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

NCT ID: NCT05020665

Last Updated: 2024-01-10

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-24
• Study Completion Date: 2023-03-30

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).

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.

Conditions

Nucleophosmin 1-mutated Acute Myeloid Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Intensive Chemotherapy + Entospletinib (ENTO)

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

Group Type: EXPERIMENTAL

Entospletinib

Intervention Type: DRUG

400 mg, Orally as tablets

Cytarabine

Intervention Type: DRUG

Continuous infusion

Anthracycline

Intervention Type: DRUG

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

Intensive Chemotherapy + Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Orally as tablets

Cytarabine

Intervention Type: DRUG

Continuous infusion

Anthracycline

Intervention Type: DRUG

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

Interventions

Entospletinib

400 mg, Orally as tablets

Intervention Type: DRUG

Placebo

Orally as tablets

Intervention Type: DRUG

Cytarabine

Continuous infusion

Intervention Type: DRUG

Anthracycline

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

Intervention Type: DRUG

Other Intervention Names

ENTO; GS-9973

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Kronos Bio

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

City of Hope

Duarte, California, United States

UCLA - Jonsson Comprehensive Cancer Center

Los Angeles, California, United States

Indiana Blood & Marrow Transplantation

Indianapolis, Indiana, United States

University of Michigan Medical School

Ann Arbor, Michigan, United States

Henry Ford Health System

Detroit, Michigan, United States

Mount Sinai Health System

New York, New York, United States

Duke Cancer Institute

Durham, North Carolina, United States

Hollings Cancer Center

Charleston, South Carolina, United States

Bon Secours St. Francis Cancer Center

Greenville, South Carolina, United States

Baylor University Medical Center

Dallas, Texas, United States

Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer

Curitiba, , Brazil

Hospital Universitário Walter Cantídio

Fortaleza, , Brazil

Hospital Amaral Carvalho

Jaú, , Brazil

Hospital de Clínicas de Porto Alegre

Porto Alegre, , Brazil

Irmandade da Santa Casa de Misericórdia Hospital - Porto Alegre

Porto Alegre, , Brazil

Instituto Nacional de Câncer - Brazil

Rio de Janeiro, , Brazil

Hospital de Base - São José do Rio Preto

Rio Preto, , Brazil

A Beneficência Portuguesa de São Paulo - Unidade Mirante

São Paulo, , Brazil

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

São Paulo, , Brazil

Juravinski Hospital

Hamilton, , Canada

Saskatchewan Cancer Agency

Saskatoon, , Canada

Princess Margaret Cancer Centre

Toronto, , Canada

Fakultni Nemocnice Brno

Brno, , Czechia

Fakultní Nemocnice Hradec Králové

Hradec Králové, , Czechia

Fakultní Nemocnice Královské Vinohrady

Prague, , Czechia

Hôpital Côte De Nacre

Caen, Calvados, France

Centre Hosptitalier Universitaire d'Angers

Angers, , France

Hôpital Claude Huriez

Lille, , France

Hôpital l'Archet

Nice, , France

Hôpital Saint-Antoine

Paris, , France

Hôpital Saint-Louis

Paris, , France

Hôpital Necker-Enfants Malades

Paris, , France

Centre Hospitalier Lyon-Sud

Pierre-Bénite, , France

Centre de Lutte Contre le Cancer - Centre Henri-Becquerel

Rouen, , France

Städtisches Klinikum Braunschweig

Braunschweig, , Germany

Helios St. Johannes Klinik

Duisburg, , Germany

Marien Hospital Düsseldorf

Düsseldorf, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Universitätsmedizin Mannheim

Mannheim, , Germany

Universitätsklinikum Münster

Münster, , Germany

Semmelweis Egyetem

Budapest, , Hungary

Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet

Budapest, , Hungary

Debreceni Egyetem Klinikai Központ

Debrecen, , Hungary

Jósa András Oktatókórház

Nyíregyháza, , Hungary

Szent-Györgyi Albert Klinikai Központ

Szeged, , Hungary

Samson Assuta Ashdod University Hospital

Ashdod, , Israel

Shamir Medical Center (Assaf Harofeh)

Be’er Ya‘aqov, , Israel

Rambam Health Care Campus

Haifa, , Israel

Hadassah University Hospital Ein Kerem

Jerusalem, , Israel

Tel Aviv Sourasky Medical Center

Tel Aviv, , Israel

Assuta Hospital - Ramat HaHayal

Tel Aviv, , Israel

Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele

Catania, Sicily, Italy

Azienda Universitaria Ospedaliera Consorziale - Policlinico di Bari

Bari, , Italy

Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi

Bologna, , Italy

Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda

Milan, , Italy

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, , Italy

Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara

Novara, , Italy

Ospedale Santa Maria delle Croci di Ravenna

Ravenna, , Italy

Uniwersyteckie Centrum Kliniczne w Gdańsku

Gdansk, , Poland

Samodzielny Publiczny Szpital Kliniczny Nr im. Prof. Tadeusza Sokołowskiego

Szczecin, , Poland

Uniwersyteckie Centrum Kliniczne WUM - Centralny Szpital Kliniczny

Warsaw, , Poland

Instytut Hematologii I Transfuzjologii

Warsaw, , Poland

Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu

Wroclaw, , Poland

Kyungpook National University Hospital

Daegu, , South Korea

Daegu Catholic University Medical Center

Daegu, , South Korea

Keimyung University Dongsan Hospital

Daegu, , South Korea

Chungnam National University Hospital

Daejeon, , South Korea

Seoul National University Hospital

Incheon, , South Korea

Gachon University Gil Medical Center

Incheon, , South Korea

Severance Hospital

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Catholic University of Korea Seoul Saint Mary's Hospital

Seoul, , South Korea

Korea University Guro Hospital

Seoul, , South Korea

Hospital Germans Trias i Pujol

Badalona, Catalonia, Spain

Institut D'Investigacions Biomédiques August Pi I Sunyer

Barcelona, , Spain

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

Barcelona, , Spain

Hospital San Pedro de Alcantara

Cáceres, , Spain

Hospital General Universitario Gregorio Marañón

Madrid, , Spain

Hospital Universitario Fundación Jiménez Díaz

Madrid, , Spain

Hospital Universitario Central de Asturias

Oviedo, , Spain

Hospital Son Llàtzer

Palma de Mallorca, , Spain

Hospital Clínico Universitario de Valencia

Valencia, , Spain

Hospital Universitari I Politecnic La Fe

Valencia, , Spain

Countries

United States; Brazil; Canada; Czechia; France; Germany; Hungary; Israel; Italy; Poland; South Korea; Spain

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2021-000761-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

KB-ENTO-3001

Identifier Type: -

Identifier Source: org_study_id