Pembrolizumab Plus Y90 Radioembolization in HCC Subjects
Pembrolizumab Plus Y90 Radioembolization in HCC Subjects
This is an open-label multi-center trial designed to evaluate the efficacy as well as the
 safety of combining pembrolizumab with Yttrium-90 (Y90) radioembolization in subjects with
 poor prognosis (high risk) HCC not eligible for liver transplant or surgical resection with
 well compensated liver function. Treatment will consist of pembrolizumab 200mg IV every 3
 weeks in conjunction with Y90 radioembolization performed one week after the first dose of
 pembrolizumab. If bilobar disease is present, a second Y90 radioembolization will be
 performed no later than 4 weeks after the first procedure to the contralateral hepatic lobe.
If a second Y90 radioembolization treatment is required for bilobar disease, this should
 occur within 4 weeks of the initial procedure (between Cycles 2 and 3 of pembrolizumab). The
 next dose of pembrolizumab should be separated from the Y90 radioembolization by at least one
 week.

 Imaging will be obtained every 9 weeks (after every 3 pembrolizumab treatment) to assess for
 tumor response and to evaluate for progression. Subjects will remain on treatment until
 documented tumor progression, unacceptable toxicity, study withdrawal or death.

 Screening Angiography (shunt study):

 During screening, subjects will undergo angiography using technetium-99-labeled
 macroaggregated albumin to detect any uptake outside the liver via measurement of
 hepatopulmonary shunting. Prior to the angiography, a local anesthetic (to numb the area
 prior to catheter insertion) and sedation will be administered to the subject, as per
 institutional standards.

 This procedure is standard of care for subjects prior to Y90 radioembolization, and will be
 performed per institutional site standards. Hepatopulmonary shunting must be < 20% for
 subject to meet eligibility criteria. Subjects will undergo a mandatory tumor biopsy on the
 same day as the screening angiography.

 Prior to administration of the first dose of pembrolizumab (i.e., Day 1 of Cycle 1), repeat
 laboratory tests will be obtained to ensure subject still meets eligibility criteria.

 Pembrolizumab 200mg IV (IV over 30 minutes) every 3 weeks Day 1 per 21 day cycle (3 weeks).

 Prior to administration of subsequent pembrolizumab doses, the following criteria must be
 met:

 ALT and AST:

 -  Among subjects with baseline (screening) ALT/AST <2×ULN: ALT/AST < 5×ULN

 -  Among subjects with baseline (screening) ALT/AST ≥2×ULN: ALT/AST < 3× the baseline level

 -  ALT/AST ≤ 500 U/L regardless of baseline level

 Total bilirubin:

 -  Among subjects with baseline levels < 1.5 mg/dL: a value of < 2.0 mg/dL

 -  Among subjects with baseline levels that are ≥ 1.5 mg/dL: a value < 2× the baseline
 level

 -  Total bilirubin ≤ 3.0 mg/dL regardless of baseline level

 Y90 radioembolization will be performed as standard of care via institutional standards.

 To be eligible for Y90 radioembolization, the following criteria must be met:

 ALT and AST:

 -  Among subjects with baseline (screening) ALT/AST < 2×ULN: ALT/AST < 5×ULN

 -  Among subjects with baseline (screening) ALT/AST ≥ 2×ULN: ALT/AST < 3× the baseline
 level

 -  ALT/AST ≤ 500 U/L regardless of baseline level

 Total bilirubin:

 -  Among subjects with baseline levels < 1.5 mg/dL: a value of < 2.0 mg/dL

 -  Among subjects with baseline levels that are ≥ 1.5 mg/dL: a value < 2× the baseline
 level

 -  Total bilirubin ≤ 3.0 mg/dL regardless of baseline level

 In addition, any non-hepatic toxicities from the prior dose(s) of pembrolizumab must have
 resolved to Grade ≤ 2.
Inclusion Criteria:

 Subject must meet all of the following applicable inclusion criteria to participate in this
 study:

 -  Written informed consent and HIPAA authorization for release of personal health
 information prior to registration. NOTE: HIPAA authorization may be included in the
 informed consent or obtained separately

 -  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 CT or dynamic contrast enhanced 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 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 HBV, viral load must be <100IU/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 systemic therapy or radiotherapy (including Y90 radioembolization or
 cyberknife) for HCC. No prior TAE or TACE allowed. Previous liver resection and
 ablation therapy is permitted. Allowed prior therapies must be completed 4 weeks prior
 to the baseline scan, and untreated measurable disease (as per RECIST1.1) must be
 present.

 -  Demonstrate adequate organ function as defined in the table below. All screening labs
 to be obtained within 28 days prior to registration:

 Hematological:

 Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L; Hemoglobin (Hgb) ≥ 9 g/dL; Platelet Count ≥
 60 x 10^9/L

 Renal:

 Calculated creatinine clearance ≥ 60 cc/min

 Hepatic:

 Bilirubin < 2.0 X ULN; Aspartate aminotransferase (AST) ≤ 5 × ULN; Alanine aminotransferase
 (ALT) ≤ 5 × ULN

 Coagulation:

 International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial
 Thromboplastin Time (aPTT) ≤1.5

 -  Females of childbearing potential must have a negative serum pregnancy test within 72
 hours prior to registration.

 -  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.

 -  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 (all subjects) and post-treatment (10
 subjects) research biopsy at the centers participating in research biopsies

 Exclusion Criteria:

 Subjects meeting any of the criteria below may not participate in the study:

 -  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 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., (i.e., ≤ Grade 1
 or baseline)) from 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 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.