Study of Sorafenib and Transarterial Chemoembolization (TACE) to Treat Hepatocellular Carcinoma

Study Overview
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Brief Summary
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This study will combine two therapies to treat patients with unresectable hepatocellular carcinoma; sorafenib, and drug eluting beads delivered intra-arterially. The purpose of the study is to establish the safety and the effectiveness of the combination therapy. The investigators hypothesize that the combination of the two therapies will not result in greater toxicities to patients than that expected for either therapy given alone.

Official Title
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Phase II Trial of Sorafenib Combined With Doxorubicin Eluting Bead-Transarterial Chemoembolization (LC Bead-TACE) for Patients With Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma, Hepatoma

Intervention / Treatment
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* Drug: sorafenib
* Procedure: LC Bead-TACE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unresectable hepatocellular carcinoma (HCC) patients with liver-predominant disease as described in section 5.1, or patients with hepatocellular carcinoma who refuse surgery. No more than 30% of the cohort should have macrovascular invasion and/or asymptomatic extrahepatic disease. Multifocal HCC is acceptable, no diffuse HCC. Age > 18 years old Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Childs class of A or B (up to 7) (see Table 5.0) Adequate end-organ function as manifested by: Absolute neutrophil count of > 1500/mm3 and platelets > 50,000/mm3 Creatinine ≤ 2.0 Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN) Total bilirubin of ≤ 3 Albumin > 2.0 International normalized ratio (INR) < 2.0 Leukocyte count >3000 cells/mm3 Amylase and lipase ≤ 1.5 the upper limit of normal Patients who have received previous hepatic surgery , radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), or cryoablation are eligible if target lesion(s) have not been treated and local therapy completed > 6 weeks prior to entry. Left ventricular ejection fraction ≥ 45% Patients with asymptomatic HIV infection are not eligible Willingness of male and female subjects, who are not surgically sterile or post menopausal, to use reliable methods of birth control for the duration of the study and for 30 days after the last dose of study medication. Patient must have signed informed consent prior to registration on study. Resolution of all acute toxic effects of any prior local treatment to Common Terminology Criteria for Adverse Events (CTCEA) Grade 1 or 0. At least one tumor lesion can be accurately measured in at least one dimension according to RECIST. The lesion has not been previously treated with local therapy (such as surgery, radiation therapy, RFA, PEI, or cryoablation) unless it has shown progression in the interim. Exclusion Criteria: Patients unable to swallow oral medications Prior embolization, systemic or radiation therapy for HCC (liver) Tumor burden in the liver exceeding 70%. Complete occlusion of the entire portal venous system Ascites refractory to diuretic therapy (minimal or trace on imaging is acceptable) Previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, and T1). Any cancer curatively treated > 3 years prior is permitted. Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry History of bleeding within the past 4 weeks (unless deemed by PI as clinically insignificant, for ex., a brief episode of epistaxis) Any contraindication to doxorubicin administration Evidence of severe or uncontrolled systemic diseases, Congestive cardiac failure > New York Heart Association (NYHA) class 2, myocardial ischemia within 6 months, active coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, unstable angina, or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial Any prior history of hypertensive crisis or hypertensive encephalopathy History of stroke or transient ischemic attack within 6 months prior to study enrollment Inadequately controlled hypertension (defined as systolic blood pressure of 150/100 mmHg on antihypertensive medications) (patients with treated hypertension are eligible) Significant vascular disease (e.g., aortic aneurysm, aortic dissection, peripheral vascular disease) History of organ allograft Presence of grade > 2 hepatic encephalopathy (see Appendix D) Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an additional experimental drug Evidence of bleeding diathesis or coagulopathy or on warfarin. Note: If a patient has been on coumadin for a period of 1 month and has been stable, they may be accepted into the protocol. Presence of clinically evident central nervous system or brain metastases Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study Vascular anatomy that precludes catheter placement or injection of LC Bead microspheres Presence of collateral vessel pathways potentially endangering normal territories during embolization Pregnant (positive pregnancy test) or lactating Inability to comply with study and/or follow-up procedures Life expectancy of less than 12 weeks Child B8, B9 and C ECOG ≥ 2 Patients with concomitant HIV infection or AIDS-related or serious acute or chronic illness Presence of porto-systemic shunt Severe atheromatosis Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of study results Active clinically serious infections (>grade 2) Patients receiving therapy for hepatitis A, B, or C. Patients with obvious and/or symptomatic extrahepatic disease. Findings of uncertain significance, such as lung lesions less than 10 mm in diameter or enlarged periportal lymph nodes will not exclude patients, however, findings highly suspicious for metastatic HCC will exclude patients from this study. Any contraindication for an arterial procedure such as impaired clotting tests (platelet count < 50.000/mm3 or prothrombin activity < 50 percent) Any contraindication for systemic chemotherapy administration (serum bilirubin > 3mg/dL, leukocyte count < 3.000 cells/mm3) Any contraindication for sorafenib administration

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: sorafenib and drug eluting beads<br>single arm | Drug: sorafenib<br>* sorafenib: given 400 mg twice per day for as long as it is beneficial<br>* Other names: sorafenib (Nexavar);Procedure: LC Bead-TACE<br>* LC Beads loaded with doxorubicin Doxorubicin loaded LC Beads: given intra-arterially into the liver, up to fours times in a 6 month period<br>* Other names: LC Beads manufactured by Biocompatibles;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Treatment toxicities assessed by CTCAE v3.0 were stratified by cycle - patients on Cycle 1, and patients on Cycles 2-5 or more. 50 patients were reviewed for toxicities for Cycle 1, and all 50 patients experienced at least one adverse event during this time period. | 6 weeks (Cycle 1) | 
| Safety Will be Assessed by Grading Toxicities Reported at Intervals Throughout the Study. Higher Grade Toxicities Will be Assessed for Their Degree of Relatedness to the Study Treatment. | Treatment toxicities assessed by CTCAE v3.0 were stratified by cycle - patients on Cycle 1, and patients on Cycles 2-5 or more. | 2 years (Cycles 2-5+) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) to Determine Response and Disease Control Rate | Efficacy as assessed by radiographic tumor response using the RECIST criteria at baseline and at 6 months post the initiation of treatment. 33 out of the original 50 patients were evaluable at this time point, with 17 out of the 50 exiting prior to 6 months or were not assessable by RECIST criteria. Complete response (CR): Disappearance of all lesions targeted with therapy Partial Response (PR): at least 30% decrease in sum of longest diameter (LD) of targeted lesions Progressive Disease (PD): at least 20% increase in the sum of LD of targeted lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD | 6 months | 
| Efficacy Assessed by European Association for the Study of the Liver (EASL) Criteria to Determine Response and Disease Control Rate | Efficacy as assessed by radiographic tumor response using the EASL criteria at baseline and at 6 months post the initiation of treatment. Complete response (CR): 100% tumor necrosis Partial Response (PR): more than 50% tumor necrosis Progressive Disease (PD): increase in tumor enhancement by more than 25% Stable Disease (SD): Cases that do not qualify for one of the above criteria | 6 months | 
| Efficacy - Median TTP After Combination Treatment With Sorafenib and TACE | Time to progression (TTP) - defined as the time from initiation of therapy to disease progression (radiological). Median TTP calculated for all subjects and stratified by Barcelona Clinic Liver Cancer (BCLC) staging. 46 patients out of 50 were reviewed for this outcome. 3 patients were excluded because they underwent liver transplantation and 1 patient was excluded for hepatic resection. | 3 years | 
| Efficacy - Overall Survival (OS) After Combination Treatment With Sorafenib and TACE | Overall survival was assessed with Kaplan-Meier estimates of survival, and the Mantel-Cox log-rank test was used to determine differences in survival. All 50 patients were included in survival analyses as all 50 received at least one dose of sorafenib. | 3 years | 
| Efficacy - Factors Associated With Overall Survival (OS) After Combination Treatment With Sorafenib and TACE | Overall survival was assessed with Kaplan-Meier estimates of survival, and the Mantel-Cox log-rank test was used to determine differences in survival. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary liver cancer, sorafenib, Nexavar, doxorubicin, drug eluting beads, transarterial chemoembolization