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    Summary
    EudraCT Number:2016-003103-56
    Sponsor's Protocol Code Number:ENTO-R-CHOP
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-03-20
    Trial results View 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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2016-003103-56
    A.3Full title of the trial
    A phase Ib - II study of Entospletinib (ENTO) in newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) patients with aaIPI ≥1 treated by R-CHOP
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Entospletinib in newly diagnosed B Lymphoma patients with poor prognosis treated by R-CHOP
    A.4.1Sponsor's protocol code numberENTO-R-CHOP
    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 SponsorLYSARC
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGILEAD
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLYSARC
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street AddressCHU Lyon Sud - Secteur Ste Eugénie - Pav 6D
    B.5.3.2Town/ cityPierre Bénite Cedex
    B.5.3.3Post code69495
    B.5.3.4CountryFrance
    B.5.4Telephone number+33472669333
    B.5.5Fax number+33426074055
    B.5.6E-mailento-rchop@lysarc.org
    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 nameEntospletinib
    D.3.2Product code GS-9973
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNENTOSPLETINIB
    D.3.9.2Current sponsor codeGS-9973, ENTO
    D.3.9.3Other descriptive nameENTOSPLETINIB
    D.3.9.4EV Substance CodeSUB182049
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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.IMP: 2
    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 nameEntospletinib
    D.3.2Product code GS-9973
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNENTOSPLETINIB
    D.3.9.2Current sponsor codeGS-9973, ENTO
    D.3.9.3Other descriptive nameENTOSPLETINIB
    D.3.9.4EV Substance CodeSUB182049
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Diffuse Large B Cell Lymphoma (DLBCL)
    E.1.1.1Medical condition in easily understood language
    B Lymphoma
    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 10012818
    E.1.2Term Diffuse large 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
    Phase I : to determine the recommended phase 2 dose (RP2D) for ENTO in patients treated with R-CHOP 21

    Phase II : to determine the CMR rate by the Lugano classification 2014 (Deauville scale 1-3) at the end of treatment
    E.2.2Secondary objectives of the trial
    Phase I
    - to evaluate the safety of ENTO in patients treated with 8 cycles of R-CHOP 21
    - to evaluate the preliminary anti-tumor activity of ENTO in patients treated with R-CHOP 21 as assessed by rate of complete metabolic response at the intermediate evaluation and at the end of treatment

    Phase II
    - to evaluate time to response, duration of response, the progression free survival (PFS) and overall survival (OS)
    - to evaluate the complete metabolic response rate at the intermediate evaluation, the overall metabolic response rate (OMRR) at the intermediate evaluation and at the end of treatment,
    - to assess the safety of 8 cycles of ENTO in patients treated with R-CHOP 21

    Exploratory Objectives
    - to assess the pharmacokinetics of ENTO in the presence of R-CHOP chemotherapy
    - analysis of circulating tumor DNA before therapy, at the end of cycle 2, at the end of cycle 4, end of treatment, 6 months after the end of treatment and in case of relapse or progression
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with histologically confirmed de novo DLBCL (CD20 positive)
    2. Age between 60 and 80 years included, on the day of the informed consent document signature
    3. Age adjusted International Prognosis Index (aaIPI) score ≥ 1
    4. No prior treatment for DLBCL. However prephase treatment with 1mg/kg/day prednisone or equivalent, for a maximum of 14 days, is permitted prior to begin the treatment
    5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (0 or 1 only for phase 1b)
    6. Life expectancy of ≥ 90 days (3 months) before starting Entospletinib
    7. Signed informed consent
    8. At least one bi-dimensionally measurable lesion defined as at least one node or tumor lesion on CT scan ≥ 1.5 cm
    9. FDG PET/CT performed at baseline with a FDG positive result
    10. Adequate hematologic functions defined as follows (unless secondary to bone marrow involvement by lymphoma):
    - Absolute neutrophil count (ANC) > 1.5 X 10^9 G/l and
    - Platelets count ≥ 75 X 10^9/l without platelet transfusion dependency during the last 7 days and
    - Haemoglobin level > 9 g/dl (may receive transfusion)
    11. Adequate liver function defined as follows:
    - Total bilirubin <1.5 upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert’s syndrome and
    - Alkaline phosphatase (in absence of bone disease), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 X ULN
    12. Adequate renal function as calculated by a creatinine clearance > 40 ml/min by local institutional formula
    13. Patients with prior Hepatitis B must be given antiviral prophylaxis and HBV DNA monitored; Patients with prior Hepatitis C are eligible if, HCV RNA is undetectable.
    14. Left ventricular ejection fraction (LVEF) ≥ 50% of echocardiography or multiple gated acquisition (MUGA) scan
    15. Adequate tissue for central retrospective testing for cell of origin (10-15 slides of tumor biopsy must be available at baseline)
    16. Heterosexually active females of childbearing potential (as defined in the protocol) must:
    - have a negative serum pregnancy test at baseline and prior to the first study drug administration (C1D-4)
    - have practiced at least 1 reliable method of contraception for at least 2 months prior to the first study drug administration (C1D-4)
    - agree to utilize highly effective methods of contraception (as defined in the protocol) from Cycle 1Day -4 until 12 months following the last treatment administration
    17. Heterosexually active males with partners of childbearing potential must agree to use reliable forms of contraception during treatment and up to 12 months after last treatment administration
    18. Male subjects must agree to avoid sperm donation from Cycle 1 Day -4 until 12 months following the last treatment administration
    E.4Principal exclusion criteria
    1. Central nervous system or meningeal involvement with DLBCL
    2. Contraindication to any drug contained in the chemotherapy regimen
    3. Prior treatment with Entospletinib or other SYK inhibitor
    4. Patients with a prior history of other malignancy, exceptions include:
    - a subject who has been disease-free after curative local treatment (surgical resection) for at least 3 years,
    - a subject with a history of a completely resected non-melanoma skin cancer or in situ carcinoma with surgical complete excision.
    5. Patients taking current therapy with proton pump inhibitors and current therapy with medicines that are strong CYP3A or CYP2C9 inducers, or moderate CYP2C9 inducers.
    6. Ongoing active pneumonitis
    7. Peripheral sensory or motor neuropathy grade > 1.
    8. Major surgery within 4 weeks before first dose of study drug (minor procedures including transcutaneous biopsy, central line placement are permitted at any time)
    9. Inability to take oral medication or malabsorption syndrome or any other uncontrolled gastrointestinal condition that would impair ability to take entospletinib
    10. Significant cardiovascular impairment: congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of first dose of entospletinib or ventricular arrhythmia
    11. Active infection as judged by the investigator
    12. Known hypersensitivity to ENTO
    13. Congenital immunodeficiency or known HIV (human immunodeficiency virus infection) or active viral hepatitis B or C
    14. Any other major illness that in the investigator’s judgement, will substantially increase the risk associated with the subject’s participation in the study
    15. Subjects who have undergone a solid organ transplant and stem cell transplant
    16. Previous treatment for B cell lymphoma or Richter’s transformation
    17. Primary Mediastinal B Cell Lymphoma
    E.5 End points
    E.5.1Primary end point(s)
    Phase I
    RP2D

    Phase II
    CMR rate by the Lugano classification 2014
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I
    RP2D = after 1 cycle of treatment (from Cycle 1/Day -4 to Cycle 2/Day-4)

    Phase II
    CMR rate = end of treatment (8 cycles)
    E.5.2Secondary end point(s)
    Phase I
    - safety
    - CMR rate

    Phase II
    - time to response (TTR), duration of response (DOR), progression free survival (PFS) and overall survival (OS)
    - complete metabolic response rate (CMR rate)
    - overall metabolic response rate (OMR rate)
    - safety

    Exploratory Objectives (all phases)
    - pharmacokinetics
    - circulating tumor DNA
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase I
    - safety : up to 30 days after the last treatment administration
    - CMR : after Cycle 4 and after Cycle 8 (or premature discontinuation)


    Phase II
    - TTR, DOR, PFS and OS = end of follow-up (30 months)
    - CMR rate = after Cycle 4
    - OMR rate = after Cycle 4 and after Cycle 8 (or premature discontinuation)
    - safety = up to 30 days after the last treatment administration

    Exploratory Objectives
    - PK= on C2D1: T0 (within 30 minutes before ENTO dose, 12 hours after the last ENTO dose on Day -1), and then T1H, 1.5H, 2H, 4H, 6H, 8H and 10H after the dose of ENTO.
    - circulating tumor DNA = before therapy, at the end of cycle 2, at the end of cycle 4, end of treatment (cycle 8), 6 months after the end of treatment and in case of relapse or progression
    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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    RP2D
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    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: 34
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 102
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 136
    F.4.2.2In the whole clinical trial 136
    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)
    Treatment or care after the subject has ended the participation in the trial is not different from the expected normal treatment of that condition
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation LYSA
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-05-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-10-18
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