Anti-PD-1/PD-L1 Antibodies Plus S-adenosyl-methionine Treatment in Patients With Advanced-Stage Hepatocellular Carcinoma

Study Overview
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Brief Summary
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This study is being done to analyze the safety, tolerability, and efficacy of treatment using combination of SAM and anti-PD-1/PDL1 antibodies for patients with advanced hepatocellular carcinoma.

Detailed Description
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This is a study of combination anti-PD-1/PD-L1 antibodies and S-adenosyl-methionine (SAM) for adult patients (≥18) with advanced hepatocellular carcinoma. SAM is a compound found naturally in the body and is available as a dietary supplement in the U.S. SAM is a prescription drug in China treating liver disease and advanced HCC with poor liver function under certain circumstances. Also, SAM has recently been shown to play a key role regulating cancer cell proliferation trough epigenetic pathway. Anti-PD-1/PD-L1 antibodies (including pembrolizumab, nivolumab, sintilimab, toripalimab, camrelizumab, tislelizumab and atezolizumab etc.) are given intravenously at assigned dose. Treatment may continue until disease progression, intolerable toxicity, or consent withdrawal. This study is aimed to evaluate the safety and efficacy of the combination of SAM and PD-1/PD-L1 monoclonal antibody in unresectable late-stage HCC patients.

Official Title
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Phase I/II Study of Anti-PD-1/PD-L1 Antibodies Combined With S-adenosyl-methionine in Patients With Advanced-Stage Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Anti-PD-1/PD-L1
* Drug: S-Adenosyl-Methionine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years old, male or female Advanced hepatocellular carcinoma (cannot be removed or metastasized) diagnosed clinically or pathologically, at least one measurable lesion without local treatment, Child-Pugh A ;Barcelona Clinic Liver Cancer(BCLC) staging is stage B or C Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 Patient has given written informed consent. The function of important organs meets the requirements Expected survival ≥12 weeks Non-surgical sterilization or women of childbearing age need to use a medically-accepted contraceptive (such as an intrauterine device, contraceptive or condom) during the study period and within 3 months after the end of the study treatment period. Exclusion Criteria: The patient has any active autoimmune disease or a history of autoimmune disease (such as the following, but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, vasculitis, nephritis, thyroid Hyperfunction; patients with vitiligo; complete remission of asthma in childhood, can be included without any intervention after adulthood; asthma patients who require bronchodilators for medical intervention cannot be included); The patient is using immunosuppressive agents or systemic hormonal therapy to achieve immunosuppressive purposes (agents amount > 10 mg / day of prednisone or other therapeutic hormones), and continue to use within 2 weeks before enrollment; Have clinical symptoms or disease that are not well controlled; Significant clinically significant bleeding symptoms or a clear bleeding tendency within 3 months prior to randomization; Arterial/venous thrombosis in the first 6 months of randomization According to the investigator, the patient has other factors that may affect the results of the study or lead to the termination of the study, such as alcohol abuse, drug abuse, other serious diseases (including mental illness) requiring combined treatment, and serious laboratory abnormalities.#with family or social factors, it will affect the safety of patients. Liver tumor burden greater than 50% of the total liver volume, or patients who have previously undergone liver transplantation;Known for a history of central nervous system metastasis or hepatic encephalopathy;Severe allergic reactions to other monoclonal antibodies;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Anti-PD-1/PD-L1 antibodies and S-adenosyl-methionine combination<br>Drug: Anti-PD-1/PD-L1 Intravenous injection for at least 6 months Drug: S-adenosyl-methionine Taken orally for at least 6 months | Drug: Anti-PD-1/PD-L1<br>* Intravenous injection at indicated dose for at least 6 months<br>Drug: S-Adenosyl-Methionine<br>* Taken orally at indicated dose for at least 6 months<br>* Other names: SAM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Safety will be monitored by addressing and recording all adverse events (AEs), serious adverse events (SAEs) and specific laboratory abnormalities (worst grade). Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. | Up to 30 days after last treatment dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate(ORR) | Evaluated by researchers based on the RECIST 1.1 standard | 2 years | 
| Progression free survival(PFS) | Evaluated by researchers based on the RECIST 1.1 standard | 2 years | 
| To the relief time (TOR) | Evaluated by researchers based on the RECIST 1.1 standard | 2 years | 
| Duration of relief(DOR) | Evaluated by researchers based on the RECIST 1.1 standard | 2 years | 
| Disease Control Rate (DCR) | Evaluated by researchers based on the RECIST 1.1 standard | 2 years | 
| 6-month survival rate | Evaluated by researchers based on the RECIST 1.1 standard | 6 months | 
| 12-month survival rate | Evaluated by researchers based on the RECIST 1.1 standard | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SAM, Hepatocellular Carcinoma, Anti-PD-1 antibody, Anti-PD-L1 antibody