E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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). |
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E.2.2 | Secondary objectives of the trial |
• 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adults 18 to 75 years with previously untreated de novo AML, AML with MDS features, or therapy-related AML. 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) < 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. b.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. 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). 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. |
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E.4 | Principal exclusion criteria |
1.Isolated myeloid sarcoma (ie, participants must have peripheral blood and/or bone marrow involvement by AML) or acute promyelocytic leukemia. 2.Known central nervous system (CNS) involvement with leukemia. 3.Active infection with hepatitis B, C, or known human immunodeficiency virus (HIV). Note: Subjects who are positive for hepatitis B surface antigen (HBsAg) are ineligible. Those who are seropositive for hepatitis B core antibody (anti-HBc) may enroll but must agree to receive hepatitis B virus (HBV) prophylaxis during the study treatment period and undergo regular surveillance for HBV reactivation at least once every 3 months. Subjects who have received curative therapy for prior HCV infection and who are seropositive for hepatitis C antibody (anti-HCV), may enroll, however must undergo regular surveillance monitoring for HCV reactivation. 4.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. 5.Disseminated intravascular coagulation with active bleeding or signs of thrombosis. 6.History of prior allogeneic hematopoietic stem cell transplant or solid organ transplant. 7.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. Note: Subjects who are on adjuvant hormonal therapy and ≥ 3 years from definitive therapy for their primary tumor are eligible to enroll. 8.Current (within 30 days of study enrollment) drug-induced liver injury, chronic active hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension. 9.Ongoing (within 6 weeks of study enrollment) hepatic encephalopathy. 10.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. H2 receptor antagonists and antacids are allowed for use during the study treatment period. 11.Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia. Note: Subjects may not receive AML-directed therapy prior to enrollment other than hydroxyurea or leukapheresis for acute management of hyperleukocytosis. 12.Concurrent (within 14 days of study enrollment) participation in an investigational drug study with therapeutic intent. 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: a.New York Heart Association Class 3 or 4 congestive heart failure, b.Acute myocardial infarction ≤ 6 months before enrollment, c.Symptomatic cardiac ischemia/unstable angina ≤ 3 months before enrollment, d.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.Subjects with a corrected QT interval (using the Fredericia formula, 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. Patients who are afebrile for ≥48 hours may enroll even while continuing antimicrobial therapy. 17.Pregnant or breastfeeding women. 18.Alcohol or drug addiction as determined by investigator. 19.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. 20.Any prior or ongoing condition that, in the opinion of the investigator, could adversely affect the safety of the subject or impair the assessment of study results. 21.Known hypersensitivity to ENTO, cytarabine, daunorubicin, or idarubicin, their metabolites, or formulation excipient. |
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E.5 End points |
E.5.1 | 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 Leukemia Network (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).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
During the course of the study |
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E.5.2 | 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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During the course of the study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Brazil |
Canada |
Israel |
Korea, Republic of |
Russian Federation |
Ukraine |
United States |
France |
Germany |
Hungary |
Italy |
Poland |
Spain |
Czechia |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will be completed when all enrolled subjects either relapse, die, or after the last subject enrolled completes 5 years of follow-up, whichever is earliest. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |