patient first received protocol treatment and the documented date of death. For a surviving patient, OS is censored by the last follow-up date when that patient is documented to be alive. | From date of initial treatment until the date of death from any cause | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular, Carcinoma, TACE, Sorafenib, Transcatheter Arterial Chemoembolization, Nexavar, Unresectable