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

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 werecandidates for intensive induction therapy.
2. Nucleophosmin-1 (NPM1)-mutated disease documented in a local or the Sponsor's centraltesting 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 appropriatesamples were sent to the Sponsor's central testing facility for NPM1-m companiondiagnostic development.
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0, 1, or 2.
4. Adequate hepatic and renal function defined as:
5. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5times the upper limit of normal (ULN), except those with hepatic involvement byAML, as documented by either computed tomography (CT) or ultrasound, in whomlevels of AST and ALT < 5 times ULN are acceptable; total bilirubin < 1.5 timesULN unless elevated due to Gilbert's Disease or hemolysis.
6. Calculated creatinine clearance > 40 mL/min or serum creatinine < 1.5 times ULN.
7. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and internationalnormalized ratio (INR) ≤ 1.5 x ULN unless receiving therapeutic anticoagulation.
8. Left ventricular ejection fraction ≥ 45% confirmed by echocardiogram (ECHO) ormulti-gated acquisition (MUGA) scan.

Exclusion Criteria:

1. Isolated myeloid sarcoma (ie, participants must had peripheral blood and/or bonemarrow involvement by AML) or acute promyelocytic leukemia.
2. Concurrent FLT3 mutation (either tyrosine kinase domain or internal tandemduplication).
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 inductiontherapy 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 withor without symptoms), who had subsequently tested negative on follow-up nasopharyngealswab and were without signs or symptoms of COVID-19 might enroll. Participants whowere 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 organtransplant.
11. Treatment with proton pump inhibitors (PPIs) from 7 days prior to enrollment until 48hours after completion of entospletinib (ENTO) or placebo. Note: PPIs were likely to interfere with ENTO absorption, thus requiring a 7-daywashout period prior to the initiation of study medication. For management of acutegastrointestinal bleeding during the study treatment period (such as that related tochemotherapy), short term concurrent use of PPIs was permitted for up to 10consecutive days. If longer durations of PPI exposure were required, participantsshould discontinue study medication. Histamine (H2) receptor antagonists and antacidswere allowed throughout the study treatment period.
12. Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment ofleukemia. Note: Participants may not receive AML-directed therapy prior to enrollment other thanhydroxyurea or leukapheresis for acute management of hyperleukocytosis.
13. Clinical signs/symptoms of leukostasis that had failed therapy including hydroxyureaand/or leukapheresis of at least 3 days duration.
14. Clinically significant heart disease defined as:
15. New York Heart Association Class 3 or 4 congestive heart failure,
16. Acute myocardial infarction ≤ 6 months before enrollment,
17. Symptomatic cardiac ischemia/unstable angina ≤ 3 months before enrollment,
18. History of clinically significant arrhythmias (eg, ventricular tachycardia orfibrillation; Torsades de Pointe) including Mobitz type II 2nd degree or 3rddegree heart block without a permanent pacemaker in place.
19. Participants with a corrected congenital long measure between Q wave and T wave in theelectrocardiogram (QT) interval (using the Fredericia formula, Fridericia correctionof the QT measure [QTcF]) > 480 msec or Long QT Syndrome.
20. Evidence of ongoing, uncontrolled systemic bacterial, fungal, or viral infection atthe time of study treatment initiation, including but not limited to persistent feveror positive cultures in the setting of appropriate antimicrobial therapy.
21. Unable to swallow tablets or concurrent disease affecting gastrointestinal functionsuch as, malabsorption syndrome, gastric or small bowel resection, bariatric surgery,inflammatory bowel disease, or bowel obstruction.