Downstaging Protocol Containing Immunotherapy for HCC Beyond the Milan Criteria Before Liver Transplantation

Study Overview
=================
Brief Summary
-----------------
Hepatocellular Carcinoma (HCC) is the most common liver malignancy and the third leading cause of cancer death worldwide. Due to the shortage of donor organs and the risk of tumor recurrence after transplantation, the restrictive Milan criteria is the standard guideline for liver transplantation (LT) in patients with HCC and liver cirrhosis. The XXL study (Mazzaferro et al, 2020) is the first prospective trial validating that effective and sustained downstage therapy could expand the selection criteria and improve the prognosis of recipients with HCC beyond Milan criteria. However, the optimal DT protocol is poorly defined, especially in the Asian population. Recently, immunotherapies such as immune-checkpoint inhibitors (ICIs) are revolutionizing the management of advanced HCC, the combination of the ICI and other treatment regimens (Anti-VEGF, locoregional therapies et al) produced superior results in patients with advanced-stage HCC compared to those with traditional therapeutic regimens. Therefore, we hypothesize an intensive downstage regimen containing immunotherapy could expand the selection criteria for HCC LT

Detailed Description
-----------------
This will be a single-arm, open-label, non-randomized phase II study aiming to access the efficacy and safety of the downstage protocol containing immunotherapy for HCC beyond Milan Criteria. This study contains 4 phases: Screening and Downstaging phase Eligible patients (See inclusion and exclusion criteria) will undergo downstaging treatment containing Anti-PD-1 inhibitor (tislelizumab, pembrolizumab, nivolumab et al). Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously. Other combination regimens, such as locoregional therapies and targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers. Patients that have reached the Criteria for Successful Downstage within 12 cycles of downstaging treatment will proceed to the observation phase, while those who fail to meet the Criteria for Successful Downstage after the maximum length of downstaging procedures will drop out from the study. Criteria for Successful Downstage Patients that meet 1-4 criteria are considered to have achieved the downstaging goal, otherwise, the downstaging treatment is considered to have failed within 12 cycles of downstaging treatment: CR or PR evaluated by iRECIST/mRECIST after at least 2 cycles of downstaging treatment. Patients with onset AFP<400ng/ml: AFP <400ng/ml at the end of downstaging therapy; Patients with onset AFP>400ng/ml: AFP levels decrease more than 30%, and must be less than 1000ng/ml at the end of downstage therapy. Estimated 5-year overall survival ≥60% at the end of downstaging therapy according to the Metroticket model (http://www.hcc-olt-metroticket.org/calculator). For patients with portal vein tumor thrombus (PVTT1-3), tumor thrombus needs to retract above the bifurcation of the main portal vein, and portal vein anastomosis is feasible during liver transplantation according to the surgeons' judgment. Observation phase Patients that have reached the Criteria for Successful Downstage within 12 cycles of downstaging treatment will proceed to the observation phase ≥ 3 months. Patients at this phase can optionally receive TKIs (sorafenib, lenvatinib et al), and other anti-tumor treatments (such as locoregional therapies, surgery, and immunotherapies et al) are not allowed at this phase. Patients with a sustained response and whose tumors still meet the Criteria for Successful Downstage at the end of the observation phase will be enrolled in the waiting list for liver transplantation, while patients with tumor progression (PD) and their tumors fail to meet the Criteria for Successful Downstage at the end of observation phase will drop out from the study. Waiting and Bridging phase During the waiting period before liver transplantation, patients can optionally receive a non-immunotherapy protocol as bridging treatment determined by the multidisciplinary team (MDT). Surgery is not allowed at this phase. Liver transplantation and post-transplantation phase Patients will undergo liver transplantation unless major medical or oncological contraindications should occur during the waiting phase.

Official Title
-----------------
A Prospective, Single-arm Study of Downstaging Protocol Containing Immunotherapy for HCC Beyond the Milan Criteria Before Liver Transplantation

Conditions
-----------------
Liver Transplantation, Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Procedure: Downstaging procedures containing immunotherapy
* Procedure: Liver transplantation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent must be obtained prior to any screening procedures. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. Patients must have pathologically or cytologically or by radiological criteria proven hepatocellular carcinoma based on the AASLD practice guidelines Patients with HCC must be beyond Milan criteria without extrahepatic metastases or lymph node metastases: 3.1 Patients without previous treatment: Barcelona clinic liver cancer B-C (China liver cancer stage IIb-IIIa) HCC with or without portal vein tumor thrombus (PVTT 1-3 according to Japanese Vp classification). 3.2 Patients with late recurrent HCC: The recurrent HCC must be identified no less than 2 years after primary curative treatment (Resection or Radiofrequency, et al), and the recurrent lesions must be localized in the liver and beyond Milan criteria. 3.3 Patients with early recurrent HCC: The recurrent HCC must be identified within 2 years after primary curative treatment (R0 resection or radiofrequency, et al), and the primary tumor must be within Milan criteria, and the accumulating tumor burden(Primary tumor plus recurrent tumor) must be beyond Milan criteria. Child-Pugh score≤7, with no encephalopathy. Ascites that can be controlled by diuretics are permitted in this study. Eastern Cooperative Oncology Group (ECOG) Scale for Assessment of Patient Performance Status (PS score) ≤ 2; KPS score ≥60. Have not received any immunotherapies 6 months before enrollment. Adequate bone marrow, liver, and renal function. The estimated survival before liver transplantation must be more than 12 weeks (Based on the Model for end-stage liver disease, MELD). No other lethal malignancy outside the liver in recent 5 years, such as leukemia, lung cancer, melanoma, et al. Patients with a history of hypertension should be well-controlled (< 140/90 mmHg) on a regimen of anti-hypertensive therapy. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and 6 months after the completion of the trial. Patients voluntarily joined the study and signed informed consent with good compliance and follow-up.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: Eligible patients will undergo downstaging treatment containing Anti-PD-1 inhibitor (tislelizumab, pembrolizumab, nivolumab et al). Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously. Other combination regimens, such as locoregional therapies and targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Downstaging group<br>Eligible patients (See inclusion and exclusion criteria) will undergo downstaging treatment containing Anti-PD-1 inhibitor (tislelizumab, pembrolizumab, nivolumab et al). Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously. Other combination regimens, such as locoregional therapies and targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers. Patients that have reached the Criteria for Successful Downstage within 12 cycles of downstaging treatment will proceed to the observation phase, while those who fail to meet the Criteria for Successful Downstage after the maximum length of downstaging procedures will drop out from the study. | Procedure: Downstaging procedures containing immunotherapy<br>* Anti-PD-1 inhibitor will be given every 3-4 weeks intravenously according to the manufacturer's instruction. Other combination regimens, such as locoregional therapies or targeted therapies will be given to patients according to the protocol decided by the multidisciplinary team of Centers.<br>Procedure: Liver transplantation<br>* Patients with successful downstaging therapy at the end of the observation phase will enroll and undergo liver transplantation unless major medical or oncological contraindications should occur during the waiting phase.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For patients with liver transplantation: The 2-year event-free survival rate | From the date of transplantation to the date of tumor recurrence or the date of tumor progression otherwise, with censoring at the date of death or last contact for event-free patients. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For patients with liver transplantation: The 2-year overall survival | The time elapsed from the liver transplantation to death during the 2-year follow-up period. | 2 years | 
| For all patients with HCC downstaging: 1, 2 year overall survival rate | The probability of survival from the beginning of treatment to the end of 1-year and 2-year follow-up. | 1, 2 years | 
| For patients with liver transplantation: Rate of early allograft dysfunction (EAD) | Number of recipients developing EAD after liver transplantation | 1 week posttransplantation | 
| For patients with liver transplantation: Rate of allograft rejection | Number of recipients developing allograft rejection after liver transplantation | 1 year | 
| For all patients with HCC downstaging: Rate of successful tumor downstaging | Number of patients reaching the successful downstaging criteria for liver transplantation | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Liver transplantation, Hepatocellular Carcinoma, Milan Criteria, Downstaging therapy, Locoregional therapies, Targeted therapy, PD1 inhibitor