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A 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

Sponsor
Kronos Bio (Industry)
Overall Status
Recruiting
CT.gov ID
NCT05020665
Collaborator
(none)
180
Enrollment
61
Locations
2
Arms
61
Anticipated Duration (Months)
3
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the efficacy of entospletinib (ENTO) compared to placebo when added to chemotherapy in previously untreated nucleophosmin-1 mutated (NPM1-m) acute myeloid leukemia (AML), as defined by the rate of molecularly defined measurable residual disease (MRD).

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

This will be a multi-center, international, double-blind, placebo-controlled study in previously untreated participants with acute myeloid leukemia (AML) harboring nucleophosmin-1 (NPM1) mutations. Upon fulfillment of all eligibility criteria, participants will be randomized 1:1 to receive intensive chemotherapy in combination with either the spleen tyrosine kinase (SYK) inhibitor entospletinib (ENTO), or placebo. The study will consist of Screening, Induction, Consolidation, End-of-Treatment, and Long-term Follow-up phases.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
180 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Nov 30, 2021
Anticipated Primary Completion Date :
Dec 30, 2023
Anticipated Study Completion Date :
Dec 30, 2026

Arms and Interventions

Arm Intervention/Treatment
Experimental: Intensive Chemotherapy + Entospletinib (ENTO)

Participants will receive intensive chemotherapy (cytarabine and anthracycline [daunorubicin or idarubicin]) in combination with entospletinib (ENTO).

Drug: Entospletinib
Orally as tablets
Other Names:
  • ENTO
  • GS-9973

    • Drug: Cytarabine
    Continuous infusion

    Drug: Anthracycline
    Either daunorubicin or idarubicin will be administered via slow intravenous (IV) push
    Placebo Comparator: Intensive Chemotherapy + Placebo

    Participants will receive intensive chemotherapy (cytarabine and anthracycline [daunorubicin or idarubicin]) in combination with the matching placebo.

    Drug: Placebo
    Orally as tablets

    Drug: Cytarabine
    Continuous infusion

    Drug: Anthracycline
    Either daunorubicin or idarubicin will be administered via slow intravenous (IV) push

    Outcome Measures

    Primary Outcome Measures

    1. Measurable Residual Disease (MRD) Negative Complete Response (CR) Rate [Cycle 1 Day 1 through Cycle 2 Day 42 (cycle is 42 days)]

    Secondary Outcome Measures

    1. Event-free Survival (EFS) [Up to 5 years]

    2. Relapse-free Survival (RFS) [Up to 5 years]

    3. Overall Survival (OS) [Up to 5 years]

    4. Complete Response (CR) Rate [Up to 5 years]

    5. Number of Participants who Experience a Treatment-emergent Adverse Event (TEAE) [Cycle 1 Day 1 to 30 days after last study treatment, cycle is 42 days (up to a maximum of 219 days)]

      Clinically significant changes in safety laboratory assessments, electrocardiograms (ECGs), echocardiogram (ECHO) / multi-gated acquisition (MUGA) scans and Eastern Cooperative Oncology Group performance status (ECOG PS) findings, as assessed by the Investigator, will be recorded as TEAEs.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 74 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Adults 18 to 74 years with previously untreated de novo acute myeloid leukemia (AML), AML with myelodysplastic syndromes (MDS) features, or therapy-related AML, who are candidates for intensive induction therapy.

    2. Nucleophosmin-1 (NPM1)-mutated disease documented in a local or the Sponsor's central testing facility.

    Note: Participants with local test results for nucleophosmin-1 mutated (NPM1-m) (and/or FMS-like tyrosine kinase 3 mutational status) may enroll, provided appropriate samples are sent to the Sponsor's central testing facility for NPM1-m companion diagnostic development.

    1. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0, 1, or 2.

    2. Adequate hepatic and renal function defined as:

    3. 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.

    4. 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.

    6. Left ventricular ejection fraction ≥ 45% confirmed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan.

    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 tyrosine kinase domain or internal tandem duplication).

    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 for induction therapy with a higher dose of daunorubicin (eg. 90 mg/m^2).

    6. Is a candidate for daily doses of cytarabine > 100 mg/m^2 in Induction Cycle 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) ribonucleic acid (RNA) or antigen.

    Note: Participants with a history of SARS-CoV-2 nasopharyngeal carriage (either with or without symptoms), who have subsequently tested negative on follow-up nasopharyngeal swab and are without signs or symptoms of COVID-19 may enroll. Participants who are fully vaccinated against SARS-CoV-2 may enroll.

    1. Disseminated intravascular coagulation with active bleeding or signs of thrombosis.

    2. History of prior allogeneic hematopoietic stem cell transplant or solid organ transplant.

    3. Treatment with proton pump inhibitors (PPIs) from 7 days prior to enrollment until 48 hours after completion of entospletinib (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, participants should discontinue study medication. Histamine (H2) receptor antagonists and antacids are allowed throughout the study treatment period.

    1. Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia.

    Note: Participants may not receive AML-directed therapy prior to enrollment other than hydroxyurea or leukapheresis for acute management of hyperleukocytosis.

    1. Clinical signs/symptoms of leukostasis that have failed therapy including hydroxyurea and/or leukapheresis of at least 3 days duration.

    2. Clinically significant heart disease defined as:

    3. New York Heart Association Class 3 or 4 congestive heart failure,

    4. Acute myocardial infarction ≤ 6 months before enrollment,

    5. Symptomatic cardiac ischemia/unstable angina ≤ 3 months before enrollment,

    6. 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 in place.

    7. Participants with a corrected congenital long measure between Q wave and T wave in the electrocardiogram (QT) interval (using the Fredericia formula, Fridericia correction of the QT measure [QTcF]) > 480 msec or Long QT Syndrome.

    8. 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.

    9. 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 City of Hope Duarte California United States 91010
    2 Indiana Blood & Marrow Transplantation Indianapolis Indiana United States 46237
    3 University of Michigan Medical School Ann Arbor Michigan United States 48109
    4 Henry Ford Health System Detroit Michigan United States 48202
    5 Mount Sinai Health System New York New York United States 10029
    6 Duke Cancer Institute Durham North Carolina United States 27710
    7 Hollings Cancer Center Charleston South Carolina United States 29425
    8 Bon Secours St. Francis Cancer Center Greenville South Carolina United States 29607
    9 Baylor University Medical Center Dallas Texas United States 75246
    10 Hospital Amaral Carvalho Jaú Brazil 17210-120
    11 Instituto Brasileiro de Controle do Câncer - São Camilo Oncologia - Unidade Mooca São Paulo Brazil 03102-002
    12 Juravinski Hospital Hamilton Canada L8V 5C2
    13 Saskatchewan Cancer Agency Saskatoon Canada S7N 4H4
    14 Fakultni Nemocnice Brno Brno Czechia 625 00
    15 Fakultní Nemocnice Hradec Králové Hradec Králové Czechia 500 05
    16 Fakultní Nemocnice Královské Vinohrady Praha Czechia 100 34
    17 Centre Hosptitalier Universitaire d'Angers Angers France 49933
    18 Hôpital Claude Huriez Lille France 59000
    19 Hôpital Saint-Antoine Paris France 75012
    20 Centre Hospitalier Lyon-Sud Pierre-Bénite France 69310
    21 Centre de Lutte Contre le Cancer - Centre Henri-Becquerel Rouen France 76038
    22 Städtisches Klinikum Braunschweig Braunschweig Germany 38114
    23 Helios St. Johannes Klinik Duisburg Germany 47166
    24 Marien Hospital Düsseldorf Düsseldorf Germany 40479
    25 Universitätsklinikum Münster Münster Germany 48149
    26 Semmelweis Egyetem Budapest Hungary 1083
    27 Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet Budapest Hungary 1097
    28 Debreceni Egyetem Klinikai Központ Debrecen Hungary 4032
    29 Jósa András Oktatókórház Nyíregyháza Hungary 4400
    30 Szent-Györgyi Albert Klinikai Központ Szeged Hungary 6725
    31 Shamir Medical Center (Assaf Harofeh) Be'er Ya'aqov Israel 7030000
    32 Rambam Health Care Campus Haifa Israel 3109601
    33 Hadassah University Hospital Ein Kerem Jerusalem Israel 9112001
    34 Tel Aviv Sourasky Medical Center Tel Aviv Israel 62431
    35 Assuta Hospital - Ramat HaHayal Tel Aviv Israel 69710
    36 Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi Bologna Italy 40138
    37 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano Italy 20122
    38 Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda Milan Italy 20162
    39 Ospedale Santa Maria delle Croci di Ravenna Ravenna Italy 48121
    40 Kyungpook National University Hospital Daegu Korea, Republic of 41944
    41 Daegu Catholic University Medical Center Daegu Korea, Republic of 42472
    42 Keimyung University Dongsan Hospital Daegu Korea, Republic of 42601
    43 Chungnam National University Hospital Daejeon Korea, Republic of 35015
    44 Seoul National University Hospital Incheon Korea, Republic of 03080
    45 Gachon University Gil Medical Center Incheon Korea, Republic of 21565
    46 Severance Hospital Seoul Korea, Republic of 03722
    47 Samsung Medical Center Seoul Korea, Republic of 06351
    48 Korea University Guro Hospital Seoul Korea, Republic of 08308
    49 Uniwersyteckie Centrum Kliniczne w Gdańsku Gdańsk Poland 80-214
    50 Samodzielny Publiczny Szpital Kliniczny Nr im. Prof. Tadeusza Sokołowskiego Szczecin Poland 71-252
    51 Uniwersyteckie Centrum Kliniczne WUM - Centralny Szpital Kliniczny Warsaw Poland 02-097
    52 Instytut Hematologii I Transfuzjologii Warsaw Poland 02-776
    53 Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu Wrocław Poland 50-367
    54 Institut D'Investigacions Biomédiques August Pi I Sunyer Barcelona Spain 08036
    55 Hospital San Pedro de Alcantara Cáceres Spain 10003
    56 Hospital General Universitario Gregorio Marañón Madrid Spain 28007
    57 Hospital Universitario Fundación Jiménez Díaz Madrid Spain 28040
    58 Hospital Universitario Central de Asturias Oviedo Spain 33011
    59 Hospital Son Llàtzer Palma De Mallorca Spain 07198
    60 Hospital Clínico Universitario de Valencia Valencia Spain 46010
    61 Hospital Universitari I Politecnic La Fe Valencia Spain 46026

    Sponsors and Collaborators

    • Kronos Bio

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Kronos Bio
    ClinicalTrials.gov Identifier:
    NCT05020665
    Other Study ID Numbers:
    • KB-ENTO-3001
    • 2021-000761-33
    First Posted:
    Aug 25, 2021
    Last Update Posted:
    Jul 21, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Kronos Bio
    Acute Myeloid Leukemia
    Nucleophosmin 1-mutated Acute Myeloid Leukemia
    Entospletinib
    ENTO
    Additional relevant MeSH terms:
    Leukemia
    Leukemia, Myeloid
    Leukemia, Myeloid, Acute
    Cytarabine

    Study Results

    No Results Posted as of Jul 21, 2022