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Nucleophosmin 1-mutated Acute Myeloid LeukemiaPhase 3NCT05020665

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

A Phase 3 study testing Entospletinib, Cytarabine and Anthracycline in people with Nucleophosmin 1-mutated Acute Myeloid Leukemia, run by Kronos Bio at 83 sites in 12 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 18 to 74 years
What is being tested?
Entospletinib, Cytarabine and Anthracycline
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
15 participants
Where
83 sitesin 12 countries
Study dates
24 Nov 2021to 30 Mar 2023
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 74 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • 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.
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0, 1, or 2.
  • Adequate hepatic and renal function defined as:
  • 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.
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  • Calculated creatinine clearance > 40 mL/min or serum creatinine < 1.5 times ULN.
  • Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) ≤ 1.5 x ULN unless receiving therapeutic anticoagulation.
  • Left ventricular ejection fraction ≥ 45% confirmed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan.

Who cannot join

  • Isolated myeloid sarcoma (ie, participants must had peripheral blood and/or bone marrow involvement by AML) or acute promyelocytic leukemia.
  • Concurrent FLT3 mutation (either tyrosine kinase domain or internal tandem duplication).
  • Known central nervous system (CNS) involvement with leukemia.
  • Was a candidate for more intensive treatment than specified in this protocol.
  • 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).
  • Was a candidate for daily doses of cytarabine > 100 mg/m^2 in Induction Cycle 1.
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  • Active infection with hepatitis B, C, or uncontrolled human immunodeficiency virus (HIV).
  • 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.
  • Disseminated intravascular coagulation with active bleeding or signs of thrombosis.
  • History of prior allogeneic hematopoietic stem cell transplant or solid organ transplant.
  • 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.
  • 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.
  • Clinical signs/symptoms of leukostasis that had failed therapy including hydroxyurea and/or leukapheresis of at least 3 days duration.
  • Clinically significant heart disease defined as:
  • New York Heart Association Class 3 or 4 congestive heart failure,
  • Acute myocardial infarction ≤ 6 months before enrollment,
  • Symptomatic cardiac ischemia/unstable angina ≤ 3 months before enrollment,
  • 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.
  • 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.
  • 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.
  • 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.

Trial locations and contacts

83 sites in 12 countries.

83 sites in 12 countries

United States10 sites

  • University of Michigan Medical School

    Ann Arbor, Michigan, 48109

  • Hollings Cancer Center

    Charleston, South Carolina, 29425

  • Baylor University Medical Center

    Dallas, Texas, 75246

  • Henry Ford Health System

    Detroit, Michigan, 48202

  • City of Hope

    Duarte, California, 91010

  • Duke Cancer Institute

    Durham, North Carolina, 27710

  • Bon Secours St. Francis Cancer Center

    Greenville, South Carolina, 29607

  • Indiana Blood & Marrow Transplantation

    Indianapolis, Indiana, 46237

  • UCLA - Jonsson Comprehensive Cancer Center

    Los Angeles, California, 90095

  • Mount Sinai Health System

    New York, New York, 10029

Other trials in United States

South Korea10 sites

  • Kyungpook National University Hospital

    Daegu, 41944

  • Daegu Catholic University Medical Center

    Daegu, 42472

  • Keimyung University Dongsan Hospital

    Daegu, 42601

  • Chungnam National University Hospital

    Daejeon, 35015

  • Seoul National University Hospital

    Incheon, 03080

  • Gachon University Gil Medical Center

    Incheon, 21565

  • Severance Hospital

    Seoul, 03722

  • Samsung Medical Center

    Seoul, 06351

  • Catholic University of Korea Seoul Saint Mary's Hospital

    Seoul, 06591

  • Korea University Guro Hospital

    Seoul, 08308

Other trials in South Korea

Spain10 sites

  • Hospital Germans Trias i Pujol

    Badalona, Catalonia, 08916

  • Institut D'Investigacions Biomédiques August Pi I Sunyer

    Barcelona, 08036

  • Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)

    Barcelona, 08908

  • Hospital San Pedro de Alcantara

    Cáceres, 10003

  • Hospital General Universitario Gregorio Marañón

    Madrid, 28007

  • Hospital Universitario Fundación Jiménez Díaz

    Madrid, 28040

  • Hospital Universitario Central de Asturias

    Oviedo, 33011

  • Hospital Son Llàtzer

    Palma de Mallorca, 07198

  • Hospital Clínico Universitario de Valencia

    Valencia, 46010

  • Hospital Universitari I Politecnic La Fe

    Valencia, 46026

Other trials in Spain

Brazil9 sites

  • Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer

    Curitiba, 81520-060

  • Hospital Universitário Walter Cantídio

    Fortaleza, 60430-372

  • Hospital Amaral Carvalho

    Jaú, 17210-120

  • Hospital de Clínicas de Porto Alegre

    Porto Alegre, 90035-903

  • Irmandade da Santa Casa de Misericórdia Hospital - Porto Alegre

    Porto Alegre, 90050-170

  • Instituto Nacional de Câncer - Brazil

    Rio de Janeiro, 20 580-120

  • Hospital de Base - São José do Rio Preto

    Rio Preto, 15090-000

  • A Beneficência Portuguesa de São Paulo - Unidade Mirante

    São Paulo, 01321001

  • Instituto Brasileiro de Controle do Câncer - São Camilo Oncologia - Unidade Mooca

    São Paulo, 03102-002

Other trials in Brazil

France9 sites

  • Centre Hosptitalier Universitaire d'Angers

    Angers, 49933

  • Hôpital Côte De Nacre

    Caen, Calvados, 14000

  • Hôpital Claude Huriez

    Lille, 59000

  • Hôpital l'Archet

    Nice, CS23079 - 06202

  • Hôpital Saint-Antoine

    Paris, 75012

  • Hôpital Saint-Louis

    Paris, 75475

  • Hôpital Necker-Enfants Malades

    Paris, 75743

  • Centre Hospitalier Lyon-Sud

    Pierre-Bénite, 69310

  • Centre de Lutte Contre le Cancer - Centre Henri-Becquerel

    Rouen, 76038

Other trials in France

Italy7 sites

  • Azienda Universitaria Ospedaliera Consorziale - Policlinico di Bari

    Bari, 70124

  • Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi

    Bologna, 40138

  • Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele

    Catania, Sicily, 95123

  • Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda

    Milan, 20162

  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

    Milan, 20122

  • Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara

    Novara, 28100

  • Ospedale Santa Maria delle Croci di Ravenna

    Ravenna, 48121

Other trials in Italy

Germany6 sites

  • Städtisches Klinikum Braunschweig

    Braunschweig, 38114

  • Helios St. Johannes Klinik

    Duisburg, 47166

  • Marien Hospital Düsseldorf

    Düsseldorf, 40479

  • Medizinische Hochschule Hannover

    Hanover, 30625

  • Universitätsmedizin Mannheim

    Mannheim, 68167

  • Universitätsklinikum Münster

    Münster, 48149

Other trials in Germany

Israel6 sites

  • Samson Assuta Ashdod University Hospital

    Ashdod, 7747629

  • Shamir Medical Center (Assaf Harofeh)

    Be’er Ya‘aqov, 7030000

  • Rambam Health Care Campus

    Haifa, 3109601

  • Hadassah University Hospital Ein Kerem

    Jerusalem, 9112001

  • Tel Aviv Sourasky Medical Center

    Tel Aviv, 62431

  • Assuta Hospital - Ramat HaHayal

    Tel Aviv, 69710

Other trials in Israel

Hungary5 sites

  • Semmelweis Egyetem

    Budapest, 1083

  • Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet

    Budapest, 1097

  • Debreceni Egyetem Klinikai Központ

    Debrecen, 4032

  • Jósa András Oktatókórház

    Nyíregyháza, 4400

  • Szent-Györgyi Albert Klinikai Központ

    Szeged, 6725

Other trials in Hungary

Poland5 sites

  • Uniwersyteckie Centrum Kliniczne w Gdańsku

    Gdansk, 80-214

  • Samodzielny Publiczny Szpital Kliniczny Nr im. Prof. Tadeusza Sokołowskiego

    Szczecin, 71-252

  • Uniwersyteckie Centrum Kliniczne WUM - Centralny Szpital Kliniczny

    Warsaw, 02-097

  • Instytut Hematologii I Transfuzjologii

    Warsaw, 02-776

  • Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu

    Wroclaw, 50-367

Other trials in Poland

Canada3 sites

  • Juravinski Hospital

    Hamilton, L8V 5C2

  • Saskatchewan Cancer Agency

    Saskatoon, S7N 4H4

  • Princess Margaret Cancer Centre

    Toronto, M5G 1X6

Other trials in Canada

Czechia3 sites

  • Fakultni Nemocnice Brno

    Brno, 625 00

  • Fakultní Nemocnice Hradec Králové

    Hradec Králové, 500 05

  • Fakultní Nemocnice Královské Vinohrady

    Prague, 100 34

Other trials in Czechia

About this study

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

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).

Read the 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.

Being tested
Entospletinib, Placebo, Cytarabine, Anthracycline
Keywords
Acute Myeloid Leukemia, Nucleophosmin 1-mutated Acute Myeloid Leukemia, Entospletinib, ENTO
Medical subject headings
Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EntospletinibDrug

    Also called ENTO, GS-9973

    400 mg, Orally as tablets

  • PlaceboDrug

    Orally as tablets

  • CytarabineDrug

    Continuous infusion

  • AnthracyclineDrug

    Either daunorubicin or idarubicin was administered via slow intravenous (IV) push

Study groups in NCT05020665
Study groupRoleWhat they receive
Intensive Chemotherapy + Entospletinib (ENTO)ExperimentalParticipants received intensive chemotherapy (cytarabine and anthracycline [daunorubicin or idarubicin]) in combination with entospletinib (ENTO).
Receives: Drug: Entospletinib; Drug: Cytarabine; Drug: Anthracycline
Intensive Chemotherapy + PlaceboPlacebo comparatorParticipants received intensive chemotherapy (cytarabine and anthracycline [daunorubicin or idarubicin]) in combination with the matching placebo.
Receives: Drug: Placebo; Drug: Cytarabine; Drug: Anthracycline

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)

Secondary outcomes (5)

  1. 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).

    Measured: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)

  2. 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.

    Measured: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)

  3. Overall Survival (OS)

    OS is defined as the time from randomization until death from any cause.

    Measured: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)

  4. 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.

    Measured: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)

  5. 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.

    Measured: Cycle 1 Day 1 to 30 days following study treatment completion, (Cycle length = 42 days) maximum up to 198 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Aug 2021
  2. Study start24 Nov 2021
  3. Primary completion30 Mar 2023
  4. Study completion30 Mar 2023

Why it stopped: Termination was due to significant challenges associated with study enrollment in a genetic subset of fit participants in the front-line acute myeloid leukemia (AML) setting and other challenges associated with post-COVID impacts.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
15 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05020665
Sponsor's protocol ID
KB-ENTO-3001
Other IDs
2021-000761-33
Status last verified
Dec 2023
First submitted
19 Aug 2021
Last updated
10 Jan 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Entospletinib, Cytarabine and Anthracycline in people with Nucleophosmin 1-mutated Acute Myeloid Leukemia, run by Kronos Bio at 83 sites in 12 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 10 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 83 sites in United States, South Korea, Spain, Brazil, France and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Jan 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Measurable Residual Disease (MRD) Negative Complete Response (CR) Rate (time frame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05020665.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jan 2024.

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