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    Summary
    EudraCT Number:2012-004490-10
    Sponsor's Protocol Code Number:2012_32
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2013-07-09
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2012-004490-10
    A.3Full title of the trial
    A Multicenter Open label Phase 2 study of Carfilzomib Weekly plus Melphalan and Prednisone in Untreated Symptomatic Elderly Multiple Myeloma.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Multicenter Open label Phase 2 study of Carfilzomib Weekly plus Melphalan and Prednisone in Untreated Symptomatic Elderly Multiple Myeloma.
    A.4.1Sponsor's protocol code number2012_32
    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 SponsorGhent University Hospital
    B.1.3.4CountryBelgium
    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
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportCHRU Lille
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGhent University Hospital
    B.5.2Functional name of contact pointBimetra Clinics
    B.5.3 Address:
    B.5.3.1Street AddressC. Heymanslaan 10
    B.5.3.2Town/ cityGhent
    B.5.3.3Post code9000
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3293320500
    B.5.5Fax number+3293320520
    B.5.6E-mailBimetra.Clinics@uzgent.be
    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 AuthorisationFrance
    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 (KYPROLIS)
    D.3.2Product code PR171
    D.3.4Pharmaceutical form Powder for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    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 code2012_32
    D.3.9.3Other descriptive nameCARFILZOMIB
    D.3.9.4EV Substance CodeSUB32911
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number20 to 70
    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
    A Multicenter Open label Phase 2 study of Carfilzomib Weekly plus Melphalan and Prednisone in Untreated Symptomatic Elderly Multiple Myeloma.
    E.1.1.1Medical condition in easily understood language
    untreated Symptomatic elderly Multiple Myeloma
    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 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
    To determine MTD of Carfilzomib Weekly based on definition of DLTs
    E.2.2Secondary objectives of the trial
    • To determine the VGPR (Very Good Partial Response) + CR (complete response) rate of Carfilzomib weekly at the MTD + MP at the end of the 9 induction cycles
    • To determine the safety profile of Carfilzomib weekly +MP for the first 9 cycles and during maintenance.
    • To determine the safety profile of Carfilzomib Weekly according to doses in the first part of the study
    • To determine the response rate (Partial response and better), the stringent CR rate (sCR) and Immunophenotypic CR (MRD; Will be performed by in Nantes, France) during the first 9 cycles and during maintenance.
    • To determine the clinical benefit response rate (CBR, Minor response and better).
    • To determine the Progression-free Survival (PFS), Event-free Survival (EFS), and Time to Progression (TTP)
    • To determine the Overall Survival
    • To determine the Time to response and Response duration
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Must be able to understand and voluntarily sign an informed consent form
    2. Must be able to adhere to the study visit schedule and other protocol requirements
    3. Age ³ 65 years (at least 65 years of age or older)
    4. Life expectancy > 6 months.
    5. Patients must have Symptomatic Measurable previously Untreated MM, as defined below:
    5.1. Symptomatic MM diagnostic criteria (all 3 required)
    • Monoclonal plasma cells in the bone marrow ≥10%
    • Monoclonal protein present in the serum and/or urine.
    • Myeloma-related organ dysfunction (at least one of the following)1
    [C] Calcium elevation in the blood (serum calcium >10.5 mg/dl or upper limit of normal)
    [R] Renal insufficiency (serum creatinine >2 mg/dL)
    [A] Anemia (hemoglobin <10 g/dL or 2 g < normal)
    [B] Lytic bone lesions and/or presence of a biopsy-proven plasmacytoma*
    1 A variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma-related.
    *If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole defining criteria, then > 30% plasma cells are required in the bone marrow or proven plasmocytic infiltration in bone marrow biopsy

    5.2. AND have measurable disease as defined by the following: Patients must have a clearly detectable and quantifiable monoclonal M-component value in the serum and/or urine.
     IgG (serum M-component > 10g/l)
     IgA (serum M-component > 5g/l)
     IgD (serum M-component > 0.5g/l)
     Light chain (serum M-component >1g/l or Bence Jones > 200mg/24H)
     Serum FLC assay: involved FLC level > 10 mg/dl provided serum FLC ratio is abnormal
    6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
    7. Adequate bone marrow function, documented within 72 hours and without transfusion 5 days prior to the first intake of investigational product (C1J1) nor growth factor support, defined as:
    • Absolute neutrophils ≥ 0.75 x109/L,
    • Untransfused Platelet count ≥ 75 x109/L
    • Hemoglobine ≥8.5 g/L
    8. Adequate organ function defined as:
    • Serum total bilirubin < 2.0 mg/dL
    • Clairance creatinine ≥ 30ml/min
    • Serum SGOT/AST or SGPT/ALT < 2.5x upper limit of normal (ULN)
    9. Subjects affiliated with an appropriate social security system.
    10. Male subjects must:
    10.1. Understand the potential teratogenic, and genotoxic risk of Melphalan if engaged in sexual activity with a pregnant female or a female of childbearing potential.
    10.2. Understand the potential genotoxic risk of Carfilzomib if engaged in sexual activity with a pregnant female or a female of childbearing potential.
    10.3. Practice complete abstinence or understand the need and agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential throughout the entire duration of study treatment, during dose interruptions and until at least 3 months after the end of treatment discontinuation of CMP, even if he has undergone a successful vasectomy. If pregnancy or a positive pregnancy test does occur in the partner of a male study patient during study participation, the investigator must be notified immediately.
    10.4. Agree not to donate semen or sperm during study drug therapy and until at least 3 months after the end of treatment discontinuation of CMP.
    E.4Principal exclusion criteria
    1. Any other uncontrolled medical condition or comorbidity that might interfere with subject’s participation.
    2. Known positive for HIV or active infectious hepatitis, type B or C.
    3. Patients with non-secretory MM and non-measurable MM
    4. Patient with terminal renal failure that require dialysis and clairance creatinine < 30 ml/min
    5. Prior history of malignancies, other than multiple myeloma, unless the patients has been free of the disease for ≥ 5 years. Exceptions include the following:
    • Basal or squamous cell carcinoma of the skin
    • Carcinoma in situ of the cervix or breast
    • Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
    6. Prior local irradiation within two weeks before first dose
    7. Evidence of central nervous system (CNS) involvement
    8. Unable to take corticotherapy at study entry (according to Summary of Cortancyl’s Characteristics)
    9. Ongoing active infection
    10. Any ongoing adverse event or medical history > grade 2 severity
    11. Refusal to participate in the study
    12. Persons protected by a legal regime (guardianship, trusteeship)
    13. Alkeran’s (Melphalan) contraindication: Hypersensitivity to Melphalan or to any other constituents.
    14. Patients with heart failure class 3 and 4 according to the NYHA criteria, or patients with past history of myocardial infarction within the last 6 months or no controlled cardiac conduction abnormalities.
    15. Patients with a left ventricular ejection fraction under or equal to 30 % (LVEF ≤ 30%).
    16. Female of childbearing potential (Females are defined as not of childbearing potential if documentation of “Natural menopause for at least 24 consecutive months, a hysterectomy, or bilateral oophorectomy”).
    E.5 End points
    E.5.1Primary end point(s)
    To determine MTD of Carfilzomib Weekly. If dose-limiting toxicities (DLTs) occur in fewer than 3 of these patients per cohort, the next cohort of 6 patients (cohort 2, 3 and 4) will be N+1 up to cohort 4. If at any time during cycle 1 of a dose cohort, > 2 subjects experience a drug-related DLT, the MTD will have been exceeded, additional enrolment within the cohort will cease, and dose escalation will stop. The MTD will be defined as the dose level below which DLT is observed in >33% (i.e. > 2 of 6) subjects in a cohort.

    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of the study when the last patient will have relapsed
    E.5.2Secondary end point(s)
    •To determine the VGPR (Very Good Partial Response) + CR (Complete Response) rate of Carfilzomib Weekly at the MTD + MP at the end of the 9 induction cycles using International Myeloma Working Group (IMWG) response criteria
    •To determine the Safety profile (type, frequency, severity, and relationship of adverse events to study treatment). Incidence of Treatment Emergent Adverse Event (TEAE), Serious Adverse Events (SAE) and laboratory abnormalities using National Cancer Institute (NCI) common toxicity criteria for the first 9 cycles and during maintenance.
    • To determine the safety profile of Carfilzomib Weekly according to doses in the first part of the study
    • To determine the Overall Response rate [Partial (PR) and better] using IMWG response criteria and to determine the sCR rate using IMWG response criteria (12) during the first 9 cycles and during maintenance.
    • Minor response will be determined using EBMT criteria
    • To determine the Progression-free Survival (PFS, from the date of inclusion to the date of the progression); Event-free Survival (EFS, from the date of inclusion to the date of any event, progression, death or any other cause for end of treatment); Time to progression (TTP, from the date of inclusion to the date of the progression or death, whichever occurs first); Overall Survival (OS, from the date of inclusion to the date of the last news);
    • To determine the Time to response (TTR, from the date of inclusion to the date of the first observation of response) and Response duration (DOR, time between first documentation of response and disease progression)
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of the study when the last patient will have relapsed
    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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    To determine MTD of Carfilzomib Weekly based on definition of DLTs
    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 No
    E.8.1.1Randomised No
    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.8.3 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 EEA44
    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
    Patients may continue study until PD develops at which time they will complete a Study Discontinuation visit as outlined in Table 1. In addition, patients who are discontinued from study treatment will be followed for survivals and subsequent MM treatment regimens
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    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) No
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 30
    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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Intergroupe Francophone du Myélome (IFM)
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-08-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-18
    P. End of Trial
    P.End of Trial StatusOngoing
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