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    Summary
    EudraCT Number:2018-003526-88
    Sponsor's Protocol Code Number:CZAR-1
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-05-31
    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 number2018-003526-88
    A.3Full title of the trial
    Efficacy and safety of Carfilzomib in combination with Ibrutinib vs. Ibrutinib alone in Waldenström’s Macroglobulinemia
    (CZAR-1)
    Wirksamkeit und Sicherheit von Carfilzomib in Kombination mit Ibru-tinib oder Ibrutinib alleine bei Patienten mit Morbus Waldenström
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of Carfilzomib in combination with Ibrutinib for patients with Waldenström's macroglobulinemia (CZAR-1)
    Wirksamkeit und Sicherheit von Carfilzomib in Kombination mit Ibru-tinib oder Ibrutinib alleine bei Patienten mit Morbus Waldenström
    A.3.2Name or abbreviated title of the trial where available
    CZAR-1
    A.4.1Sponsor's protocol code numberCZAR-1
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04263480
    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 SponsorUniversity Hospital Ulm
    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 supportAmgen Inc.
    B.4.2CountryEuropean Union
    B.4.1Name of organisation providing supportJanssen Pharmaceutica NV
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Ulm
    B.5.2Functional name of contact pointChristian Buske
    B.5.3 Address:
    B.5.3.1Street AddressAlbert-Einstein-Allee 23
    B.5.3.2Town/ cityUlm
    B.5.3.3Post code89081
    B.5.3.4CountryGermany
    B.5.4Telephone number+4973150065800
    B.5.5Fax number+4973150065802
    B.5.6E-mailczar.mw@uniklinik-ulm.de
    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 Kyprolis
    D.2.1.1.2Name of the Marketing Authorisation holderAmgen Europe B.V.
    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.3.4Pharmaceutical form Powder 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 INNCarfilzomib
    D.3.9.1CAS number 868540-17-4
    D.3.9.3Other descriptive nameCARFILZOMIB
    D.3.9.4EV Substance CodeSUB32911
    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.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 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.IMP: 2
    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 Imbruvica
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen Pharmaceutica NV
    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.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIbrutinib
    D.3.9.1CAS number 936563-96-1
    D.3.9.3Other descriptive nameIBRUTINIB
    D.3.9.4EV Substance CodeSUB120863
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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.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 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
    Waldenström's Macroglobulinemia
    E.1.1.1Medical condition in easily understood language
    Waldenström's Macroglobulinemia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10047801
    E.1.2Term Waldenstrom's macroglobulinaemia
    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
    The primary objective of the study is to explore the efficacy of Carfilzomib in combination with Ibrutinib compared to Ibrutinib alone in patients with treatment naïve or relapsed WM.
    E.2.2Secondary objectives of the trial
    Secondary study endpoints: Response rate (CR, VGPR, PR, MR) 12 and 24 months after the start of treatment, Best response, Time to best response, Time to first response, Time to treatment failure, Remission Duration, Progression free survival, Cause specific survival, Overall survival, Safety, Quality of life.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Proven clinicopathological diagnosis of WM as defined by consensus panel one of the Second IWWM4.
    • De novo or relapsed / refractory WM independent of the genotype.
    • Patients must have at least one of the following criteria to start study treatment as partly defined by consensus panel criteria from the Seventh IWWM[5].
    • World Health Organization (WHO) / ECOG performance status ≤ 2.
    • Left ventricular ejection fraction ≥ 40% as assessed by transthoracic echocardiogram (TTE).
    • Other criteria: Age ≥ 18 years (male and female), Life expectancy > 3 months in the opinion of the investigator, adequate laboratory values.
    • Women of childbearing potential (WCBP), i.e. fertile, following menarche and until becoming postmenopausal, must agree to use a highly effective method of birth control for the duration of the therapy up to 6 months after end of therapy with Carfilzomib or Ibrutinib.
    • Men must agree not to father a child for the duration of therapy and 6 months after (use of a condom) and must agree to advice a female partner to use a highly effective method of birth control. Males must refrain from sperm donation for at least 6 months after the last dose of Carfilzomib or Ibrutinib.
    • Each patient must sign an informed consent form in a fluent language of the patient indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
    E.4Principal exclusion criteria
    • Previous treatments with following substances: Prior exposure to Ibrutinib or other BTK inhibitors. Prior exposure to Carfilzomib. Prior exposure to other proteasome inhibitors are allowed if the patients were not refractory, that is, had a remission (at least minor response) duration of ≥ 6 months. Prior plasmapheresis and short-term administration of corticosteroids ≤ 6 weeks administered at a dose equivalent to ≤ 20 mg/day of prednisone is also allowed.
    • Serious medical or psychiatric illness (especially undergoing treatment) likely to interfere with participation in this clinical study.
    • Active HIV, HBV or HCV infection.
    • Central Nervous System involvement by lymphoma.
    • History of a non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for ≥ 1 year prior to randomization, other Stage 1 or 2 cancer treated with a curative intent and currently in complete remission, for ≥ 3 years.
    • Uncontrolled illness including, but not limited to: Uncontrolled diabetes mellitus (as indicated by metabolic derangements and / or severe diabetes mellitus related uncontrolled organ complications), Chronic symptomatic congestive heart failure (Class NYHA III or IV) or LVEF < 40%, Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months prior to randomization, Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia, Known pericardial disease, Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, Primary amyloidosis.
    • Recent major surgery within 30 days prior to randomization.
    • Known cirrhosis (meeting child-pugh stage C).
    • Approved or investigational anticancer treatment within 21 days prior to randomization.
    • Glucocorticoid therapy within 14 days prior to randomization that exceeds a cumulative dose of 160 mg of Dexamethasone or equivalent dose of other corticosteroids.
    • Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to randomization (i.e. prior radiation must have been to less than 30% of the bone marrow).
    • Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs.
    • Active infection within 14 days prior to randomization requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents. Such infection must be fully resolved prior to randomization.
    • Ascites requiring paracentesis within 14 days prior to randomization.
    • Uncontrolled hypertension, defined as an average systolic blood pressure > 159 mmHg or diastolic > 99 mmHg despite optimal treatment (measured according European Society of Hypertension/European Society of Cardiology [ESH / ESC] 2013 guidelines[57].
    • History of stroke or intracranial hemorrhage within 6 months prior to randomization.
    • Known interstitial lung disease.
    • Infiltrative pulmonary disease, known pulmonary hypertension.
    • Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal.
    • Known severe persistent asthma within the past 2 years (see also https://www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf), or currently has uncontrolled asthma of any classification or at time of screening has an FEV1 of < 50% of predicted normal.
    • Autologous or allogeneic stem cell transplant less than 100 days prior to randomization.
    • Vaccination with live attenuated vaccines within 30 days prior to randomization.
    • Patients who require strong or moderate inducers or inhibitors for cytochrome P450, family 3 or subfamily A (CYP3A).
    • Patients who have an uncontrolled bleeding disorder or require an anticoagulant (e.g. warfarin or other vitamin K antagonists) at time of screening.
    • History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or sponsor, if consulted, would pose a risk to patient safely or interfere with the study evaluation, procedures or completion.
    E.5 End points
    E.5.1Primary end point(s)
    The aim of this study is to investigate the rate of CR or VGPR 12 months after the start of treatment using the response criteria updated at the Sixth IWWM (CR/VGPR).
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 12 months
    E.5.2Secondary end point(s)
    Secondary study endpoints:
    Response rate (CR, VGPR, PR, MR) and ORR (CR, VGPR, PR) 12 and 24 months after the start of treatment, Best response, Time to best response, Time to first response, Time to treatment failure, Remission Duration, Progression free survival, Cause specific survival, Overall survival, Safety, Quality of life.
    E.5.2.1Timepoint(s) of evaluation of this end point
    after 12 and 24 months
    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 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 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) Yes
    E.8.2.2Placebo No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 years7
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    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: 49
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 99
    F.4.2.2In the whole clinical trial 99
    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 benefit from Ibrutinib treatment will receive further treatment with Ibrutinib after7 years after first patient in. Further Treatment and follow up is in the direction 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 German Lymphoma Alliance - GLA
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-07-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-11-25
    P. End of Trial
    P.End of Trial StatusOngoing
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