the Effect of Grazoprevir/Elbasvir and TACE vs. TACE Alone in Prolonging Survival of Patients With Non-resectable HCV Associated HCC.

Study Overview
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Brief Summary
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Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths in the world. Hepatitis C virus (HCV) is the most common underlying cause of cirrhosis and HCC in the western world. Most patients with HCC present with either non-resectable tumor and/or severe underlying liver dysfunction, and are not suitable candidates for curative treatments by resection or transplantation. Thus, for the majority of patients with HCV related HCC, the only option is prolongation of life without a chance for cure. These patients generally have a poor prognosis with a median survival of less than 1 year. Arterial obstruction of branches of the hepatic artery and simultaneous infusion of chemotherapy (Trans-arterial chemo-embolization or TACE) induces ischemic tumor necrosis with a high rate of objective tumor responses (30-60%). Overall, the median survival after TACE for intermediate HCC is about 20 months, an improvement over supportive care. Treatment with Grazoprevir/Elbasvir showed excellent results in phase 3 studies for patients with HCV genotype 1 (a and b) and genotype 4 infection and is approved for HCV treatment in the USA, Europe and Israel. Anti-HCV therapies may influence HCC biology by decreasing inflammation and may thus alter the tumor microenvironment.

Detailed Description
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Single center, open label, prospective pilot study. The study will include 20 HCV genotype 1 (a and b) cirrhotic patients (Child Pugh A compensated cirrhosis) with advanced, un-resectable HCC who are eligible for TACE. This pilot study will have one arm which will be compared to historical controls. All patients participating in the study will receive Grazoprevir/Elbasvir treatment according to established guidelines together with regular TACE treatments. The historical controls will refer to patients who received regular TACE treatments alone (standard of HCC care). Follow up will be for up to 24 months from TACE initiation.

Official Title
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Pilot Study to Assess the Effect of Grazoprevir/Elbasvir (ZEPATIER™) and Transarterial Chemoembolization (TACE) vs. TACE Alone in Prolonging Survival of Patients With Non-resectable HCV Associated Hepatocellular Carcinoma

Conditions
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HCV, HCC

Intervention / Treatment
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* Drug: Grazoprevir/Elbasvir
* Other: Medical records
* Procedure: Transarterial Chemoembolization


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with chronic HCV genotype 1 (a and b) infection and un-resectable HCC who are eligible for TACE Ages 18-75 years Willing to take part in a clinical trial and have signed an informed consent Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less Child-Pugh liver function class A Patients with expected survival of less than 1 year Adequate hematologic function (plt≥60, 000 /L; Hb≥8.5 g/dl; and INR≤1.7 Adequate hepatic function (albumin ≥3.5 g/dl; total bilirubin, ≤2 mg/dl; ALT and AST ≤5 times the upper limit of the normal range) Adequate renal function (serum creatinine ≤1.5 times the upper limit of normal range). Exclusion Criteria: Patients unwilling to sign the informed consent Patients unwilling or not capable to complete the anti-viral treatment with Grazoprevir/Elbasvir CPT score >7 Patients ineligible for TACE Patients with contraindications to elbasvir/grazoprevir Patients suffering from other underlying liver disease (HBV, HIV, PSC, PBC, AIH etc.) Patients with malignancies other than HCC Patients with previous anti-HCC treatment (RFA, TACE, SIRT or sorafenib) Active alcohol or substance use Previous liver transplantations Child Pugh B or C cirrhosis Total serum bilirubin >1.9 mg/dL Extra-hepatic spread (metastases) Pregnant/lactating women, minors and disabled/incapacitated persons

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: This is a single center, open label, prospective pilot study. The study will enroll 20 HCV genotype 1 cirrhotic patients with advanced and un-resectable HCC who are eligible for TACE. The patients will receive Grazoprevir/Elbasvir anti-viral treatment in accordance with established guidelines together with regular TACE treatments. Follow up will be for up to 24 months from TACE initiation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HCV patients with un-resectable HCC<br>HCV genotype 1 (a and b) cirrhotic patients (child pugh A compensated cirrhosis) with advanced and un-resectable HCC who are eligible for TACE . The patients will receive Grazoprevir/Elbasvir and Transarterial Chemoembolization. Their outcomes will be compared to the medical records of patients who underwent Transarterial Chemoembolization only, in the past. | Drug: Grazoprevir/Elbasvir<br>* anti-viral treatment for HCV<br>Other: Medical records<br>* Medical records of patients who underwent Transarterial Chemoembolization only, in the past.<br>Procedure: Transarterial Chemoembolization<br>* A minimally invasive procedure performed in interventional radiology to restrict a tumor's blood supply. Small embolic particles coated with chemotherapeutic drugs are injected selectively through a catheter into an artery directly supplying the tumor. These particles both block the blood supply and induce cytotoxicity, attacking the tumor in several ways.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | 15% or more increase in survival with the combination treatment of Grazoprevir/Elbasvir and TACE vs. historical control of TACE alone; Time Frame: from start of treatment to death from any cause, or last known date of survival | assessed up to 24 months | 
| Adverse events and serious adverse events (AEs, SAEs) | will be assessed in all patients receiving at least one dose of a combination therapy, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | 24 months | 
| Time to progression (TTP) | Time from start of treatment until the first documented event of symptomatic progression. | Assessed, up to 24 months | 
| SVR12 rates | : proportion of patients achieving SVR12 | 12 weeks after the last actual dose of Grazoprevir/Elbasvir | 
| Hepatic de-compensation as assessed by clinical end-points | development of ascites, and will undergo repeated liver function tests every 2 weeks to detect CPT increase. | Once a month up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to radiologic progression | a decrease in tumor in 15 % or more of the patients undergoing combination therapy vs. historical control of TACE alone | The time from start of treatment to disease progression, according to mRECIST, assessed up to 24 months. | 
| Disease-control rate | The percentage of patients who had a best-response rating of complete response, partial response, or stable disease (according to mRECIST) that was maintained for at least 28 days after the first demonstration of that rating on the basis of independent radiologic review | at least 28 days after the first demonstration of that rating on the basis of independent radiologic review | 
| decrease in tumor markers | A 50 % decrease in tumor markers in 15 % or more patients undergoing combination therapy vs. TACE alone | Screening and 24 months. | 
| quality of life | Assess quality of life as measured by SF-36 questionnaire | At screening, and months 3,13,22. | 
| Symptom severity score | Assess severity of symptoms as measured by FSHI8 questionnaire | At screening, and months 3,13,22. |