Natural Killer (NK) Cell Therapy in Locally Advanced HCC

Study Overview
=================
Brief Summary
-----------------
This Phase 2a trial will evaluate the safety and efficacy of NK cell therapy combined with the hepatic artery infusion chemotherapy (HAIC) in patients with intermediate and/or locally advanced hepatocellular carcinoma (HCC). We hypothesized that 5-fluorouracil (FU) with immunomodulatory functions would relieve the immunosuppressive microenvironment from the myeloid-derived suppressor cells (MDSCs), thereby enhancing the anti-tumor activity of NK cells. Thus, the subsequent infusion of autologous NK cells (VAX-NK/HCC) following HAIC treatment may further improve the anti-tumor activity in patients with advanced HCC.

Detailed Description
-----------------
Primary Objective I. To assess the objective response rate (ORR) of administering VAX-NK/HCC, autologous NK cells combined with HAIC in patients with locally advanced HCC. Secondary Objectives I. To assess the efficacy of administering VAX-NK/HCC combined with HAIC. II. To assess the safety of administering VAX-NK/HCC combined with HAIC. III. To assess the immune responses of administering VAX-NK/HCC combined with HAIC. OUTLINE: This is a Phase 2a study. Patients receive HAIC treatment every 4 week for up to 4 cycles followed by ex-vivo expanded autologous NK cell infusions. The NK cell treatment repeats every 4 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients will be followed until the disease progression.

Official Title
-----------------
A Phase 2a Study Using Natural Killer (NK) Cell Therapy Combined With Hepatic Artery Infusion Chemotherapy (HAIC) in Patients With Locally Advanced Hepatocellular Carcinoma

Conditions
-----------------
Locally Advanced Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Biological: Vax-NK/HCC


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects with intermediate and/or locally advanced HCC histologically confirmed by biopsy or by typical radiological findings. Subjects who were not suitable for or failed curative treatments such as surgical resection, local ablation therapy, transarterial chemoembolization (TACE), sorafenib, atezolizumab, bevacizumab, etc. Child-Pugh liver function class A or B. Subjects' ECOG performance status of 0 or 1. The presence of macrovascular invasion. Adequate liver, renal, and hematologic functions. Exclusion Criteria: Subjects who received the immune cell-based therapy within 6 months before the screening visit. Subjects with a history of a malignancy other than HCC within the last 5 years, liver transplantation, and hypersensitivity to 5-FU or cisplatin. Subjects with extra-hepatic metastases. Subjects who have ongoing autoimmune disease. Female subjects who are pregnant or lactating or women of child-bearing potential but unable to take adequate contraception.

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous NK cell infusion combined with HAIC<br>HAIC of 5-FU (500 mg/m2, Q4W) and cisplatin (15 mg/m2, Q4W) will be administered for up to 4 cycles to patients with locally advanced HCC. Subjects who achieved sustained SD or better based on the mRECIST criteria after 2nd cycle of HAIC will be enrolled to receive 1x10^9 cells VAX-NK/HCC infusion. | Biological: Vax-NK/HCC<br>* autologous NK cells expanded ex vivo.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) of administering VAX-NK/HCC combined with HAIC | ORR will be measured as the proportion of patients with a best overall response of complete response (CR) and partial response (PR) of administering VAX-NK/HCC combined with HAIC. | average 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) of administering VAX-NK/HCC combined with HAIC | ORR will be measured as the proportion of patients with a best overall response of complete response (CR), partial response (PR), and stable disease (SD) of administering VAX-NK/HCC combined with HAIC. | average 6 months | 
| Time to progression (TTP) of administering VAX-NK/HCC combined with HAIC | TTP will be measured by time to progression, defined as time from enrollment to disease progression. | average 6 months | 
| Overall survival (OS) of administering VAX-NK/HCC combined with HAIC | OS will be measured as time from enrollment to death due to any cause. | average 12 months | 
| Quality of Life of administering VAX-NK/HCC combined with HAIC | The assessment will be performed using the Korean versions of European Organization for Research and Treatment of Cancer (EORTC) Questionnaire 30 (QLQ-C30) consisting of 30 items. Total score: Range 0-100. | average 6 months | 
| Adverse Events (AEs) and Serious Adverse Events (SAEs) of administering VAX-NK/HCC combined with HAIC | The assessment will be measured by determining the number of patients that experience AEs and SAEs graded according to the NCI-CTCAE (Version 4.0) | average 6 months | 
| The proportions of T and NK cells | This will be measured by determining the relative percentages of CD4+CD8+ T cells and CD3- CD56+ NK cells in patients' peripheral blood. | average 6 months | 
| The lymphocyte/monocyte ratio (LMR) | LMR will be calculated by dividing the absolute lymphocyte count by the absolute monocyte count in patients' peripheral blood. | average 6 months | 
| The NK cell cytotoxicity | This will be measured by determining percent cell lysis of target cells (K562) in patients' peripheral blood. | average 6 months | 
| The serum cytokine levels | The serum concentrations of IFN-γ, IL-10, and TGF-β will be measured in patients' serum using the Enzyme-Linked immunosorbent assays. | average 6 months |