Neoadjuvant Anti-PD1 in HCC

Study Overview
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Brief Summary
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This is a phase 2, single-arm trial designed to assess the clinical benefit of treatment with nivolumab administered in patients with untreated, borderline resectable HCC.

Official Title
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Neoadjuvant Immunotherapy With Anti-PD1 in Borderline Resectable Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma, HCC, Liver Cancer

Intervention / Treatment
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* Drug: Nivolumab
* Procedure: Hepatectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent form prior to the screening procedures. Age ≥ 18 years. Histological proof of HCC. Willingness to undergo a pre-dosing fresh tumour biopsy. Patients for whom fresh biopsy may not be feasible will be ineligible for enrollment. Intermediate or locally-advanced HCC (according to HKLC tumour status categorization) with the option of resection for potential cure as assessed by surgeon. Child-Pugh score ≤ 7 with no symptomatic ascites or ascites requiring therapeutic paracentesis. ECOG performance status ≤ 1. Life expectancy of ≥ 12 weeks. Adequate organ function (blood transfusion or use of biologic response modifiers is not permitted). Measurable disease according to RECIST v1.1. Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception. Able and willing to meet all protocol-required treatments, investigations and visits. Exclusion Criteria: Patients who have history of organ transplantation. History of allergy or hypersensitivity to study drug components. Patients who have active, known or suspected autoimmune disease. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition adequately treated with hormonal replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger or deemed by the investigator not to affect safety assessment. Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody (or any other antibody targeting T cell co-regulatory pathways). Receipt of any cancer therapy in the pre-operative period. Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicine) intended for general health support or to treat the disease under study within 2 weeks prior to treatment. Active, acute, or chronic clinically significant infections requiring therapy with the exception of hepatitis B or C virus infection. Patients with chronic HBV infection must be on antiviral therapy and have HBV DNA < 500 IU/ml. Active or chronic co-infection with hepatitis B and C, or hepatitis B and D is not allowed. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Symptomatic congestive heart failure, defined as ≥ Class II of the New York Heart Association functional classification system or known LVEF < 50% at baseline. Active angina pectoris or recent myocardial infarction (within 6 months). Chronic atrial fibrillation or QTcF > 470 msec. History of other previous cancer that would interfere with the determination of safety or efficacy of nivolumab with respect to HCC. Women who are pregnant or breast-feeding. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of study results.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br> | Drug: Nivolumab<br>* 3 mg/kg on Day 1 of each 2-weekly cycle for 3 doses<br>Procedure: Hepatectomy<br>* Hepatectomy will be performed approximately 2 weeks after the 3rd dose of nivolumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological tumour response rate | Proportion of patients with resected tumours having ≥30% necrosis | After surgery (normally 6 weeks after the start of nivolumab) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival | The time from resection to disease recurrence or death from any cause | At least 3 months after surgery | 
| Overall survival | The time from start of treatment to the date of death from any cause or last follow-up date | At least 3 months after surgery | 
| Short-term surgery outcomes | Operation time, blood loss during surgery, transfusion requirement during surgery, and complication rate within 2 weeks following surgery | 2 weeks after surgery | 
| Safety and tolerability of nivolumab | The incidence, severity as graded by NCI CTCAE v5.0, seriousness and relationship to study medication of adverse events (AEs) | 6 months |