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    Summary
    EudraCT Number:2016-002272-27
    Sponsor's Protocol Code Number:DSHNHL2015-1
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-06-03
    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 ConcernedAustria - BASG
    A.2EudraCT number2016-002272-27
    A.3Full title of the trial
    Improvement of Outcome in Elderly Patients or Patients not eligible for high-dose chemotherapy with Aggressive Non-Hodgkin Lymphoma in first Relapse or Progression by adding Nivolumab to Gemcitabine, Oxaliplatin plus Rituximab in case of B-cell lymphoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Improvement of Outcome in Elderly Patients or Patients not eligible for high-dose chemotherapy with Aggressive Non-Hodgkin Lymphoma in first Relapse or Progression by adding Nivolumab to a standard chemotherapy.
    A.3.2Name or abbreviated title of the trial where available
    NIVEAU
    A.4.1Sponsor's protocol code numberDSHNHL2015-1
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03366272
    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 SponsorSaarland University
    B.1.3.4CountryGermany
    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 supportBristol-Myers Squibb
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDSHNHL
    B.5.2Functional name of contact pointKlinik fuer Innere Medizin I
    B.5.3 Address:
    B.5.3.1Street AddressKirrbergerstr
    B.5.3.2Town/ cityHomburg
    B.5.3.3Post code66421
    B.5.3.4CountryGermany
    B.5.6E-maildshnhl@uks.eu
    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 Opdivo
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb
    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 nameOpdivo
    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 INNOpdivo
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    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) 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
    Patients with first relapse or progression of aggressive Non-Hodgkin’s Lymphoma who are not eligible neither for autologous nor allogeneic stem cell transplantation
    E.1.1.1Medical condition in easily understood language
    Patients with first relapse or progression of aggressive Non-Hodgkin’s Lymphoma who are not eligible neither for autologous nor allogeneic stem cell transplantation
    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 22.0
    E.1.2Level PT
    E.1.2Classification code 10029547
    E.1.2Term Non-Hodgkin's 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
    Improvement of 1-yr PFS by nivolumab plus (R)-GemOx followed by nivolumab consolidation instead of (R)-GemOx alone in patients with progressed or relapsed aggressive NHLs not eligible neither for autologous nor allogeneic stem cell transplantation
    E.2.2Secondary objectives of the trial
    - To determine whether survival can be increased by adding nivolumab to standard (R)-GemOx.
    - To determine whether outcome can be improved by adding nivolumab to standard (R)-GemOx.
    - To determine toxicity and protocol adherence of standard (R)-GemOx with or without nivolumab.
    - To evaluate quality of life of patients with relapsed or refractory aggressive Non-Hodgkin’s Lymphoma treated with (R)-GemOx with or without Nivolumab.
    - To analyze outcome according to biological parameters.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age: all patient >65 years of age or > 18 years if not eligible for neither
    autologous nor allogeneic stem cell transplantation
    2. Ineligibility for neither autologous nor allogeneic stem cell transplantation as defined as:
    >65 years of age or
    older than 18 years if HCT-CI score > 2 (cf. Appendix 24.2) or
    patients who underwent prior autologous stem cell transplantation and
    are not eligible for allogeneic stem cell transplantation
    3. Risk group: All risk groups (IPI 0 to 5)
    4. Histology: Diagnosis of aggressive Non-Hodgkin’s lymphoma, based on an
    excisional biopsy of a lymph node or on an appropriate sample of a
    lymph node or of an extranodal involvement at initial diagnosis or
    relapse or progression.The entities treated in the study will be based
    on the WHO 2017 classification62.
    B-NHL:
     Follicular lymphoma grade IIIb
     DLBCL, not otherwise specified (NOS)
     T-cell/histiocyte-rich large B-cell lymphoma
     primary cutaneous DLBCL, leg type
     EBV-positive DLBCL, NOS
     DLBCL associated with chronic inflammation
     primary mediastinal (thymic) large B-cell lymphoma
     intravascular large B-cell lymphoma
     ALK-positive large B-cell lymphoma
     plasmablastic lymphoma
     primary effusion lymphoma
     HHV8+ DLBCL, NOS
     high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
     high-grade B-cell lymphoma, NOS
     B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and
    classical Hodgkin lymphoma
    T-NHL:
     Aggressive NK cell leukemia
     Enteropathy-associated T-cell lymphoma
     Hepatosplenic T-cell lymphoma
     Primary cutaneous gamma-delta T-cell lymphoma
     Peripheral T-cell lymphoma, NOS
     Angioimmunoblastic T-cell lymphoma
     Anaplastic large cell lymphoma, ALK-positive
     Anaplastic large cell lymphoma, ALK-negative
     Peripheral T-cell lymphoma with TFH phenotype
     Monomorphic epitheliotropic intestinal T-cell lymphoma
     Subcutaneous panniculitis-like T-cell lymphoma
    5. Performance status: Performance status ECOG 0 – 2. Also patients with performance
    status 0 – 2 are eligible when assessed after prephase treatment.
    The performance status of each patient should be assessed before
    the initiation and after the end of prephase treatment which, as
    experience has shown, can result in its significant improvement. A
    definition of the performance status is provided in Appendix 24.3.
    6. Previous therapy: Patients must have only one prior chemotherapy regimen including an
    anthracycline. The last cytotoxic drug must be given at least four
    weeks prior randomization. Rituximab must be part of the first-line
    regimen in case of B-cell lymphoma (except for primary CD20-
    negative lymphoma). Patients may have received prior radiation
    therapy as part of their first-line therapy.
    7.Men who are sexually active with women of childbearing potential (WOCBP) must use any
    contraceptive method with a failure rate of less than 1% per year.
    Men who are sexually active with women of childbearing potential
    (WOCBP) must not father a child during and up to 6 months after
    GemOx and up to 12 months after Rituximab and/or Nivolumab. They
    are advised to do cryoconservation of sperm prior to treatment.
    Women who are not of childbearing potential ie, who are
    postmenopausal or surgically sterile as well as azoospermic men do
    not require contraception. A WOCBP is defined as any female who
    has experienced menarche and who has not undergone surgical
    sterilization (hysterectomy or bilateral oophorectomy) or who is not
    postmenopausal. Menopause is defined clinically as 12 months of
    amenorrhea in a woman over 45 in the absence of other biological or
    physiological causes. In addition, women under the age of 62 must
    have a documented serum follicle stimulating hormone (FSH) level
    higher than 40 mIU/mL.
    8. Written informed consent of the patient
    9. Patient must be covered by social security system.
    E.4Principal exclusion criteria
    1. Already initiated lymphoma therapy after first relapse or progression (except for the
    prephase treatment, cf. 8.6.1).
    2. Serious accompanying disorder or impaired organ function (except when due to lymphoma
    involvement), in particular:
     heart: angina pectoris CCS >2, cardiac failure e.g. NYHA >2
     liver: total bilirubin >1.5 times the upper reference limit (except
    subjects with Gilbert Syndrome, who can have total bilirubin
    <51 μmol/l), aspartate transaminase (AST) or alanine
    transaminase (ALT) >3 x institutional upper reference limit
     kidney: creatinine clearance < 30 ml/min
    3. WBC < 2.5 G/l, Neutrophils <2 G/l, Platelets <100G/l (does not apply if cytopenia is caused
    by lymphoma)
    4. Prolongation of QTc interval > 450 ms, demonstrated in one electrocardiogram (done as
    triplicate). This does not apply for patients with a block of the right and/or left bundle branch.
    5. Family history for Long QT-syndrome
    6. Patients with an active, known or suspected autoimmune disease. Subjects are permitted
    to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
    autoimmune condition only requiring hormone replacement, psoriasis not requiring
    systemic treatment, or conditions not expected to recur in the absence of an external
    trigger
    7. There must also be no requirement for immunosuppressive doses of systemic
    corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study
    drug administration (except for treatment of lymphoma).
    8. Chronic active hepatitis B or C as defined either HBs Ag positive or HBc Ac positive with
    detectable viral DNA or hepatitis C virus ribonucleic acid positive.
    9. HIV-infection
    10. Patients with a severe immunodeficiency
    11. Previous therapy with Nivolumab, Gemcitabine or Oxaliplatin.
    12. Patients with a “currently active” second malignancy other than non-melanoma skin cancer.
    Patients are not considered to have a “currently active” malignancy if they have completed
    therapy since 6 months and are considered by their physician to be less than 30% risk of
    relapse within one year.
    13. CNS involvement of lymphoma (intracerebral, meningeal, intraspinal intradural) or primary
    CNS lymphoma
    14. Persistent neuropathy grade >2 (NCI CTC-AE v4.03) (unless due to lymphoma
    involvement)
    15. Pregnancy or breast-feeding women
    16. Women of childbearing potential (WOCBP). A WOCBP is defined as any female who has
    experienced menarche and who has not undergone surgical sterilization (hysterectomy or
    bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as
    12 months of amenorrhea in a woman over 45 in the absence of other biological or
    physiological causes. In addition, women under the age of 62 must have a documented
    serum follicle stimulating hormone (FSH) level higher than 40 mIU/mL.
    17. Active serious infections not controlled by oral and/or intravenous antibiotics or antifungal
    medication
    18. Any medical condition which in the opinion of the investigator places the subject at an
    unacceptably high risk for toxicities
    19. Lymphomas other than those listed in the inclusion criteria notably indolent lymphoma,
    Mantle cell lymphoma, Burkitt lymphoma, adult T-cell leukemia/lymphoma.
    20. Persons not able to understand the impact, nature, risks and consequences of the trial
    (including language barrier)
    21. Persons not agreeing to the transmission of their pseudonymous data
    22. Persons depending on sponsor or investigator
    23. Persons from highly protected groups
    24. Allergies and Adverse Drug Reaction History to study drug components
    25. Participation in another clinical trial with drug intervention within 4 weeks prior to start of the first cycle and during the study. However, participation in a clinical trial of firstline therapy of lymphoma is allowed.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 year
    (data collected during the restagings and the follow-up assessments as planned in the protocol (cf. chapter 8.9 in the protocol))
    E.5.2Secondary end point(s)
    •complete response rate
    •partial response rate
    •overall response rate
    •duration of response
    •progression rate
    •rate of treatment-related deaths
    •relapse rate
    •Event-free survival
    •Overall survival
    •Toxicity
    •Protocol adherence
    •quality of life as assessed by the EQ-5D-5L.
    •outcome according to PD-L1 and PD-1 expression, cell of origin, 9p24.1 alterations
    E.5.2.1Timepoint(s) of evaluation of this end point
    •complete response rate , partial response rate, overall response rate : (data collected during the restagings and the follow-up assessments as planned in the protocol (cf. chapter 8.9 in the protocol))
    •duration of response : end of study
    •progression rate : end of study
    •rate of treatment-related deaths : end of study
    •relapse rate : end of study
    •Event-free survival : end of study
    •Overall survival : end of study
    •Toxicity : end of study
    •Protocol adherence : end of study
    •quality of life as assessed by the EQ-5D-5L : end of study
    •outcome according to PD-L1 and PD-1 expression, cell of origin, 9p24.1 alterations : end of study

    (data collected during the restagings and the follow-up assessments as planned in the protocol (cf. chapter 8.9 in the protocol))
    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 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) 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 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 Yes
    E.8.2.3.1Comparator description
    Standard chemotherapy with Gemcitabine, Oxaliplatin and rituximab in case of B-cell lymphoma
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA76
    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
    Israel
    Austria
    Belgium
    Czechia
    France
    Germany
    Netherlands
    Poland
    Portugal
    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 years7
    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 years7
    E.8.9.2In all countries concerned by the trial months0
    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: 38
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 350
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 378
    F.4.2.2In the whole clinical trial 388
    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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation LYSA
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-05-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2025-01-15
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