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    The EU Clinical Trials Register currently displays   38876   clinical trials with a EudraCT protocol, of which   6392   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2015-001088-38
    Sponsor's Protocol Code Number:BAY80-6946/17833
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-11-12
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    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 combination with standard immunochemotherapy versus standard immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (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.
    A.3.2Name or abbreviated title of the trial where available
    Phase III study of copanlisib with standard immunochemotherapy in relapsed iNHL
    A.4.1Sponsor's protocol code numberBAY80-6946/17833
    A.5.4Other Identifiers
    Name:Pi3K InhibitorNumber:BAY80-6946
    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 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 AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street Address-
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post codeD-13342
    B.5.4Telephone number+4930300139003
    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 Lyophilisate 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 INNCopanlisib
    D.3.9.2Current sponsor codeBAY 84-1236
    D.3.9.3Other descriptive nameBAY 80-6946 (AS DIHYDROCHLORID BAY 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 No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 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
    D.8.3Pharmaceutical form of the placeboLyophilisate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    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
    E.1.1.1Medical condition in easily understood language
    Relapsed indolent non-Hodgkin's lymphoma
    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 part
    Primary 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 study

    Phase 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 at least one, but at most three lines of treatment, including rituximab-based immunochemotherapy and alkylating agents, and for whom the combination of rituximab with either bendamustine or CHOP represents a valid therapeutic option
    E.2.2Secondary objectives of the trial
    Safety run-in part
    The secondary objectives are to evaluate (for patients that stay on treatment after Cycle 1):
    Radiological and clinical indicators of treatment efficacy
    Safety and tolerability of copanlisib in combination with R-B/R-CHOP

    Phase 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
    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 G3a
    o Small lymphocytic lymphoma (SLL) with absolute lymphocyte count <5x109/L at study entry
    o Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM)
    o Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
    -- Patients must have relapsed (recurrence after complete response or presented progression after partial response) or progressed after at least one but at most three prior lines of therapy, including rituximab-based immunochemotherapy and alkylating agents (if given concomitantly is considered one line of therapy). A previous regimen is defined as one of the following: at least 2 months of single-agent therapy (less than 2 months of therapy with single agent rituximab can be considered a previous regimen in the case the patient responded to it); at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to other PI3K inhibitors (except copanlisib) is acceptable provided there is no resistance (resistance defined as no response (response defined as partial response [PR] or complete response [CR]) at any time during therapy, or PD after any response (PR/CR) or after stable disease within 6 months from the end of the therapy with a PI3K inhibitor.
    - Non-WM patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the Lugano Classification. For patients with splenic MZL this requirement may be restricted to splenomegaly alone since that is usually the only manifestation of measurable disease.
    - 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 and positive immunofixation test.
    - 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.
    - Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and 12 months (for WOCBP) and 6 months (for men) after the last administration of study treatment. The use of condoms by male patients is required unless the female partner is permanently sterile.
    - Adequate baseline laboratory values as assessed within 7 days before starting study treatment.
    - Left ventricular ejection fraction ≥ 50%.
    E.4Principal exclusion criteria
    Main criteria for exclusion:
    - Histologically confirmed diagnosis of follicular lymphoma (FL) grade 3b
    or transformed disease, or chronic lymphocytic leukemia. In patients
    with clinical suspicion of transformed disease, a fresh biopsy is
    - Rituximab resistance at any line of therapy (resistance defined as lack
    of response, or progression within 6 months of the last date of rituximab administration, including rituximab maintenance).
    - 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.
    - HbA1c > 8.5% at Screening.
    - Known history of human immunodeficiency virus (HIV) infection.
    - Hepatitis B (HBV) or C (HCV) infection. Patients positive for hepatitis B
    surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be
    eligible if they are negative for HBV-DNA, these patients should receive
    prophylactic antiviral therapy as per rituximab label. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.
    - Previous or concurrent history of malignancies other than indolent non-
    Hodgkin's lymphoma within 5 years prior to study treatment except for
    curatively treated: Cervical carcinoma in situ, Non-melanoma skin
    cancer, Superficial bladder cancer (Ta [non-invasive tumor], Tis
    [carcinoma in situ] and T1 [tumor invades lamina propria]), Localized
    prostate cancer
    - Congestive heart failure > New York Heart Association (NYHA) class 2.
    - Unstable angina (angina symptoms at rest), new-onset angina (begun
    within the last 3 months). Myocardial infarction less than 6 months
    before start of test drug.
    - Uncontrolled hypertension despite optimal medical management (per
    investigator's assessment).
    - Arterial or venous thrombotic or embolic events such as
    cerebrovascular accident (including transient ischemic attacks), deep
    vein thrombosis or pulmonary embolism within 3 months before the
    start of study medication.
    - Non-healing wound, ulcer, or bone fracture.
    - Active, clinically serious infections (> CTCAE grade 2).
    - Patients with seizure disorder requiring medication
    - Patients with evidence or history of bleeding diathesis. Any
    hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks of start
    of study medication.
    - Known hypersensitivity to any of the study drugs, study drug classes,
    or excipients in the formulation.
    - Proteinuria of CTCAE Grade 3 or estimated by urine protein : creatinine
    ratio > 3.5 (> 396 mg/mmol)on a random urine sample
    - Unresolved toxicity higher than NCI-CTCAE grade 1 attributed to any
    prior therapy/procedure excluding alopecia.
    - Concurrent diagnosis of pheochromocytoma.
    - Pregnant or breast-feeding patients. Women of childbearing potential
    must have a pregnancy test performed a maximum of 7 days before start
    of treatment, and a negative result must be documented before start of
    - Substance abuse, medical, psychological or social conditions that may
    interfere with the patient's participation in the study or evaluation of the
    study results.
    - Any illness or medical conditions that are unstable or could jeopardize
    the safety of the patients and their compliance in the study.
    - Prior treatment with copanlisib
    - Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at
    baseline will not be eligible.
    CMV PCR test is considered positive if the result can be interpreted as a CMV viremia according to local SOC
    - Live vaccination, including virus vaccination and yellow fever
    vaccination, within 6 months before start of study treatment.
    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 approximately 256 PFS events in the FAS are observed.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The analysis will be performed when approximately 256 PFS events in the FAS are observed.
    E.5.2Secondary end point(s)
    Secondary efficacy variables are objective response rate (ORR), duration of 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).
    E.5.2.1Timepoint(s) of evaluation of this end point
    All secondary efficacy endpoints will be analyzed in the FAS at the time of the analysis of the primary efficacy endpoint. Depending on study success in the primary efficacy variable in the FAS, the secondary efficacy variables ORR, time to deterioration and time to improvement in DRS-P subscale of FLymSI-18 of at least 3 points will be tested hierarchically in the FAS.

    ORR will be tested first and, if successful, will be followed by time to deterioration in DRS-P, and finally, if all previous tests are successful, will be followed by time to improvement of DRS-P.
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA105
    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
    Czech Republic
    Hong Kong
    Korea, Republic of
    Russian Federation
    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 years4
    E.8.9.1In the Member State concerned months10
    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.1.1.1In 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: 206
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 206
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 183
    F.4.2.2In the whole clinical trial 520
    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)
    Further therapy is at the discretion of the investigator.
    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 NIHR CRN Co-ordinating Centre Alder Hey Children's NHS Foundation Trust
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-01-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-06-30
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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