Testing immunotherapy for patients with liver cancer and moderatelyaltered liver functions

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Oct 2023 → ongoing

Decision date (initial)

2024-08-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Beigene

External identifiers

EU CT number

2024-516443-57-00

EudraCT number

2020-003108-15

ClinicalTrials.gov

NCT05622071

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

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 3

1. To assess safety of anti-PD-1
2. To assess efficacy in terms of: o Objective Response Rate based on best overall response across all time-point according to mRECIST and iRECIST tumor response evaluation o Overall survival (OS) o Progression-free survival (PFS) o Time to progression (TTP)
3. To assess Quality of Life according to EORTC QLQ-C30 and HCC-18

Conditions and MedDRA coding

Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh B, ALBI grade 1 or 2 liver function, pretreated or not by tyrosine kinase inhibitors and not pretreated with immunotherapy.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

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 (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: 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
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 protein-based 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 19

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: 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
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: 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
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: 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)
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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The Objective Response Rate defined as the proportion of patients with Complete Response or Partial Response to treatment based on best overall response according to RECIST 1.1, recorded from treatment initiation to the end of treatment.

Secondary endpoints 7

1. Frequency of limiting toxicity (LT), defined as any adverse event related to the experimental drug, and leading to definitive treatment discontinuation according to the investigator, before the second injection
2. Frequency of related and not related adverse events occurring during the treatment period and until 3 months after treatment discontinuation. Adverse events will be coded and categorized according MedDRA classification and CTCAE V5.0 grade for severity.
3. Objective Response Rate defined as the proportion of patients with Complete Response or Partial Response to treatment based on best overall response according to mRECIST and iRECIST recorded from treatment initiation to the end of treatment.
4. Overall survival, defined as the time between date of inclusion and death from any cause. Patients lost to follow-up will be censored at the date of last known to be alive.
5. Progression-free survival, defined as the time between date of inclusion and disease progression or death, whichever occurs first. Disease progression will be evaluated 3 times according to RECIST v1.1, mRECIST and iRECIST, respectively. Patients lost to follow-up and patients who could benefit from secondary surgery for HCC will be censored at the date of last news and date of surgery, respectively.
6. Time to progression is defined as the time between the date of inclusion and the date of radiological progression according RECIST v1.1. Death will be censored.
7. Health Related Quality of Life according to EORTC QLQ-C30 and HCC-18

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications