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    Summary
    EudraCT Number:2017-002605-35
    Sponsor's Protocol Code Number:HO151
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2018-03-28
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-002605-35
    A.3Full title of the trial
    A phase II study evaluating the feasibility and clinical efficacy of atezolizumab consolidation treatment in high risk diffuse large B-cell lymphoma.
    Een fase 2 studie naar de werkzaamheid van atezolizumab als aanvullende behandeling bij patiënten met een hoog risico diffuus grootcellig B-cel lymfoom
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase II study evaluating the feasibility and clinical efficacy of atezolizumab consolidation treatment in high risk diffuse large B-cell lymphoma.
    Een fase 2 studie naar de werkzaamheid van atezolizumab als aanvullende behandeling bij patiënten met een hoog risico diffuus grootcellig B-cel lymfoom
    A.4.1Sponsor's protocol code numberHO151
    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 SponsorHOVON Foundation
    B.1.3.4CountryNetherlands
    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 supportHoffmann la Roche
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC, HOVON Data Center
    B.5.2Functional name of contact pointHOVON Data Center (EE2155)
    B.5.3 Address:
    B.5.3.1Street AddressDr. Molewaterplein 40
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015 GD
    B.5.3.4CountryNetherlands
    B.5.6E-mailhdc@erasmusmc.nl
    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 Yes
    D.2.1.1.1Trade name Tecentriq
    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 nameatezolizumab
    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 INNATEZOLIZUMAB
    D.3.9.3Other descriptive nameatezolizumab
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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
    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
    E.1.1.1Medical condition in easily understood language
    Diffuse large B-cell Lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    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
    •To evaluate the 2-year DFS for patients in complete metabolic remission after R-CHOP induction.
    E.2.2Secondary objectives of the trial
    •To evaluate toxicity and assess the relation of adverse events in time to recovery of the T-cell repertoire
    •To evaluate the 2-year OS.
    •To evaluate MRD status at the end of induction therapy, during consolidation treatment and at the end of consolidation.
    •To evaluate the recovery of the T-cell and NK cell repertoire after induction therapy and during consolidation treatment in relation to toxicity and efficacy.

    • To explore the PDL1/HLA expression, mutational load, gene expression immune profile, soluble PDL1, microbiome and T-cell clonality of patients in relation to MRD status and MRD conversion.
    •To explore the tumor characteristics and mutational dynamics in patients who relapse.
    •To assess the crossing of the blood-brain barrier of atezolizumab by measuring atezolizumab concentrations in het cerebrospinal fluid.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age 18-75 (inclusive) years
    • Patients with a confirmed histologic diagnosis of diffuse large B-cell lymphoma (DLBCL-NOS) based upon a representative histology specimen according to the WHO classification, revision 2016
    • Ann Arbor stages II-IV
    • WHO performance status 0 – 1
    • IPI >=3 at diagnosis
    • Complete metabolic remission (Deauville 1-3) after 6-8 cycles of R-CHOP according to the Lugano criteria
    • Negative pregnancy test at study entry
    • Patient is willing and able use adequate contraception during and until 6 months after the last protocol treatment.
    • Written informed consent
    • Patient is capable of giving a written informed consent
    E.4Principal exclusion criteria
    Diagnosis
    • All histopathological diagnoses other than DLBCL-NOS according to the WHO classification, revision 2016,including:
    -High-grade B-cell lymphoma with a double/triple translocation with MYC, BCL2 and/or BCL6. Please note that patients with an isolated MYC translocation or an isolated BCL2 translocation or an isolated BCL-6 translocation are eligible (single hit translocation).
    -Testicular large B-cell lymphoma
    -Primary mediastinal B cell lymphoma
    -Transformed indolent lymphoma
    -Post-transplant lymphoproliferative disorder

    Organ dysfunction
    • Clinical signs of severe pulmonary dysfunction.
    • Clinical signs of heart failure (NYHA classification II-IV).
    • Symptomatic coronary artery disease or cardiac arrhythmias not well controlled with medication.
    • Myocardial infarction during the last 6 months.
    •Significant renal dysfunction (serum creatinine ≥ 150 umol/l or clearance ≤ 30ml/min
    Creatinine clearance may be calculated by Cockcroft –Gault formula.
    •Inadequate hematological function: hemoglobin < 5.5 mmol/L , ANC < 1.0x109/L or platelets < 75x109 /L
    •Signs or known history of bleeding disorder
    •Significant hepatic dysfunction (total bilirubin ≥ 1.5x upper limit of normal (ULN) or transaminases ≥ 2.5 x ULN), unless related to Gilberts syndrome.
    •Clinical signs of severe cerebral dysfunction
    •Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs
    •Major surgery within the last 4 weeks

    Known or suspected infection
    • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 before date of registration. Suspected active or latent tuberculosis needs to be confirmed by positive interferon gamma (IFN-γ) release assay
    • Patients known to be HIV-positive
    • Active chronic hepatitis B or C infection
    • Administration of a live, attenuated vaccine within 4 weeks before date of registration or anticipation that such a live attenuated vaccine will be required during the study and for a period of 5 months after discontinuation of atezolizumab.

    Auto-immune
    • Any active or history of documented autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
    The following exceptions are allowed: Patients with autoimmune-related hypothyroidism or type 1 diabetes mellitus who are on stable treatment.
    • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening.
    • Patients with uncontrolled asthma or allergy, requiring systemic steroid treatment
    • Regular treatment with corticosteroids within the 4 weeks prior to date of registration, unless administered for indications other than NHL at a dose equivalent to < 30 mg/day prednisone/prednisolone.

    General
    • Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease)
    • Current participation in another clinical trial interfering with this trial
    • History of active cancer during the past 5 years, except basal cell carcinoma of the skin, stage 0 cervical carcinoma or carcinoma in situ (for which no systemic treatment was indicated)
    • Life expectancy < 6 months
    • Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

    Prior treatment
    • Prior treatment with atezolizumab, or anti PD-1 or PDL-1 antibodies.
    • Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4 therapeutic antibodies.
    • Treatment with systemic immunostimulatory agents (including but not limited to IFN, interleukin [IL]-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to date of registration.
    • Treatment with systemic immunosuppressive medications, including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents within 2 weeks prior to date of registration; inhaled corticosteroids and mineralocorticoids are allowed.
    E.5 End points
    E.5.1Primary end point(s)
    • Disease free survival measured from the date of registration to relapse or death from any cause whichever comes first.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The endpoint will be evaluated when applicable data for all patients are available
    E.5.2Secondary end point(s)
    • (Severe) Adverse Events and the relation of adverse events in time to the recovery of the T-cell repertoire
    • Overall survival, calculated from registration until death from any cause. Patients still alive or lost to follow up are censored at the last date known to be alive.
    • The relationship between MRD status at the end-of-induction and end-of-consolidation therapy.
    • The relation between MRD conversion and 2-years DFS and OS
    • The relationship between T-cell repertoire, PDL1/HLA expression, mutational load, gene immune signature, microbiome and effect of atezolizumab on MRD conversion.
    • The relation between the T-cell and NK cell repertoire and adverse events.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The endpoint will be evaluated when applicable data for all patients are available
    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 No
    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) 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 No
    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 concerned27
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA32
    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 years6
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    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: 67
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 42
    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 state90
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 109
    F.4.2.2In the whole clinical trial 109
    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)
    None
    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 Decision2018-03-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-28
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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