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    Summary
    EudraCT Number:2021-000761-33
    Sponsor's Protocol Code Number:KB-ENTO-3001
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-09-20
    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 number2021-000761-33
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Entospletinib in Combination With Intensive Induction and Consolidation Chemotherapy in Adults With Newly Diagnosed Nucleophosmin 1-mutated Acute Myeloid Leukemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Combining chemotherapy with either the medication entospletinib or a placebo for adults with acute myeloid leukemia that has a nucleophosmin-1 abnormality
    A.4.1Sponsor's protocol code numberKB-ENTO-3001
    A.5.4Other Identifiers
    Name:IND: Number:116416
    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 SponsorKronos Bio, Inc.
    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 supportKronos Bio, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKronos Bio, Inc.
    B.5.2Functional name of contact pointDirector, Clinical Operations
    B.5.3 Address:
    B.5.3.1Street Address1300 So. El Camino Real Suite 400
    B.5.3.2Town/ citySan Mateo
    B.5.3.3Post codeCA 94402
    B.5.3.4CountryUnited States
    B.5.6E-mailSandra.Ospina@kronosbio.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/3/17/1922
    D.3 Description of the IMP
    D.3.1Product nameEntospletinib
    D.3.2Product code ENTO
    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 INNEntospletinib (GS-9973)
    D.3.9.2Current sponsor codeGS-9973-02
    D.3.9.3Other descriptive nameEntospletinib
    D.3.9.4EV Substance CodeSUB182049
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 placeboFilm-coated tablet
    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
    Acute Myeloid Leukemia
    E.1.1.1Medical condition in easily understood language
    Acute 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 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 evaluate the efficacy of ENTO compared to placebo when added to chemotherapy in previously untreated NPM1-m AML, as defined by the rate of molecularly defined measurable residual disease (MRD).
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of ENTO compared to placebo when added to chemotherapy in previously untreated NPM1-m AML, as defined by relapse-free, event-free, and overall survival.
    • To evaluate the efficacy of ENTO compared to placebo when added to chemotherapy in previously untreated NPM1-m as defined by CR rate.
    • To evaluate the safety of ENTO compared to placebo when added to intensive chemotherapy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adults 18 to 74 years with previously untreated de novo AML, AML with MDS features, or therapy-related AML AML who are candidates for intensive induction therapy.
    2. NPM1-mutated disease documented in a local or the Sponsor’s central testing facility.
    Note: Subjects with concurrent FLT3 mutation but without access to midostaurin (eg, either for lack of health authority approval or reimbursement) may also enroll; subjects with a concurrent FLT3 mutation will not be allowed to receive a FLT3 inhibitor at any time during the study treatment period.
    Note: Subjects with local test results for NPM1-m (and/or FLT3 mutational status) may enroll, provided appropriate samples are sent to the Sponsor’s central testing facility for NPM1-m companion diagnostic development (see Section 4.1).
    3.Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0, 1, or 2.
    4.Adequate hepatic and renal function defined as:
    a.Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times the upper limit of normal (ULN), except those with hepatic involvement by AML, as documented by either computed tomography (CT) or ultrasound, in whom levels of AST and ALT < 5 times ULN are acceptable; total bilirubin < 1.5 times ULN unless elevated due to Gilbert’s Disease or hemolysis.
    b.Calculated creatinine clearance > 40 mL/min or serum creatinine < 1.5 times ULN.
    5.Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) ≤ 1.5 x ULN unless receiving therapeutic anticoagulation. Note: Transition from a Vitamin K or Factor Xa antagonist to a low-molecular weight heparin preparation is recommended prior to the start of induction chemotherapy (see Appendix 8 for guidelines on anticoagulation management).
    6.Left ventricular ejection fraction ≥ 45% confirmed by echocardiogram (ECHO) or multi gated acquisition (MUGA) scan.
    7.Negative serum ß-HCG test in women of childbearing potential (WOCBP).
    8.For WOCBP, willingness to abstain from heterosexual intercourse OR to use a protocol-recommended method of contraception from 7 days prior to C1D1 throughout the study treatment period and for 90 days following the last dose of ENTO/placebo or as recommended in the prescribing information for other co-administered study drugs (whichever is later).See Appendix 3 for contraceptive guidance.
    9.For male subjects with female sexual partners of childbearing potential, willingness to abstain from heterosexual intercourse OR use a protocol recommended method of contraception beginning 7 days prior to C1D1 throughout the study treatment period and for 90 days following the last dose of ENTO/placebo or as recommended in the prescribing information for other co-administered study drugs (whichever is later), AND to refrain from sperm donation from the start of study treatment throughout the study treatment period and for 90 days following the last dose of ENTO/placebo or as recommended in the prescribing information for other co-administered study drugs (whichever is later).
    10.Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
    11.Willingness to comply with scheduled study visits, procedures, and treatment plan.
    E.4Principal exclusion criteria
    1.Isolated myeloid sarcoma (ie, participants must have peripheral blood and/or bone marrow involvement by AML) or acute promyelocytic leukemia.
    2. Concurrent FLT3 mutation (either TKD or ITD).
    3. Known central nervous system (CNS) involvement with leukemia.
    4. Is a candidate for more intensive treatment than specified in this protocol.
    5. Either not a candidate for any anthracycline therapy or a candidate forinduction therapy with a higher dose of daunorubicin (eg. 90 mg/m2).
    6. Is a candidate for daily doses of cytarabine > 100 mg/m2 in InductionCycle 1.
    7. Active infection with hepatitis B, C, or uncontrolled human immunodeficiency virus (HIV).
    8. Known active coronavirus disease 2019 (COVID-19) either symptomatic or asymptomatic, as determined by nasopharyngeal swab for severe acute respiratory syndrome (SARS) coronavirus 2 (SARS CoV-2) RNA or antigen.Note: Subjects with a history of SARS-CoV-2 nasopharyngeal carriage (either with or without symptoms), who have subsequently tested negative on follow-
    XML File Identifier: 0iw5XkwDc7vQF8LAuWry/KZuxJk=Page 11/24up nasopharyngeal swab and are without signs or symptoms of COVID-19 may enroll. Subjects who are fully vaccinated against SARS-CoV-2 may enroll. 9. Disseminated intravascular coagulation with active bleeding or signs of thrombosis.
    10. History of prior allogeneic hematopoietic stem cell transplant or solidorgan transplant.
    11. History of non-myeloid malignancy except for the following: adequately treated localized basal cell or squamous cell carcinoma of the skin; cervical carcinoma in situ; superficial bladder cancer; asymptomatic prostate cancer without knownmetastatic disease and with no requirement for therapy or requiring only hormonal therapy (which may be continued while on study) and with normal prostate specific antigen for > 1 year prior to start of study therapy; or any other cancer that has been in complete remission without treatment for ≥ 3 years prior to enrollment.
    12. Current (within 30 days of study enrollment) drug-induced liver injury, chronic active hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cholangitis with inadequate response to ursodeoxycholic acid or other health-authority approved therapy, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
    13. Ongoing (within 6 weeks of study enrollment) hepatic encephalopathy.
    14. Treatment with proton pump inhibitors (PPIs) from 7 days prior to enrollment until 48 hours after completion of ENTO or placebo. Note: PPIs are likely to interfere with ENTO absorption, thus requiring a 7-day washout period prior to the initiation of study medication. For management of acute gastrointestinal bleeding during the study treatment period (such as that related to chemotherapy), short term concurrent use of PPIs is permitted for up to 10 consecutive days. If longer durations of PPI exposure are required, subjects should discontinue study medication. H2 receptor antagonists and antacids are allowed throughout the study treatment period.
    15. Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia.
    16. Concurrent (within 14 days of study enrollment) participation in an investigational drug study with therapeutic intent.
    17. Clinical signs/symptoms of leukostasis that have failed therapy including hydroxyurea and/or leukapheresis of at least 3 days duration.
    18. Clinically significant heart disease defined as:a. New York Heart Association Class 3 or 4 congestive heart failure,b. Acute myocardial infarction ≤ 6 months before enrollment,c. Symptomatic cardiac ischemia/unstable angina ≤ 3 months before enrollment, d. History of clinically significant arrhythmias (eg, ventricular tachycardia or fibrillation; Torsades de Pointe) including Mobitz type II 2nd degree or 3rd degree heart block without a permanent pacemaker inplace.
    19. Subjects with a corrected QT interval (using the Fredericia formula, QTcF) > 480 msec or Long QT Syndrome
    20. Evidence of ongoing, uncontrolled systemic bacterial, fungal, or viral infection at the time of study treatment initiation, including but not limited to persistent fever or positive cultures in the setting of appropriate antimicrobial therapy. Patients who are afebrile for ≥48 hours may enroll even while continuing antimicrobial therapy.
    21. Pregnant or breastfeeding women.
    22. Alcohol or drug addiction as determined by investigator.
    23. Unable to swallow tablets or concurrent disease affecting gastrointestinal function such as, malabsorption syndrome, gastric or small bowel resection, bariatric surgery, inflammatory bowel disease, or bowel obstruction.
    24. Any prior or ongoing condition that, in the opinion of the investigator, could adversely affect the safety of the subject or impair the assessment of study results.
    25. Known hypersensitivity to ENTO, cytarabine, daunorubicin, or idarubicin, their metabolites, or formulation excipient.
    E.5 End points
    E.5.1Primary end point(s)
    MRD negative complete response (CR) rates after completion of 2 cycles of chemotherapy plus either ENTO or placebo.
    Note: MRD negative CR requires CR as defined by the European Leukemia Network (ELN) 2017 criteria (with minor modification for neutrophil and
    platelet count thresholds as defined by the International Working Group [IWG]) as assessed by study site investigators, and MRD negativity (<0.01%) in bone marrow as measured by a molecular NPM1-m assay (eg, by next generation sequencing) in a central laboratory upon recovery of peripheral blood counts following completion of 2 cycles of chemotherapy (ie, no later than Day 42 of Cycle 2).
    E.5.1.1Timepoint(s) of evaluation of this end point
    During the course of the study
    E.5.2Secondary end point(s)
    • Event-free survival, defined as the time from randomization to the earliest occurrence of induction treatment failure, relapse from CR, or death from any cause.
    Note: Induction treatment failure is failure to achieve morphological CR after completion of the last cycle of induction chemotherapy (no later than Day 42 of the last cycle of induction).
    • Relapse-free survival, defined as the time from CR until relapse or death from any cause as assessed by study site investigators.
    • Overall survival defined as the time from randomization until death from any cause.
    • CR rates after 2 cycles of chemotherapy, as defined by ELN 2017 criteria (with minor modification for neutrophil and platelet count thresholds as defined by the IWG) as assessed by study site investigators.
    • Type, incidence, severity, and outcome of adverse events; changes from baseline in safety laboratory assessments, ECGs, ECHO/MUGA scans, ECOG PS.
    E.5.2.1Timepoint(s) of evaluation of this end point
    During the course of 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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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) 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 Yes
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Brazil
    Canada
    Israel
    Korea, Democratic People's Republic of
    United States
    France
    Poland
    Spain
    Czechia
    Germany
    Italy
    Hungary
    Russian Federation
    Ukraine
    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
    The study will be completed when all enrolled subjects either relapse, die, or after the last subject enrolled completes 5 years of follow-up, whichever is earliest.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 180
    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)
    Study medication will not be provided to subjects following completion of consolidation. Subjects may elect to receive follow-on therapy in consultation with their treating physician at their own expense.
    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 OHSU Knight Cancer Institute
    G.4.3.4Network Country United States
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Canopy Biosciences
    G.4.3.4Network Country United States
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation NovoVita Histopath
    G.4.3.4Network Country United States
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-12-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-21
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2022-11-08
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