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    Summary
    EudraCT Number:2014-001633-84
    Sponsor's Protocol Code Number:20140106
    National Competent Authority:Romania - National Agency for Medicines and Medical Devices
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-04-19
    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 ConcernedRomania - National Agency for Medicines and Medical Devices
    A.2EudraCT number2014-001633-84
    A.3Full title of the trial
    Phase 1b/2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 1b/2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia
    A.4.1Sponsor's protocol code number20140106
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02303821
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/016/2021
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOnyx Therapeutics, Inc., an Amgen Inc. subsidiary
    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., an Amgen Inc. subsidiary
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen Romania SRL
    B.5.2Functional name of contact pointDepartamentul medical
    B.5.3 Address:
    B.5.3.1Street AddressBucharest Business Park, 1A Bucuresti-Ploiesti Road, Building A2, 2nd floor
    B.5.3.2Town/ cityBucharest
    B.5.3.3Post code013681
    B.5.3.4CountryRomania
    B.5.4Telephone number0040215273000
    B.5.6E-mailmedinfo-romania@amgen.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 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.3.1Product nameCarfilzomib Lyophilisate for Solution for Injection
    D.3.2Product code PR-171
    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 Acute Lymphoblastic Leukemia
    E.1.1.1Medical condition in easily understood language
    A group of cancers that usually begins in the bone marrow and results in high numbers of abnormal white blood cells.
    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 10025230
    E.1.2Term Lymphatic leukemia
    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
    Phase 1b:
    - To assess the safety and tolerability of carfilzomib, alone and in combination with induction chemotherapy, for the treatment of children with relapsed or refractory acute lymphoblastic leukemia (ALL)
    -To determine the maximum tolerated dose (MTD) of carfilzomib in combination with induction chemotherapy and to recommend a phase 2 dose of carfilzomib in combination with induction chemotherapy

    Phase 2:
    - Compare the rate of CR of CFZ-VXLD at the end of induction therapy to an appropriate external control.
    E.2.2Secondary objectives of the trial
    Phase 1:
    -To characterize the pharmacokinetics (PK) of carfilzomib alone and in combination with induction chemotherapy
    -To evaluate the combined rate of bone marrow complete response (CR) and bone marrow CR without platelet recovery (CRp) at the end of the Induction Cycle
    -To estimate the proportion of subjects who achieve minimal residual disease (MRD) status ≤ 10-3 and ≤ 10-4 lymphoblasts at the end of the Induction Cycle

    Phase 2:
    -Compare the rate of CR, CRp, CRh, and CRi of CFZ-VXLD at the end of induction therapy relative to an appropriate external control
    -Compare EFS for CFZ VXLD to an appropriate external control
    -Compare OS for CFZ-VXLD relative to an appropriate external control
    -Estimate the DOR for CFZ-VXLD relative to an appropriate external control
    -Estimate the rate of MRD[-] at the end of induction in subjects receiving CFZ-VXLD

    refer to protocol for additional secondary objectives

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Phase 1b:
    1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the time of study treatment initiation.
    2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5 % blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease.
    • To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined as:
    o Early first relapse (≤ 36 months from original diagnosis) after achieving a CR (B-ALL) or first relapse any time following the original diagnosis after achieving a CR (T-ALL) OR
    o First refractory bone marrow relapse occurring any time after original diagnosis after achieving a CR (ie, ≥ 1 failed attempt to induce a second remission) OR
    o Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2 relapses) OR
    o Failing to achieve a CR from original diagnosis after at least 1 induction attempt
    3. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
    4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit of normal (ULN) according to age. If serum creatinine level is ≥ 1.5 × ULN, the subject must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2, or for children ≤ 2 years of age, ≥ 50mL/min/1.73 m2.
    5. Adequate liver function, defined as both of the following:
    o Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert Syndrome
    o Alanine aminotransferase (ALT) ≤ 5 × institutional ULN
    6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤ 16 years old, respectively.

    see protocol for additional phase 1b inclusion criteria

    Phase 2:

    1. Subject’s legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
    2. Age ≥ 1 month to ≤ 21 years. Subjects ≥ 18 years must have had their original diagnosis at < 18 years of age
    3. Subjects must be diagnosed with relapsed or refractory relapsed ALL
    4. Subjects must have a documented first remission, ≤ 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease.
    5. T-cell ALL with bone marrow relapse (defined as ≥ 5% leukemia blasts in bone marrow) or refractory relapse with or without extramedullary disease.
    OR
    B-cell ALL with bone marrow relapse or refractory relapse (defined as ≥5% leukemia blasts in bone marrow) after having received a targeted B-cell immune therapy as treatment for a prior relapse (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or without extramedullary disease. Subjects that received blinatumomab for treatment of MRD positive disease during first remission or for primary induction failure to achieve a first remission do not qualify.

    see protocol for additional Phase 2 inclusion criteria
    E.4Principal exclusion criteria
    phase 1b:

    1. Known allergy to any of the drugs used in the study. (Subjects who have had a previous allergy to PEG-asparaginase are eligible and if able, may receive receive Erwinia asparaginase at the investigator’s discretion)
    2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
    3. Left ventricular fractional shortening ≤30%
    4. History of ≥ Grade 2 pancreatitis
    5. Active graft versus host disease requiring systemic treatment
    6. Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment
    7. Down Syndrome
    8. Prior therapy restrictions:
    o Subjects must have completed therapy with granulocyte colony stimulating factor (G CSF) or other myeloid growth factors at least 7 days before study treatment initiation, or at least 14 days before study treatment initiation, if pegylated myeloid growth factors were administered.
    o Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
    o At least 3 antibody half lives must have elapsed since the last dose of monoclonal antibody (e.g., 66 days for rituximab, 69 days for epratuzumab and 36 days for inotuzumab) before subjects may initiate study treatment.
    o Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
    o Subjects must not have received other antineoplastic agents with therapeutic intent, excluding hydroxyurea and antimetabolites administered as part of maintenance chemotherapy, within 7 days prior to study treatment initiation
    9. Hepatitis B infection with positive hepatitis B DNA

    see protocol for addition phase 1b exclusion criteria

    Phase 2:

    1. Prior treatment with carfilzomib.
    2. Prior treatment with a proteasome inhibitor (other than carfilzomib) within < 3 months of enrollment or to which a subject did not respond (response is defined as bone marrow with < 5% blasts).
    3. Treatment with a chemotherapy regimen including a vinca alkaloid, steroid, L asparaginase, and anthracycline combination with or without other chemotherapy agents within 2 months of enrollment (eg VXLD, VPLD, R3).
    4. Intolerance, hypersensitivity, or inability to receive any of the chemotherapy components of the VXLD regimen (or acceptable substitutes as listed in the protocol). An exception is allowed for allergy to asparaginase products if Erwinia Asparaginase is unable to be administered.
    5. Autologous HSCT within 6 weeks prior to start of study treatment.
    6. Allogeneic HSCT within 3 months prior to start of study treatment.

    Please see protocol for additional phase 2 exclusion criteria
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b:
    • Safety and tolerability of carfilzomib alone and in combination with induction
    chemotherapy as defined by the type, incidence, severity, and outcome of adverse events (AEs); changes from baseline in key laboratory analytes, vital signs, and physical findings. Time to toxicity will be evaluated to differentiate single-agent carfilzomib from carfilzomib in combination with induction chemotherapy
    • Determination of the MTD as the dose that has the highest posterior probability of having a DLT rate within the target toxicity interval (20% – 33%), while the posterior probability of excessive/unacceptable toxicity (> 33% – 100%) is less than 40% (per BLRM algorithm), or the stopping rules as specified in Section 5.2, and per CSRC recommendation.

    Phase 2:
    • CR after induction therapy between days 29 and 45 or initiation of next therapy, whichever comes first for subjects ≥ 12 months of age at screening
    • CR after induction therapy between days 36 and 50 or initiation of next therapy, whichever comes first for subjects < 12 months of age at screening
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1 : End of the Induction Cycle

    Phase 2: The OR for the PoCR for CFZ-VXLD versus external control.
    E.5.2Secondary end point(s)
    Phase 1b:
    •Pharmacokinetic parameters, principally maximum plasma concentration (Cmax) and area under the curve (AUC), alone and in combination with induction
    chemotherapy, derived from levels of carfilzomib assayed in PK samples
    • Combined proportion of subjects who achieve CR or CRp at the end of the
    Induction Cycle
    • Proportion of subjects who achieve MRD status ≤ 10-3 and ≤ 10-4 lymphoblasts at the end of the Induction Cycle as assessed by quantitative immunoglobulin/T-cell receptor (Ig/TcR) polymerase chain reaction (PCR)

    Phase 2:

    • CR, CRp, CRh, and CRi at the end of induction therapy
    • EFS, defined as time from initiation of therapy until treatment failure (defined as failure to reach at least a CRi after consolidation or after induction in subjects that do not receive consolidation), relapse, or death from any cause
    • OS defined as time from initiation of therapy until death from any cause
    • DOR, defined as time from earliest of CR, CRp, CRh, or CRi to relapse or death from any cause
    • MRD level using NGS < 10-4 after induction therapy in subjects achieving CR
    • MRD level using NGS < 10-3 and < 10 4 by NGS in subjects achieving CR, CRp, CRh, or CRi after induction and consolidation therapy
    • Occurrence of a stem cell transplant or CAR-T, without an intervening relapse after the end of protocol specified therapy
    • treatment-emergent and treatment-related adverse events and severe adverse events and laboratory abnormalities during the induction therapy and consolidation therapy
    • CR, CRp, CRh, and CRi after consolidation therapy between days 29 and 45 or initiation of next therapy, whichever comes first, for subjects ≥ 12 months of age at screening
    • CR, CRp, CRh, and CRi after consolidation therapy between days 36 and 50 or initiation of next therapy, whichever comes first, for subjects < 12 months of age at screening
    • Carfilzomib pharmacokinetic parameters, including AUC, Cmax, and if feasible, t1/2


    E.5.2.1Timepoint(s) of evaluation of this end point
    End of the Induction Cycle
    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 Yes
    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
    dose-escalation study
    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) Information not present in EudraCT
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    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
    Argentina
    Australia
    Brazil
    Canada
    Hong Kong
    Israel
    Korea, Republic of
    Mexico
    Russian Federation
    Singapore
    Taiwan
    Turkey
    United States
    Austria
    Denmark
    France
    Germany
    Greece
    Italy
    Poland
    Portugal
    Bulgaria
    Netherlands
    Romania
    Spain
    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 study per protocol is defined as, the end of study assessments must be completed 30 days (± 4 days) following the last dose of study treatment.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 144
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 24
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 60
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 60
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects are under 18 years old.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 52
    F.4.2.2In the whole clinical trial 144
    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)
    As per protocol
    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 ITCC Gustave Roussy ENCCA
    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 Decision2021-04-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-25
    P. End of Trial
    P.End of Trial StatusOngoing
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