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    Summary
    EudraCT Number:2018-000665-36
    Sponsor's Protocol Code Number:20180015
    National Competent Authority:Slovakia - SIDC (Slovak)
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-06-08
    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 ConcernedSlovakia - SIDC (Slovak)
    A.2EudraCT number2018-000665-36
    A.3Full title of the trial
    A Randomized, Open-label, Phase 3 Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination with Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (A.R.R.O.W.2)
    Randomizované, otvorené klinické skúšanie fázy 3, ktoré porovnáva užívanie karfilzomibu raz týždenne verzus dvakrát týždenne, v kombinácii s lenalidomidom a dexametazónom, u pacientov s relabujúcim alebo refraktérnym mnohopočetným myelómom (A.R.R.O.W.2)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination with Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma
    A.3.2Name or abbreviated title of the trial where available
    A.R.R.O.W.2
    A.4.1Sponsor's protocol code number20180015
    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 SponsorAmgen Inc
    B.1.3.4CountryUnited States
    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 supportAmgen Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen Slovakia s.r.o.
    B.5.2Functional name of contact pointMedicínske informačné centrum
    B.5.3 Address:
    B.5.3.1Street AddressDigital park, Einsteinova 23
    B.5.3.2Town/ cityBratislava
    B.5.3.3Post code85101
    B.5.3.4CountrySlovakia
    B.5.4Telephone number+421232111449
    B.5.6E-maileuskmedinfo@amgen.sk
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/08/548
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for 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 INNcarfilzomib
    D.3.9.1CAS number 868540-17-4
    D.3.9.2Current sponsor codePR-171
    D.3.9.3Other descriptive nameCARFILZOMIB
    D.3.9.4EV Substance CodeSUB32911
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    Relapsed or Refractory Multiple Myeloma
    E.1.1.1Medical condition in easily understood language
    Bone marrow Cancer
    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 LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    compare efficacy of
    56 mg/m2 carfilzomib administered
    once-weekly in combination with
    lenalidomide and dexamethasone
    (KRd 56 mg/m2) to
    27 mg/m2 carfilzomib administered
    twice-weekly in combination with
    lenalidomide and dexamethasone
    (KRd 27 mg/m2) in subjects with
    RRMM with 1 to 3 prior lines of
    therapy
    E.2.2Secondary objectives of the trial
    *compare progression-free survival
    (PFS) between treatment arms
    *compare patient-reported
    convenience with carfilzomib-dosing
    schedule between treatment arms
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    *Subject has provided informed consent prior to initiation of any study-specific
    activities or procedures or subject’s legally acceptable representative has
    provided informed consent prior to any study-specific activities/procedures being
    initiated when the subject has any kind of condition that, in the opinion of the
    Investigator, may compromise the ability of the subject to give written informed
    consent.
    *Males or females ≥ 18 years of age.
    *Documented relapse or progressive multiple myeloma after last treatment
    (Subjects refractory to the most recent line of therapy are eligible, unless last
    treatment contained PI or lenalidomide and dexamethasone).
    *Subjects must have at least PR to at least 1 line of prior therapy.
    *Subjects must have received at least 1 but not more than 3 prior lines of therapy
    for multiple myeloma (induction therapy followed by stem cell transplant and
    consolidation maintenance therapy will be considered as 1 line of therapy). See
    Section 12.8 for guidelines for documenting prior treatment.
    * Prior therapy with a PI or the combination of lenalidomide and dexamethasone
    are allowed if,
    • the patient had at least a PR to the most recent therapy with a PI or lenalidomide
    and dexamethasone,
    • neither PI or lenalidomide and dexamethasone in combination were ceased
    due to toxicity, (unless at the time of enrollment that toxicity was neuropathy not exceeding grade
    2 which has either resolved or if ongoing is ≤ grade 1),
    • the patient has not received a PI and has not received lenalidomide and
    dexamethasone in combination in the 6 months prior to first study
    treatment. (Patients are permitted to have received single agent
    lenalidomide as maintenance therapy during the 6-months prior to first study
    treatment).
    *Previous treatment with a lenalidomide and dexamethasone containing regimen
    is allowed, as long as the subject did not progress during the first 3 months after
    initiating lenalidomide and dexamethasone containing therapy.
    Measurable disease with at least 1 of the following assessed within 28 days prior
    to randomization:
    • IgG multiple myeloma: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL
    • IgA, IgD, IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL
    • urine M-protein ≥ 200 mg per 24 hours
    • in subjects without measurable serum or urine M-protein, serum-free light
    chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum
    kappa lambda ratio
    *Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0  2
    (see Section 12.9).
    E.4Principal exclusion criteria
    Disease-related
    *Waldenström macroglobulinemia.
    *Multiple myeloma of IgM subtype.
    *POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal
    protein, and skin changes).
    *Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard
    differential).
    *Primary amyloidosis (patients with multiple myeloma with asymptomatic
    deposition of amyloid plaques found on biopsy would be eligible if all other
    criteria are met).
    *Myelodysplastic syndrome.
    Other Medical Conditions
    *History of other malignancy within the past 5 years, with the following exceptions:
    • Malignancy treated with curative intent and with no known active disease
    present for ≥ 3 years before enrollment and felt to be at low risk for
    recurrence by the treating physician
    • Adequately treated non-melanoma skin cancer or lentigo maligna without
    evidence of disease
    • Adequately treated cervical carcinoma in situ without evidence of disease
    • Adequately treated breast ductal carcinoma in situ without evidence of
    disease
    • Prostatic intraepithelial neoplasia without evidence of prostate cancer
    • Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in
    situ
    • Treated medullary or papillary thyroid cancer
    • Similar neoplastic conditions with an expectation of > 95% 5-year
    disease-free survival
    * Known HIV infection, hepatitis C infection (subjects with hepatitis C that achieve
    a sustained virologic response after antiviral therapy are allowed), or hepatitis B
    infection (subjects with hepatitis B surface antigen or core antibody that achieve
    sustained virologic response with antiviral therapy are permitted with a
    requirement for regular monitoring for reactivation for the duration of
    treatment on the study).
    *Ongoing graft-vs-host disease.
    *Acute active infection requiring systemic antibiotics, antifungal, antiviral (except
    antiviral therapy directed at hepatitis B) agents within 14 days prior to
    randomization.
    *Known cirrhosis.
    *Significant neuropathy (grades 3 to 4, or grade 2 with pain) within 14 days prior
    to randomization.
    *Subjects with pleural effusions requiring thoracentesis or ascites requiring
    paracentesis within 14 days prior to randomization.
    Cardiopulmonary Conditions
    * Uncontrolled hypertension, defined as subject whose blood pressure exceeds
    ≥ 160 mmHg - systolic or ≥ 100 mmHg diastolic when taken in accordance with the European Society of Hypertension/European Society of Cardiology 2018 guidelines. (Section 12.10; Williams et al, 2018).
    *Active congestive heart failure (New York Heart Association Class III to IV),
    symptomatic ischemia, uncontrolled arrhythmias, screening ECG with corrected
    QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction
    within 4 months prior to randomization.
    *Intolerance to hydration due to pre-existing pulmonary or cardiac impairment.
    *History of interstitial lung disease or ongoing interstitial lung disease.
    Prior/Concomitant Therapy
    *Immunotherapy within 28 days prior to randomization.
    *Monoclonal antibody therapy within 28 days prior to randomization.
    *Chemotherapy with approved anticancer therapeutic within 28 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 28 days
    prior to randomization (ie, prior radiation must have been to < 30% of the bone
    marrow).
    *Major surgery (except kyphoplasty) within 28 days prior to randomization.
    *Autologous or allogeneic stem cell transplant within 90 days prior to
    randomization.
    *Contraindication or intolerance to lenalidomide, dexamethasone, or carfilzomib.
    *Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize
    carfilzomib).
    *Subject has known hypersensitivity to any of the products or components to be
    administered during dosing, including hypersensitivity to antiviral drugs.
    Prior/Concurrent Clinical Study Experience
    *Currently receiving treatment in another investigational device or drug study, or
    < 28 days since ending treatment on another investigational device or drug
    study(ies).
    Organ Function Assessments
    * Hepatic dysfunction within 28 days prior to randomization:
    • direct bilirubin ≥ 1.5x the upper limit of normal (ULN)
    • aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
    ≥ 2.5 x ULN
    *Left ventricular ejection fraction < 40% assessed by transthoracic
    echocardiogram (ECHO).
    *Absolute neutrophil count (ANC) < 1 x 109/L within 28 days prior to
    randomization. Screening ANC should be independent of growth factor support
    for ≥ 1 week.
    E.5 End points
    E.5.1Primary end point(s)
    overall response rate (ORR, defined
    as the proportion of best overall
    response of stringent complete
    response [sCR], complete response
    [CR], very good partial response
    [VGPR], and partial response [PR] per
    International Myeloma Working Group
    Uniform Response Criteria [IMWG-URC]) over the duration of the study
    E.5.1.1Timepoint(s) of evaluation of this end point
    Over the duration of the study
    E.5.2Secondary end point(s)
    * PFS over the duration of the study
    *convenience as measured by the
    Patient-reported Convenience With
    Carfilzomib-dosing Schedule Question
    after cycle 4 of treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    *1-year PFS
    *convenience as measured by the
    Patient-reported Convenience With
    Carfilzomib-dosing Schedule Question
    after cycle 4 of 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 Yes
    E.6.7Pharmacodynamic Yes
    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.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) 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA115
    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
    Austria
    Bulgaria
    Canada
    Czechia
    Finland
    France
    Germany
    Greece
    Japan
    Lithuania
    Netherlands
    Romania
    Russian Federation
    Slovakia
    Spain
    Sweden
    Turkey
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    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: 230
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 230
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 254
    F.4.2.2In the whole clinical trial 460
    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 Decision2020-09-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-21
    P. End of Trial
    P.End of Trial StatusOngoing
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