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.
