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    Summary
    EudraCT Number:2020-004437-20
    Sponsor's Protocol Code Number:JS001-027-III-HCC
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-02-12
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2020-004437-20
    A.3Full title of the trial
    A prospective, randomized, placebo-controlled, double-blind, multicenter phase III registration clinical study to compare toripalimab (JS001) combined with lenvatinib versus placebo combined with lenvatinib as the 1st-line therapy for advanced hepatocellular carcinoma (HCC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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)
    A.4.1Sponsor's protocol code numberJS001-027-III-HCC
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorShanghai Junshi Biosciences Co., Ltd
    B.1.3.4CountryChina
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportShanghai Junshi Biosciences Co., Ltd
    B.4.2CountryChina
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShanghai Junshi Biosciences Co., Ltd
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street AddressRoom 1003, 10th Floor, Building 2, No.36 58 Haiqu Road, Pudong New Area
    B.5.3.2Town/ cityShanghai
    B.5.3.3Post codeNot applicable
    B.5.3.4CountryChina
    B.5.6E-mailJS001_027_III_HCC@junshipharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameToripalimab
    D.3.2Product code TAB001 and JS001
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTORIPALIMAB
    D.3.9.2Current sponsor codeJS001
    D.3.9.4EV Substance CodeSUB197996
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    advanced hepatocellular carcinoma (HCC)
    E.1.1.1Medical condition in easily understood language
    liver cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10073071
    E.1.2Term Hepatocellular carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10077738
    E.1.2Term Hepatocellular carcinoma metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.0
    E.1.2Level LLT
    E.1.2Classification code 10077736
    E.1.2Term Hepatocellular carcinoma stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.0
    E.1.2Level LLT
    E.1.2Classification code 10077737
    E.1.2Term Hepatocellular carcinoma stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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) and progression-free survival (PFS).
    E.2.2Secondary objectives of the trial
    - 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);
    - 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;
    - To evaluate the pharmacokinetics (PK) profile of toripalimab;
    - To evaluate the immunogenicity of toripalimab.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    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 ≥1.5×109/L;
    - Platelet count ≥ 75×109/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
    E.4Principal exclusion criteria
    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 PD-1/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, anti-angiogenesis drug.
    24. Other participants who are unsuitable for inclusion as judged by the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival (OS);
    E.5.1.1Timepoint(s) of evaluation of this end point
    from C1D1 till end of survival follow-up
    E.5.2Secondary end point(s)
    Efficacy:
    - ORR, DOR, DCR, TTP and PFS evaluated per RECIST v1.1 and mRECIST
    - Six-month and one-year PFS rate and one-year and two-year OS rate in both groups.

    Safety:
    - 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.

    PK and immunogenic parameters:
    - PK profile of toripalimab.
    - Analysis of anti-drug antibody (ADA) during treatment.
    - Immunogenicity of toripalimab: including incidence and titer of anti-drug
    antibody (ADA), and the presence of neutralising antibody (Nab) in ADA-positive samples (if necessary).

    Other study endpoints:
    - ORR, DOR, DCR, TTP and PFS evaluated by investigators using iRECIST criteria;
    - 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    from C1D1 till end of survival follow-up
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Singapore
    Ukraine
    China
    United States
    Italy
    Poland
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end time of the study is defined as the date of the last visit of the last patient (LPLV), or the date of collection of the last data required for statistical analysis, whichever comes earlier. The last data point needed in statistical analysis will be defined in statistical analysis plan in details.
    The sponsor has the right to decide to terminate this study at any time due to specific reasons (such as important safety concerns or force majeure).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 400
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 119
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 519
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients who are receiving treatment with toripalimab and/or lenvatinib mesylate at the end-of-study will enter an extension study to continue to receive treatment, until they meet protocol-specified criteria for treatment discontinuation.

    After the consent is withdrawn, the subject will not be followed up for any reason. There will be
    no replacement for subjects who withdraw
    from the study.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-05-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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