Conditions: BCLC Stage B Hepatocellular Carcinoma BCLC Stage C Hepatocellular Carcinoma Hepatitis C Infection Refractory Liver Carcinoma Stage III Hepatocellular Carcinoma AJCC v7 Stage IIIA Hepatocellular Carcinoma AJCC v7 Stage IIIB Hepatocellular Carcinoma AJCC v7 Stage IIIC Hepatocellular Carcinoma AJCC v7 Stage IV Hepatocellular Carcinoma AJCC v7 Stage IVA Hepatocellular Carcinoma AJCC v7 Stage IVB Hepatocellular Carcinoma AJCC v7
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
This will be a Phase II study investigating single agent pembrolizumab (Keytruda®) as a second-line therapy for subjects with hepatocellular carcinoma (HCC) who either progressed on or after sorafenib or did not tolerate sorafenib.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the tolerability of intravenous (V) administration of pembrolizumab as second-line systemic therapy in subjects with advanced hepatocellular carcinoma. (Arm A and Arm B).

II. To evaluate the efficacy of pembrolizumab in combination with elbasvir/grazoprevir (Zepatier) as assessed by the proportion of subjects with hepatitis C virus (HCV) GT1 or GT4 achieving Sustained Virologic Response 12 weeks after the end of all HCV study therapy (SVR12), defined as HCV ribonucleic acid (RNA) below the lower limit of quantitation (LLOQ) (either target detected unquantifiable \[TD(u)\] or target not detected \[TND\]) 12 weeks after the end of all study therapy. (Arm B)

SECONDARY OBJECTIVES:

I. To estimate the objective response rate (ORR), per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by MD Anderson radiology.

II. To estimate the duration of response (DOR), disease control rate (DCR), time to progression (TTP), and progression-free survival (PFS) per RECIST 1.1 assessed by MD Anderson Department of Diagnostic Imaging.

III. To evaluate the safety of pembrolizumab in combination with Zepatier as assessed by the proportion of subjects with HCV GT1 or GT4 achieving SVR12 and SVR24, defined as HCV RNA below the LLOQ (either TD\[u\] or TND) 12 and 24 weeks after the end of all study therapy.

EXPLORATORY OBJECTIVES:

I. To estimate ORR, DOR, DCR, TTP, PFS and overall survival (OS) per immune response RECIST (irRECIST) as assessed by MD Anderson radiology.

II. To explore the relationship between progression on sorafenib versus intolerance of sorafenib and response to pembrolizumab.

III. To perform exploratory biomarker research to study the correlation between immunological and molecular changes in tumor tissues and peripheral blood with TTP, OS, and rate of adverse events (AEs).

IV. To explore the association between PD-1 ligand (PD-L1) expression by immunohistochemistry (IHC), somatic gene expression profiling (GEP) and antitumor efficacy of pembrolizumab based on RECIST 1.1.

V. To explore predictive biomarkers to study the correlation of independent effect of cirrhosis grade and severity of portal hypertension by magnetic resonance imaging (MRI) classification on OS.

VI. To explore retrospective risk stratification of the degree of the underlying liver dysfunction by IGF score.

To explore retrospective risk stratification of the degree of the underlying liver dysfunction by IGF-1 score. See section 2.1. VII. To assess whether pembrolizumab in combination with Zepatier affects the course of viral infections in subjects with underlying HCV GT1 or GT4. We hypothesize that pembrolizumab in combination with Zepatier will help to reduce viral loads in those with untreated HCV.

VIIII. To evaluate the response of HCV GT1 and GT4 to treatment as assessed by sustained virologic response at 4 and 12 weeks after the end of 12 to 16 weeks of pembrolizumab in combination with Zepatier dosing. Sustained virologic response is defined as defined as HCV RNA below the LLOQ (either TD\[u\] or TND).

IX. To evaluate the emergence of viral resistance-associated variants (RAVs) to pembrolizumab in combination with Zepatier in subjects with HCV GT1 or GT4 without RAVs as baseline .

X. To evaluate the efficacy of pembrolizumab in combination with Zepatier as assessed by the proportion of subjects with HCV GT1 or GT4 achieving undetectable (TND) HCV RNA and HCV RNA below the LLOQ at Weeks 2, 4, 12 and Follow- Up Week 4 (SVR4), Week 12 (SVR12), and Week 24 (SVR24).

XI. To explore the relationship between genetic variation and subject response to the treatment(s) administered.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive pembrolizumab as in arm A. Patients also receive elbasvir/grazoprevir orally (PO) once daily (QD) and ribavirin PO QD on days 1-28. Treatment continues for 12-16 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30-90 days and then every 12 weeks.

Arms:
arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive pembrolizumab as in arm A. Patients also receive elbasvir/grazoprevir orally PO QD and ribavirin PO QD on days 1-28. Treatment continues for 12-16 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Elbasvir/Grazoprevir intervention 2: Laboratory Biomarker Analysis intervention 3: Pembrolizumab intervention 4: Ribavirin
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given IV intervention 4: Given PO

Protocol document:
Prot_SAP_000.pdf: 
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