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    The EU Clinical Trials Register currently displays   35918   clinical trials with a EudraCT protocol, of which   5893   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2015-001969-49
    Sponsor's Protocol Code Number:N15TON
    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:2015-08-25
    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 number2015-001969-49
    A.3Full title of the trial
    Adaptive phase II randomized non-comparative trial of nivolumab after induction treatment in triple-negative breast cancer (TNBC) patients: TONIC-trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase II study with nivolumab (anti-PD1) in patients with triple negative breast cancer after induction treatment.
    Fase II studie met nivolumab (anti-PD1) bij triple negatieve borstkanker patiënten na een immuunrespons inductie behandeling: TONIC-studie
    A.3.2Name or abbreviated title of the trial where available
    TONIC
    A.4.1Sponsor's protocol code numberN15TON
    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 SponsorNKI-AvL
    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 supportNKI-AvL
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNKI-AvL
    B.5.2Functional name of contact pointDr. M. Kok
    B.5.3 Address:
    B.5.3.1Street AddressPlesmanlaan 121
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1066 CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31205126162
    B.5.5Fax number31205122572
    B.5.6E-mailm.kok@nki.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 nameNivolumab
    D.3.2Product code BMS-936558
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Intravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNivolumab
    D.3.9.2Current sponsor codeBMS-93655801
    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
    Triple negative breast cancer (TNBC) patients with metastatic disease
    E.1.1.1Medical condition in easily understood language
    Breast cancer, triple negative, metastastic
    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 LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 100000020826
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the activity of nivolumab after four different immune response induction treatments in TNBC patients with metastatic disease. We hypothesize that short-term induction treatment induces an anticancer immune response resulting in increased activity of nivolumab as compared to unprimed, single agent nivolumab.
    E.2.2Secondary objectives of the trial
    To evaluate the safety of nivolumab treatment after short-term induction therapy with radiation, doxorubicin, cyclophosphamide or cisplatin.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Metastatic triple negative breast cancer with conformation of ER and HER2 negativity (ER <10%, and HER2 0,1 or 2 in the absence of amplification as determined by in situ hybridization) on a histological biopsy of a metastatic lesion
    • 18 years or older
    • Metastatic lesion accessible for histological biopsy (Mandatory biopsies: pre-treatment induction treatment, post-induction treatment, 12-weeks. Optional biopsies: at progression, of irradiated site)
    • Maximum of three previous lines of chemotherapy for metastatic disease
    • Evaluable disease according to RECIST 1.1
    E.4Principal exclusion criteria
    • known history of leptomeningeal disease localization
    • history of having received other anticancer therapies within 2 weeks of start of the study drug
    • history of immunodeficiency, autoimmune disease, conditions requiring immunosuppression (>10 mgl daily prednisone equivalents) or chronic infections.
    • prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody
    • live vaccine within 30 days of planned start of study therapy.
    • active other cancer
    • positive test for hepatitis B surface virus surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
    • current pregnancy or breastfeeding
    E.5 End points
    E.5.1Primary end point(s)
    • Progression-free survival (PFS, time from randomisation to tumor progression or death) Progression as defined by RECIST 1.1 will be used.
    • For the first stage of the trial, proportion of patients with PFS of at least 12 weeks in each treatment arm. Treatment arms with >30% of patients with PFS of at least 12 weeks will continue to stage II of the study. Progression as defined by RECIST 1.1 will be used.
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 6, week 12 and every 12 weeks thereafter until progression of disease
    E.5.2Secondary end point(s)
    • Progression-free survival (=PFS1, time from randomization to tumor progression or death from any cause) Progression as defined by modified RECIST 1.1 for immune-based therapeutics (iRECIST) ]will be used.
    • Progression-free survival (=PFS2, time from nivolumab treatment initiation to tumor progression) Progression as defined by RECIST 1.1 and iRECIST will be used.
    • Overall response rate ORR (complete response CR or partial response PR) according to RECIST 1.1 and iRECIST will be used.
    • Clinical benefit rate (CR+PR+stable disease ≥ 6 months and CR+PR+stable disease ≥ 3 months) according to RECIST 1.1 [10] and iRECIST will be used.
    • Overall survival (OS, time from start nivolumab to death from any cause)
    • Percentage of patients with toxicity (classified according to CTCAE v4.0 and immune-related toxicity
    E.5.2.1Timepoint(s) of evaluation of this end point
    Response; week 6, week 12 and every 12 weeks thereafter until progression of disease
    Toxicity; every 2 weeks until 30 days after last treatment
    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 Yes
    E.6.11Pharmacogenomic Yes
    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 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
    Different types of immune response induction treatments
    E.8.2.4Number of treatment arms in the trial5
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 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 months0
    E.8.9.1In the Member State concerned 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: 74
    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 state84
    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 Decision2015-09-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-08-17
    P. End of Trial
    P.End of Trial StatusOngoing
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