Revumenib in Combination With Azacitidine + Venetoclax in Patients NPM1-mutated or KMT2A-rearranged AML

Inclusion Criteria:

In order to be eligible to participate in this study, a patient must meet all of the following criteria:

1. Patient with newly diagnosed NPM1-mutated AML, consistent with NPM1c, according tothe 2022 International Consensus Classification (i.e. ≥ 10% blasts). OR Patient with newly diagnosed KMT2A-rearranged AML according to the 2022International Consensus Classification (i.e. ≥ 10% blasts). KMT2A partial tandemduplications or deletions are NOT eligible. Of note: in case both NPM1 and IDH1 are mutated and both EVOLVE-1 (HO173) andEVOLVE-2 (HO177) are open for inclusion at your site, then patients can only beincluded in the EVOLVE-1 trial (HO173)

2. Central confirmation of NPM1 mutation or KMT2A rearrangement in one of the dedicatedcentral genetic laboratories.

3. Age ≥ 18 years, no upper age limit.

4. Patient is ineligible for intensive induction chemotherapy by meeting at least 1 ofthe following criteria:

• ≥ 75 years of age: ineligible for intensive chemotherapy per physician'sdiscretion (with an ECOG performance status 0-2) .

• 18-74 years: patient is not eligible for standard chemotherapy because any ofthe following co-morbidities: o ECOG performance status 2 or 3 .

• Cardiac history of chronic heart failure requiring treatment; or with anejection fraction ≤50%; or chronic stable angina.

• DLCO ≤ 65% or FEV1 ≤ 65%.

• Creatinine clearance ≥ 30 mL/min to <45 ml/min calculated by the CockcroftGault formula.

• Moderate hepatic impairment with total bilirubin > 1.5 to < 3.0 x upperlimit of normal (ULN).

• Any other comorbidity that the local physician assesses to be incompatiblewith intensive chemotherapy must be reviewed and approved by the Sponsor's (co-) Principal Investigator (written approval must be sent toHO177@erasmusmc.nl before study enrolment).

5. Patient must have a projected life expectancy of at least 12 weeks (as assessed bythe treating physician).

6. Patient must have a white cell blood (WBC) count of < 25 x 109/L. Hydroxyurea can beused prior to study enrolment to reduce the WBC count to meet this criterion.

7. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × upper limit of norm (ULN) or creatinine clearance >30 mL/min based on the Cockcroft-Gault glomerularfiltration rate (GFR).

8. Adequate hepatic function as evidenced by:

• Serum total bilirubin ≤ 3.0 × ULN unless considered due to Gilbert's disease,or leukemic involvement following written approval by the sponsor (Co-)Principal Investigator (copy in HO177@erasmusmc.nl).

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkalinephosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvementfollowing written approval by the sponsor (Co-)Principal Investigator (copy inHO177@erasmusmc.nl).

9. Female patient must:

• be of nonchildbearing potential:o postmenopausal (defined as at least 1 year without any menses).o documented surgically sterile (e.g. documented hysterectomy, bilateraloophorectomy, bilateral salpingectomy or congenital sterile) or status posthysterectomy (at least 1 month prior to screening).

• or, if of childbearing potential (not surgically sterile and notpostmenopausal) agree to avoid pregnancy during the study and for 6 monthsafter the final study drug administration.o and have a negative urine or serum pregnancy test at screening.o and, if heterosexually active, agree to consistently apply one highlyeffective* method of birth control in combination to a barrier method for theduration of the study and for 6 months after the final study drugadministration. *Highly effective forms of birth control include

• Consistent and correct usage of established hormonal contraceptives thatinhibit ovulation for at least 1 month prior to taking study drug. (hormonal contraception is only a highly effective method of birthcontrol, if a combined [estrogen and progestogen containing] hormonalcontraception or a progestogen-only hormonal contraception - bothassociated with inhibition of ovulation - is used.

• Established intrauterine device (IUD) or intrauterine system (IUS)

• Bilateral tubal occlusion

• Vasectomy - a vasectomy is highly effective contraception method providedthe absence of sperm has been confirmed. If not, an additional highlyeffective method of contraception should be used.

• Male is sterile due to a bilateral orchiectomy.

• Sexual abstinence is considered a highly effective method only if definedas refraining from heterosexual activity during the entire period of riskassociated with the study drug. The reliability of sexual abstinence needsto be evaluated in relation to the duration of the clinical study and thepreferred and usual lifestyle of the patient. List is not all inclusive. Prior to enrolment, the investigator is responsible forconfirming patient will utilize highly effective forms of birth control incombination with a barrier method according to locally accepted standards during theprotocol defined period.

• agree not to breastfeed starting at screening and throughout the study period.

• agree not to donate ova starting at screening and throughout the study period,and for 6 months after the final study drug administration.

10. Men must use a latex condom during any sexual contact with women of childbearingpotential (WOCBP), even if they have undergone a successful vasectomy and must agreeto avoid to father a child (while on therapy and for 6 months after the final studydrug administration). In addition, their female partners of childbearing potentialmust use a highly effective method of birth control.

11. Male patient must not donate sperm starting at screening and throughout the studyperiod and for 6 months after the final study drug administration.

12. Able to understand and willing to sign an informed consent form (ICF).

13. Institutional Review Board/Independent Ethics Committee-approved written informedconsent as per national regulations must be obtained from the patient prior to anystudy-related procedures (including consent for withdrawal of prohibited medication,if applicable).

Exclusion Criteria:

Subject has previously been treated for AML; a treatment period with hydroxyurea to control WBC counts is allowed; prior treatment with a hypomethylating agent for MDS-EB is not allowed; prior treatment with erythropoiesis-stimulating agents or luspatercept for MDS is allowed.

2. Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2); PML-RARA; or one ofthe other pathognomonic variant chromosomal translocations / fusion genes. 3. AMLwith BCR-ABL1; or myeloid blast crisis of CML. 4. Significant active cardiac diseasewithin 3 months prior to the start of study treatment, including:

• New York Heart Association (NYHA) class III or IV congestive heart failure

• Myocardial infarction

• Unstable angina

• Severe cardiac arrhythmias

• Congenital long QT syndrome of family member with this condition QTcF >450 msec onscreening electrogram for males and >470msec on screening electrogram for females (mean of triplicate recordings; calculated using Fridericia's correction). 5. Severeobstructive or restrictive ventilation disorder. 6. History of stroke orintracranial hemorrhage within 6 months prior to randomization.

7. Clinical symptoms suggestive of active central nervous system (CNS) leukemia orknown CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening isonly required if there is a clinical suspicion of CNS involvement by leukemiaduring screening. 8. Active infection, including hepatitis B or hepatitis C orHuman Immunodeficiency Virus (HIV) infection, that is uncontrolled prior tofirst dose of study treatment and may interfere with the study objectives orwhich could expose the patient to undue risk through the participation in theclinical trial; an infection controlled with an approved antibiotic/ antiviral/antifungal treatment that is not a strong or moderate CYP3A inducer is allowed.Patients with COVID-19 infection can be enrolled, if the patient has nosymptoms and was tested negative twice by PCR test prior to inclusion in thetrial. 9. Immediate life-threatening, severe complications of leukemia such asuncontrolled bleeding and/or disseminated intravascular coagulation. 10.Conditions that limit the ingestion or gastrointestinal absorption of orallyadministered drugs.

8. Patient with a currently active second malignancy. Patients are not consideredto have a currently active malignancy, if they have completed therapy and areconsidered by their physician to be at < 30% risk of relapse within one year.However, patients with 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, attenuatedvaccine within 30 days prior to the study inclusion (NOTE: patient, if enrolled,should not receive live vaccine during the study and until 6 months after thetherapy).

13. Severe neurological or psychiatric disorder interfering with ability to give aninformed consent.

14. Known or suspected hypersensitivity to any of the anti-leukemic agents used.

15. Participation in other prospective studies with anti-leukemic and/orinvestigational agents.

16. Patient taking Dabigatran unless they can be transferred to other medicationswithin ≥5 half-lives prior to dosing. Patients taking other P-gPtransporter-sensitive medications (see Appendix H) should be properly monitoredduring the study if they cannot be transferred to other medications.

17. Patient taking known strong cytochrome P450 (CYP) 3A4 inducers , unless theycan be transferred to other medications within ≥5 half-lives prior to dosing.The patient is a pregnant or lactating woman, or plans to become pregnantduring the study.

18. Patient who has once been screened and randomized into this HO177 trial but wasconsidered ineligible cannot re-enter this trial at a later date.