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    Summary
    EudraCT Number:2017-003540-21
    Sponsor's Protocol Code Number:CPKC412E2301
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-11-26
    Trial results View 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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2017-003540-21
    A.3Full title of the trial
    A phase III, randomized, double-blind study of chemotherapy with daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation plus midostaurin (PKC412) or chemotherapy plus placebo in newly diagnosed patients with FLT-3 mutation negative acute myeloid leukemia (AML)
    Randomizowane badanie fazy III prowadzone metodą podwójnie ślepej próby, oceniające użycie daunorubicyny lub idarubicyny wraz z cytarabiną w leczeniu indukcyjnym oraz pośrednią dawkę cytarabiny w leczeniu konsolidacyjnym, w skojarzeniu z midostauryną (PKC412) lub chemioterapię plus placebo, u pacjentów z nowo zdiagnozowaną ostrą białaczką szpikową (AML) bez mutacji FLT3
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study of chemotherapy plus midostaurin (PKC412) or chemotherapy plus placebo in newly diagnosed patients with FLT-3 mutation negative acute myeloid leukemia (AML)
    A.4.1Sponsor's protocol code numberCPKC412E2301
    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 SponsorNovartis Pharma AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma Services AG
    B.5.2Functional name of contact pointPunkt informacyjny badania kliniczn
    B.5.3 Address:
    B.5.3.1Street AddressForum 1, Novartis Campus / Lichtstrasse 35
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4056
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+41 61 3241 111
    B.5.5Fax number+41 61 3248 001
    B.5.6E-mailclinicaltrial.enquiries@novartis.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 Rydapt
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    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/3/04/214
    D.3 Description of the IMP
    D.3.2Product code PKC412
    D.3.4Pharmaceutical form Capsule, soft
    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 INNmidostaurin
    D.3.9.1CAS number 120685-11-2
    D.3.9.3Other descriptive nameMIDOSTAURIN
    D.3.9.4EV Substance CodeSUB21040
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, soft
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    newly diagnosed FLT3 non-mutated acute myeloid leukemia
    E.1.1.1Medical condition in easily understood language
    newly diagnosed FLT3 non-mutated 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 21.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid 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
    To determine if the addition of midostaurin to standard induction and consolidation therapy, followed by single agent post-consolidation therapy improves EFS in patients with newly diagnosed FLT3-MN (SR<0.05) AML.
    E.2.2Secondary objectives of the trial
    Key: determine if addition of midostaurin to standard induction + consolidation, followed by single agent post-consolidation improves OS in pts with newly diagnosed FLT3-MN AML
    1. Compare CR + CRi with adequate recovery rate in the 2 treatment groups
    2. Compare percentage of pts who reached MRD neg status in the 2 groups
    3. Compare percentage of pts with MRD neg status in the post-consolidation phase in the 2 groups
    4. Compare time to MRD neg bone marrow between the 2 treatment arms in the 2 groups
    5. Compare DFS, as well as CIR and CID in the 2 groups
    6. Compare time to CR or CRi
    7. Compare time to neutrophil recovery in the 2 groups
    8. Compare time to platelet recovery in the 2 treatment groups
    9. Assess safety and tolerability of midostaurin in combination with chemotherapy and as monotherapy during post-consolidation
    10. Characterize PK of midostaurin, CGP52421 and CGP62221
    11. Assess impact of midostaurin on health related quality of life and AML symptom reduction
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Diagnosis of AML (≥20% blasts in the bone marrow based on WHO 2016 classification). Patients with APL (acute promyelocytic leukemia) with PML-RARA are not eligible.
    2. Suitability for intensive induction chemotherapy in the judgment of the investigator
    3. Documented absence of an ITD and TKD activating mutation at codons D835 and I836 in the FLT3 gene, as determined by analysis in a Novartis designated FLT3 screening laboratory using a validated clinical trial assay with clinical cutoff of 0.05 mutant to wild type ratio.
    4. Age ≥ 18 years
    5. Laboratory values that indicate adequate organ function assessed locally at the screening visit:
    • AST ≤ 3 times ULN
    • Alanine aminotransferase (ALT) ≤ 3 times ULN
    • Serum total bilirubin ≤ 1.5 times ULN, unless in case of hyperbilirubinemia due to an isolated Gilbert syndrome
    • Estimated (by Cockcroft-Gault) creatinine clearance ≥ 30ml/min
    6. Written informed consent must be obtained prior to any screening procedures.
    E.4Principal exclusion criteria
    1. Central nervous system (CNS) leukemia
    2. Therapy-related secondary AML
    3. Isolated extramedullary leukemia
    4. Prior therapy for leukemia or myelodysplasia with the following exceptions:
    a) Emergency leukapheresis
    b) Emergency treatment for hyperleukocytosis with hydroxyurea or low-dose cytarabine for ≤ 7 days
    c) Cranial RT for CNS leukostasis (one dose only)
    d) Hematopoietic Growth factor/cytokine support
    e) Other supportive therapy including antibiotics at the discretion of the investigator
    5. AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine)
    6. Any investigational agent within 30 days or 5 half-lives, whichever is greater, prior to Day 1. An investigational agent is defined as an agent with no approved medical use in adults or in pediatric patients.
    7. Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)
    8. Strong CYP3A4/5 enzyme inducing drugs unless they can be discontinued or replaced prior to enrollment.
    9. Any other known disease or concurrent severe and/or uncontrolled medical condition (e.g., cardiovascular disease including congestive heart failure or active uncontrolled infection) that could compromise participation in the study.
    10. Abnormal chest X-ray with corresponding clinical symptoms or findings that indicate an active infection, or other pulmonary conditions that are currently clinically significant.
    11. Impairment of gastrointestinal (GI) function or GI disease that might alter significantly the absorption of midostaurin.
    12. Known confirmed diagnosis of HIV infection or active viral hepatitis (testing is not mandatory to exclude these viral infections).
    13. Cardiovascular abnormalities, including any of the following:
    • History of MI, angina pectoris, CABG within 6 months prior to starting study treatment
    • Clinically uncontrolled cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
    • Uncontrolled congestive heart failure
    • Left ventricular ejection fraction of <50%,
    • Poorly controlled hypertension
    14. Pregnant or nursing (lactating) women
    15. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 4 months after stopping medication.
    Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
    16. Sexually active males unless they use a condom during intercourse while taking the drug during treatment, and for at least 4 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via semen.
    17. Unwillingness or inability to comply with the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    EFS defined as the time from randomization to failure to obtain a CR or CRi with adequate blood count recovery in induction, relapse after CR or CRi with adequate blood count recovery or death due to any cause, whichever occurs first as assessed by the investigator.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Response disease assessment at end of each cycle and every 3 months during post-treatment follow-up
    Interim analysis at 12 and 20 months, final analysis at 39 months
    E.5.2Secondary end point(s)
    Key secondary endpoint: Overall survival is defined as the time from randomization to date of death due to any cause.
    1. CR and CRi with adequate recovery rate according to the International Working Group (IWG) for AML (Cheson et al 2003, ELN 2017) as per investigator assessment.
    2. Percentage of patients with MRD negative status.
    3. Percentage of patients with MRD negative status during post-consolidation phase
    4. Number of days from date of randomization to first documented MRD negative
    5. DFS, as measured from the date of first CR or CRi with adequate blood count recovery to relapse or death from any cause, whichever occurs first.
    CIR is defined for patients with CR or CRi with adequate blood count recovery: time from achieving CR or CRi with adequate blood count recovery until onset of relapse. Patients without relapse are censored at the last adequate response assessment. Patients who died without relapse are counted as a competing cause of failure.
    CID is defined for patients with CR or CRi with adequate blood count recovery: time from achieving CR or CRi with adequate blood count recovery until death. Patients who did not die are censored at the last contact date. Patients who relapsed are counted as a competing cause of failure.
    6. Number of days from date of randomization to first documented CR or
    CRi with adequate blood count recovery.
    7. Number of days from the first day of a chemotherapy cycle to first day neutrophils ≥0.5 x 10^9/L.
    Number of days from day 1 of commencing induction therapy to first day neutrophils ≥1.0 x 10^9/L.
    8. Number of days from the first day of a chemotherapy cycle to first day platelets ≥50 x 10^9/L.
    Number of days from day 1 of commencing induction therapy to first day platelets ≥100 x10^9/L.
    9. Frequency/severity of AEs, and laboratory abnormalities.
    10. Plasma concentrations and pharmacokinetic parameters for midostaurin, CGP52421 and CGP62221.
    11. Change from baseline score for each time point for the FACT-Leu and
    the EQ5D-5L (visual analogue scale (VAS)) by treatment arm.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Key secondary endpoint: at 20, 39 and 64 months
    1. at end of each cycle and every 3 months during post-treatment follow-up
    2.-4. MRD assessed at end of each induction cycle, first cycle of consolidation, end of consolidation phase, cycle 4, cycle 7 and cycle 10 of post-consolidation and every 3 months during post-treatment
    5. at end of each cycle and every 3 months during post-treatment follow-up
    6. at end of each induction cycle
    7. and 8. at various points throughout the duration of the trial (see protocol for details)
    9. throughout the trial
    10. at various points throughout the duration of the trial (see protocol for details)
    11. start of each induction cycle, end of each consolidation cycle, start of each post-consolidation cycle, every 6 months during post-treatment follow-up
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 EEA113
    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
    Austria
    Belgium
    Brazil
    Bulgaria
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Israel
    Italy
    Japan
    Norway
    Poland
    Portugal
    Spain
    Switzerland
    Taiwan
    Turkey
    United States
    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
    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 months0
    E.8.9.1In the Member State concerned days20
    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 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: 452
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 334
    F.4.2.2In the whole clinical trial 502
    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 Decision2018-12-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-02-12
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