University of Kansas Medical Center

(IC): - Adults, age ≥60 yrs at diagnosis unless in a specific known cytogenetic & genomic group for which treatment in Group A, B, or C is allowed by the substudy where age 18+ is allowed. Patients <60 yrs who are screened but do not fall w/in the cytogenetic & genomic open substudies would still be followed on the M1 Master Protocol (MP) & not considered screen fails - Patients must be able to understand & provide written informed consent - Group A: Patients must have previously untreated AML according to WHO classification w/ no prior treatment other than hydroxyurea. Patients w/ myeloid malignancies [eg, myelodysplastic syndrome (MDS) or other disease], will be allowed to enroll to this group. For previously untreated subjects w/ ≥20% blasts in bone marrow or blood only: Prior therapy for MDS, myeloproliferative syndromes (MPD), or aplastic anemia is permitted. For select group, patients who cannot wait or choose not to wait for results of genomic testing, will be allowed to enroll to select substudies that allow enrollment & treatment of all patients regardless of their genomic mutations or cytogenetics. For this group, genomic samples will be collected to be analyzed retrospectively after patients' enrollment - Group B: Patients must have relapsed or refractory AML according to WHO classification. For study purposes, refractory AML is defined as failure to ever achieve a complete response (CR) or recurrence of AML w/in 6 months of achieving CR; relapsed AML is defined as all others w/ disease after prior remission. For select genomic aberrations specified in substudies, patients ≥18 yrs may be allowed to enroll in this portion of the study. Patients w/ relapsed or refractory myeloid malignancies (eg, MDS or other diseases) will be allowed to enroll to this group - Group C: For select sites not part of Beat AML core sites. These sites will only participate in select substudies. Patients in this group will enroll under the Beat AML M1 MP w/ the intent to enroll into these select substudies & following screening on Beat M1 MP, they will come off M1 MP

(EC): - Acute promyelocytic leukemia (APL) - Clinically active CNS involvement by AML. A patient may be considered eligible if CNS leukemia is showing response to treatment at study entry & should continue to receive intrathecal therapy as clinical indicated. Patients who require or are undergoing craniospinal irradiation of disease control are not eligible for participation - Signs of leukostasis requiring urgent therapy - Disseminated intravascular coagulopathy (DIC) w/ active bleeding or signs of thrombosis - Patients w/ psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol (including failure to collect genomics samples for screening), or complying w/ study treatment & follow-up - Any other significant medical condition, including psychiatric illness or lab abnormality, that would preclude patient participation in the trial or would confound interpretation of trial results S17 - IC 1. Age ≥60 yrs at diagnosis w/ untreated AML according to International Consensus Classification (ICC) 2022 & have NPM1 mutated or KMT2A rearrangement disease & are not candidates for or do not wish to pursue intensive chemotherapy 2. Patients must be able to understand & provide written informed consent 3. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 4. Aspartate aminotransferase (AST) <5 x upper limit of normal (ULN), alanine aminotransferase (ALT) <5 x ULN, & total bilirubin <2 x ULN (except for patients w/ known or suspected Gilbert's syndrome & w/ direct bilirubin w/in normal range) for the local lab 5. Adequate renal function as defined by calculated creatinine clearance ≥60 mL/min for the local lab 6. Females must be non-childbearing, postmenopausal, surgically sterile or meet certain criteria if of childbearing potential. Males must adhere to criteria if w/ females of childbearing potential 7. Patients must have previously untreated AML w/ no prior treatment other than hydroxyurea. No chemotherapy for AML outside of hydroxyurea for treatment of leukostasis or ATRA for initially suspected APL (that is ruled out) is allowed as well as 1 dose of intrathecal chemotherapy for suspected CNS involvement (that is ruled out) is allowed. Prior therapy for MDS allowed except for hypomethylating agents 8. If patient has co-morbid illness or malignancy, life expectancy attributed to this must be >2 yrs S17 - EC 1. Isolated myeloid sarcoma (must have blood or marrow involvement w/ AML) 2. APL (FAB M3) 3. Favorable risk cytogenetics (Core Binding Factor AML) 4. Active CNS involvement by AML 5. Signs of leukostasis requiring urgent therapy 6. WBC ≥25,000/μl (WBC <25,000/μl to begin therapy, Hydroxyurea may be used to obtain this level) 7. Willing & able to receive intensive chemotherapy 8. DIC w/ active bleeding or signs of thrombosis 9. Patients w/ psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or complying w/ study treatment & follow-up 10. Any significant medical condition, including psychiatric illness or lab abnormality, that would preclude the patient participating in the trial or would confound trial result interpretation 11. Known active HIV, active hepatitis B or C infections 12. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (CHF), unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction (MI) as presentation of AML, New York Heart Association (NYHA) Class III or IV heart failure, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients w/ medical comorbidities that will preclude safety evaluation of the combination should not be enrolled 13. Patients w/ uncontrolled infection shall not be enrolled until infection is treated & brought under control 14. Patients who have received an investigational agent (for any indication) w/in 5 half-lives of the agent & until toxicity from this has resolved to ≤ grade 1; if half-life of the agent is unknown, patients must wait 4 wks prior to first dose of study treatment. 15. Patients w/ QTcF >450 ms (males), >468 (females); patients w/ right, left, or partial bundle branch blocks (BBB) or pacemaker that may confound interpretation of this reading excluded provided they lack history of primary arrhythmic events & are cleared by cardiology for enrollment in the trial. Any factors that increase risk of QTc prolongation or risk of arrhythmic event such as congenital long QT syndrome or family history of long QT syndrome S24 - IC 1. ≥60 yrs at AML diagnosis 2. ECOG score of 0, 1, or 2 3. AST <2.5 x ULN, ALT <2.5 x ULN, & total bilirubin <1.5 x ULN (except for patients w/ known Gilbert's syndrome) for the local lab. If due to disease, higher values may be approved after discussion w/ medical monitor 4. Adequate renal function as defined by calculated creatinine clearance >40 mL/min per the local lab 5. Patients must be able to understand & provide written informed consent 6. Females must be non-childbearing, postmenopausal, surgically sterile or meet certain criteria if of childbearing potential 7. Males must adhere to criteria if w/ females of childbearing potential 8. No prior chemotherapy for leukemia (hydroxyurea to control leukocytosis & ATRA for initially suspected APL allowed). Prior therapy for MDS or myeloproliferative neoplasm (MPN) allowed (except for hypomethylating agents) 9. If patient has co-morbid illness or malignancy, life expectancy attributed to this must be >2 yrs S24 - EC 1. Patients able & willing to receive intensive chemotherapy for underlying AML 2. Isolated myeloid sarcoma (must have blood or marrow involvement w/ AML) 3. APL 4. Known active CNS involvement by AML 5. Clinical signs/symptoms of leukostasis requiring urgent therapy 6. Known active HIV, active hepatitis B or C infections 7. DIC w/ active bleeding or signs of thrombosis 8. Patients who have received an investigational agent (for any indication) w/in 5 half-lives of the agent; if half-life of the agent is unknown, patients must wait 1 wk prior to first dose of study treatment 9. Systemic antineoplastic therapy (for any indication) w/in 5 half-lives or radiation therapy w/in 1 wk prior to starting protocol except for hydroxyurea, which is allowed to control WBC counts 10. Patients w/ psychological, familial, social, or geographic factors, any other significant medical condition, or a lab abnormality that otherwise precludes them from giving informed consent, following the protocol, or complying w/ study treatment & follow-up, or would confound trial result interpretation 11. Uncontrolled intercurrent illness including, but not limited to, symptomatic CHF, unstable angina pectoris, serious cardiac arrhythmia, MI w/in 6 months prior to enrollment (Troponin leak alone not included if no residual dysfunction) NYHA Class III or IV heart failure, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients w/ medical comorbidities that will preclude safety evaluation of the combination should not be enrolled 12. Patients w/ uncontrolled infection shall not be enrolled until infection is treated & brought under control 13. Patients who require treatment w/ concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A 14. Patients who require treatment w/ concomitant drugs that are strong inhibitors or inducers of P-glycoprotein (P-gp) w/ the exception of drugs that are considered absolutely essential for care of the patient S25/HO181 IC 1. ≥18 yrs (or legal age of majority in jurisdiction where study is taking place, whichever is greater) at time of informed consent 2. New diagnosis of AML (≥10% blasts in BM or peripheral blood) w/ mutated NPM1 or w/ recurring rearrangements involving KMT2A according to ICC 2022 criteria 3. Considered eligible for intensive chemotherapy 4. WHO/ECOG score ≤2 5. Adequate renal & hepatic functions prior to randomization S25/HO181 EC 1. Prior (chemo-)therapy for AML, including prior treatment w/ hypomethylating agents 2. Known active leukemic involvement of CNS 3. Recipient of solid organ transplant 4. Cardiac disease: 1. Any of the following w/in 6 months of randomization: MI, uncontrolled/unstable angina, CHF (NYHA Class III or IV), uncontrolled or symptomatic arrhythmias, stroke, or transient ischemic attack 2. QTcF ≥470 ms. Prolonged QTc interval associated w/ BBB or pacemaking is permitted 3. Left ventricular ejection fraction (LVEF) <40% by ECHO or MUGA scan obtained w/in 28 days prior to start of study treatment 4. Previously received cumulative dose of any combination of anthracyclines or anthracenediones of ≥500 mg/m2 5. Chronic respiratory disease requiring supplemental oxygen S26/HO177 - IC 1. Patient w/ newly diagnosed NPM1-mutated AML, consistent w/ NPM1c, according to 2022 ICC (ie, ≥10% blasts). OR Patient w/ newly diagnosed KMT2A-rearranged AML according to 2022 ICC (ie, ≥10% blasts). KMT2A partial tandem duplications or deletions are NOT eligible 2. Central confirmation of NPM1 mutation or KMT2A rearrangement in 1 of the dedicated central genetic labs 3. Age ≥18 yrs, no upper age limit 4. Patient is ineligible for intensive chemotherapy by meeting at least 1 of the following criteria: A. ≥75 yrs: ineligible for intensive chemotherapy per physician's discretion (w/ an ECOG score 0-2) B. 18-74 yrs: patient is not eligible for standard chemotherapy because any of the following co-morbidities: i. ECOG score 2 or 3 ii. Cardiac history of chronic heart failure requiring treatment; or w/ an ejection fraction ≤50%; or chronic stable angina iii. DLCO ≤65% or FEV1 ≤65% iv. Creatinine clearance ≥30 mL/min to <45 ml/min calculated by Cockcroft Gault formula v. Moderate hepatic impairment w/ total bilirubin >1.5 to <3.0 x ULN vi. Any other comorbidity that local physician assesses to be incompatible w/ intensive chemotherapy must be reviewed & approved by Sponsor's (co-) Principal Investigator 5. Patient must have a projected life expectancy of at least 12 wks (as assessed by treating physician) 6. Patient must have a WBC count of <25 x 109/L. Hydroxyurea can be used prior to study enrollment to reduce WBC count to meet this criterion 7. Adequate renal function as evidenced by serum creatinine ≤2.0 × ULN or creatinine clearance >30 mL/min based on Cockcroft-Gault glomerular filtration rate (GFR) 8. Adequate hepatic function as evidenced by: A. Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert's disease, or leukemic involvement following written approval by sponsor (Co-)Principal Investigator B. AST, ALT, & alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following written approval by sponsor (Co-)Principal Investigator 9. Female patient must: A. be of nonchildbearing potential: o postmenopausal (defined as at least 1 yr w/out any menses). o documented surgically sterile (eg, documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy or congenital sterile) or status post hysterectomy (at least 1 month prior to screening) B. or, if of childbearing potential (not surgically sterile & not postmenopausal) agree to avoid pregnancy during the study & for 6 months after the final study drug administration i. and have a negative urine or serum pregnancy test at screening ii. and, if heterosexually active, agree to consistently apply 1 highly effective* method of birth control in combination to a barrier method for the duration of the study & for 6 months after final study drug administration *Highly effective forms of birth control include: 1. Consistent & correct usage of established hormonal contraceptives that inhibit ovulation for at least 1 month prior to taking study drug. Hormonal contraception qualifies as a highly effective birth control method only when it includes combined estrogen/progestogen contraception or progestogen-only contraception, each associated with inhibition of ovulation 2. Established intrauterine device (IUD) or intrauterine system (IUS) 3. Bilateral tubal occlusion 4. Vasectomy - a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used 5. Male is sterile due to a bilateral orchiectomy -- Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated w/ the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study & the preferred & usual lifestyle of the patient. List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control in combination w/ a barrier method according to locally accepted standards during the protocol defined period C. agree not to breastfeed starting at screening & throughout the study period D. agree not to donate ova starting at screening & throughout the study period, & for 6 months after the final study drug administration 10. Men must use a latex condom during any sexual contact w/ women of childbearing potential, even if they have undergone a successful vasectomy & must agree to avoid fathering a child (while on therapy & for 6 months after the final study drug administration). In addition, their female partners of childbearing potential must use a highly effective method of birth control 11. Male patient must not donate sperm starting at screening & throughout the study period & for 6 months after the final study drug administration 12. Able to understand & willing to sign an informed consent form (ICF) 13. Institutional Review Board/Independent Ethics Committee-approved written informed consent as per national regulations must be obtained from the patient prior to any study-related procedures (including consent for withdrawal of prohibited medication, if applicable) S26/HO177 - EC 1. Previously treated for AML; a treatment period w/ hydroxyurea to control WBC counts allowed; prior treatment w/ a hypomethylating agent for MDS-EB is not allowed; prior treatment w/ erythropoiesis-stimulating agents or luspatercept for MDS is allowed 2. APL w/ t(15;17)(q24.1;q21.2); PML-RARA; or other pathognomonic variant chromosomal translocation/fusion gene 3. AML w/ BCR-ABL1; or myeloid blast crisis of CML 4. Significant active cardiac disease w/in 3 months prior to start of study treatment, including: - NYHA class III or IV CHF - MI - Unstable angina - Severe cardiac arrhythmias - Congenital long QT syndrome of family member w/ this condition - QTcF >450 msec for males & >470 msec for females on screening electrogram (mean of triplicate recordings; calculated using Fridericia's correction) 5. Severe obstructive or restrictive ventilation disorder 6. History of stroke or intracranial hemorrhage w/in 6 months prior to randomization 7. Clinical symptoms suggestive of active CNS leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening 8. Active infection, including hepatitis B or C or HIV infection, that is uncontrolled prior to first dose of study treatment & may interfere w/ study objectives or could expose patient to undue risk through participation in the trial; an infection controlled w/ an approved antibiotic/antiviral/antifungal treatment that is not a strong or moderate CYP3A inducer is allowed. Patients w/ COVID-19 infection can be enrolled if they have no symptoms & tested negative twice by PCR test prior to inclusion in the trial 9. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or DIC 10. Conditions that limit ingestion or gastrointestinal absorption of orally administered drugs 11. Patient w/ currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy & are considered by their physician to be at < 30% risk of relapse w/in 1 yr. However, patients w/ the following history/concurrent conditions are allowed: - Basal or squamous cell carcinoma of the skin - Carcinoma in situ of the cervix - Carcinoma in situ of the breast - Incidental histologic finding of prostate cancer 12. Receipt of live, attenuated vaccine w/in 30 days prior to study inclusion (NOTE: patient, if enrolled, should not receive live vaccine during the study & until 6 months after therapy) 13. Severe neurological or psychiatric disorder interfering w/ ability to give informed consent 14. Contraindication to AZA or VEN (as per Summary of Product Characteristics) 15. Weighing <40 kg at registration 16. Participation in other prospective studies w/ anti-leukemic and/or investigational agents 17. Taking Dabigatran, unless patient can be transferred to other medications w/in ≥5 half-lives prior to dosing. Patients taking other P-gP transporter-sensitive medications should be properly monitored during the study if they cannot be transferred to other medications 18. Taking known strong cytochrome P450 (CYP) 3A4 inducers, unless patient can be transferred to other medications w/in ≥5 half-lives prior to dosing 19. Pregnant or lactating woman or plans to become pregnant during the study 20. Patient screened & randomized into this S26/HO177 trial but considered ineligible cannot re-enter this trial at later date