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

Tel-Aviv Sourasky Medical Center20 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Patients with chronic HCV genotype 1 (a and b) infection and un-resectable HCC who are eligible for TACE 2. Ages 18-75 years 3. Willing to take part in a clinical trial and have signed an informed consent 4. Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less 5. Child-Pugh liver function class A 6. Patients with expected survival of less than 1 year 7. Adequate hematologic function (plt≥60, 000 /L; Hb≥8.5 g/dl; and INR≤1.7 8. 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) 9. Adequate renal function (serum creatinine ≤1.5 times the upper limit of normal range). Exclusion Criteria: 1. Patients unwilling to sign the informed consent 2. Patients unwilling or not capable to complete the anti-viral treatment with Grazoprevir/Elbasvir 3. CPT score \>7 4. Patients ineligible for TACE 5. Patients with contraindications to elbasvir/grazoprevir 6. Patients suffering from other underlying liver disease (HBV, HIV, PSC, PBC, AIH etc.) 7. Patients with malignancies other than HCC 8. Patients with previous anti-HCC treatment (RFA, TACE, SIRT or sorafenib) 9. Active alcohol or substance use 10. Previous liver transplantations 11. Child Pugh B or C cirrhosis 12. Total serum bilirubin \>1.9 mg/dL 13. Extra-hepatic spread (metastases) 14. Pregnant/lactating women, minors and disabled/incapacitated persons

Outcomes

Primary Outcomes

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

Time frame: 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

Time frame: 24 months

Time to progression (TTP)

Time from start of treatment until the first documented event of symptomatic progression.

Time frame: Assessed, up to 24 months

SVR12 rates

: proportion of patients achieving SVR12

Time frame: 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.

Time frame: Once a month up to 24 months

Secondary Outcomes

Time to radiologic progression

a decrease in tumor in 15 % or more of the patients undergoing combination therapy vs. historical control of TACE alone

Time frame: 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

Time frame: 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

Time frame: Screening and 24 months.

quality of life

Assess quality of life as measured by SF-36 questionnaire

Time frame: At screening, and months 3,13,22.

Symptom severity score

Assess severity of symptoms as measured by FSHI8 questionnaire