Pembrolizumab and Yttrium-90 Microsphere Radioembolization in Treating Patients with Locally Advanced Liver Cancer

Inclusion Criteria

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information prior to registration; NOTE: HIPAA authorization may be included in the informed consent or obtained separately
• Age >= 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Locally advanced HCC as defined by: 1) tissue diagnosis OR 2) alpha-fetoprotein (AFP) > 400 ng/mL with compatible mass on contrast-enhanced imaging OR 3) compatible mass on dual phase computed tomography (CT) or dynamic contrast enhanced magnetic resonance imaging (MRI) demonstrating both arterial hypervascularity and delayed washout
• Hepatopulmonary shunting < 20% as documented via hepatic artery perfusion study
• No evidence of extrahepatic metastatic disease
• Subjects must be considered poor prognosis by the following parameters: 1) right or left portal vein involvement (NOTE: subjects with main portal vein involvement are excluded), 2) multi-focal disease (more than 3 tumors regardless of size) AND/OR 3) diffuse disease considered amenable to liver directed therapy
• Subjects with chronic infection by hepatitis C virus (HCV) who are untreated or who failed previous therapies for HCV are allowed on study; in addition, subjects with successful HCV treatment (defined as sustained virologic response [SVR] 12 or SVR 24) are allowed as long as patients are not actively receiving anti-HCV treatment at the time of study enrollment; investigators can stop anti-HCV treatment at their discretion prior to enrolling patients on study
• If active hepatitis B virus (HBV), viral load must be < 100 IU/mL; if active HBV, subjects must be on anti-viral medication for >= 3 months prior to study registration and remain on the same anti-viral regimen throughout study treatment; NOTE: those subjects who are positive for hepatitis B core antibody (anti-HBc), negative for hepatitis B surface antigen (HBsAg) and negative for hepatitis B surface antibody (anti-HBs), and have an HBV viral load < 100 IU/mL do not require HBV anti-viral prophylaxis
• Not eligible for surgical resection or liver transplant or have refused such procedures
• All disease must be amenable to embolization in one or two procedures
• Childs-Pugh cirrhotic status A or B with a maximum score of 7
• No evidence of clinically apparent ascites or active encephalopathy, and/or varices that have not been treated; subjects with controlled ascites or encephalopathy are eligible so long as they meet Childs-Pugh score criterion; please note that controlled ascites and encephalopathy require scores of 2 each when calculating the C-P score
• No prior Y90 radioembolization for HCC is permitted; therapies below are allowed but must be completed 4 weeks prior to baseline scan: * Prior transarterial embolization (TAE) or transarterial chemoembolization (TACE) * One treatment of stereotactic body radiation therapy (SBRT) * Liver resection * Ablation therapy
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained within 28 days prior to registration)
• Hemoglobin (Hgb) >= 9 g/dL (without erythrocyte stimulating agent or transfusion within 7 days of screening) (obtained within 28 days prior to registration)
• Platelet count >= 60 x 10^9/L (obtained within 28 days prior to registration)
• Creatinine < 1.5 x upper limit of normal (ULN) (obtained within 28 days prior to registration), OR
• Calculated creatinine clearance >= 60 cc/min (Cockcroft-Gault formula will be used to calculate creatinine clearance) (obtained within 28 days prior to registration)
• Bilirubin < 2.0 X ULN (obtained within 28 days prior to registration)
• Aspartate aminotransferase (AST) =< 5 x ULN (obtained within 28 days prior to registration)
• Alanine aminotransferase (ALT) =< 5 x ULN (obtained within 28 days prior to registration)
• International normalized ratio (INR) or prothrombin time (PT) activated partial thromboplastin time (aPTT) =< 1.5 (obtained within 28 days prior to registration)
• Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to registration; NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy at least 6 weeks prior to study registration) or they are naturally postmenopausal for at least 12 consecutive months without an alternative medical cause
• Females of childbearing potential and males must be willing to abstain from heterosexual activity* or to use effective methods of contraception from the time of informed consent until 120 days after treatment discontinuation; acceptable contraception methods can be comprised of an intrauterine device (IUD), vasectomy of a female subject’s male partner, contraceptive rod implanted into the skin, or use of two of the following: diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), hormonal contraceptive * Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
• Is willing to undergo a mandatory pre-treatment research biopsy at the centers participating in research biopsies; a cohort of 10 patients from the University of North Carolina (UNC) will undergo a post-treatment research biopsy after 3 cycles of pembrolizumab

Exclusion Criteria

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of study registration
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy (other than oral contraceptives) or any other form of immunosuppressive therapy within 7 days prior to registration
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
• Known history of active tuberculosis (TB)
• Hypersensitivity to pembrolizumab or any of its excipients
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to registration or who has not recovered (i.e., =< grade 1 or baseline) from adverse events due to agents administered > 4 weeks prior
• Has had prior chemotherapy, targeted small molecule therapy or radiation therapy within 2 weeks prior to registration, or who has not recovered (i.e., =< grade 1 or baseline) from adverse events (AEs) due to previously administered agents
• If had major surgery, subject must have recovered adequately from the toxicity and/or complications from the intervention prior to study registration
• Complete portal vein occlusion
• Vascular abnormalities or bleeding diathesis that indicates hepatic artery catheterization is contraindicated
• Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody
• Known history of human immunodeficiency virus (HIV)
• Untreated active HBV
• Dual infection with HBV/HCV or other hepatitis combinations at study entry
• Known history of, or any evidence of active, non-infectious pneumonitis
• History of organ or stem cell transplantation including previous history of liver transplantation
• Active infection requiring systemic therapy
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
• Has history or current evidence of any condition, therapy or laboratory abnormality that may confound results or interfere with subject’s participation in the trial
• Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least three years
• Has received a live vaccine within 30 days of planned start of study therapy