An Exploratory Study of Single-Dose Neoadjuvant Nivolumab Without Surgical Delay in Patients With Resectable HCC

Prior treatment

• Receiving or planning to receive other anti-cancer therapy before surgery
• Major surgical procedure within 4 weeks prior to registration
• Prior therapy with an anti-PD-1, anti-PD-L1, anti-CTLA-4, or drug specifically targeting T-cell co-stimulation or checkpoint pathways
• Requirement of systemic corticosteroids (\> 10 mg/day prednisolone equivalent) or other immunosuppressive medications (except inhaled or topical steroids) within 14 days before registration
• Prior organ allograft or allogeneic bone marrow transplantation
• Subjects with uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
  • Cardiovascular disorders including symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias
  • Uncontrolled hypertension defined as sustained systolic blood pressure (BP) \> 150 mmHg, or diastolic BP \> 100 mm Hg despite optimal antihypertensive treatment
  • Stroke (including transient ischemic attack), myocardial infarction, or other ischemic event within 6 months
  • History of gastrointestinal (GI) perforation or fistula formation/bleeding or active disorders associated with high risk: tumors invading the GI tract, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric/bowel obstruction within 6 months prior to registration
  • Any clinically significant disorders that are judged by investigators to be unsuitable for the clinical trial

Other illness

• Known human immunodeficiency virus (HIV) infection
• History of malignancies other than HCC (except those treated with curative intent with no evidence of disease for 2 years)
• Any active autoimmune disease or history of known autoimmune disease requiring systemic treatment, or a history of severe/known autoimmune disease that the investigator considers inappropriate for immunotherapy.
• Dementia, significantly altered mental status, or major systemic disease that the investigator considers inappropriate for participation

Other

• Pregnant or lactating females

• Understood and signed the informed consent form
• Age ≥ 18 years at time of signing Informed Consent Form with the ability to comply with the study protocol, in the investigator's judgment
• ECOG performance status 0 or 1
• Child-Pugh class A
• Hepatic tumor(s) with imaging features suggestive of hepatocellular carcinoma on four phase contrast-enhanced ultrasound (CEUS), multidetector computed tomography (MDCT),magnetic resonance imaging (MRI), or Primovist-MRI, as determined by the treating investigator.
• Preoperative liver function considered suitable for planned hepatectomy according to the Makuuchi criteria, including indocyanine green retention rate at 15 minutes (ICG-R15), as assessed by the treating surgeon.
• The tumor(s) must be considered definitely resectable by the treating surgeon, and the tumor extent fulfilling all of the following criteria:
  • Number of tumors ≤ 3
  • Largest tumor size ≥ 5 cm (no upper limit) if no vascular invasion or portal vein thrombosis
  • No minimum size limitation if Vp1-2 portal vein tumor thrombosis is present
  • Absence of extrahepatic metastasis or Vp3-4 portal vein tumor thrombosis
• No prior local treatment to the tumor(s) planned for resection
• Patients with chronic hepatitis B virus (HBV) infection (HBsAg positive) must start antiviral therapy before registration
• Patients with resolved or chronic hepatitis C (HCV) infection are eligible
• Adequate hemogram and organ function:
  • White blood cells (WBC) ≥ 3,000/μL and absolute neutrophil count (ANC) ≥ 1,200/μL without granulocyte colony stimulating factor (G-CSF) support within 1 week before registration
  • Platelets (PLT) ≥ 60,000/μL without transfusion within 1 week before registration
  • Hemoglobin (Hb) ≥ 8 g/dL without transfusion within 1 week before registration
  • Serum creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN) or calculated creatinine clearance ≥ 40 mL/min (using the Cockcroft-Gault equation)
  • PT INR ≤ 1.5
  • aPTT ≤ 1.5 × Upper Limit of Normal (ULN)
  • Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) ≤ 3 × ULN
  • Serum total bilirubin (T-Bil) ≤ 1.5 × ULN
  • Serum albumin (Alb) ≥ 35 g/L (3.5 g/dL)
• Consent to undergo tumor biopsy if subjects have no archived tumor tissue for the largest planned resected tumor within 3 months before enrollment
• For women of childbearing potential: agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate \< 1% per year for at least 6 months after the administration of nivolumab.
  • A women is considered to be of childbearing potential if she has not achieved postmenopausal (no menstrual period for at least 12 consecutive months) or has not received surgical sterilization (removal of ovaries and/or uterus).
  • Contraceptive methods with a failure rate of \< 1% per year include: bilateral tubal ligation,male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing/copper intrauterine devices
• For men: agree to remain abstinent (refrain from heterosexual intercourse) or use a condom plus additional contraceptive methods leading to a failure rate of \<1% per year (with female partner of childbearing potential), and agreement to refrain from donating sperm for at least 6 months after the administration of nivolumab.