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

NCT05020665 | Terminated Phase 3 Results DMC FDA Drug

• 2 other identifiers: KB-ENTO-30012021-000761-33
• Study Type: interventional
• Target: 15
• Locations: 12 countries
• Sites: 83

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).

Conditions

Nucleophosmin 1-mutated Acute Myeloid Leukemia

Keywords

Acute Myeloid Leukemia; Nucleophosmin 1-mutated Acute Myeloid Leukemia; Entospletinib; ENTO

Outcome Measures

Primary Outcomes (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.

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

Secondary Outcomes (5)

• Event-free Survival (EFS)

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

• Relapse-free Survival (RFS)

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

• Overall Survival (OS)

  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

  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)

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

Study Arms (2)

Intensive Chemotherapy + Entospletinib (ENTO)

EXPERIMENTAL

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

Drug: Entospletinib; Drug: Cytarabine; Drug: Anthracycline

Intensive Chemotherapy + Placebo

PLACEBO COMPARATOR

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

Drug: Placebo; Drug: Cytarabine; Drug: Anthracycline

Interventions

Entospletinib DRUG

400 mg, Orally as tablets

Also known as: ENTO, GS-9973

Intensive Chemotherapy + Entospletinib (ENTO)

Placebo DRUG

Orally as tablets

Intensive Chemotherapy + Placebo

Cytarabine DRUG

Continuous infusion

Intensive Chemotherapy + Entospletinib (ENTO); Intensive Chemotherapy + Placebo

Anthracycline DRUG

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

Intensive Chemotherapy + Entospletinib (ENTO); Intensive Chemotherapy + Placebo

Eligibility Criteria

• Age: 18 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Kronos Bio: lead

Study Sites (83)

City of Hope

Duarte, California, 91010, United States

Location

UCLA - Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

Indiana Blood & Marrow Transplantation

Indianapolis, Indiana, 46237, United States

Location

University of Michigan Medical School

Ann Arbor, Michigan, 48109, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

Mount Sinai Health System

New York, New York, 10029, United States

Location

Duke Cancer Institute

Durham, North Carolina, 27710, United States

Location

Hollings Cancer Center

Charleston, South Carolina, 29425, United States

Location

Bon Secours St. Francis Cancer Center

Greenville, South Carolina, 29607, United States

Location

Baylor University Medical Center

Dallas, Texas, 75246, United States

Location

Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer

Curitiba, 81520-060, Brazil

Location

Hospital Universitário Walter Cantídio

Fortaleza, 60430-372, Brazil

Location

Hospital Amaral Carvalho

Jaú, 17210-120, Brazil

Location

Hospital de Clínicas de Porto Alegre

Porto Alegre, 90035-903, Brazil

Location

Irmandade da Santa Casa de Misericórdia Hospital - Porto Alegre

Porto Alegre, 90050-170, Brazil

Location

Instituto Nacional de Câncer - Brazil

Rio de Janeiro, 20 580-120, Brazil

Location

Hospital de Base - São José do Rio Preto

Rio Preto, 15090-000, Brazil

Location

A Beneficência Portuguesa de São Paulo - Unidade Mirante

São Paulo, 01321001, Brazil

Location

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

São Paulo, 03102-002, Brazil

Location

Juravinski Hospital

Hamilton, L8V 5C2, Canada

Location

Saskatchewan Cancer Agency

Saskatoon, S7N 4H4, Canada

Location

Princess Margaret Cancer Centre

Toronto, M5G 1X6, Canada

Location

Fakultni Nemocnice Brno

Brno, 625 00, Czechia

Location

Fakultní Nemocnice Hradec Králové

Hradec Králové, 500 05, Czechia

Location

Fakultní Nemocnice Královské Vinohrady

Prague, 100 34, Czechia

Location

Hôpital Côte De Nacre

Caen, Calvados, 14000, France

Location

Centre Hosptitalier Universitaire d'Angers

Angers, 49933, France

Location

Hôpital Claude Huriez

Lille, 59000, France

Location

Hôpital l'Archet

Nice, CS23079 - 06202, France

Location

Hôpital Saint-Antoine

Paris, 75012, France

Location

Hôpital Saint-Louis

Paris, 75475, France

Location

Hôpital Necker-Enfants Malades

Paris, 75743, France

Location

Centre Hospitalier Lyon-Sud

Pierre-Bénite, 69310, France

Location

Centre de Lutte Contre le Cancer - Centre Henri-Becquerel

Rouen, 76038, France

Location

Städtisches Klinikum Braunschweig

Braunschweig, 38114, Germany

Location

Helios St. Johannes Klinik

Duisburg, 47166, Germany

Location

Marien Hospital Düsseldorf

Düsseldorf, 40479, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Universitätsmedizin Mannheim

Mannheim, 68167, Germany

Location

Universitätsklinikum Münster

Münster, 48149, Germany

Location

Semmelweis Egyetem

Budapest, 1083, Hungary

Location

Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet

Budapest, 1097, Hungary

Location

Debreceni Egyetem Klinikai Központ

Debrecen, 4032, Hungary

Location

Jósa András Oktatókórház

Nyíregyháza, 4400, Hungary

Location

Szent-Györgyi Albert Klinikai Központ

Szeged, 6725, Hungary

Location

Samson Assuta Ashdod University Hospital

Ashdod, 7747629, Israel

Location

Shamir Medical Center (Assaf Harofeh)

Be’er Ya‘aqov, 7030000, Israel

Location

Rambam Health Care Campus

Haifa, 3109601, Israel

Location

Hadassah University Hospital Ein Kerem

Jerusalem, 9112001, Israel

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 62431, Israel

Location

Assuta Hospital - Ramat HaHayal

Tel Aviv, 69710, Israel

Location

Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele

Catania, Sicily, 95123, Italy

Location

Azienda Universitaria Ospedaliera Consorziale - Policlinico di Bari

Bari, 70124, Italy

Location

Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi

Bologna, 40138, Italy

Location

Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda

Milan, 20162, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara

Novara, 28100, Italy

Location

Ospedale Santa Maria delle Croci di Ravenna

Ravenna, 48121, Italy

Location

Uniwersyteckie Centrum Kliniczne w Gdańsku

Gdansk, 80-214, Poland

Location

Samodzielny Publiczny Szpital Kliniczny Nr im. Prof. Tadeusza Sokołowskiego

Szczecin, 71-252, Poland

Location

Uniwersyteckie Centrum Kliniczne WUM - Centralny Szpital Kliniczny

Warsaw, 02-097, Poland

Location

Instytut Hematologii I Transfuzjologii

Warsaw, 02-776, Poland

Location

Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu

Wroclaw, 50-367, Poland

Location

Kyungpook National University Hospital

Daegu, 41944, South Korea

Location

Daegu Catholic University Medical Center

Daegu, 42472, South Korea

Location

Keimyung University Dongsan Hospital

Daegu, 42601, South Korea

Location

Chungnam National University Hospital

Daejeon, 35015, South Korea

Location

Seoul National University Hospital

Incheon, 03080, South Korea

Location

Gachon University Gil Medical Center

Incheon, 21565, South Korea

Location

Severance Hospital

Seoul, 03722, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Catholic University of Korea Seoul Saint Mary's Hospital

Seoul, 06591, South Korea

Location

Korea University Guro Hospital

Seoul, 08308, South Korea

Location

Hospital Germans Trias i Pujol

Badalona, Catalonia, 08916, Spain

Location

Institut D'Investigacions Biomédiques August Pi I Sunyer

Barcelona, 08036, Spain

Location

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

Barcelona, 08908, Spain

Location

Hospital San Pedro de Alcantara

Cáceres, 10003, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, 28007, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, 28040, Spain

Location

Hospital Universitario Central de Asturias

Oviedo, 33011, Spain

Location

Hospital Son Llàtzer

Palma de Mallorca, 07198, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, 46010, Spain

Location

Hospital Universitari I Politecnic La Fe

Valencia, 46026, Spain

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; Cytarabine; Anthracyclines

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Limitations and Caveats

Early termination was due to significant unforeseen challenges associated with global enrollment of participants with genetically-defined, newly diagnosed, AML who are candidates for intensive induction therapy and other challenges associated with post-COVID impacts.

Results Point of Contact

• Title: VP, Corporate Affairs
• Organization: Kronos Bio, Inc.

media@kronosbio.com

+16507815200

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 19, 2021
• First Posted: August 25, 2021
• Study Start: November 24, 2021
• Primary Completion: March 30, 2023
• Study Completion: March 30, 2023
• Last Updated: January 10, 2024
• Results First Posted: January 10, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

IT (7); KR (10); CZ (3); ES (10); HU (5); BR (9); IL (6); CA (3); PL (5); FR (9); US (10); DE (6)