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    Summary
    EudraCT Number:2017-003511-20
    Sponsor's Protocol Code Number:201700599
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-09-26
    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 number2017-003511-20
    A.3Full title of the trial
    Molecular imaging of zirconium-89-labeled atezolizumab in high-risk diffuse large B-cell lymphoma prior to atezolizumab treatment
    Moleculaire beeldvorming middels Zirkonium-89-gelabeled Atezolizumab als een instrument om de biodistributie van atezolizumab in hoog risico diffuus grootcellig B-cellymfoom te onderzoeken
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Imaging with a radioactively-labeled antibody against PDL-1 in patients with lymphoma
    Beeldvorming met een radioactief gelabelde antilichaam gericht tegen PDL-1 in patienten met lymfoom
    A.3.2Name or abbreviated title of the trial where available
    PDL1 imaging in DLBCL
    PDL1 imaging in DLBCL
    A.4.1Sponsor's protocol code number201700599
    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 supportHoffman 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 AddressWytemaweg 80
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015 CN
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31107041560
    B.5.5Fax number+31107041028
    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 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 name89ZR-N-SUCDF-ATEZOLIZUMAB
    D.3.2Product code 89ZR-N-SUCDF-MPDL3280A
    D.3.4Pharmaceutical form Solution for injection
    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 nameMPDL3208
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit MBq megabecquerel(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number37
    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) 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 Yes
    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
    Diffuus grootcellig B-cellymfoom
    E.1.1.1Medical condition in easily understood language
    Diffuse large B-cell Lymphoma
    Diffuus grootcellig B-cellymfoom
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10012819
    E.1.2Term Diffuse large B-cell lymphomas
    E.1.2System Organ Class 100000004851
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10012820
    E.1.2Term Diffuse large B-cell lymphoma NOS
    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 biodistribution of 89Zr-atezolizumab in patients with high risk DLBCL at diagnosis.
    E.2.2Secondary objectives of the trial
    • Assess the heterogeneity of 89Zr-atezolizumab tumor uptake in high-risk DLBCL before R-CHOP
    • Correlate 89Zr-atezolizumab biodistribution with PD-L1 expression on tumor cells and cells in the micro-environment as assessed by immunohistochemistry on archival tumor biopsies, soluble PD-L1 measurements and PD-L1 RNA expression
    • Evaluate 89Zr-atezolizumab biodistribution in metabolic complete remission following R-CHOP and assess the relation with minimal residual disease
    • Assess the 89Zr-atezolizumab biodistribution at relapse after treatment with atezolizumab for patients treated in the HOVON 151 trial
    • Correlate 89Zr-atezolizumab tumor uptake dynamics and biodistribution to potential adverse reactions of atezolizumab treatment for patients treated in the HOVON 151 trial
    • Establish the baseline characteristics for the T-cell and NK-cell repertoire and dynamics induced by R-CHOP
    • Establish the baseline characteristics for the microbiome and the dynamics induced by R-CHOP
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to receive information on the dynamics induced by R-CHOP, patients should preferably be included before standard R-CHOP therapy (at Part A). Alternatively, patients who are eligible can also be included after having achieved complete remission with standard R-CHOP therapy (i.e. at Part B).

    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 (see appendix A)
    • Ann Arbor stages II-IV (see appendix B)
    • WHO performance status 0 – 1 (see appendix E)
    • IPI ≥ 3 at diagnosis (see appendix C)
    • Negative pregnancy test at study entry
    • Patient is willing and able use adequate contraception during and until 5 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 (see appendix A), including:
    - High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 translocations
    - 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:
    CrCl = (140 - age [in years]) x weight [kg] (x 0.85 for females) /
    (0.815 x serum creatinine [μmol/L])
    • Inadequate hematological function: hemoglobin < 5.5 mmol/L ANC < 1.0x10^9/L or platelets < 75x10^9 /L
    • Spontaneous INR > 1.5, aPTT >33
    • 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 weeks 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 or stage 0 cervical carcinoma
    • 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)
    • Description of 89Zr-atezolizumab biodistribution in DLBCL by measuring standardized uptake value (SUV) on the 89Zr-atezolizumab-PET scans
    E.5.1.1Timepoint(s) of evaluation of this end point
    Data analysis will be performed on an ongoing basis after every patient
    E.5.2Secondary end point(s)
    • Tumor and immune cell PD-L1 expression analysis in an archival pre-treatment biopsy, will be correlated to 89Zr-atezolizumab tumor uptake, evaluated by measuring standardized uptake value (SUV) on the 89Zr-atezolizumab-PET
    • Correlation analysis of tumor 89Zr-atezolizumab uptake, evaluated by measuring standardized uptake value (SUV) and sPD-L1 levels in patient serum, assessed using ELISA
    • Correlation analysis of tumor 89Zr-atezolizumab uptake, evaluated by assessing immune signature by GEP
    • Correlation analysis of 89Zr-atezolizumab uptake and MRD status
    • Correlation analysis between 89Zr-atezolizumab off-target uptake and atezolizumab toxicity
    • Analysis of predictive value of 89Zr-atezolizumab imaging in high-risk DLBCL patients

    Exploratory study endpoints:
    • Establish baseline characteristics and dynamics for T-cell repertoire and microbiome after R-CHOP
    E.5.2.1Timepoint(s) of evaluation of this end point
    Data analysis will be performed on an ongoing basis after every patient
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy No
    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 concerned2
    E.8.5The trial involves multiple Member States No
    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 No
    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 of this study is marked by the last study procedure, i.e. the last 89Zr-atezolizumab-PET scan. Patients eligible for atezolizumab treatment will be followed up for 5 years according to HOVON 151 protocol.
    Patients, who participated in the imaging trial and who are not eligible for atezolizumab treatment, will be followed 28±3 days (after tracer injection), or until the last (serious) adverse event related to the tracer or unlabeled atezolizumab administration has resolved.
    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 months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months4
    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: 10
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 20
    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 participating in the 89Zr-atezolizumab imaging study are eligible for participation in the HOVON 151 study which aims at increasing disease free survival via consolidation therapy with atezolizumab.
    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 Decision2018-09-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-30
    P. End of Trial
    P.End of Trial StatusOngoing
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