Phase II Evaluation of Tislelizumab Monotherapy in Hepatocellular Carcinoma Patients with Child-Pugh B and ALBI Grade 1/2 Liver Function

Trial ID: 2024-516443-57-00
Protocol: UC-GIG-2003
Sponsor: Unicancer

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Diseases & Conditions

Hepatocellular carcinoma

Objectives

The primary objective of this study is to evaluate the **efficacy** of anti-PD1 therapy, specifically Tislelizumab, in patients with **Hepatocellular Carcinoma** (HCC) who have Child-Pugh B and ALBI grade 1 or 2 liver function. The efficacy will be measured in terms of the Objective Response Rate (ORR) based on the Best Overall Response across all time-points as defined by RECIST v1.1. This is clinically relevant as it aims to determine the potential of Tislelizumab as a monotherapy option for this specific patient population, which includes those pretreated or not by tyrosine kinase inhibitors and not pretreated with immunotherapy.

The secondary objectives include: - Assessing the safety of anti-PD-1 therapy. - Evaluating efficacy in terms of Objective Response Rate based on best overall response across all time-points according to mRECIST and iRECIST tumor response evaluation, Overall Survival (OS), Progression-Free Survival (PFS), and Time to Progression (TTP). - Assessing Quality of Life according to EORTC QLQ-C30 and HCC-18. These secondary objectives provide a comprehensive understanding of the treatment's impact on patient safety, survival outcomes, and quality of life, which are crucial for holistic patient care.

Participants

The clinical trial involves participants diagnosed with **Hepatocellular Carcinoma (HCC)**, specifically those with Child-Pugh B cirrhosis and ALBI grade 1 or 2 liver function. The study population includes both male and female subjects aged 18 years and older. Participants may have been pretreated with tyrosine kinase inhibitors but not with immunotherapy. The trial does not provide information on the total number of participants, as the sponsor has not disclosed this data. Selection criteria include the presence of measurable and evaluable disease according to RECIST v1.1, and participants must have an ECOG Performance status of 2 or less. Lifestyle considerations such as the use of effective birth control methods are required for both men and women during the study and for 120 days after the last dose of the study drug. Participants must also consent to the use of their tumor specimens and blood samples for future scientific research. The trial population is considered vulnerable, and all participants must be affiliated with a social security regimen.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy of **tislelizumab** in patients with **Hepatocellular Carcinoma** (HCC) who have Child-Pugh B cirrhosis and ALBI grade 1 or 2 liver function. The trial aims to assess the **Objective Response Rate** (ORR) based on the Best Overall Response across all time-points as defined by RECIST v1.1. The study is expected to run until December 15, 2028, with recruitment starting on October 11, 2023. The trial will involve multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease measurability, and organ function. Participants will then undergo regular follow-up visits to monitor treatment response and adverse events, with the end-of-study visit marking the conclusion of their involvement.

Participants are expected to be involved in the study for a maximum treatment period of 24 months, with conditions for early termination including the occurrence of limiting toxicity or adverse events leading to treatment discontinuation. The primary endpoint is the ORR, defined as the proportion of patients achieving a Complete Response or Partial Response to treatment. Secondary endpoints include the frequency of adverse events, overall survival, progression-free survival, and health-related quality of life. The study will ensure that all participants provide informed consent and adhere to birth control requirements during and after the trial. The trial's methodology and design are structured to provide robust data on the efficacy and safety of tislelizumab in the specified patient population.

Treatment

The clinical trial involves the administration of **Tevimbra**, a **100 mg concentrate for solution for infusion**. The active substance in Tevimbra is **tislelizumab**, a protein-based therapeutic agent. Tislelizumab is administered intravenously, with a maximum daily dose of 200 mg and a total maximum dose of 3400 mg over the course of the treatment. The treatment period is set for a maximum of 24 weeks. The pharmaceutical form of Tevimbra is a solution for infusion, and it is manufactured by BeiGene Ireland Limited. The product is not a pediatric formulation and is not classified as an orphan drug.

In this trial, Tevimbra is used as a monotherapy for patients with **Hepatocellular Carcinoma** who have a Child-Pugh B and ALBI grade 1 or 2 liver function score. The trial aims to assess the efficacy of this anti-PD1 therapy in terms of Objective Response Rate (ORR) based on the Best Overall Response across all time-points as defined by RECIST v1.1. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the trial protocol. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, which is defined as the proportion of patients achieving a Complete Response or Partial Response to treatment. This will be evaluated based on the best overall response according to RECIST v1.1 criteria, recorded from the initiation of treatment to the end of the treatment period. Secondary endpoints include the frequency of limiting toxicity, overall survival, progression-free survival, time to progression, and health-related quality of life. The frequency of limiting toxicity will be determined by the occurrence of any adverse event related to the experimental drug that leads to definitive treatment discontinuation before the second injection. Adverse events will be categorized using the MedDRA classification and CTCAE V5.0 for severity.

Overall survival will be measured as the time from inclusion to death from any cause, with patients lost to follow-up censored at the last known date alive. Progression-free survival will be assessed as the time from inclusion to disease progression or death, evaluated three times according to RECIST v1.1, mRECIST, and iRECIST criteria. Time to progression will be defined as the time from inclusion to radiological progression per RECIST v1.1, with death being censored. Health-related quality of life will be evaluated using the EORTC QLQ-C30 and HCC-18 instruments. These efficacy parameters will be collected and analyzed at specified time points throughout the trial to ensure comprehensive assessment of the treatment's impact on patients with Hepatocellular Carcinoma.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥18 years old,
Patient presenting with histologically-proven Hepatocellular Carcinoma (HCC), or HCC defined by typical imaging findings (EASL criteria), if no biopsy could be performed safely.
Pretreated or not by tyrosine kinase inhibitors (e.g., sorafenib, lenvatinib, regorafenib, cabozantinib)
Child-Pugh B cirrhosis
ALBI (Albumin-Bilirubin) grade 1 or 2
BCLC (Barcelona Clinic Liver Cancer Group) B or C
Availability of biopsy specimen at study enrolment (with the exception of cases where biopsy could not be performed safely).
ECOG Performance status ≤2
Adequate organ function as indicated by the following laboratory values: a. Patients must not have required a blood transfusion or growth factor support ≤14 days before sample collection at screening for the following:  Absolute neutrophil count (ANC) ≥ 1 x 109/L  Platelets ≥ 50 x 109/L  Hemoglobin ≥90 g/L b. Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated Glomerular Filtration Rate ≥60 mL/min/1.73 m2 c. Liver function: ASAT and ALAT ≤5 ULN, albumin >2.0 g/dL
Presence of measurable and evaluable disease according to RECIST v1.1
Women of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and ≥120 days after the last dose of tislelizumab, and have a negative urine or serum pregnancy test ≤7 days of first dose of study drug. In case of a urine pregnancy test, it must be a highly sensitive urine pregnancy test.
Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥120 days after the last dose of tislelizumab. A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. Males with known “low sperm counts” (consistent with “sub-fertility”) are not to be considered sterile for purposes of this study.
Patients must have provided consent for the study by signing and dating a written informed consent form prior to any study specific procedures, sampling, or analyses. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent
Patient consent to the use of their collected tumour specimen, as well as blood samples as detailed in the protocol for future scientific research which includes but not limited to DNA, RNA, and protein-based biomarker detection.
Patient affiliated to a social security regimen
Men and women patients must consent to not donate or bank sperm or ova during treatment and for 120 days after treatment stop

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Exclusion Criteria

More than 50% of the liver is affected by the HCC (according to investigators evaluation)
Fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
Previous treatment with immunotherapy (anti-PD-1, anti-PD-L1, or anti-CTLA-4 agents)
History of active autoimmune disease. Note: Patients with the following diseases are not excluded and may proceed to further screening: a. Type I diabetes, b. Hypothyroidism (provided it is managed with hormone replacement therapy only), c. Controlled celiac disease, d. Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia), e. Any other disease that is not expected to recur in the absence of external triggering factors
History of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases
Any of the following cardiovascular risk factors: a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before first dose of study drug b. Pulmonary embolism ≤ 28 days before first dose of study drug c. Any history of acute myocardial infarction ≤ 6 months before first dose of study drug d. Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV ≤ 6 months before first dose of study drug e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before first dose of study drug f. Any history of cerebrovascular accident ≤ 6 months before first dose of study drug g. Uncontrolled hypertension: systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 100 mmHg despite anti-hypertension medications before first dose of drug h. Any episode of syncope or seizure before first dose of study drug
Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers whose HBV DNA is > 500 IU/mL or patients with active hepatitis C virus (HCV) should be excluded. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL), and cured hepatitis C patients can be enrolled
Known primary immunodeficiency or active HIV
Immunosuppression, including subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalent) ≤ 14 days before inclusion. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent) b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen)
Live vaccine within 4 weeks of first dose of study drug. Note: Seasonal vaccines for influenza are generally inactivated vaccines and Covid vaccination with non-live vaccine are allowed. Intranasal vaccines are live vaccines, and are not allowed.
Transplanted liver, or patient with intent for transplantation
Received locoregional therapy to the liver (TACE, transcatheter embolization, hepatic arterial infusion, radiation, radioembolization or ablation) in the 4 weeks before inclusion
Prior malignancy active within the previous 3 years of inclusion except for locally curable cancers considered cured or successfully resected, such as basal or squamous cell skin cancers, superficial bladder cancer, or gastric cancers, or carcinoma in situ of the prostate, cervix, or breast carcinomas. Any oncological concomitant treatment are not allowed during the treatment period.
Has received any herbal medicine used to control cancer with immunostimulant properties that may interfere with liver function within 14 days of the first study drug administration.
Pregnant woman or breast-feeding women or patient with no adequate contraception
Participation in another therapeutic trial within the 30 days prior to study inclusion
Patients deprived of their liberty or under protective custody or guardianship
Patients unable to adhere to the protocol for geographical, social, or psychological reasons
Patients eligible for treatment by TACE or SIRT are not allowed