A clinical study to compare Toripalimab (JS001) combined with Lenvatinib versus placebo combined with Lenvatinib as the 1st-line therapy for advanced hepatocellular carcinoma (HCC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Shanghai Junshi Biosciences Co. Ltd.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

8 Jul 2021 → ongoing

Decision date (initial)

2024-09-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Shanghai Junshi Biosciences Co., Ltd

External identifiers

EU CT number

2024-514207-34-00

EudraCT number

2020-004437-20

ClinicalTrials.gov

NCT04523493

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To observe, compare and evaluate the efficacy of toripalimab combined with lenvatinib (experimental group) versus placebo combined with lenvatinib (control group) as the 1st-line therapy for patients with advanced hepatocellular carcinoma (HCC) through evaluation of overall survival (OS).

Secondary objectives 4

1. To evaluate and compare the efficacy of toripalimab combined with lenvatinib versus placebo combined with lenvatinib as the 1st-line therapy for patients with advanced HCC through evaluation of progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR) and time to progression (TTP) using the response evaluation criteria in solid tumors version 1.1 (RECIST v 1.1 criteria) and modified RECIST for HCC (mRECIST);
2. To evaluate the safety and tolerability of toripalimab combined with lenvatinib versus placebo combined with lenvatinib as the 1st-line therapy for patients with advanced HCC;
3. To evaluate the pharmacokinetics (PK) profile of toripalimab;(Applicable to China only)
4. To evaluate the immunogenicity of toripalimab.(Applicable to China only)

Conditions and MedDRA coding

Advanced hepatocellular carcinoma (HCC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Age of 18-75 full years (inclusive), male or female.
2. Histopathologically or cytologically confirmed HCC or participants with liver cirrhosis meet the clinical diagnostic criteria for HCC of the American Association for the Study of Liver Diseases (AASLD).
3. Stage B (intermediate stage) or C (advanced stage) HCC determined in accordance with Barcelona Clinic Liver Cancer staging system (BCLC stage), be unsuitable for surgery and/or local therapy, or have progression of disease after surgery and/or local therapy.
4. No previous use of any systemic therapy for HCC (mainly including systemic chemotherapy, antiangiogenic drugs or other molecular targeted therapy, immunotherapy containing CTLA-4, PD-1/PD-L1 monoclonal antibody).
5. Having ≥ 1 measurable lesion in accordance with RECIST v1.1. Requirement: the selected target lesion has not been treated locally before, or is located in the area of previous local therapy and subsequently determined as PD through radiological examination and in accordance with RECIST v1.1.
6. Child-Pugh class A or ≤7 class B, with no history of hepatic encephalopathy.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score 0-1.
8. Expected survival ≥12 weeks.
9. Main organ function meets the following requirements: no blood transfusion within 14 days prior to screening, no use of hematopoietic stimulating factor (including G-CSF, GM-CSF, EPO and TPO etc.) or human albumin preparation. ⚫ Absolute neutrophil count ≥1.5×10 9 /L; ⚫ Platelet count ≥ 75×10 9 /L; ⚫ Haemoglobin ≥ 90 g/L; ⚫ Serum albumin ≥ 29 g/L; ⚫ Serum total bilirubin ≤2 × upper limit of normal (ULN); ⚫ Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 5×ULN; ⚫ Serum creatinine (Cr) ≤1.5×ULN or Cr clearance ≥50 mL/min (calculated by Cockcroft-Gault formula) ⚫ International normalized ratio (INR) ≤2 and prothrombin time (PT) ≤6 seconds exceeding ULN; ⚫ Urine protein < 2+ (If urine protein ≥2+, 24h urine protein quantification should be performed, the patients with 24h urine protein quantification <1.0g can be enrolled).
10. In case of HBsAg (+) and/or HBcAb (+), HBV DNA is required to be < 1000 IU/mL (if the lowest detectable value at the local center is higher than 1000IU/mL, enrollment can be determined based on the specific condition after discussed with sponsor), and it is required to continue original anti-HBV therapy in the full course, or start to use Entecavir or tenofovir in the full course after screening during the study.
11. Female patients of childbearing potential must receive serum pregnancy test within 7 days before randomization, have negative result, and are willing to use reliable and effective contraceptive methods during the trial and within 5 months after last administration. Male patients whose partners are women of childbearing potential must agree to use reliable and effective contraceptive methods during the trial and within 5 months after last administration.
12. Being voluntary to participate in the study, sufficiently informed consent and sign the written informed consent form, with good compliance.

Exclusion criteria 24

1. Known cholangiocellular carcinoma (ICC) or mixed hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma and hepatic fibrolamellar carcinoma.
2. Malignant tumor except HCC within 5 years: however, localized tumor cured in the study is excluded, including cervical carcinoma in situ, skin basal cell carcinoma and carcinoma in situ of prostate.
3. Hepatic surgery and/or local therapy or treatment with investigational product for HCC within 4 weeks prior to randomization; palliative radiation therapy for bone metastatic lesion within 2 weeks prior to randomization; use of Chinese medicine preparations with anti-liver cancer effect within two weeks prior to randomization. Toxicity induced by previous therapy (except alopecia) not recovered to ≤ grade 1 (NCI-CTCAE v5.0).
4. Prior use of other anti-PD-1 antibody or other immunotherapy targeting PD1/PD-L1.
5. Uncontrolled pericardial effusion, uncontrolled pleural effusion or clinically obvious moderate or severe peritoneal effusion at screening, defined as reaching the following criteria: having clinical symptoms and pleural and peritoneal effusion detected in physical examination at screening; or puncture for drainage required for pleural and peritoneal effusion and/or intracavitary administration during screening.
6. History of gastrointestinal hemorrhage within 6 months prior to randomization or clear tendency of gastrointestinal hemorrhage (including severe esophageal-gastric varices with hemorrhagic risk, locally active peptic ulcer, persistent fecal occult blood (+)).
7. Having ≥ grade 3 (NCI-CTCAE v5.0) gastrointestinal or non-gastrointestinal fistula at present.
8. Cancer thrombus invasion in the main trunk of portal vein (Vp4) (more than 1/2 of the lumen), inferior vena cava cancer thrombus or cardiac involvement in accordance with CT/MRI.
9. Serious cardiovascular and cerebrovascular diseases: ⚫ New York Heart Association (NYHA) class II or above congestive heart failure, unstable angina pectoris, myocardial infarction, cerebrovascular accident or poorly controlled arrhythmia within 12 months prior to randomization. ⚫ Left ventricular ejection fraction (LVEF) <50% in color Doppler echocardiography. ⚫ Corrected QT interval (QTc) >480 ms (calculated using Fridericia method, in case of abnormal QTc, it can be detected for consecutive three times at an interval of 2 minutes and the average will be taken). ⚫ Hypertension that can not be controlled by drug (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100mmHg) (based on the mean value obtained from ≥2 measurements). ⚫ Previous occurrence of hypertensive crisis or hypertensive encephalopathy.
10. Other obvious hemorrhagic tendency or evidence on important coagulation disorder: ⚫ Clinically significant hemoptysis or tumor hemorrhage for any reason within two weeks prior to randomization; ⚫ Thrombosis or embolic event within 6 months prior to randomization; ⚫ Use of anticoagulation therapy for therapeutic purpose within two weeks prior to randomization (except low molecular weight heparin); ⚫ Requiring antiplatelet therapy.
11. Medium to large surgical treatment within 4 weeks prior to randomization, not including diagnostic biopsy.
12. Know central nervous system metastasis; cranial and/or spinal MRI is needed for exclusion if central nervous system metastasis is suspected.
13. Serious, uncured wound, active ulcer or untreated bone fracture.
14. Vaccination of live vaccine within 30 days prior to randomization.
15. Presence of immunodeficiency or receiving long-term systemic steroid therapy within 7 days prior to randomization (daily dose >10 mg Prednisone or other equivalent glucocorticoid), or other immunosuppressive therapy.
16. Active autoimmune diseases requiring systemic treatment (i.e., immunomodulatory drug, corticosteroid or immunosuppressant) in the past two years; however, replacement therapy (e.g., thyroxine, insulin or physiological corticosteroid replacement therapy for renal or pituitary insufficiency) will not be considered as systemic therapy and is allowed to be used.
17. History of clear interstitial lung disease or non-infectious pneumonia, unless induced by local radiotherapy.
18. Active tuberculosis or received antituberculosis therapy within 1 year prior to randomization.
19. Any serious acute and chronic infection requiring systemic antibacterial, antifungal or antiviral therapy at screening, not including viral hepatitis.
20. Known history of human immunodeficiency virus (HIV) infection.
21. Previously receiving allogeneic stem cell or solid organ transplantation.
22. Inability to swallow tablets, malabsorption syndrome or any other condition that affects gastrointestinal absorption.
23. Known history of serious allergy to any monoclonal antibody, antiangiogenesis drug.
24. Other participants who are unsuitable for inclusion as judged by the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival (OS)

Secondary endpoints 4

1. Efficacy: 1. ORR, DOR, DCR, TTP and PFS evaluated per RECIST v1.1 and mRECIST. 2. Six-month and one-year PFS rate and one-year and two-year OS rate in both groups.
2. Safety: 1. Incidence, severity and prognosis of adverse event (AE) and serious adverse event (SAE) judged in accordance with NCI-CTCAE v5.0; vital signs, ECG and abnormal laboratory examinations.
3. PK and immunogenic parameters: 1. PK profile of toripalimab. 2. Analysis of anti-drug antibody (ADA) during treatment. 3. Immunogenicity of toripalimab: including incidence and titer of antidrug antibody (ADA), and the presence of neutralising antibody (Nab) in ADA-positive samples (if necessary).
4. Other study endpoints: 1. ORR, DOR, DCR, TTP and PFS evaluated by investigators using iRECIST criteria; 2. Correlation between PD-L1 expression level in tumor tissue, proportion of strong positive expression of PD-L1, tumor mutation burden (TMB) and the efficacy of toripalimab combined with lenvatinib

Investigational products

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

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Shanghai Junshi Biosciences Co. Ltd.

Sponsor organisation

Shanghai Junshi Biosciences Co. Ltd.

Address

Building 2 13th Floor, No. 36 And 58 Haiqu Road, Pudong New Area No. 36 And 58 Haiqu Road Pudong New Area

City

Shanghai

Postcode

201203

Country

China

Scientific contact point

Organisation

Shanghai Junshi Biosciences Co. Ltd.

Contact name

Chenxi Wang

Public contact point

Organisation

Shanghai Junshi Biosciences Co. Ltd.

Contact name

Niannian Wang

Third parties 2

Locations

2 EU/EEA countries · 5 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 18 files

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

Application history

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