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    Summary
    EudraCT Number:2020-000736-21
    Sponsor's Protocol Code Number:HLX01-FL03
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-04-29
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2020-000736-21
    A.3Full title of the trial
    A Phase 3 Multi-Centre, Randomised, Double-Blind, Parallel-Arm Study to Evaluate the Efficacy and Safety of HLX01 Versus Rituximab (Mabthera®) as First Line Treatment in Patients With Low Tumour Burden Follicular Lymphoma.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 study to evaluate the efficacy and safety of HLX01 versus rituximab (Mabthera®) as treatment for patients with low tumour burden follicular lymphoma.
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberHLX01-FL03
    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 Henlius Biotech Inc.
    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 Henlius Biotech, Inc.
    B.4.2CountryChina
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShanghai Henlius Biotech,Inc.
    B.5.2Functional name of contact pointGlobal Clinical Medical Affairs
    B.5.3 Address:
    B.5.3.1Street AddressRoom 303 & 304, Block 7, No. 1999 Zhangheng Road
    B.5.3.2Town/ cityShanghai
    B.5.3.3Post code201210
    B.5.3.4CountryChina
    B.5.4Telephone number+86021 3339 5800
    B.5.5Fax number+86021 3339 5801
    B.5.6E-mailGCMA_EMA@henlius.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 nameRecombinant Human-Mouse Chimeric Anti-CD20 Monoclonal Antibody Injection
    D.3.2Product code HLX01
    D.3.4Pharmaceutical form Concentrate for 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeHLX01 DS
    D.3.9.3Other descriptive nameHLX01
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeBiosimilar medicinal product, monoclonal antibody
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name Mabthera®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameMabthera®
    D.3.4Pharmaceutical form Concentrate for 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.3Other descriptive nameRITUXIMAB
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Low tumour burden follicular lymphoma
    E.1.1.1Medical condition in easily understood language
    Disease of the lymph tissue (part of the immune system) that affects a type of white blood cell called B-Lymphocytes.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10003899
    E.1.2Term B-cell lymphoma
    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 compare the ORR up to Week 28 of HLX01 versus Mabthera® in patients with low tumour burden, previously untreated Follicular Lymphoma (FL)
    E.2.2Secondary objectives of the trial
    - To obtain additional estimates of the efficacy of HLX01 and Mabthera® in patients with FL;
    - To compare the safety profile of HLX01 and Mabthera®;
    - To evaluate the immunogenicity of HLX01 and Mabthera®;
    - To measure the exposure to rituximab following HLX01 or Mabthera® treatment
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Voluntary written informed consent before any study-related activities;
    2. ≥ 18 years of age;
    3. Histologically-confirmed, stage II to IV non-Hodgkin lymphoma (NHL) (CD20+ FL of grades 1, 2, or 3a) by World Health Organization classification of lymphoid neoplasms (2016 revision);
    4. Low tumour burden according to the GELF criteria:
    - No nodal or extranodal involvement of more than 7 cm in diameter;
    - Less than 3 masses >3 cm;
    - No B symptoms: B symptoms are defined as patients with lymphoma having one of the following symptoms:
    1. Fever with a temperature >38℃ for 3 consecutive days
    2. Weight loss without trying, exceeding 10% of body weight in 6 months
    3. Drenching night sweats
    - No splenomegaly: spleen ≤16 cm by computed tomography (CT) scan
    - No complications such as ascites or organ compression
    - No pleural or peritoneal serous effusions
    - No leukaemic phase: <5,000 circulating tumour cells per L
    - No cytopenias: platelets ≥100 × 109/L, haemoglobin ≥10 g/dL, and absolute neutrophil count ≥1.5 × 109/L.
    5. The Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
    6. Availability of tumour sample within 12 months before start of study drug treatment;
    7. At least 1 bi-dimensionally measurable nodal lesion >1.5 cm or extranodal lesion >1 cm in its longest diameter by CT scan as defined by the Modified Lugano Response Classification 2014;
    8. Adequate organ function:
    - Creatinine clearance ≥50 ml/minute as assessed by the Cockcroft-Gault formula
    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN);
    - Alkaline phosphatase (ALP) ≤2.5 × ULN;
    - Bilirubin ≤1.5 × ULN (≤2 × ULN if hyperbilirubemia is due to Gilbert’s syndrome or haemolysis)
    9. Women of childbearing potential (WOCBP) or male patients whose sexual partners are WOCBP, must be able and willing to use at least 1 highly effective method of contraception during the study.
    For male patients, reliable methods of contraception should be used from the start of study drug treatment and for at least 12 months after the last study drug administration. For female patients, reliable methods of contraception should be used from at least 1 month before the start of study drug treatment and for at least 12 months after last study drug administration.
    Highly effective methods of contraception:
    - Combined (containing oestrogen and progestogen) hormonal contraception associated with inhibition of ovulation (administration may be oral, intravaginal, or transdermal);
    - Progestogen-only hormonal contraception associated with inhibition of ovulation (administration may be oral, injectable, or implantable)
    - Intrauterine device;
    - Intrauterine hormone-releasing system;
    - Bilateral tubal ligation or occlusion;
    - Vasectomy (provided that the male has a medical assessment of surgical success);
    - Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk in relation to the duration of the clinical study, in line with the preferred and usual lifestyle of the patient);
    10. Ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the Investigator and to comply with the requirements of the entire study.
    E.4Principal exclusion criteria
    1. Prior treatment for FL. Patients previously treated with radiotherapy for stage I FL may be eligible provided they have a measurable lesion located outside the radiation field;
    2. Transformation to high-grade lymphoma;
    3. Patients with advanced disease that are considered for treatment with combined chemo-immunotherapy;
    4. Presence or history of central nervous system (CNS) lymphoma involvement;
    5. Treatment with an investigational agent within 28 days of the first dose of study drug infusion;
    6. Prior treatment with a chimeric antibody, including HLX01 and Mabthera®;
    7. History of another malignancy within 2 years of screening, with the exception of curatively treated non-melanoma skin cancer, carcinoma in situ of the uterine cervix, breast or bladder, localised prostate cancer stage T1c or less – and provided that the patient remains relapse free;
    8. Major surgery within 28 days of the first dose of study drug infusion (excluding lymph node biopsy);
    9. Known human immunodeficiency virus (HIV) infection (Serological test for HIV should be performed at screen unless prohibited by local regulations);
    10. Active and/or severe infections, including any ongoing infection requiring IV anti-microbial treatment;
    11. Have a current diagnosis of active tuberculosis;
    12. Active hepatitis B (HBV) and a positive serological test for HBV (except seropositive due to HBV vaccination) or hepatitis C virus (HCV);
    13. Ongoing immunosuppressant treatment; corticosteroid treatment exceeding 20 mg/day prednisone or equivalent within 7 days of the first dose of study drug infusion;
    14. Known hypersensitivity or allergy to the active principle and/or formulations’ ingredients; history of severe allergy or anaphylaxis to murine or biologic agents;
    15. Live or live attenuated vaccine within 28 days of first dose of study drug infusion;
    16. History of significant cardiac or vascular disease including, but not limited to: history of stroke, unstable angina, myocardial infarction or ventricular arrhythmia requiring medication or mechanical control within 6 months before randomisation; congestive heart failure according to the New York Heart Association (NYHA) Functional Classification class III or IV;
    17. History of drug abuse or alcohol abuse;
    18. Unstable or uncontrolled medical or psychological condition;
    19. Pregnant or breastfeeding female subject.
    E.5 End points
    E.5.1Primary end point(s)
    ORR up to Week 28, defined as the proportion of patients achieving either complete response (CR) or partial response (PR) as best response from the first dose of study drug through Week 28 as assessed by a blinded independent review committee according to the Modified Lugano Response Classification 2014.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 28
    E.5.2Secondary end point(s)
    - Efficacy:
    Time-to-progression of disease (TTPD), progression-free survival (PFS), and overall survival (OS), plus ORR at each assessable time point;

    - Safety and tolerability:
    Adverse events (AEs), serious adverse events (SAEs), adverse events of special interest (AESI), laboratory abnormalities, physical examination, vital signs, and 12-lead electrocardiogram (ECG)

    - Immunogenicity:
    Anti-drug antibody (ADA) and neutralising antibody

    - Pharmacokinetics (PK):
    The maximum serum concentration (Cmax) and trough serum concentration (Ctrough) after each dose during induction period and selected doses thereafter

    - Pharmacodynamics:
    Depletion of B cell counts: absolute count and change from baseline
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence Yes
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    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) Yes
    E.8.2.2Placebo No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    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
    Australia
    Belgium
    China
    Czech Republic
    France
    Hungary
    India
    Italy
    Poland
    Romania
    Russian Federation
    Spain
    Ukraine
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days14
    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: 159
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 53
    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 state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 176
    F.4.2.2In the whole clinical trial 212
    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)
    Study drug will not be available on completion of the trial. The subject would continue under the care of their oncologist.
    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 Decision2020-07-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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