Clinical trial NCT05020665: Entospletinib Plus Intensive Induction/Consolidation Chemotherapy in Newly Diagnosed NPM1-mutated AML
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Nucleophosmin 1-mutated Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia
Nucleophosmin 1-mutated Acute Myeloid Leukemia
Entospletinib
ENTO
Lead sponsor: Kronos Bio
Sponsor class: INDUSTRY
First posted: 2021-08-25
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Participants With Measurable Residual Disease (MRD) Negative Complete Response (CR) Rate
timeFrame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
Secondary outcomes:
measure: Event-free Survival (EFS)
timeFrame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
measure: Relapse-free Survival (RFS)
timeFrame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
measure: Overall Survival (OS)
timeFrame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
measure: Number of Participant With Complete Response (CR) After 2 Cycles of Chemotherapy
timeFrame: Cycle 1 Day 1, up to Day 42 of chemotherapy cycle 2 (Cycle length = 42 days)
measure: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
timeFrame: Cycle 1 Day 1 to 30 days following study treatment completion, (Cycle length = 42 days) maximum up to 198 days
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: UCLA - Jonsson Comprehensive Cancer Center
state: California
city: Indianapolis
country: United States
facility: Indiana Blood & Marrow Transplantation
state: Indiana
city: Ann Arbor
country: United States
facility: University of Michigan Medical School
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: New York
country: United States
facility: Mount Sinai Health System
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Charleston
country: United States
facility: Hollings Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: Bon Secours St. Francis Cancer Center
state: South Carolina
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer
city: Fortaleza
country: Brazil
facility: Hospital Universitário Walter Cantídio
city: Jaú
country: Brazil
facility: Hospital Amaral Carvalho
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
city: Porto Alegre
country: Brazil
facility: Irmandade da Santa Casa de Misericórdia Hospital - Porto Alegre
city: Rio De Janeiro
country: Brazil
facility: Instituto Nacional de Câncer - Brazil
city: Rio Preto
country: Brazil
facility: Hospital de Base - São José do Rio Preto
city: São Paulo
country: Brazil
facility: A Beneficência Portuguesa de São Paulo - Unidade Mirante
city: São Paulo
country: Brazil
facility: Instituto Brasileiro de Controle do Câncer - São Camilo Oncologia - Unidade Mooca
city: Hamilton
country: Canada
facility: Juravinski Hospital
city: Saskatoon
country: Canada
facility: Saskatchewan Cancer Agency
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
city: Brno
country: Czechia
facility: Fakultni Nemocnice Brno
city: Hradec Králové
country: Czechia
facility: Fakultní Nemocnice Hradec Králové
city: Praha
country: Czechia
facility: Fakultní Nemocnice Královské Vinohrady
city: Caen
country: France
facility: Hôpital Côte De Nacre
state: Calvados
city: Angers
country: France
facility: Centre Hosptitalier Universitaire d'Angers
city: Lille
country: France
facility: Hôpital Claude Huriez
city: Nice
country: France
facility: Hôpital l'Archet
city: Paris
country: France
facility: Hôpital Saint-Antoine
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon-Sud
city: Rouen
country: France
facility: Centre de Lutte Contre le Cancer - Centre Henri-Becquerel
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig
city: Duisburg
country: Germany
facility: Helios St. Johannes Klinik
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf
city: Hanover
country: Germany
facility: Medizinische Hochschule Hannover
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Budapest
country: Hungary
facility: Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Központ
city: Nyíregyháza
country: Hungary
facility: Jósa András Oktatókórház
city: Szeged
country: Hungary
facility: Szent-Györgyi Albert Klinikai Központ
city: Ashdod
country: Israel
facility: Samson Assuta Ashdod University Hospital
city: Be'er Ya'aqov
country: Israel
facility: Shamir Medical Center (Assaf Harofeh)
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah University Hospital Ein Kerem
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Tel Aviv
country: Israel
facility: Assuta Hospital - Ramat HaHayal
city: Catania
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele
state: Sicily
city: Bari
country: Italy
facility: Azienda Universitaria Ospedaliera Consorziale - Policlinico di Bari
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Milan
country: Italy
facility: Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda
city: Novara
country: Italy
facility: Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci di Ravenna
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Daegu
country: Korea, Republic of
facility: Daegu Catholic University Medical Center
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Hospital
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital
city: Incheon
country: Korea, Republic of
facility: Seoul National University Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Catholic University of Korea Seoul Saint Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne w Gdańsku
city: Szczecin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr im. Prof. Tadeusza Sokołowskiego
city: Warsaw
country: Poland
facility: Uniwersyteckie Centrum Kliniczne WUM - Centralny Szpital Kliniczny
city: Warsaw
country: Poland
facility: Instytut Hematologii I Transfuzjologii
city: Wrocław
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Catalonia
city: Barcelona
country: Spain
facility: Institut D'Investigacions Biomédiques August Pi I Sunyer
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Palma De Mallorca
country: Spain
facility: Hospital Son Llàtzer
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari I Politecnic La Fe
Study officials:
References: