Sorafenib With Capecitabine for Patients With Measurable Hepatocellular Carcinoma

Study Overview
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Brief Summary
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This research study will evaluate Sorafenib (Nexavar®) and Capecitabine (Xeloda®) to see the following: how effective this combination of study drugs will be in treating HCC how long subjects respond to these study drugs what types of side effects can be expected, and how severe the side effects are All subjects in this study will receive: Sorafenib twice a day by mouth Capecitabine twice a day by mouth Treatment will be given in a 28-day treatment cycle. Subjects will take sorafenib every day of the cycle. Subjects will take capecitabine on days 1-7 and 15-21 of the cycle

Detailed Description
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Hepatocellular carcinoma (HCC), also known as primary liver cancer, is the most common form of liver cancer and is responsible for 80 percent of the primary malignant liver tumors in adults. It is the fifth most common cancer in the world. HCC disproportionately affects men, with four times as many men developing the disease as women. In 2002, approximately 626,000 cases of HCC were reported worldwide (15,000 in the United States and 53,600 in Europe), and more than 600,000 deaths (about 13,000 Americans and 57,000 Europeans) due to HCC were reported. The five-year relative survival rate is about seven percent. The Gem-Ox regimen has been used in the treatment of pancreatic cancer with encouraging results. Preliminary results of the Gem-Ox combination have been encouraging as well.Based on these observations the possibility of adding bevacizumab, a monoclonal antibody against VEGF, is being studied by other investigators. However, the combination of GEM-OX with bevacizumab is unlikely to be tolerated by HCC patients with Child-Pugh class B and C liver cirrhosis especially those with significant thrombocytopenia.It would seem therefore that the agents that could be tolerated by cirrhotic patients with advanced HCC would include capecitabine, erlotinib and sorafenib. We propose this phase II trial of sorafenib + capecitabine combination in patients with HCC and advanced liver cirrhosis who have a platelet count of ≥ 40,000 and a Child-Pugh (C-P) class A-and B liver cirrhosis with a life expectancy of ≥16 weeks.

Official Title
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Sorafenib in Combination With Capecitabine for Patients With Measurable Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Sorafenib & Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of hepatocellular carcinoma The lesion or lesions are not resectable with curative intent. Prior loco-regional treatment (resection, RFA, chemoembolization) is allowed. Adequate bone marrow function: Absolute neutrophil count (AGC) >1500/µL Platelet count >60,000 /µL Renal function: Serum creatinine < 2.0 mg/dl, and a calculated CCT of > 30 mL/min. Hepatic function:(Patients with a Child-Pugh (C-P) class A-B) Bilirubin < 2.8 mg/dl (provided the Child-Pugh class of liver cirrhosis is A or B (7) (ie. The Child-Pugh score is only 7 points) ALT and AST ≤ 5.0 times the ULN • Hemoglobin > 8.5 g/dl ECOG/Zubrod/SWOG Performance Status = 0>1 Life expectancy > 16 weeks Male or female' age >18 years Patients of childbearing potential must be using an effective means of contraception. INR < 1.5 or a PT/PTT within normal limits. Exclusion Criteria: Any prior systemic therapy including chemotherapy of targeted agents Uncontrolled ascites defined as not easily controlled by stable doses of diuretics. Pregnant or lactating females 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. Uncontrolled' clinically significant dysrhythmia History of prior malignancy within the prior 3 years, with the exception of non-melanoma carcinomas of the skin, carcinoma in situ of the cervix or breast, Rai Stage I chronic lymphocytic leukemia and superficial bladder cancer. Prior radiotherapy to an indicator lesion unless there is objective evidence of tumor growth in that lesion Uncontrolled metastatic disease of the central nervous system Radiotherapy within the 2 weeks before Cycle 1' Day 1 Surgery within the 2 weeks before Cycle 1' Day 1 Any co morbid condition that' in the view of the attending physician' renders the patient at high risk from treatment complications. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management. Known human immunodeficiency virus (HIV) infection. Patients with chronic Hepatitis B or C infections are eligible. 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. 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. Evidence or history of bleeding diathesis or coagulopathy. 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
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Minimum Age: 18 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: Arm 1: Sorafenib & Capecitabine<br>Intervention: Sorafenib & Capecitabine: Sorafenib twice a day by mouth (400mg) Capecitabine twice a day by mouth (850mg) | Drug: Sorafenib & Capecitabine<br>* Intervention: Sorafenib twice a day by mouth (400mg), Capecitabine twice a day by mouth (850mg). One cycle of treatment will consist of capecitabine on days 1-7 and 15-22 while sorafenib will be given daily continuously. Cycles will be repeated every 28 days.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Adverse Events | The primary objective of the study is to evaluate safety and tolerability of the study treatment regimen. The analyses will be descriptive and no formal hypotheses testing will be performed. Toxicities (i.e. Adverse Events) are evaluated prior to each treatment and during any clinical visit. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate of Response (DCR) | Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Target lesions are assessed by computerized tomography (CT) or magnetic resonance imaging (MRI:) Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient decrease in the sum of the longest diameter of target lesions to qualify for PR nor sufficient increase in the sum of the longest diameter of target lesions to qualify for Progressive Disease; Progressive Disease (PD), 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Disease control rate (DCR) is the sum of the percentages of patients achieving complete and partial responses and stable disease | 6 months | 
| Overall Survival (OS) | The time from treatment initiation to death by any cause | 5 years | 
| Progression Free Survival (PFS) | The time from treatment initiation to disease progression or death by any cause. Progression is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Target lesions are assessed by computerized tomography (CT) or magnetic resonance imaging (MRI:) Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient decrease in the sum of the longest diameter of target lesions to qualify for PR nor sufficient increase in the sum of the longest diameter of target lesions to qualify for Progressive Disease; Progressive Disease (PD), 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INST 0820, sorafenib, capecitabine, hepatocellular carcinoma, lung, nexavar, xeloda, liver cancer