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    Summary
    EudraCT Number:2019-003836-22
    Sponsor's Protocol Code Number:FLG-V001
    National Competent Authority:Finland - Fimea
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-10-22
    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 ConcernedFinland - Fimea
    A.2EudraCT number2019-003836-22
    A.3Full title of the trial
    TWO-STAGE, TWO-ARM, OPEN-LABEL PHASE II STUDY OF VENETOCLAX IN COMBINATION WITH AZACYTIDINE IN ACUTE MYELOID LEUKEMIA PATIENTS SELECTED USING EX VIVO DRUG SENSITIVITY SCREENING
    Vaiheen II kaksiosainen, kaksihaarainen avoin tutkimus, jossa venetoklaksia annetaan yhdessä atsasitidiinin kanssa akuuttia myelooista leukemiaa sairastaville potilaille, joiden hoito valitaan koeputkessa tehdyn lääkeherkkyystutkimuksen perusteella.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    STUDY OF VENETOCLAX IN COMBINATION WITH AZACYTIDINE IN ACUTE MYELOID LEUKEMIA PATIENTS SELECTED USING EX VIVO DRUG SENSITIVITY SCREENING
    Lääketutkimus, jossa venetoklaksia annetaan yhdessä atsasitidiinin kanssa akuuttia myelooista leukemiaa sairastaville potilaille, joiden hoito valitaan koeputkessa tehdyn lääkeherkkyystutkimuksen perusteella.
    A.3.2Name or abbreviated title of the trial where available
    VenEx
    A.4.1Sponsor's protocol code numberFLG-V001
    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 SponsorHUS Helsinki University Hospital
    B.1.3.4CountryFinland
    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 supportHelsinki University
    B.4.2CountryFinland
    B.4.1Name of organisation providing supportFiCAN South
    B.4.2CountryFinland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHUS Helsinki University Hospital
    B.5.2Functional name of contact pointMika Kontro
    B.5.3 Address:
    B.5.3.1Street AddressHaartmaninkatu 4, PO Box 372
    B.5.3.2Town/ cityHelsinki
    B.5.3.3Post code00290
    B.5.3.4CountryFinland
    B.5.6E-mailmika.kontro@helsinki.fi
    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 Venclyxto
    D.2.1.1.2Name of the Marketing Authorisation holderAbbVie Ltd
    D.2.1.2Country which granted the Marketing AuthorisationFinland
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    Acute myeloid leukemia in patients who are non-fit for standard induction therapy (except acute promyelocytic leukemia) and present with de novo, secondary, released or refractory AML
    E.1.1.1Medical condition in easily understood language
    Newly diagnosed, relapsed, resistant or secondary acute myeloid leukemia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10000880
    E.1.2Term Acute myeloid leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate usability of ex vivo drug sensitivity testing for patient selection and to validate the ex vivo/in vivo drug sensitivity correlation.
    E.2.2Secondary objectives of the trial
    -To evaluate resistance mechanisms of venetoclax in primary patient samples
    -To evaluate venetoclax based combinations in resistant samples to overcome resistance
    -To unravel biomarkers (i.e. gene expression, protein levels and phosphorylation status of specific proteins, etc.) for sensitivity/resistance
    -To evaluate the correlation of venetoclax blood concentrations on treatment responses
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Substudy included in protocol
    -To evaluate resistance mechanisms of venetoclax in primary patient samples
    -To evaluate venetoclax based combinations in resistant samples to overcome resistance
    -To unravel biomarkers (i.e. gene expression, protein levels and phosphorylation status of specific proteins, etc.) for sensitivity/resistance
    -To evaluate the correlation of venetoclax blood concentrations on treatment responses
    E.3Principal inclusion criteria
    1. Written informed consent
    2. Patients who present with one of the following (except acute promyelocytic leukemia)
    a. De novo or secondary AML patients who are non-fit for standard induction therapy (see below)
    b. Relapsed or refractory AML patients following at least 1 line of prior therapies (see below)

    3. Ex vivo sensitivity testing performed to assess venetoclax sensitivity
    a. Validation cohort: All participants are treated with venetoclax+azacitidine irrespective of the ex vivo screening results.
    b. Study cohort: Only the participants exhibiting ex vivo sensitivity to venetoclax are included to study therapy.

    4. Participant must have ECOG Performance status ≤ 2 for participants ≥ 75 years of age OR ≤ 3 for participants ≥ 18 to 74 years of age

    5. Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion.

    6. Participant must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.

    7. Participant must have adequate liver function as demonstrated by
    a. alanine aminotransferase (ALT) ≤ 4.0 × ULN
    b. bilirubin ≤ 1.5 × ULN

    8. Specific inclusion criteria for participants non-fit for standard chemotherapy
    Participant must be:
    ≥ 70 years of age;
    OR
    ≥ 18 to 69 years of age and ineligible for intensive chemotherapy meeting at least one of the criteria following:
    • Clinically significant comorbidities, as reflected by at least 1 of:
    - Left ventricular ejection fraction (LVEF) < 50%.
    - Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected.
    - Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected.
    - Chronic stable angina or congestive heart failure controlled with medication.
    - Alanine aminotransferase (ALT) 3.0-4.0 × ULN

    • Other contraindication(s) to anthracycline therapy (must be documented)
    • Adverse risk karyotype associated with poor outcome with standard chemotherapy
    • Patient’s refusal from intensive chemotherapy

    9. Specific inclusion criteria for relapsed patients
    Participant must be:
    ≥ 55 years of age with non-CBF AML relapse
    OR
    ≥ 18 to 54 years of age and meeting at least one of the criteria following:
    • Not candidate for intensive chemotherapy (see the criteria 8.)
    • The duration of remission < 12 months.
    • Relapse after allogeneic transplantation.
    • 2nd (or higher) relapse.

    10. Specific inclusion criteria for refractory patients
    The patients who fail to achieve a complete or partial remission after induction chemotherapy (two cycles of chemotherapy containing cytarabine or clofarabine, in compilation with topoisomerase II inhibitor (e.g. anthracycline or mitoxantrone)
    E.4Principal exclusion criteria
    1. Participant has acute promyelocytic leukemia (APL)
    2. The leukemic cell content (blast percentage) in bone marrow/peripheral blood (depending which is used for drug sensitivity testing) is ≤ 10 %
    3. ECOG >3 (see also inclusion criteria 4)
    4. Participant has known CNS involvement with AML (note: CSF or radiological investigations are not required without clinical suspicion)
    5. Participant with known HIV infection or active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection that is not controlled with anti-viral medication.
    6. Participant has cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which participants are comfortable at rest but ordinary physical activity results in palpitations, fatigue, dyspnea, or anginal pain.
    7. Evidence of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participation in this study (including but not limited to):
    a. Participant has a chronic respiratory disease that requires continuous oxygen use
    b. Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal)
    c. Malabsorption syndrome or other condition that precludes enteral route of administration.
    d. Uncontrolled GVHD.
    8. Participant has a history of other malignancies prior to study entry, with the exception of previous malignancy treated with curative intent.
    E.5 End points
    E.5.1Primary end point(s)
    CR/CRi rate before Cycle 4
    E.5.1.1Timepoint(s) of evaluation of this end point
    Bone marrow examinations before C4
    E.5.2Secondary end point(s)
    The correlation of ex vivo sensitivity and specific responses (OS, DOR, EFS, MRD status)
    The correlation of venetoclax blood concentrations specific responses (OS, DOR, EFS, MRD status)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Entire 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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    To evaluate usability of ex vivo drug sensitivity testing for patient selection and to validate the ex vivo/in vivo drug sensitivity correlation.
    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.8.3 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 concerned5
    E.8.5The trial involves multiple Member States No
    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 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 years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state94
    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 Decision2019-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-11
    P. End of Trial
    P.End of Trial StatusOngoing
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