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    EudraCT Number:2022-003069-39
    Sponsor's Protocol Code Number:VARIANT
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2023-01-17
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2022-003069-39
    A.3Full title of the trial
    Venetoclax after TKI to target persisting stem cells in CML
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Venetoclax after TKI-Therapy in CML
    A.4.1Sponsor's protocol code numberVARIANT
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05701215
    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 SponsorFriedrich-Schiller-Universität Jena
    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 supportAbbvie
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCML-Study Group
    B.5.2Functional name of contact pointCML-Study Group
    B.5.3 Address:
    B.5.3.1Street AddressAm Klinikum 1
    B.5.3.2Town/ cityJena
    B.5.3.3Post code07747
    B.5.4Telephone number+4936419396670
    B.5.5Fax number+4936419399973
    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. name Venclyxto
    D. of the Marketing Authorisation holderAbbVie Deutschland GmbH & Co. KG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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/3/12/1080
    D.3 Description of the IMP
    D.3.1Product nameVenclyxto
    D.3.2Product code Venetoclax
    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.3.9.4EV 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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Chronic Myeloid Leukemia
    E.1.1.1Medical condition in easily understood language
    Chronic Myeloid Leukemia
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10009700
    E.1.2Term CML
    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
    Reduction of BCR::ABL1 stem cells measured by quantitative genomic PCR in bone marrow after venetoclax administration.
    E.2.2Secondary objectives of the trial
    • Molecular relapse free survival (RFS) with relapse defined as loss of major molecular remission (MMR), that is, an increase of the BCR::ABL1 level (IS) to > 0.1%.
    • Incidence of adverse events grade 1-5.
    • Quality of life.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with diagnosis of chronic phase CML with cytogenetic confirmation of Philadelphia (Ph) chromosome
    2. Ph negative cases or patients with variant translocations who are BCR::ABL1 positive in multiplex PCR are also eligible
    3. Typical b2a2 and/or b3a2 BCR::ABL1 transcripts
    4. Subject must be ≥ 18 years of age
    5. Stored DNA from initial diagnosis (prior TKI treatment) for BCR::ABL1 breakpoint analysis
    6. BCR::ABL1 transcript level according to the international scale (IS) of MR4 or better which has been confirmed three times within the past 13 months and was assessed by an IS-certified reference laboratory, such as of the University Jena , the University Mannheim, or another MR4-certified laboratory in Germany
    7. At least 3 years of TKI therapy
    8. Patients who failed to discontinue TKI in a prior discontinuation attempt are still eligible if they fulfill criteria 6. after retreatment with TKI
    9. WHO performance status 0-2
    10. Adequate end organ function as defined by:
    • Total bilirubin (TBL) < 3 x Upper Limit of Normal (ULN); patients with Gilbert’s syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN,
    • Creatinine Clearance (CrCl) ≥ 30 millilitres per minute (mL/min) as calculated using Cockcroft-Gault formula, Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis.
    11. Patients must have the following laboratory values within normal limits or corrected to within normal limits with supplements:
    • Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with CrCl ≥ 90 mL/min),
    • Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with CrCl ≥ 90 mL/min),
    • Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with CrCl ≥ 90 mL/min),
    • For patients with mild to moderate renal impairment (CrCl ≥ 30 mL/min and <90 mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium should be within normal limits or corrected to within normal limits with supplements.
    12. Women of childbearing age must use a highly effective method of contraception while using venetoclax. Women using hormonal contraceptives should also use a barrier method.
    13. Negative pregnancy test in women of childbearing potential
    14. Subject must voluntarily sign and date an informed consent
    E.4Principal exclusion criteria
    1. Concomitant use of strong CYP3A-Inhibtors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, ritonavir) is contraindicated 7 days prior to venetoclax.
    2. Concomitant use of moderate CYP3A-Inhibitors (e.g., ciprofloxacin, diltiazem, erythromycin, fluconazole, verapamil) should be avoided.
    3. Grapefruit products, Seville oranges, and starfruit (carambola) should be avoided during treatment with venetoclax as they contain inhibitors of CYP3A
    4. Concomitant use of venetoclax with P-gp and BCRP inhibitors
    5. Concomitant use of venetoclax with strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin) or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided
    6. Concomitant use of preparations containing St. John´s wort
    7. Patients with severe renal impairment (Crea-Clearance < 30 ml/min) or on dialysis
    8. Patients with severe hepatic impairment
    9. Patients who are pregnant or breast feeding, or females of reproductive potential not employing an effective method of birth control. Female patients must agree to employ an effective barrier method of birth control throughout the study and for and for at least 30 days after ending venetoclax treatment
    10. Known impaired cardiac function
    11. Impaired gastrointestinal function or disease that may alter the absorption of study drug
    12. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
    13. Active or uncontrolled infections at the time of enrolment
    14. Known HIV sero-positivity or known active hepatitis B or C infection (HIV testing is not required)
    15. Participation in another clinical study with other investigational drugs within 14 days prior to enrolment
    16. Any medical, mental, psychological or psychiatric condition that in the opinion of the investigator would not permit the patient to complete the study or understand the patient information
    17. Subject has acute leukemia
    18. Subject has known active CNS involvement
    19. Hypersensitivity to venetoclax or any component of the formulation
    E.5 End points
    E.5.1Primary end point(s)
    Reduction of BCR::ABL1 stem cells measured by quantitative genomic PCR in bone marrow after venetoclax administration.
    E.5.1.1Timepoint(s) of evaluation of this end point
    month 6 and month 12 after start of Venetoclax
    E.5.2Secondary end point(s)
    • Molecular relapse free survival (RFS) with relapse defined as loss of major molecular remission (MMR), that is, an increase of the BCR::ABL1 level (IS) to > 0.1%.
    • Incidence of adverse events grade 1-5.
    • Quality of life.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Molecular relapse free survival (RFS) with relapse defined as loss of major molecular remission (MMR), that is, an increase of the BCR::ABL1 level (IS) to > 0.1%: monthly until month 15
    • Incidence of adverse events grade 1-5: monthly until month 15
    • Quality of life: month 6 and 12
    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 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. 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 concerned2
    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
    Last Visit Last Subject (at latest 15 months after start of Venetoclax-Therapy of the last recruited subject)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 8
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 state10
    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)
    Treatment decision following the trial treatment is at the discretion of the investigator. There will be no specific treatment instructed recommentions by Sponsor after end of Trial. Patients should be given the opportunity to benefit from other therapies.
    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 CML Study Group
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2023-06-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-03-03
    P. End of Trial
    P.End of Trial StatusOngoing
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