A 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 Overview
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Brief Summary
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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
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This will be 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 will be randomized 1:1 to receive intensive chemotherapy in combination with either the spleen tyrosine kinase (SYK) inhibitor entospletinib (ENTO), or placebo. The study will consist of Screening, Induction, Consolidation, End-of-Treatment, and Long-term Follow-up phases.

Official Title
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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

Conditions
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Nucleophosmin 1-mutated Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Entospletinib
* Drug: Placebo
* Drug: Cytarabine
* Drug: Anthracycline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 are 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 are 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. Exclusion Criteria: Isolated myeloid sarcoma (ie, participants must have 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. Is 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). Is 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 have subsequently tested negative on follow-up nasopharyngeal swab and are without signs or symptoms of COVID-19 may enroll. Participants who are fully vaccinated against SARS-CoV-2 may 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 are 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 is permitted for up to 10 consecutive days. If longer durations of PPI exposure are required, participants should discontinue study medication. Histamine (H2) receptor antagonists and antacids are 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. Clinical signs/symptoms of leukostasis that have 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. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intensive Chemotherapy + Entospletinib (ENTO)<br>Participants will receive intensive chemotherapy (cytarabine and anthracycline [daunorubicin or idarubicin]) in combination with entospletinib (ENTO). | Drug: Entospletinib<br>* Orally as tablets<br>* Other names: GS-9973;Drug: Cytarabine<br>* Continuous infusion<br>Drug: Anthracycline<br>* Either daunorubicin or idarubicin will be administered via slow intravenous (IV) push<br>|
| Placebo Comparator: Intensive Chemotherapy + Placebo<br>Participants will receive intensive chemotherapy (cytarabine and anthracycline [daunorubicin or idarubicin]) in combination with the matching placebo. | Drug: Placebo<br>* Orally as tablets<br>Drug: Cytarabine<br>* Continuous infusion<br>Drug: Anthracycline<br>* Either daunorubicin or idarubicin will be administered via slow intravenous (IV) push<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurable Residual Disease (MRD) Negative Complete Response (CR) Rate |  | Cycle 1 Day 1 through Cycle 2 Day 42 (cycle is 42 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) |  | Up to 5 years | 
| Relapse-free Survival (RFS) |  | Up to 5 years | 
| Overall Survival (OS) |  | Up to 5 years | 
| Complete Response (CR) Rate |  | Up to 5 years | 
| Number of Participants who Experience a Treatment-emergent Adverse Event (TEAE) | Clinically significant changes in safety laboratory assessments, electrocardiograms (ECGs), echocardiogram (ECHO) / multi-gated acquisition (MUGA) scans and Eastern Cooperative Oncology Group performance status (ECOG PS) findings, as assessed by the Investigator, will be recorded as TEAEs. | Cycle 1 Day 1 to 30 days after last study treatment, cycle is 42 days (up to a maximum of 219 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Nucleophosmin 1-mutated Acute Myeloid Leukemia, Entospletinib, ENTO