Sorafenib Tosylate and Pembrolizumab in Treating Patients With Advanced or Metastatic Liver Cancer

Study Overview
=================
Brief Summary
-----------------
This phase Ib/II trial studies how well sorafenib tosylate and pembrolizumab work in treating patients with liver cancer that has spread to other parts of the body. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving sorafenib tosylate and pembrolizumab may work better in treating patients with liver cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To assess the overall response rate (ORR) related to the combination of sorafenib tosylate (sorafenib) + pembrolizumab in advanced hepatocellular carcinoma patients. SECONDARY OBJECTIVES: I. To assess time to tumor progression in patients who received the combination therapy of sorafenib + pembrolizumab compared to historical data on sorafenib only treatment in patients with advanced hepatocellular carcinoma. TERTIARY OBJECTIVES: I. To obtain data on changes in immune cell function and in the tumor microenvironment pre- and post-treatment to screen for potential biomarkers that may be able to predict clinical benefit. - All patients will be followed for survival OUTLINE: Patients receive sorafenib tosylate orally (PO) twice daily (BID) on days -28 to -1 and 1-21. Patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 3 months for up to 1 year, then every 6 months thereafter.

Official Title
-----------------
A Phase Ib/ II Study of Sorafenib and Pembrolizumab in Advanced Hepatocellular Cancer (HCC)

Conditions
-----------------
Advanced Adult Hepatocellular Carcinoma, Child-Pugh Class A, Stage III Hepatocellular Carcinoma, Stage IIIA Hepatocellular Carcinoma, Stage IIIB Hepatocellular Carcinoma, Stage IIIC Hepatocellular Carcinoma, Stage IV Hepatocellular Carcinoma, Stage IVA Hepatocellular Carcinoma, Stage IVB Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Other: Laboratory Biomarker Analysis
* Biological: Pembrolizumab
* Drug: Sorafenib Tosylate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant must have histologically or radiographically confirmed hepatocellular cancer (HCC) that is advanced or metastatic and if archival tissue is available, have archival tissue submitted for PD-L1, PD-L2 testing Participants with measurable disease that has progressed are eligible if prior surgery or locoregional therapy occurred > 28 days prior to enrollment Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Karnofsky >= 60%) Child-Pugh class-A liver function Absolute neutrophil count (ANC) >= 1,500/ mcL Hemoglobin >= 8.5 g/dL Platelets >= 75,000/ mcL Total bilirubin =< 2.0 mg/dL Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5 X ULN Serum Creatinine <= 1.5 upper limit of normal (ULN)or Creatinine clearance > 50 mL/minute if serum creatinine is elevated above 1.5 X ULN Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present Ability to swallow and retain oral medication Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure Participants with past or ongoing hepatitis C virus (HCV) infection will be eligible for the study. The treated participants must have completed their treatment at least 1 month prior to starting study intervention. Participants with controlled hepatitis B will be eligible as long as they meet the following criteria: Antiviral therapy for HBV must be given for at least 12 weeks and HBV viral load must be less than 100 IU/ml prior to first dose of study drug. Participants on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study treatment Participants who are anti-HBc , negative for Hepatitis B surface antigen (HBsAg) and negative or positive for anti-HBs, and who have an HBV viral load under 100 IU/mL , do not require HBV anti-viral prophylaxis Exclusion Criteria: One prior line of therapy that may include a PDL1 blocker allowed, no prior sorafenib or PD1 blocker allowed. Participants who have had radiotherapy or chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Any evidence of bleeding diathesis (patients on therapeutic warfarin or heparin will be excluded) Participants with a history of variceal bleed within 6 months prior to enrollment Known human immunodeficiency virus (HIV)-positive participants (even if on combination retrovirals, participant will be excluded Participants with chronic autoimmune disease Participants with known brain metastases should be excluded from this clinical trial Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Has known history of, or any evidence of active, non-infectious pneumonitis Pregnant or nursing female participants Unwilling or unable to follow protocol requirements Any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study drug Received a live vaccine within 30 days prior to start of study treatment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (sorafenib tosylate, pembrolizumab)<br>Patients receive sorafenib tosylate PO BID on days -28 to -1 and 1-21. Patients also receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Drug: Sorafenib Tosylate<br>* Given PO<br>* Other names: sorafenib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate defined as partial or complete response per immune-related Response Evaluation Criteria in Solid Tumors | The response rate will be estimated as the binomial proportion of responders among evaluable patients, and supported by Jeffreys? 95% confidence interval. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Will be estimated using the Kaplan-Meier method. | From the date of study enrollment to the time of death from any cause, assessed up to 1 year | 
| Time to tumor progression | Will be estimated using the Kaplan-Meier method. Statistics describing the time to event distributions will be obtained from Kaplan-Meier methods and proportional hazards models. Continuous variables will be summarized with commonly used statistics (mean, standard deviation, median, etc.), with subgroup associations tested using the Wilcoxon rank sum test. Categorical variables will be summarized in contingency tables, with associations of interest assessed using Fisher?s exact test. | From the date of study enrollment to the first observation of progressive disease, assessed up to 1 year |