Entospletinib Plus Intensive Induction/Consolidation Chemotherapy in Newly Diagnosed NPM1-mutated AML
- Conditions
- Nucleophosmin 1-mutated Acute Myeloid Leukemia
- Interventions
- Registration Number
- NCT05020665
- Lead Sponsor
- Kronos Bio
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 15
-
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.
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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.
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Was a candidate for more intensive treatment than specified in this protocol.
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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.
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Disseminated intravascular coagulation with active bleeding or signs of thrombosis.
-
History of prior allogeneic hematopoietic stem cell transplant or solid organ transplant.
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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.
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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.
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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.
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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.
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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.
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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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Intensive Chemotherapy + Entospletinib (ENTO) Anthracycline Participants received intensive chemotherapy (cytarabine and anthracycline \[daunorubicin or idarubicin\]) in combination with entospletinib (ENTO). Intensive Chemotherapy + Placebo Placebo Participants received intensive chemotherapy (cytarabine and anthracycline \[daunorubicin or idarubicin\]) in combination with the matching placebo. Intensive Chemotherapy + Placebo Anthracycline Participants received intensive chemotherapy (cytarabine and anthracycline \[daunorubicin or idarubicin\]) in combination with the matching placebo. Intensive Chemotherapy + Entospletinib (ENTO) Cytarabine Participants received intensive chemotherapy (cytarabine and anthracycline \[daunorubicin or idarubicin\]) in combination with entospletinib (ENTO). Intensive Chemotherapy + Placebo Cytarabine Participants received intensive chemotherapy (cytarabine and anthracycline \[daunorubicin or idarubicin\]) in combination with the matching placebo. Intensive Chemotherapy + Entospletinib (ENTO) Entospletinib Participants received intensive chemotherapy (cytarabine and anthracycline \[daunorubicin or idarubicin\]) in combination with entospletinib (ENTO).
- Primary Outcome Measures
Name Time Method Number of Participants With Measurable Residual Disease (MRD) Negative Complete Response (CR) Rate Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days) 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.
- Secondary Outcome Measures
Name Time Method Event-free Survival (EFS) Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days) 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).
Relapse-free Survival (RFS) Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days) RFS is defined as the time from CR until relapse or death from any cause as assessed by study site investigators.
Overall Survival (OS) Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days) OS is defined as the time from randomization until death from any cause.
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) 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.
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 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.
Trial Locations
- Locations (83)
Mount Sinai Health System
🇺🇸New York, New York, United States
Hôpital Côte De Nacre
🇫🇷Caen, Calvados, France
Hollings Cancer Center
🇺🇸Charleston, South Carolina, United States
Fakultni Nemocnice Brno
🇨🇿Brno, Czechia
City of Hope
🇺🇸Duarte, California, United States
University of Michigan Medical School
🇺🇸Ann Arbor, Michigan, United States
Bon Secours St. Francis Cancer Center
🇺🇸Greenville, South Carolina, United States
Severance Hospital
🇰🇷Seoul, Korea, Republic of
Uniwersyteckie Centrum Kliniczne WUM - Centralny Szpital Kliniczny
🇵🇱Warsaw, Poland
Catholic University of Korea Seoul Saint Mary's Hospital
🇰🇷Seoul, Korea, Republic of
UCLA - Jonsson Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Indiana Blood & Marrow Transplantation
🇺🇸Indianapolis, Indiana, 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
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Duke Cancer Institute
🇺🇸Durham, North Carolina, United States
Hospital Amaral Carvalho
🇧🇷Jaú, Brazil
Hospital de Clínicas de 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
Princess Margaret Cancer Centre
🇨🇦Toronto, Canada
Debreceni Egyetem Klinikai Központ
🇭🇺Debrecen, Hungary
Juravinski Hospital
🇨🇦Hamilton, Canada
Fakultní Nemocnice Hradec Králové
🇨🇿Hradec Králové, Czechia
Saskatchewan Cancer Agency
🇨🇦Saskatoon, Canada
Centre Hosptitalier Universitaire d'Angers
🇫🇷Angers, France
Fakultní Nemocnice Královské Vinohrady
🇨🇿Praha, Czechia
Assuta Hospital - Ramat HaHayal
🇮🇱Tel Aviv, Israel
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
Universitätsmedizin Mannheim
🇩🇪Mannheim, Germany
Semmelweis Egyetem
🇭🇺Budapest, Hungary
Marien Hospital Düsseldorf
🇩🇪Düsseldorf, Germany
Universitätsklinikum Münster
🇩🇪Münster, Germany
Medizinische Hochschule Hannover
🇩🇪Hanover, Germany
Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet
🇭🇺Budapest, Hungary
Jósa András Oktatókórház
🇭🇺Nyíregyháza, Hungary
Szent-Györgyi Albert Klinikai Központ
🇭🇺Szeged, Hungary
Rambam Health Care Campus
🇮🇱Haifa, Israel
Shamir Medical Center (Assaf Harofeh)
🇮🇱Be'er Ya'aqov, Israel
Samson Assuta Ashdod University Hospital
🇮🇱Ashdod, Israel
Hadassah University Hospital Ein Kerem
🇮🇱Jerusalem, Israel
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele
🇮🇹Catania, Sicily, Italy
Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi
🇮🇹Bologna, Italy
Azienda Universitaria Ospedaliera Consorziale - Policlinico di Bari
🇮🇹Bari, Italy
Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
🇮🇹Milan, Italy
Ospedale Santa Maria delle Croci di Ravenna
🇮🇹Ravenna, Italy
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
🇮🇹Milano, Italy
Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara
🇮🇹Novara, Italy
Daegu Catholic University Medical Center
🇰🇷Daegu, Korea, Republic of
Kyungpook National University Hospital
🇰🇷Daegu, Korea, Republic of
Keimyung University Dongsan Hospital
🇰🇷Daegu, Korea, Republic of
Chungnam National University Hospital
🇰🇷Daejeon, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Gachon University Gil Medical Center
🇰🇷Incheon, Korea, Republic of
Korea University Guro Hospital
🇰🇷Seoul, Korea, Republic of
Uniwersyteckie Centrum Kliniczne w Gdańsku
🇵🇱Gdańsk, Poland
Samodzielny Publiczny Szpital Kliniczny Nr im. Prof. Tadeusza Sokołowskiego
🇵🇱Szczecin, Poland
Instytut Hematologii I Transfuzjologii
🇵🇱Warsaw, Poland
Institut D'Investigacions Biomédiques August Pi I Sunyer
🇪🇸Barcelona, Spain
Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu
🇵🇱Wrocław, Poland
Hospital Germans Trias i Pujol
🇪🇸Badalona, Catalonia, Spain
Hospital San Pedro de Alcantara
🇪🇸Cáceres, Spain
Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
🇪🇸Barcelona, Spain
Hospital General Universitario Gregorio Marañón
🇪🇸Madrid, Spain
Hospital Son Llàtzer
🇪🇸Palma De Mallorca, Spain
Hospital Universitario Fundación Jiménez Díaz
🇪🇸Madrid, Spain
Hospital Clínico Universitario de Valencia
🇪🇸Valencia, Spain
Hospital Universitario Central de Asturias
🇪🇸Oviedo, Spain
Hospital Universitari I Politecnic La Fe
🇪🇸Valencia, Spain
Irmandade da Santa Casa de Misericórdia Hospital - Porto Alegre
🇧🇷Porto Alegre, Brazil
Instituto Brasileiro de Controle do Câncer - São Camilo Oncologia - Unidade Mooca
🇧🇷São Paulo, Brazil
Seoul National University Hospital
🇰🇷Incheon, Korea, Republic of