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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

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ClinicalTrials.gov Identifier: NCT05020665
Recruitment Status : Recruiting
First Posted : August 25, 2021
Last Update Posted : May 18, 2022
Sponsor:
Information provided by (Responsible Party):
Kronos Bio

Study Description
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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).

Condition or disease Intervention/treatment Phase
Nucleophosmin 1-mutated Acute Myeloid Leukemia Drug: Entospletinib Drug: Placebo Drug: Cytarabine Drug: Anthracycline Phase 3

Detailed Description:
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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : November 30, 2021
Estimated Primary Completion Date : December 30, 2023
Estimated Study Completion Date : December 30, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Intensive Chemotherapy + Entospletinib (ENTO)
Participants will receive intensive chemotherapy (cytarabine and anthracycline [daunorubicin or idarubicin]) in combination with entospletinib (ENTO).
 Drug: Entospletinib
Orally as tablets
Other Names:
  • ENTO
  • GS-9973

Drug: Cytarabine
Continuous infusion

Drug: Anthracycline
Either daunorubicin or idarubicin will be administered via slow intravenous (IV) push
Placebo Comparator: Intensive Chemotherapy + Placebo
Participants will receive intensive chemotherapy (cytarabine and anthracycline [daunorubicin or idarubicin]) in combination with the matching placebo.
 Drug: Placebo
Orally as tablets

Drug: Cytarabine
Continuous infusion

Drug: Anthracycline
Either daunorubicin or idarubicin will be administered via slow intravenous (IV) push


Outcome Measures
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Primary Outcome Measures :
  1. Measurable Residual Disease (MRD) Negative Complete Response (CR) Rate [ Time Frame: Cycle 1 Day 1 through Cycle 2 Day 42 (cycle is 42 days) ]

Secondary Outcome Measures :
  1. Event-free Survival (EFS) [ Time Frame: Up to 5 years ]
  2. Relapse-free Survival (RFS) [ Time Frame: Up to 5 years ]
  3. Overall Survival (OS) [ Time Frame: Up to 5 years ]
  4. Complete Response (CR) Rate [ Time Frame: Up to 5 years ]
  5. Number of Participants who Experience a Treatment-emergent Adverse Event (TEAE) [ Time Frame: Cycle 1 Day 1 to 30 days after last study treatment, cycle is 42 days (up to a maximum of 219 days) ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 are 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 are 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 have 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. Is 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. Is 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 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.

  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 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.

  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 have 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05020665


Contacts
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Contact: Director of Clinical Operations 650-484-1583 clinicaltrials@kronosbio.com

Locations
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Sponsors and Collaborators
Kronos Bio
More Information
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Responsible Party: Kronos Bio
ClinicalTrials.gov Identifier: NCT05020665    
Other Study ID Numbers: KB-ENTO-3001
2021-000761-33 ( EudraCT Number )
First Posted: August 25, 2021    Key Record Dates
Last Update Posted: May 18, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kronos Bio:
Acute Myeloid Leukemia
Nucleophosmin 1-mutated Acute Myeloid Leukemia
Entospletinib
ENTO
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Antimetabolites, Antineoplastic
Antimetabolites
 Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs