Ipilimumab and Nivolumab with Stereotactic Body Radiotherapy Followed by Surgical Resection for the Treatment of Locally Advanced Borderline Resectable Hepatocellular Cancer

Inclusion Criteria

• Histologically or cytologically confirmed hepatocellular cancer
• Locally advanced/borderline resectable HCC as defined by: * Solitary tumor > 5 cm, OR * Unilobar multifocal disease either with > 3 tumors or one tumor > 3 cm, OR * Bilobar disease with adequate future liver remnant, still technically resectable, OR * High risk disease features (tumor > 3 cm with macrovascular invasion or tumor > 3 cm with AFP > 400)
• No extrahepatic spread, no nodal disease, and no bilateral left and right branch portal vein involvement
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator
• Age ≥ 18 years old on the day of consent
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Absolute neutrophil count (ANC) ≥ 1000/ucl
• Platelet count ≥ 90,000/ucl
• Hemoglobin ≥ 8.5 mg/dl
• Have adequate renal function, as determined by: * Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR * Measured or calculated creatinine clearance ≥ 40 mL/min using the Cockcroft-Gault formula
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal
• Total bilirubin < 2 mg/dL
• Albumin ≥ 2.8 g/dL
• International normalized ratio (INR) or prothrombin time (PT) ≤ 2 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants
• Absence of cirrhosis or cirrhosis grade of Child-Pugh class A
• Absence of hepatic encephalopathy within 12 months prior to study registration
• Female participant has a negative serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment, or is of nonchildbearing potential. Nonchildbearing potential is defined as follows (by other than medical reasons): * ≥ 45 years of age and has not had menses for > 1 year * Patients who have been amenorrhoeic for < 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. Information must be captured appropriately within the site's source documents ** Note: Abstinence is acceptable if this is the established and preferred contraception for the patient
• Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent
• Patients with chronic or acute hepatitis B virus (HBV) infection (as characterized by positive hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibodies [anti-HBcAb] with detectable HBV DNA [≥ 10 IU/ml]) must be treated with effective antiviral therapy, as per institutional practices, prior to enrollment and for the duration of the study therapy. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (< 10 IU/ml) do not require anti-viral therapy prior to enrollment however these subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥ 10 IU/ml)

Exclusion Criteria

• History of another primary malignancy except for: * Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study drug(s) and of low potential risk for recurrence * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease
• Diagnosis of fibrolamellar carcinoma or mixed HCC
• Direct tumor extension into stomach, duodenum, small or large bowel
• Known additional malignancy that is expected to require active treatment within two years, or is likely to be life-limiting in the opinion of the treating investigator would be excluded. Superficial bladder cancer, non-melanoma skin cancers, or localized prostate cancer not would not exclude participation in this trial
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 28 days of the first dose of study drug(s)
• Ascites that requires ongoing paracentesis, within 6 weeks prior to the first scheduled dose, to control symptoms
• Active or prior documented gastrointestinal (GI) variceal bleed or history of upper GI bleeding, ulcers, or esophageal varices with bleeding within 60 days prior to study entry; adequate endoscopic therapy according to institutional standards is required for patients with history of esophageal variceal bleeding or assessed as high risk for esophageal variceal by the treating investigator
• Prior external beam radiation therapy to the liver, prior yttrium-90 radioembolization * Note: Prior surgical resection with recurrence, or palliative local therapy (including transarterial chemoembolization [TACE], yttrium y-90 [Y-90] resin microspheres, etc.) would not exclude trial participation, but must have been performed at least 30 days prior to enrollment
• Prior systemic chemotherapy or investigational agent for HCC
• Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel) * Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 12 weeks before randomization, and who have had no complications from a thromboembolic event or the anticoagulation regimen
• Active co-infection with both HBV and hepatitis C virus (HCV) (detectable HCV ribonucleic acid [RNA] plus positive HBV surface antigen or HBV DNA)
• Diagnosis of immunodeficiency, or is receiving systemic steroid therapy above physiologic replacement dose, or any other form of immunosuppressive therapy
• 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)
• Uncontrolled intercurrent illness including, but not limited to: Symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Previously identified allergy or hypersensitivity to any component of the study treatment formulations
• Major surgery ≤ 3 weeks prior to initiating protocol therapy * Note: Participant must have recovered from any surgical effects of prior surgery
• Active or untreated central nervous system (CNS) and leptomeningeal metastases
• Serious, uncontrolled medical disorder, or nonmalignant systemic disease. Examples include, but are not limited to uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome
• Unstable angina, new onset angina within last 3 months, myocardial infarction within last 6 months and current congestive heart failure New York Heart Association class II or higher
• Known history of human immunodeficiency virus (HIV) infection
• Active tuberculosis infection or other microbial infection or any active systemic infection requiring parenteral antibiotic therapy. All prior infections must have resolved following optimal therapy
• History of organ transplantation including allogeneic bone marrow transplantation
• Psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant, lactating, breastfeeding, or intending to become pregnant during the study and for 180 days after the study
• Simultaneously enrolled in any therapeutic clinical trial