Entospletinib Plus Intensive Induction/Consolidation Chemotherapy in Newly Diagnosed NPM1-mutated AML

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

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).

Study Overview

• Status: Terminated
• Conditions: Nucleophosmin 1-mutated Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Cytarabine; Drug: Placebo; Drug: Entospletinib; Drug: Anthracycline

Detailed Description

This is 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 were randomized 1:1 to receive intensive chemotherapy in combination with either the spleen tyrosine kinase (SYK) inhibitor entospletinib (ENTO), or placebo. The study consisted of Screening, Induction, Consolidation, End-of-Treatment, and Long-term Follow-up phases.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Curitiba, Brazil, 81520-060
    • Hospital Erasto Gaertner - Liga Paranaense de Combate Ao Câncer
  • Fortaleza, Brazil, 60430-372
    • Hospital Universitario Walter Cantidio
  • Jaú, Brazil, 17210-120
    • Hospital Amaral Carvalho
  • Porto Alegre, Brazil, 90035-903
    • Hospital de Clinicas de Porto Alegre
  • Porto Alegre, Brazil, 90050-170
    • Irmandade da Santa Casa de Misericórdia Hospital - Porto Alegre
  • Rio De Janeiro, Brazil, 20 580-120
    • Instituto Nacional de Câncer - Brazil
  • Rio Preto, Brazil, 15090-000
    • Hospital de Base - São José do Rio Preto
  • São Paulo, Brazil, 01321001
    • A Beneficência Portuguesa de São Paulo - Unidade Mirante
  • São Paulo, Brazil, 03102-002
    • Instituto Brasileiro de Controle do Câncer - São Camilo Oncologia - Unidade Mooca
• Canada
  • Hamilton, Canada, L8V 5C2
    • Juravinski Hospital
  • Saskatoon, Canada, S7N 4H4
    • Saskatchewan Cancer Agency
  • Toronto, Canada, M5G 1X6
    • Princess Margaret Cancer Centre
• Czechia
  • Brno, Czechia, 625 00
    • Fakultni nemocnice Brno
  • Hradec Králové, Czechia, 500 05
    • Fakultní nemocnice Hradec Králové
  • Praha, Czechia, 100 34
    • Fakultní nemocnice Královské Vinohrady
• France
  • Angers, France, 49933
    • Centre Hosptitalier Universitaire d'Angers
  • Lille, France, 59000
    • Hôpital Claude Huriez
  • Nice, France, CS23079 - 06202
    • Hôpital l'Archet
  • Paris, France, 75012
    • Hopital Saint-Antoine
  • Paris, France, 75475
    • Hopital Saint-Louis
  • Paris, France, 75743
    • Hôpital Necker-Enfants Malades
  • Pierre-Bénite, France, 69310
    • Centre Hospitalier Lyon-Sud
  • Rouen, France, 76038
    • Centre de Lutte Contre le Cancer - Centre Henri-Becquerel
  • Calvados
    • Caen, Calvados, France, 14000
      • Hopital Cote de Nacre
• Germany
  • Braunschweig, Germany, 38114
    • Städtisches Klinikum Braunschweig
  • Duisburg, Germany, 47166
    • Helios St. Johannes Klinik
  • Düsseldorf, Germany, 40479
    • Marien Hospital Dusseldorf
  • Hanover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Mannheim, Germany, 68167
    • Universitätsmedizin Mannheim
  • Münster, Germany, 48149
    • Universitätsklinikum Münster
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem
  • Budapest, Hungary, 1097
    • Del-pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Kozpont
  • Nyíregyháza, Hungary, 4400
    • Jósa András Oktatókórház
  • Szeged, Hungary, 6725
    • Szent-Györgyi Albert Klinikai Központ
• Israel
  • Ashdod, Israel, 7747629
    • Samson Assuta Ashdod University Hospital
  • Be'er Ya'aqov, Israel, 7030000
    • Shamir Medical Center (Assaf Harofeh)
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus
  • Jerusalem, Israel, 9112001
    • Hadassah University Hospital Ein Kerem
  • Tel Aviv, Israel, 62431
    • Tel Aviv Sourasky Medical Center
  • Tel Aviv, Israel, 69710
    • Assuta Hospital - Ramat HaHayal
• Italy
  • Bari, Italy, 70124
    • Azienda Universitaria Ospedaliera Consorziale - Policlinico di Bari
  • Bologna, Italy, 40138
    • Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi
  • Milan, Italy, 20162
    • Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
  • Milano, Italy, 20122
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
  • Novara, Italy, 28100
    • Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara
  • Ravenna, Italy, 48121
    • Ospedale Santa Maria delle Croci di Ravenna
  • Sicily
    • Catania, Sicily, Italy, 95123
      • Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele
• Korea, Republic of
  • Daegu, Korea, Republic of, 41944
    • Kyungpook National University Hospital
  • Daegu, Korea, Republic of, 42601
    • Keimyung University Dongsan Hospital
  • Daegu, Korea, Republic of, 42472
    • Daegu Catholic University Medical Center
  • Daejeon, Korea, Republic of, 35015
    • Chungnam National University Hospital
  • Incheon, Korea, Republic of, 21565
    • Gachon University Gil Medical Center
  • Incheon, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital
  • Seoul, Korea, Republic of, 08308
    • Korea University Guro Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 06591
    • Catholic University of Korea Seoul Saint Mary's Hospital
• Poland
  • Gdańsk, Poland, 80-214
    • Uniwersyteckie Centrum Kliniczne w Gdańsku
  • Szczecin, Poland, 71-252
    • Samodzielny Publiczny Szpital Kliniczny Nr im. Prof. Tadeusza Sokołowskiego
  • Warsaw, Poland, 02-776
    • Instytut Hematologii i Transfuzjologii
  • Warsaw, Poland, 02-097
    • Uniwersyteckie Centrum Kliniczne WUM - Centralny Szpital Kliniczny
  • Wrocław, Poland, 50-367
    • Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu
• Spain
  • Barcelona, Spain, 08908
    • Institut Catala d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
  • Barcelona, Spain, 08036
    • Institut d'Investigacions Biomèdiques August Pi i Sunyer
  • Cáceres, Spain, 10003
    • Hospital San Pedro de Alcantara
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Oviedo, Spain, 33011
    • Hospital Universitario Central de Asturias
  • Palma De Mallorca, Spain, 07198
    • Hospital Son Llatzer
  • Valencia, Spain, 46026
    • Hospital Universitari I Politecnic La Fe
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • Catalonia
    • Badalona, Catalonia, Spain, 08916
      • Hospital Germans Trias i Pujol
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90095
      • UCLA - Jonsson Comprehensive Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Indiana Blood & Marrow Transplantation
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical School
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Health System
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center
    • Greenville, South Carolina, United States, 29607
      • Bon Secours St. Francis Cancer Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 were 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 were sent to the Sponsor's central testing facility for NPM1-m companion diagnostic development.

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

4. Adequate hepatic and renal function defined as:

   1. 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.
   2. 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 had 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. Was 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. Was 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 had subsequently tested negative on follow-up nasopharyngeal swab and were without signs or symptoms of COVID-19 might enroll. Participants who were fully vaccinated against SARS-CoV-2 might enroll.

9. Disseminated intravascular coagulation with active bleeding or signs of thrombosis.
10. History of prior allogeneic hematopoietic stem cell transplant or solid organ transplant.

11. Treatment with proton pump inhibitors (PPIs) from 7 days prior to enrollment until 48 hours after completion of entospletinib (ENTO) or placebo.

    Note: PPIs were 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 was permitted for up to 10 consecutive days. If longer durations of PPI exposure were required, participants should discontinue study medication. Histamine (H2) receptor antagonists and antacids were allowed throughout the study treatment period.

12. 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.

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

14. Clinically significant heart disease defined as:

    1. New York Heart Association Class 3 or 4 congestive heart failure,
    2. Acute myocardial infarction ≤ 6 months before enrollment,
    3. Symptomatic cardiac ischemia/unstable angina ≤ 3 months before enrollment,
    4. 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.
15. 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.
16. 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.
17. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intensive Chemotherapy + Entospletinib (ENTO); Participants received intensive chemotherapy (cytarabine and anthracycline [daunorubicin or idarubicin]) in combination with entospletinib (ENTO).	Drug: Cytarabine; Continuous infusion; Drug: Entospletinib; 400 mg, Orally as tablets; Other Names: GS-9973; ENTO; Drug: Anthracycline; Either daunorubicin or idarubicin was administered via slow intravenous (IV) push
Placebo Comparator: Intensive Chemotherapy + Placebo; Participants received intensive chemotherapy (cytarabine and anthracycline [daunorubicin or idarubicin]) in combination with the matching placebo.	Drug: Cytarabine; Continuous infusion; Drug: Placebo; Orally as tablets; Drug: Anthracycline; Either daunorubicin or idarubicin was administered via slow intravenous (IV) push

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Measurable Residual Disease (MRD) Negative Complete Response (CR) Rate	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 International Working Group [IWG]) as assessed by study site investigators, and MRD negativity (<0.01%) in bone marrow as measured by a molecular nucleophosmin-1 mutated (NPM1-m) assay (eg, next generation sequencing) in a central laboratory upon recovery of peripheral blood counts following completion of 2 cycles of chemotherapy, no later than Day 42 of Cycle 2.	Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free Survival (EFS)	EFS is defined as the time from randomization to the earliest occurrence of induction treatment failure, relapse from CR, or death from any cause. 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).	Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
Relapse-free Survival (RFS)	RFS is defined as the time from CR until relapse or death from any cause as assessed by study site investigators.	Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
Overall Survival (OS)	OS is defined as the time from randomization until death from any cause.	Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
Number of Participant With Complete Response (CR) After 2 Cycles of Chemotherapy	CR as defined by ELN 2017 criteria (with minor modification for neutrophil and platelet count thresholds as defined by IWG) as assessed by study site investigators.	Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)	A TEAE is any untoward medical occurrence in a clinical study participant, beginning or worsening from Cycle 1, Day 1 through 30 days following study treatment completion, temporarily associated with the use of treatment, whether or not considered related to the study treatment. TEAEs were recorded according to the most current version of the Medical Dictionary for Regulatory Activities (MedDRA). Clinically significant changes in safety laboratory assessments, electrocardiograms, echocardiogram / multi-gated acquisition scans and Eastern Cooperative Oncology Group performance status findings, as assessed by the Investigator, were recorded as TEAEs.	Cycle 1 Day 1 to 30 days following study treatment completion, (Cycle length = 42 days) maximum up to 198 days

Collaborators and Investigators

• Sponsor: Kronos Bio

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2021
• Primary Completion (Actual): March 30, 2023
• Study Completion (Actual): March 30, 2023

Study Registration Dates

• First Submitted: August 19, 2021
• First Submitted That Met QC Criteria: August 19, 2021
• First Posted (Actual): August 25, 2021

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; Nucleophosmin 1-mutated Acute Myeloid Leukemia; Entospletinib; ENTO
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Cytarabine
• Other Study ID Numbers: KB-ENTO-3001; 2021-000761-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No