Sorafenib Therapy Prior to Radiofrequency Ablation for Intermediate Sized Hepatocellular Cancer

Study Overview
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Brief Summary
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The purpose of this research study is to determine if sorafenib improves the effectiveness of a procedure called radiofrequency ablation (RFA) for the treatment of hepatocellular cancer (HCC). Radiofrequency ablation has been used to treat many types of tumors, including hepatocellular cancers. During RFA a needle is inserted into the tumor tissue and heat is used to kill the tumor cells. Sorafenib has been approved by the FDA for the treatment of hepatocellular cancer that cannot be treated with surgery. Pre-clinical data suggests that sorafenib may improve the efficacy of RFA.

Detailed Description
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Hepatocellular cancer (HCC) has a poor prognosis with increasing mortality in the United States. Because HCC generally develops in patients with underlying liver disease, resection is often not possible. Liver transplant improves survival for HCC patients but given the national organ donor shortage often patients have to wait a considerable time for transplant. Liver-directed therapies such as radiofrequency ablation (RFA) remain important tools to control tumor growth and to potentially bridge patients to liver transplant. However, liver-directed therapies for HCC tumors greater than 3cm in size are suboptimal, leaving a critical unmet need. Antiangiogenic systemic agents, such as oral sorafenib, reduce tumor blood flow and have been shown to improve RFA efficacy in animal and in computer models.

Official Title
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Randomized, Double-Blind, Placebo-Controlled, Phase II Trial Of Short Course Sorafenib Therapy Prior to Radiofrequency Ablation for Intermediate Sized (3.5 to 7cm) Hepatocellular Cancer

Conditions
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Hepatocellular Cancer

Intervention / Treatment
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* Drug: Sorafenib
* Procedure: radiofrequency ablation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed hepatocellular cancer (HCC) by pathology or by NCCN imaging guidelines All HCC stages are allowed. May be a liver transplant candidate. At least one tumor (index tumor) accurately measured as 3.5-7cm in diameter (long and short axis diameter to be recorded, but only one needs to meet this criteria) on baseline imaging. No prior therapy for the index tumor No prior systemic treatment for HCC within 4 weeks and no prior anti-VEGF therapy within 8 weeks of study entry. Life expectancy > 8 weeks. ECOG >=0 or 1 RFA clinically indicated for index tumor. Acceptable overall RFA and anesthesia risk. Adequate bone marrow, liver and renal function: Hemoglobin >9.0 g/dl; Absolute neutrophil count (ANC)>1,500/mm3; Platelet count correctable to >50,000/mm3; compensated liver function (Child-Turcotte-Pugh A, B7 or B8); Creatinine <1.5 times ULN; INR correctable to <1.5. Ability to take oral medication and no evidence of impaired absorption. Exclusion Criteria Urgent treatment of the index tumor anticipated. Participants who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Participants currently receiving any other study agents. Known brain metastases History of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib. Participants receiving medications or substances that are inducers of CYP3A4 (rifampicin, St. John's wort, phenytoin, carbamazepine, phenobarbital and dexamethasone) or that are metabolized/eliminated by predominantly UGT1A1 pathway or by CYP2B6 and CYP2C8. Decompensated liver disease Uncontrolled hypertension Thrombolic or embolic events within the past 6 months. Hemorrhage/bleeding event within 4 weeks Serious non-healing wound, ulcer, or bone fracture. Evidence of severe or uncorrectable bleeding diathesis or coagulopathy Major surgery, open biopsy or significant traumatic injury within 4 weeks of study entry. Contraindication to or inability to undergo the RFA procedure, Contraindication to or inability to undergo imaging with MRI Uncontrolled intercurrent illness Individuals with a history of a different malignancy unless disease-free for at least 5 years and are deemed by the Investigator to be at low risk for recurrence. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. HIV-positive individuals on combination antiretroviral therapy For additional inclusion/exclusion criteria details contact Study Site.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib<br>Participants received a nine-day course of oral sorafenib 400 mg twice a day and radiofrequency ablation (RFA) on Day 10. Tumors in each group underwent RFA using a standard regimen (1 cm tip, 70 ± 2º C, 5 min). | Drug: Sorafenib<br> <br> * Other names: Nexavar;Procedure: radiofrequency ablation<br> <br> * Other names: RFA;|
| Placebo Comparator: Placebo<br>Participants received a nine-day course of placebo pills twice a day and radiofrequency ablation (RFA) on Day 10. Tumors in each group underwent RFA using a standard regimen (1 cm tip, 70 ± 2º C, 5 min). | Procedure: radiofrequency ablation<br> <br> * Other names: RFA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coagulation Zone Diameter-Short Axis | The size of the coagulation zone was determined on CT imaging obtained after RFA for the single index tumor. | Up to day 50 from study enrollment (target 30 days after RFA) | 
| Coagulation Zone Diameter-Long Axis | The size of the coagulation zone was determined on CT imaging obtained after RFA for the single index tumor. | Up to day 50 from study enrollment (target 30 days after RFA) | 
| Coagulation Zone Volume | The size of the coagulation zone was determined on CT imaging obtained after RFA for the single index tumor. | Up to day 50 from study enrollment (target 30 days after RFA) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility Rate | Feasibility rate is defined as the percentage of participants completing radiofrequency ablation following 9 days of sorafenib or placebo therapy. | Up to day 14 since enrollment | 
| Number of Treatment-Related Grade 1-4 Adverse Events (AEs) by Day 9 | AEs were assessed based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0). The number of Grade 1-4 AEs with treatment attribution possibly, probably or definitely related up to day 9 of study drug treatment were counted for this outcome. Worst grade by patient within AE type was calculated. Participants could have multiple different AE types within a grade. | Day 9 | 
| Number of Treatment-Related Grade 1-4 Adverse Events (AEs) on Day of Radiofrequency Ablation (RFA) | AEs were assessed based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0). The number of Grade 1-4 AEs with treatment attribution possibly, probably or definitely related on day of RFA treatment were counted for this outcome. Worst grade by patient within AE type was calculated. Participants could have multiple AE types within a grade. | Up to day 14 (target day 10 RFA) | 
| Number of Treatment-Related Grade 1-4 Adverse Events (AEs) One Month After Radiofrequency Ablation (RFA) | AEs were assessed based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v3.0). The number of Grade 1-4 AEs with treatment attribution possibly, probably or definitely related one month after RFA treatment were counted for this outcome. Worst grade by patient within AE type was calculated. Participants could have multiple AE types within a grade. | Up to day 40 post RFA (target 30 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular Cancer, HCC, Liver Cancer, radiofrequency ablation, RFA, sorafenib, nexavaar, liver directed therapy, interventional radiology