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    Summary
    EudraCT Number:2014-005325-12
    Sponsor's Protocol Code Number:CFZ014
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-11-05
    Trial results View 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 ConcernedGreece - EOF
    A.2EudraCT number2014-005325-12
    A.3Full title of the trial
    A Randomized, Open-label, Phase 3 Study in Subjects with Relapsed and Refractory Multiple Myeloma Receiving
    Carfilzomib in Combination with Dexamethasone, Comparing Once-weekly versus Twice-weekly Carfilzomib Dosing
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study comparing carfilzomib (study drug) given in combination with dexamethasone once a week to twice-weekly carfilzomib in combination with dexamethasone, at the same dose, in patients with cancer of plasma cells which has re-occurred after previous successful treatment or did not show any improvement under previous treatment.
    A.3.2Name or abbreviated title of the trial where available
    A.R.R.O.W.
    A.4.1Sponsor's protocol code numberCFZ014
    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 SponsorOnyx Therapeutics, 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 supportOnyx Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOnyx Therapeutics
    B.5.2Functional name of contact pointMedical Monitor Sanjay Aggarwal, MD
    B.5.3 Address:
    B.5.3.1Street Address249 East Grand Ave
    B.5.3.2Town/ citySouth San Francisco, CA
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1(650) 266-1459
    B.5.6E-mailsaggarwal@onyx.com
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/08/548
    D.3 Description of the IMP
    D.3.1Product nameCarfilzomib
    D.3.2Product code PR-171
    D.3.4Pharmaceutical form Lyophilisate 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 nameFP-101; 506160 - CARFILZOMIB
    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.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
    Multiple Myeloma
    E.1.1.1Medical condition in easily understood language
    Cancer of plasma cells, a type of white blood cell normally responsible for producing antibodies
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Compare the ORR between once-weekly carfilzomib dosing in combination with dexamethasone to twice-weekly carfilzomib dosing in combination with dexamethasone in subjects with relapsed and refractory multiple myeloma who have received prior treatment with bortezomib and an IMiD
    E.2.2Secondary objectives of the trial
     Progression-free survival (PFS)
     Overall survival (OS)
     Safety and tolerability
     Pharmacokinetics (PK) of carfilzomib using sparse sampling
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    INTENSIVE PHARMACOKINETICS/PHARMACODYNAMICS SUBSTUDY
    &
    SPARSE PHARMACOKINETIC SAMPLING
    E.3Principal inclusion criteria
    1. Age ≥ 18 years
    2. Able to provide written informed consent in accordance with federal, local, and institutional
    guidelines
    3. Relapsed multiple myeloma
    4. Refractory multiple myeloma defined as meeting 1 or more of the following:
    a. Nonresponsive to most recent therapy (stable disease only or PD while on treatment), or
    b. Disease progression within 60 days of discontinuation from most recent therapy
    5. At least 2 but no more than 3 prior therapies for multiple myeloma
    6. Prior exposure to an immunomodulatory agent (IMiD)
    7. Prior exposure to a proteasome inhibitor (PI)
    8. Documented response of at least partial response (PR) to 1 line of prior therapy
    9. Measurable disease with at least 1 of the following assessed within the 21 days prior to
    randomization:
    a. Serum M-protein ≥ 0.5 g/dL
    b. Urine M-protein ≥ 200 mg/24 hours
    c. In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) ≥ 100
    mg/L (involved light chain) and an abnormal serum kappa lambda ratio
    10. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
    11. Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days prior to randomization
    12. Adequate organ and bone marrow function within the 21 days prior to randomization defined by:
    a. Bilirubin < 1.5 times the upper limit of normal (ULN)
    b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
    < 3 times the ULN
    c. Absolute neutrophil count (ANC) ≥ 1000/mm3 (screening ANC should be independent of growth
    factor support for ≥ 1 week)
    d. Hemoglobin ≥ 8.0 g/dL (Use of erythropoietic stimulating factors and red blood cell [RBC]
    transfusion per institutional guidelines is allowed, however the most recent RBC transfusion may
    not have been done within 7 days
    prior to obtaining screening hemoglobin.)
    e. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone marrow is > 50%.
    Subjects should not have received platelet transfusions for at least 1 week prior to obtaining the
    screening platelet count.)
    f. Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min
    Calculation should be based on the Cockcroft and Gault formula:
    [(140 – Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if female
    13. Females of childbearing potential (FCBP) must have a confirmed negative serum pregnancy test
    within the 21 days prior to randomization (performed at a central laboratory).
    14. Females of childbearing potential and male subjects who are sexually active with
    FCBP must agree to use effective concomitant method(s) of contraception during
    the study and for 30 days following the last study drug treatment administration.
    E.4Principal exclusion criteria
    1. Waldenström macroglobulinemia
    2. Multiple myeloma of Immunoglobin M (IgM) subtype
    3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin
    changes)
    4. Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential)
    5. Myelodysplastic syndrome
    6. Second malignancy within the past 5 years except:
    a. Adequately treated basal cell or squamous cell skin cancer b. Carcinoma in situ of the
    cervix
    c. Prostate cancer < Gleason score 6 with stable prostate-specific antigen
    (PSA) over 12 months
    d. Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)
    e. Treated medullary or papillary thyroid cancer
    f. Similar condition with an expectation of > 95% five-year disease-free survival
    7. History of or current amyloidosis
    8. Cytotoxic chemotherapy within the 28 days prior to randomization
    9. Immunotherapy within the 21 days prior to randomization
    10. Glucocorticoid therapy within the 14 days prior to randomization that exceeds a cumulative
    dose of 160 mg of dexamethasone or 1000 mg prednisone
    11. Radiation therapy:
    a. Focal therapy within the 7 days prior to randomization
    b. Extended field therapy within the 21 days prior to randomization
    12. Prior treatment with either carfilzomib or oprozomib
    13. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize
    carfilzomib)
    14. Contraindication to dexamethasone or any of the required concomitant drugs or supportive
    treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to
    pre-existing pulmonary or cardiac impairment
    15. Active congestive heart failure (New York Heart Association [NYHA] Class III or IV, refer to
    Appendix F), symptomatic ischemia, conduction abnormalities uncontrolled by conventional
    intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial
    infarction within 6 months prior to enrollment
    16. Active infection within the 14 days prior to randomization requiring systemic antibiotics
    17. Pleural effusions requiring thoracentesis within the 14 days prior to randomization
    18. Ascites requiring paracentesis within the 14 days prior to randomization
    19. Ongoing graft-versus-host disease
    20. Uncontrolled hypertension or uncontrolled diabetes despite medication
    21. Significant neuropathy (≥ Grade 3) within the 14 days prior to randomization
    22. Known cirrhosis
    23. Known human immunodeficiency virus (HIV) seropositivity, hepatitis C infection,
    or hepatitis B infection (subjects with past hepatitis B virus (HBV) infection or
    resolved HBV infection defined as having a negative HBsAg test and a positive
    antibody to hepatitis B core antigen [anti HBc] antibody test are eligible; subjects
    positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain
    reaction (PCR) is negative for HCV RNA.)
    24. Participation in another interventional study within the 28 days prior to
    randomization
    25. Major surgery (except kyphoplasty) within the 28 days prior to randomization
    26. Female subjects who are pregnant or lactating
    27. Any other clinically significant medical disease or social condition that, in the
    investigator’s opinion, may interfere with protocol adherence or a subject’s ability
    to give informed consent, be compliant with study procedures, or provide accurate
    information.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is ORR, which is defined as the proportion of subjects who achieved a
    confirmed PR, VGPR, CR, or sCR according to the IMWG-URC
    E.5.1.1Timepoint(s) of evaluation of this end point
    * Assessment every 4 weeks to collect lab-data (Blood and Urine) for response assessment bone-marrow biopsy (only once) in case of to confirm CR/sCR or if progression in bone-marrow plasma-cell – percentage suspected. If baseline soft tissue plasmacytoma present, repetition of this imaging if progressive disease suspected clinically or to confirm MR or better in case of given clinical evidence. All these until progressive disease is demonstrated
    o After discontinuation of study drug treatment and demonstration of disease progression, survival follow up every 3 months (short questionnaire may be done via telephone-call) until death confirmed
    E.5.2Secondary end point(s)
    The secondary endpoints of the study are as follows:
     PFS defined as the time in months from randomization to the earlier of disease
    progression or death due to any cause.
     OS defined as the time in months from randomization to death due to any cause.
     Safety and tolerability
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Interim analysis of PFS is expected to occur at the time of analysis of ORR, approximately 19 months after the first subject is randomized. Final PFS analysis is expected to occur approximately 25 months after the first subject is randomized.
    • Interim analysis of OS is expected to occur at the time of analysis of ORR, approximately 19 months after the first subject is randomized. Final OS analysis is expected to occur approximately 25 months after the first subject is randomized.
    • Data will be collected till 30 days after the last administration of study treatment.nter information in English and add any other language that is applicable
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    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 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 EEA85
    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
    Belgium
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Greece
    Hungary
    Italy
    Japan
    Poland
    Spain
    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
    End of the study defined as when the final OS analysis takes place
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days3
    E.8.9.2In all countries concerned by the trial years4
    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: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 300
    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 state46
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 418
    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)
    Standard of Care
    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 Decision2015-08-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-01-07
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