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    EudraCT Number:2015-001088-38
    Sponsor's Protocol Code Number:BAY80-6946/17833
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-02-23
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-001088-38
    A.3Full title of the trial
    A Phase III, randomized, double-blind, controlled, multicenter study of intravenous PI3K inhibitor copanlisib in combinatione with standard immunochemiotherapy versus standard immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL) - CHRONOS-4
    Studio di Fase III, randomizzato, in doppio cieco, controllato, multicentrico, sull’inibitore endovenoso di PI3K copanlisib in associazione con l’immunochemioterapia standard in confronto all’immunochemioterapia standard in pazienti affetti da linfoma non-Hodgkin indolente recidivato (iNHL) - CHRONOS-4
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating copanlisib in combination with standard treatment versus standard treatment alone in order to see if copanlisib improves the response to standard treatment in patients with relapsed indolent non-Hodgkin's lymphoma.
    Studio di Fase III su copanlisib con immunochemioterapia standard nell’iNHL recidivato
    A.3.2Name or abbreviated title of the trial where available
    Phase III study of copanlisib with standard immunochemotherapy in relapsed iNHL
    Studio di Fase III su copanlisib con immunochemioterapia standard nell’iNHL recidivato
    A.4.1Sponsor's protocol code numberBAY80-6946/17833
    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 SponsorBAYER HEALTHCARE AG
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBayer HealthCare AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer HealthCare AG
    B.5.2Functional name of contact pointBayer Clin. Trials Contact CTP Team
    B.5.3 Address:
    B.5.3.1Street AddressBayer Pharma AG, S102, Level 2, Room 156
    B.5.3.2Town/ cityBerlino
    B.5.3.3Post code13342
    B.5.4Telephone number000
    B.5.5Fax number000
    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 nameCOPANLISIB
    D.3.2Product code BAY84-1236
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCOPANLISIB
    D.3.9.2Current sponsor codeBAY 84-1236
    D.3.9.4EV Substance CodeSUB32033
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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. cell therapy medicinal product Information not present in EudraCT
    D. therapy medical product Information not present in EudraCT
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL)
    pazienti affetti da linfoma non-Hodgkin indolente recidivato (iNHL)
    E.1.1.1Medical condition in easily understood language
    relapsed indolent non-Hodgkin’s lymphoma
    linfoma non-Hodgkin indolente recidivato
    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 10029600
    E.1.2Term Non-Hodgkin's lymphoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Safety run-in partPrimary objective is to determine:The recommended phase III dose (RP3D) of copanlisib in combination with standard immunochemotherapy (rituximab and bendamustine [RB] or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone[R-CHOP]) to be used in the subsequent phase III part of the studyPhase III part (randomized, controlled trial)Primary objective is:To evaluate whether copanlisib in combination with standard immunochemotherapy, is superior to standard immunochemotherapy in prolonging progression-free survival (PFS), in patients with relapsed indolent non-Hodgkin's lymphoma, who have received one or more lines of treatment, including rituximab and alkylating agents, and for whom the combination of rituximab with either bendamustine or CHOP represents a valid therapeutic option
    Per la parte di SAFETY RUN-IN obiettivo primario è determinare la dose raccomandata della Fase III (RP3D) di copanlisib in associazione con l’immunochemioterapa standard (rituximab e bendamustine [R¬B] o rituximab, ciclofosfamide, doxorubicina, vincristina e prednisone [R-CHOP]) da usare nella successiva parte della Fase III dello studio
    Per la Fase III (studio randomizzato, controllato) l’obiettivo primario è quello di:
    · Valutare se copanlisib, in associazione con l’immunochemioterapia standard, sia superiore all’immunochemioterapia standard nel prolungare la sopravvivenza senza progressione della malattia (PFS) in pazienti affetti da linfoma non-Hodgkin indolente recidivato, che hanno ricevuto una o più linee di trattamento, comprendente rituximab ed alchilanti, e per i quali l’associazione di rituximab con bendamustine o CHOP rappresenti una valida opzione terapeutica.
    E.2.2Secondary objectives of the trial
    Safety run-in partThe secondary objectives are to evaluate (for patients that stay on treatment after Cycle 1):Radiological and clinical indicators of treatment efficacySafety and tolerability of copanlisib in combination with R-B/R-CHOPPhase III part (randomized, controlled trial)Secondary objectives are to evaluate:Other radiological and clinical indicators of treatment efficacy (objective response rate (ORR), duration of response (DOR), complete response rate (CRR), time to progression (TTP), time to next antilymphoma treatment (TTNT), overall survival (OS, 5 year survival rate), time to improvement and the time to deterioration in diseaserelated symptoms -physical)Safety and tolerability of copanlisib in combination with R-B/R-CHOP
    Per la fase di “Safety run in”:
    Gli obiettivi secondari sono quelli di valutare (per i pazienti che restano in trattamento dopo il Ciclo 1):

    · Indicatori radiologici e clinici dell’efficacia del trattamento
    · Sicurezza e tollerabilità di copanlisib in associazione con R-B/R-CHOP

    Ulteriori obiettivi da valutare:
    · Farmacocinetica (PK) di copanlisib
    · Biomarcatori dell’efficacia, effetto correlato al meccanismo d’azione, sicurezza e/o meccanismo patologico della malattia
    Per la Fase III obiettivi secondari sono quelli di valutare
    altri indicatori radiologici e clinici dell’efficacia del trattamento (ORR), DOR,CRR, TTP, TTNT, OS, tasso di sopravvivenza a 5 anni, tempo al miglioramento e tempo al peggioramento dei sintomi correlati alla malattia - fisici ) - · Sicurezza e tollerabilità di copanlisib iin associazione con R-B/R-CHOP
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Main criteria for inclusion:- Histologically confirmed diagnosis of CD20 positive iNHL with histological subtype limited to:o Follicular lymphoma (FL) G1, G2, or G3ao Small lymphocytic lymphoma (SLL) with absolute lymphocyte count <5x109/L at the time of diagnosis and at study entryo Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM)o Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)- Patients must have relapsed after at least 1 prior line of therapy, including rituximab and alkylating agents. A previous regimen is defined as one of the following: at least 2 months of single-agent therapy; at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to PI3K inhibitors is acceptable provided there is no resistance (treatment stopped for other reasons than progressive disease).- Non-WM patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the Lugano Classification.- Patients affected by WM who do not have at least one bi-dimensionally measurable lesion in the baseline radiologic assessment must have measurable disease defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x upper limit of normal.- Male or female patients ≥ 18 years of age.- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.- Life expectancy of at least 3 months.- Availability of fresh tumor tissue and/or archival tumor tissue at Screening.- Adequate baseline laboratory values as assessed within 7 days before starting study treatment.- Left ventricular ejection fraction ≥ 50%.
    Principali criteri di inclusione:
    · Diagnosi istologicamente confermata di iNHL CD20-positivo con sottotipo istologico limitato a:
    o Linfoma follicolare (FL) G1, G2, o G3a
    o Piccolo linfoma linfocitico (SLL) con conta linfocitaria assoluta
    <5x1 09/L al momento della diagnosi ed all’ingresso nello studio
    o Linfoma linfoplasmocitico/macroglobulinemia di Waldenström
    o Linfoma della zona marginale (MZL) (splenico, nodale, o extra-nodale)
    · I pazienti devono avere avuto una recidiva dopo almeno una precedente linea di terapia comprendente rituximab ed alchilanti. Un precedente regime terapeutico è definito come uno dei seguenti: almeno 2 mesi di monoterapia; almeno 2 cicli consecutivi di polichemioterapia; trapianto autologo; radioimmunoterapia. Una precedente esposizione ad inibitori di PI3K è accettabile purché non si abbia resistenza (trattamento sospeso per ragioni diverse dalla malattia progressiva).
    · I pazienti non affetti da WM devono avere almeno una lesione misurabile bidimensionalmente (che non sia stata precedentemente irradiata) secondo la Classificazione di Lugano.
    · I pazienti affetti da WM che non abbiano almeno una lesione misurabile bidimensionalmente nella valutazione radiologica di base devono avere una malattia misurabile, definita come la presenza della paraproteina dell’immunoglobulina M (IgM) con un livello minimo di IgM ≥ 2 volte il limite superiore di normalità.
    · Pazienti maschi o femmine di ≥ 18 anni d’età.
    · Performance Status secondo l’Eastern Cooperative Oncology Group (ECOG) ≤ 2.
    · Aspettativa di vita di almeno 3 mesi.
    · Disponibilità di tessuto tumorale fresco e/o di tessuto tumorale archiviato allo screening.
    · Adeguati valori di laboratorio di base valutati entro 7 giorni prima di iniziare il trattamento in studio.
    · Frazione di eiezione del ventricolo sinistro ≥ 50%.
    E.4Principal exclusion criteria
    Main criteria for exclusion:- Histologically confirmed diagnosis of follicular lymphoma (FL) grade 3bor transformed disease, or chronic lymphocytic leukemia. In patients with clinical suspicion of transformed disease, a fresh biopsy is recommended.- Rituximab resistance at any line of therapy (resistance defined as lack of response, or progression within 6 months of the last course of treatment with a rituximab containing regimen).- Type I or II diabetes mellitus with HbA1c > 8.5% or fasting plasma glucose > 160 mg/dL at Screening.- History or concurrent condition of interstitial lung disease and/or severely impaired lung function (as judged by the investigator).- Known lymphomatous involvement of the central nervous system.- Human immunodeficiency virus (HIV) infection.- Hepatitis B (HBV) and C (HCV) infection. Patients with serologic markers of HBV immunization due to vaccination (HBsAg negative, Anti-HBc negative and Anti-HBs positive) will be eligible.- Congestive heart failure > New York Heart Association (NYHA) class 2.- Uncontrolled hypertension (systolic blood pressure > 150 mmHg ordiastolic pressure > 90 mmHg despite optimal medical management).
    Principali criteri di esclusione:
    · Diagnosi istologicamente confermata di linfoma follicolare (FL) di grado 3b o
    malattia trasformata o leucemia linfocitica cronica. In pazienti con sospetto clinico di malattia trasformata, si raccomanda di eseguire una bopsia recente.· Resistenza a rituximab in qualsiasi linea di terapia (resistenza definita come mancata risposta o progressione della malattia entro 6 mesi dall’ultimo ciclo di trattamento con un regime contenente rituximab).
    · Diabete mellito di Tipo I o II con HbA1c > 8,5% o glicemia a digiuno > 160 mg/dL allo screening.
    · Anamnesi o concomitanza di pneumopatia interstiziale e/o
    di funzione polmonare gravemente alterata (a giudizio dello sperimentatore).
    · Noto interessamento linfomatoso del sistema nervoso centrale.
    · Infezione da parte del virus dell’immunodeficienza umana (HIV).
    · Infezione da parte del virus dell’epatite B (HBV) e C (HCV). Saranno eleggibile i pazienti con marker sierologici di immunizzazione all’HBV a causa della vaccinazione (HBsAg-negativi, anti-HBc-negativi ed anti-HBs-positivi).
    · Insufficienza cardiaca congestizia >classe 2 secondo la New York Heart Association (NYHA)
    · Ipertensione non controllata (pressione sistolica > 150 mmHg o pressione diastolica > 90 mmHg nonostante un trattamento medico ottimale).
    E.5 End points
    E.5.1Primary end point(s)
    The primary completion event for this study is PFS (progression assessed by central review or death from any cause if death occurs before progression). The analysis will be performed when approximately273 PFS events in FL patients occur.
    Safety run-in: La variabile primaria della sicurezza è la comparsa di DLT al Ciclo 1.
    Fase III: La variabile primaria dell’efficacia è la PFS, definita come il tempo (in giorni) dalla randomizzazione alla PD valutata mediante revisione centrale indipendente o alla morte per qualsiasi causa (se non è documentata alcuna progressione).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The analysis will be performed when approximately 273 PFS events in FLpatients occur.
    Safety run-in: Circa 6-8 mesi
    Fase III: La durata dello studio per il completamento primario della PFS è di circa 45 mesi con un periodo di arruolamento di 24 mesi e 21 mesi di follow-up.
    E.5.2Secondary end point(s)
    Secondary efficacy variables are objective response rate (ORR), durationof response (DOR), complete response rate (CRR), time to progression (TTP), time to next anti-lymphoma treatment (TTNT), overall survival (OS, 5 year survival rate), time to improvement and the time to deterioration in disease-related symptoms - physical (disease-related symptoms - physical (DRS-P)) of at least 3 points of lymphoma as measured by the FLymSI-18 questionnaire (FLymSI = NCCN-FACT Lymphoma Symptom Index).
    ORR, DOR, CRR, TTP, TTNT, OS, 5 anni, tempo al miglioramento e al peggioramento nei sintomi correlati alla malattia - DRS-P di almeno 3 punti linfoma misucrato secondo questionario FLymSI-18 (FLymSI = NCCN-FACT Lymphoma Symptom Index).
    E.5.2.1Timepoint(s) of evaluation of this end point
    The analysis will be performed when approximately 273 PFS events in FLpatients occur.
    Al raggiungimento di circa 273 eventi PFS pazienti FL
    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 Yes
    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. 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Czech Republic
    European Union
    Hong Kong
    Korea, Republic of
    New Zealand
    Russian Federation
    Saudi Arabia
    South Africa
    United Kingdom
    United States
    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
    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
    E.8.9.2In all countries concerned by the trial years5
    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.1.1Number of subjects for this age range: 1
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 600
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 Yes
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 450
    F.4.2.2In the whole clinical trial 700
    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)
    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 Decision2015-12-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-07
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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