Testing Immunotherapy for Patients With Liver Cancer and Moderately Altered Liver Functions

A Multicentric National Phase II Trial Assessing TIslelizumab in Monotherapy for Patients With Hepatocellular Carcinoma Child-Pugh B and ALBI Grade 1 or 2 Liver Function Score

Liver cancer is the third leading cause of cancer-related deaths worldwide. The majority of primary liver cancers occur as hepatocellular carcinoma (HCC), the incidence of which is increasing in many parts of the world. The vast majority of HCC cases occur in the setting of liver cirrhosis, usually due to chronic viral infections with hepatitis C or hepatitis B, alcohol consumption, non-alcoholic fatty liver disease or diabetes. The degree of underlying liver disease, as well as the stage of the tumour and the general condition of the patients, should therefore be taken into account when deciding on the treatment of HCC. Most patients with HCC have advanced disease at the time of diagnosis, or have recurrent disease after potentially curative treatments.

Tislelizumab showed enhanced cellular functional activities by blocking PD-1-mediated reverse signal transduction and activating human T cells and primary peripheral blood mononuclear cells in vitro.

Based on this preliminary safety profile, and knowing that there is antitumour activity, we can offer tislelizumab as a single agent in patients with unresectable HCC.

HESTIA study is a multicentric French national phase II trial assessing tislelizumab in monotherapy for patients with Hepatocellular Carcinoma Child-Pugh B and ALBI grade 1 or 2 liver function score.

It is planned to include 50 patients in the study. All patients will be recruited in France. The study will be presented to eligible patients at participating centres and an information note will be provided. No advertising material is planned for this study.

To be eligible, patients must meet all the following criteria to be ≥18 years old, with histologically proven Hepatocellular Carcinoma (HCC), pre-treated or not with a tyrosine kinase inhibitor and Child-Pugh B cirrhosis, ALBI (Albumin-Bilirubin) grade 1 or 2 and BCLC (Barcelona Clinic Liver Cancer Group) B or C and with no more than 50% liver invasion of tumour disease.

The primary objective is to assess efficacy of anti-PD1 (in terms of Objective Response Rate [ORR] based on Best Overall Response across all time-points as defined by RECIST v1.1) in the Child-Pugh B / ALBI grade 1/2 population.

Secondary objectives are :

• To assess safety of anti-PD-1

• To assess efficacy in terms of:

  • Objective Response Rate based on best overall response across all time-point according to mRECIST and iRECIST tumor response evaluation
  • Overall survival (OS)
  • Progression-free survival (PFS)
  • Time to progression (TTP)

• To assess Quality of Life according to EORTC QLQ-C30 and HCC-18.

In order to confirm the eligibility of patients, a clinical examination, biological blood tests, ECG, CT scan and a urine or blood pregnancy test for women of childbearing age will be performed. A quality of life questionnaire will be administered to patients. Patients will also be asked to agree to a full eye examination by an ophthalmologist prior to the start of treatment to determine that there is no risk of worsening the patient's visual acuity with treatment with tislelizumab.

After enrolment in the study, the patient will be required to visit the hospital every 3 weeks to receive intravenous treatment for up to 2 years.

Once the treatment is completed, the patient will be seen at follow-up visits for 2 years, initially every 3 months for the first year and then every 6 months for the second year.

Assessment of tumour response by CT or MRI will be done after the start of treatment at weeks 9, 18, 27, 54 and every 12 weeks until disease progression and throughout the treatment period. Tumour assessment by CT or MRI will be performed 2 years after the start of treatment or upon disease progression.

Patients will be asked to consent to the use of a collected tumour sample, as well as to the collection of blood samples, for future scientific research which includes, but is not limited to, the detection of DNA, RNA and protein biomarkers.

An independent Study Monitoring Board (DSMB), with expertise and experience in the pathology, and without direct involvement in the conduct of the study, will be set up specifically to ensure optimal safety monitoring during the early phase of the study and the feasibility of at least 2 treatment injections (6 weeks from inclusion), an early stopping rule has been defined for the first 20 patients included. This method was chosen for the evaluation of serious adverse events (SAEs), which may occur relatively early in this trial. A high frequency of occurrence may necessitate early termination of the trial.

Inclusion Criteria:

1. Age ≥18 years old

2. Patient presenting with histologically-proven Hepatocellular Carcinoma (HCC), or HCC defined by typical imaging findings (EASL criteria), if no biopsy could be performed safely

3. Pretreated or not by tyrosine kinase inhibitors (e.g., sorafenib, lenvatinib, regorafenib, cabozantinib)

4. Child-Pugh B cirrhosis

5. ALBI (Albumin-Bilirubin) grade 1 or 2

6. BCLC (Barcelona Clinic Liver Cancer Group) B or C

7. Availability of biopsy specimen at study enrolment (taken within 3 months of enrolment with the exception of cases where biopsy could not be performed safely)

8. ECOG Performance status ≤2

9. Adequate organ function as indicated by the following laboratory values:

   1. 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) ≥1.5 x 10⁹/L
      • Platelets ≥75 x 10⁹/L
      • Hemoglobin ≥90 g/L

   2. Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated Glomerular Filtration Rate ≥60 mL/min/1.73 m²

   3. Serum total bilirubin ≤3 mg/dL

   4. Liver function: ASAT and ALAT ≤5 ULN, albumin >2.0 g/dL

10. Presence of measurable and evaluable disease according to RECIST v1.1

11. 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

12. 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

13. 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

14. 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 proteinbased biomarker detection

15. Patient affiliated to a social security regimen

16. Men and women patients must consent to not donate or bank sperm or ova during treatment and for 120 days after treatment stop

Exclusion Criteria:

1. More than 50% of the liver is affected by the HCC (according to investigators evaluation)

2. Fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC

3. Previous treatment with immunotherapy (anti-PD-1, anti-PD-L1, or anti-CTLA-4 agents)

4. History of active autoimmune disease. Note: Patients with the following diseases are not excluded and may proceed to further screening:

   1. Type I diabetes
   2. Hypothyroidism (provided it is managed with hormone replacement therapy only)
   3. Controlled celiac disease
   4. Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia)
   5. Any other disease that is not expected to recur in the absence of external triggering factors

5. History of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases

6. Any of the following cardiovascular risk factors:

   1. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤28 days before first dose of study drug
   2. Pulmonary embolism ≤28 days before first dose of study drug
   3. Any history of acute myocardial infarction ≤6 months before first dose of study drug
   4. Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV ≤6 months before first dose of study drug
   5. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤6 months before first dose of study drug
   6. Any history of cerebrovascular accident ≤ 6 months before first dose of study drug
   7. Uncontrolled hypertension: systolic pressure ≥160 mmHg or diastolic pressure ≥100 mmHg despite anti-hypertension medications before first dose of drug
   8. Any episode of syncope or seizure before first dose of study drug

7. 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

8. Known primary immunodeficiency or active HIV

9. 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:

   1. Adrenal replacement steroid (dose ≤10 mg daily of prednisone or equivalent)
   2. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption
   3. 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)

10. 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

11. Transplanted liver, or patient with intent for transplantation

12. Received locoregional therapy to the liver (TACE, transcatheter embolization, hepatic arterial infusion, radiation, radioembolization or ablation) in the 4 weeks before inclusion

13. 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

14. 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

15. Pregnant woman or breast-feeding women or patient with no adequate contraception

16. Participation in another therapeutic trial within the 30 days prior to study inclusion

17. Patients deprived of their liberty or under protective custody or guardianship

18. Patients unable to adhere to the protocol for geographical, social, or psychological reasons

19. Patients eligible for treatment by TACE or SIRT are not allowed