Acute Myeloid Leukemia MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Entospletinib
Product Code: ENTO
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Entospletinib (GS-9973)
Current Sponsor code: GS-9973-02
Other descriptive name: Entospleti
Sponsors
Kronos Bio, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Adults 18 to 74 years with previously untreated de novo AML, AML with MDS features, or therapy-related AML who are candidates for intensive induction therapy. 2. NPM1-mutated disease documented in a local or the Sponsor’s central testing facility. Note: Subjects with concurrent FLT3 mutation but without access to midostaurin (eg, either for lack of health authority approval or reimbursement) may also enroll; subjects with a concurrent FLT3 mutation will not be allowed to receive a FLT3 inhibitor at any time during the study treatment period. Note: Subjects with local test results for NPM1-m (and/or FLT3 mutational status) may enroll, provided appropriate samples are sent to the Sponsor’s central testing facility for NPM1-m companion diagnostic development (see Section 4.1). 3.Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0, 1, or 2. 4.Adequate hepatic and renal function defined as: a.Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 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. Note: Transition from a Vitamin K or Factor Xa antagonist to a low-molecular weight heparin preparation is recommended prior to the start of induction chemotherapy (see Appendix 8 for guidelines on anticoagulation management). 6.Left ventricular ejection fraction = 45% confirmed by echocardiogram (ECHO) or multi gated acquisition (MUGA) scan. 7.Negative serum ß-HCG test in women of childbearing potential (WOCBP). 8.For WOCBP, willingness to abstain from heterosexual intercourse OR to use a protocol-recommended method of contraception from 7 days prior to C1D1 throughout the study treatment period and for 90 days following the last dose of ENTO/placebo or as recommended in the prescribing information for other co-administered study drugs (whichever is later). See Appendix 3 for contraceptive guidance. 9.For male subjects with female sexual partners of childbearing potential, willingness to abstain from heterosexual intercourse OR use a protocol recommended method of contraception beginning 7 days prior to C1D1 throughout the study treatment period and for 90 days following the last dose of ENTO/placebo or as recommended in the prescribing information for other co-administered study drugs (whichever is later), AND to refrain from sperm donation from the start of study treatment throughout the study treatment period and for 90 days following the last dose of ENTO/placebo or as recommended in the prescribing information for other co-administered study drugs (whichever is later). 10.Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 11.Willingness to comply with scheduled study visits, procedures, and treatment plan. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range
Exclusion criteria
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 TKD or ITD). 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/m2). 6. Is a candidate for daily doses of cytarabine > 100 mg/m2 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) RNA or antigen. Note: Subjects 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. Subjects 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. History of non-myeloid malignancy except for the following: adequately treated localized basal cell or squamous cell carcinoma of the skin; cervical carcinoma in situ; superficial bladder cancer; asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy (which may be continued while on study) and with normal prostate specific antigen for > 1 year prior to start of study therapy; or any other cancer that has been in complete remission without treatment for = 3 years prior to enrollment. 12. Current (within 30 days of study enrollment) drug-induced liver injury, chronic active hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cholangitis with inadequate response to ursodeoxycholic acid or other health authority approved therapy, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension. 13. Ongoing (within 6 weeks of study enrollment) hepatic encephalopathy. 14. Treatment with proton pump inhibitors (PPIs) from 7 days prior to enrollment until 48 hours after completion of 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, subjects should discontinue study medication. H2 receptor antagonists and antacids are allowed throughout the study treatment period. 15. Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia. 16. Concurrent (within 14 days of study enrollment) participation in an investigational drug study with therapeutic intent. 17. Clinical signs/symptoms of leukostasis that have failed therapy including hydroxyurea and/or leukapheresis of at least 3 days duration. 18. Clinically significant heart disease defined as: a. New York Heart Association Class 3 or 4 congestive h
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of ENTO compared to placebo when added to chemotherapy in previously untreated NPM1-m AML, as defined by the rate of molecularly defined measurable residual disease (MRD).;Secondary Objective: To evaluate the efficacy of ENTO compared to placebo when added to chemotherapy in previously untreated NPM1-m AML, as defined by relapse-free, event-free, and overall survival. • To evaluate the efficacy of ENTO compared to placebo when added to chemotherapy in previously untreated NPM1-m as defined by CR rate. • To evaluate the safety of ENTO compared to placebo when added to intensive chemotherapy. ;Primary end point(s): MRD negative complete response (CR) rates after completion of 2 cycles of chemotherapy plus either ENTO or placebo. Note: MRD negative CR requires CR as defined by the European LeukemiaNetwork (ELN) 2017 criteria (with minor modification for neutrophil and platelet count thresholds as defined by the International Working Group [IWG]) as assessed by study site investigators, and MRD negativity (<0.01%) in bone marrow as measured by a molecular NPM1-m assay (eg, by next generation sequencing) in a central laboratory upon recovery of peripheral blood counts following completion of 2 cycles of chemotherapy (ie, no later than Day 42 of Cycle 2). ;Timepoint(s) of evaluation of this end point: During the course of the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Event-free survival, defined as the time from randomization to the earliest occurrence of induction treatment failure, relapse from CR, or death from any cause. Note: 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, defined as the time from CR until relapse or death from any cause as assessed by study site investigators. • Overall survival defined as the time from randomization until death from any cause. • CR rates after 2 cycles of chemotherapy, as defined by ELN 2017 criteria (with minor modification for neutrophil and platelet count thresholds as defined by the IWG) as assessed by study site investigators. • Type, incidence, severity, and outcome of adverse events; changes from baseline in safety laboratory assessments, ECGs, ECHO/MUGA scans, ECOG PS.;Timepoint(s) of evaluation of this end point: During the course of the study | — |
Countries
Brazil, Canada, Czechia, Czech Republic, France, Germany, Hungary, Israel, Italy, Korea, Democratic People's Republic of, Poland, Russian Federation, Spain, Ukraine, United States
Contacts
Public ContactDirector, Clinical Operations
Kronos Bio, Inc.
Outcome results
None listed