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    Summary
    EudraCT Number:2019-004340-30
    Sponsor's Protocol Code Number:M15-538
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-04-24
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2019-004340-30
    A.3Full title of the trial
    A Phase 2, Open-Label, Multi-Center Study of Venetoclax in Combination with Carfilzomib and Dexamethasone in Subjects with Relapsed or Refractory Multiple Myeloma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Venetoclax in Combination With Carfilzomib and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (MM)
    A.4.1Sponsor's protocol code numberM15-538
    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 SponsorAbbVie Deutschland GmbH & Co. KG
    B.1.3.4CountryGermany
    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 supportAbbVie Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAbbVie Ltd.
    B.5.2Functional name of contact pointEU Clinical Trials Helpdesk
    B.5.3 Address:
    B.5.3.1Street AddressAbbVie House, Vanwall Business Park, Vanwall Road
    B.5.3.2Town/ cityMaidenhead, Berkshire
    B.5.3.3Post codeSL6 4UB
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441628561090
    B.5.5Fax number+441628461153
    B.5.6E-maileu-clinical-trials@abbvie.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/3/16/1767
    D.3 Description of the IMP
    D.3.1Product nameVenetoclax
    D.3.2Product code ABT-199 (GDC-0199)
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNVENETOCLAX
    D.3.9.1CAS number 1257044-40-8
    D.3.9.2Current sponsor codeABT-199 (GDC-0199)
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Krypolis
    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.3.4Pharmaceutical 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.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
    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 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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To assess the safety and tolerability of venetoclax in combination with carfilzomib and dexamethasone when administered in subjects with relapsed or refractory multiple myeloma (RRMM).
    o assess the objective response rate (ORR) and very good partial response (VGPR) or better rate of venetoclax carfilzomib dexamethasone (VenKd) at the target dose combination in subjects with RRMM, and in t(11;14)-positive RRMM subjects.
    - To explore and compare safety and preliminary efficacy of VenKd combination at 400 mg or 800 mg venetoclax dose levels with carfilzomib dexamethasone (Kd) (control) regimen. International Myeloma Working Group (IMWG) response rates (per investigator) including ORR, VGPR, or better rate, and complete response (CR) or better rate will be investigated.
    E.2.2Secondary objectives of the trial
    • To investigate the IMWG response rates for subjects with high BCL-2 expression, and for subjects with prior exposure to lenalidomide.
    • To assess the time-to-event endpoints: progression-free survival (PFS), time to response (TTR), time to progression (TTP), duration of response (DOR), and overall survival (OS) of the VenKd combination in RRMM subjects.
    • To characterize the pharmacokinetics (PK) in plasma of venetoclax and carfilzomib.
    • To assess minimal residual disease (MRD) in the bone marrow by next generation sequencing (NGS).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
    2. Subject has documented RRMM on or after any regimen or is refractory to the most recent line of therapy.
    - Relapsed myeloma is defined as previously treated myeloma that progresses and requires initiation of salvage therapy, but does not meet criteria for refractory myeloma.
    - Refractory myeloma is defined as disease that is nonresponsive (failure to achieve minimal response or development of progressive disease [PD]) while on primary or salvage therapy, or progresses within 60 days of last therapy.
    - For Part 4, subjects must meet the above criteria and also be positive for translocation t(11;14) as determined by an analytically validated Fluorescent In Situ Hybridization (FISH) assay per central laboratory testing.
    3. Subject has received prior treatment with at least one prior line of therapy for MM.
    - Parts 1, 2, 3: Subject has received prior treatment with one to three prior lines of therapy.
    - Part 4: Subject has received prior treatment with at least one prior line of therapy.
    - A line of therapy consists of ≥ 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens.
    4. Subject has measurable disease at Screening, defined as at least one of the following:
    - Serum M-protein ≥ 0.5 g/dL (≥ 5 g/L), OR
    - Urine M-protein ≥ 200 mg/24 hours, OR
    - Serum free light chain (FLC) ≥ 10 mg/dL, provided serum FLC ratio is abnormal.
    5. Subject must meet the following laboratory parameters within 2 weeks prior to first dose, per laboratory reference range:
    - Absolute neutrophil count (ANC) ≥ 1000/μL; subject may use growth factor support to achieve ANC eligibility criteria.
    - Platelet count:
    o ≥ 50,000/mm3 for subject with ≤ 50% myeloma involvement in the bone marrow;
    o ≥ 30,000/mm3 for subject with > 50% myeloma involvement in the bone marrow;
    o Subject may not have received a platelet transfusion within 72 hours prior to the platelet count used for eligibility.
    - Hemoglobin ≥ 8.0 g/dL; subject may receive red blood cell (RBC) transfusions in accordance with institutional guidelines to meet this criteria.
    - AST and ALT ≤ 3 × upper limit of normal (ULN).
    - Total bilirubin ≤ 1.5 × ULN; subject with documented Gilbert's syndrome may have bilirubin > 1.5 × ULN with the approval of the Primary Therapeutic Area Medical Director.
    - Creatinine clearance ≥ 30 mL/min, measured by 24-hour urine collection or calculated using the Cockcroft-Gault formula.
    E.4Principal exclusion criteria
    1. Subject has any of the following conditions:
    - Non-secretory or oligo-secretory MM
    - Active plasma cell leukemia, i.e., either 20% of peripheral white blood cells or > 2.0 × 109/L circulating plasma cells by standard differential
    - Waldenström's macroglobulinemia
    - Primary amyloidosis
    - POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
    - Active hepatitis B or C infection based on screening blood testing
    - Significant cardiovascular disease, including uncontrolled angina, hypertension, arrhythmia, recent myocardial infarction within 6 months of first dose, congestive heart failure New York Heart Association (NYHA) Class ≥ 3, and/or left ventricular ejection fraction ≤ 40% as assessed by multiple gated acquisition scan (MUGA) or ECHO.
    - Major surgery within 4 weeks prior to first dose
    - Acute infections requiring antibiotic, antifungal, or antiviral therapy within 14 days prior to first dose.
    - Peripheral neuropathy ≥ Grade 3 or ≥ Grade 2 with pain within 2 weeks prior to first dose
    - Uncontrolled diabetes or uncontrolled hypertension within 14 days prior to first dose
    - Any other medical condition that, in the opinion of the Investigator, would adversely affect the subject's participation in the study.
    2. Subject has a history of other active malignancies, including myelodysplastic syndrome (MDS), within the past 3 years prior to study entry, with the following exceptions:
    - Adequately treated in situ carcinoma of the cervix uteri or the breast,
    - Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin,
    - Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment,
    - Previous malignancy with no evidence of disease confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.
    3. If subject had a prior allogeneic stem cell transplant (SCT), subject has evidence of ongoing graft-versus-host disease (GvHD).
    4. Subject has had prior treatment with carfilzomib or has a hypersensitivity or allergy to captisol (a cyclodextrin derivative used to solubilize carfilzomib) or dexamethasone.
    5. Subject is refractory to any BCL-2 family inhibitor.
    6. Subject has been treated or received any of the following:
    - Allogeneic or syngeneic SCT within 6 months prior to first dose.
    - Autologous SCT within 12 weeks prior to first dose.
    - Immunization with live vaccine within 8 weeks prior to first dose.
    - Monoclonal antibodies within 6 weeks prior to first dose.
    - Any anti-myeloma therapy (other than monoclonal antibodies), including chemotherapy, radiotherapy, biological, immunotherapy or an investigational therapy, including targeted small molecule agents within 5 half-lives (or 14 days if half-life is unknown) prior to first dose.
    - Corticosteroid therapy at a dose equivalent to ≥ 4 mg/day of dexamethasone within 3 weeks prior to first dose.
    - A strong or moderate CYP3A inhibitor or inducer within 1 week prior to first dose.
    E.5 End points
    E.5.1Primary end point(s)
    · To assess the safety and tolerability of venetoclax in combination with carfilzomib and dexamethasone when administered in subjects with relapsed or refractory multiple myeloma (RRMM).

    · To assess the objective response rate (ORR) and very good partial response (VGPR) or better rate of venetoclax carfilzomib dexamethasone (VenKd) at the target dose combination in subjects with RRMM, and in t(11;14)-positive RRMM subjects.

    ·To explore and compare safety and preliminary efficacy of VenKd combination at 400 mg or 800 mg venetoclax dose levels with carfilzomib dexamethasone (Kd) (control) regimen. International Myeloma Working Group (IMWG) response rates (per investigator) including ORR, VGPR, or better rate, and complete response (CR) or better rate will be investigated.

    E.5.1.1Timepoint(s) of evaluation of this end point
    · Safety will be monitored throughout the subject’s participation in the study.

    · IMWG response rates are dependent on the individual subject’s response to therapy. All subjects will be treated until progressive disease, unacceptable toxicity or other reason for discontinuation.
    E.5.2Secondary end point(s)
    · To investigate the IMWG response rates for subjects with high BCL-2 expression, and for subjects with prior exposure to lenalidomide.

    · To assess the time-to-event endpoints: progression-free survival (PFS), time to response (TTR), time to progression (TTP), duration of response (DOR), and overall survival (OS) of the VenKd combination in RRMM subjects.

    · To characterize the pharmacokinetics (PK) in plasma of venetoclax and carfilzomib.

    · To assess minimal residual disease (MRD) in the bone marrow by next generation sequencing (NGS).

    E.5.2.1Timepoint(s) of evaluation of this end point
    · IMWG response rates are dependent on the individual subject’s response to therapy. All subjects will be treated until progressive disease, unacceptable toxicity or other reason for discontinuation.

    · PFS will be monitored throughout the study for first documented progressive disease or death due to any cause, whichever comes first.

    · Safety and biomarker research will be monitored throughout the subject’s participation in the study.
    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 Yes
    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 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.8.2.4Number of treatment arms in the trial3
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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
    Australia
    Hungary
    Spain
    United States
    E.8.7Trial has a data monitoring committee No
    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 years8
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days14
    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: 48
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 72
    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 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 state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 16
    F.4.2.2In the whole clinical trial 120
    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)
    Please refer to Statement on Treatment After Study End document.
    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 Decision2020-06-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-05
    P. End of Trial
    P.End of Trial StatusOngoing
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