Revumenib in Combination With 7+3 + Midostaurin in AML

Inclusion Criteria:

• Patients with AML who are newly diagnosed according to the WHO 2022 Classificationand previously untreated except for hydroxyurea. ATRA pretreatment for suspected APLfor less than 5 days is allowed. Eligible patients with AML arising from anantecedent hematologic disease (AHD) including MDS, may have been treated for theirprior hematologic disease (except for allogenic transplant).

• Patients must be ≥ 18 and < 75 years old.

• Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.

• Presence of FLT3-ITD and/or TKD mutation(s) AND NPM1 mutation in bone marrow orperipheral blood

• Dose escalation phase only: Presence of any of the following adverse risk geneticcharacteristics:

• 2022 ELN adverse risk genetic features:

• t(6;9)(p23.3;q34.1)/DEK::NUP214

• t(v;11q23.3)/KMT2A-rearranged

• t(9;22)(q34.1;q11.2)/BCR::ABL1

• t(8;16)(p11.2;p13.3)/KAT6A::CREBBP

• inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/ GATA2, MECOM(EVI1)

• t(3q26.2;v)/MECOM(EVI1)-rearranged

• -5 or del(5q); -7; -17/abn(17p)

• Complex karyotype, monosomal karyotype

• Mutations in either one of these genes: ASXL1, BCOR, EZH2, RUNX1, SF3B1,SRSF2, STAG2, U2AF1, and/or ZRSR2

• Mutated TP53

• NPM1 + FLT3-ITD + DNMT3A mutation

• LVEF ≥ 50% by MUGA or ECHO at screening.

• Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 60mL/min; determined by the Cockcroft Gault formula.

• Adequate liver function as demonstrated by:

• aspartate aminotransferase (AST) ≤ 2.5 × ULN*

• alanine aminotransferase (ALT) ≤ 2.5× ULN*

• total bilirubin ≤ 1.5 × ULN* * Unless considered due to leukemic organinvolvement. Note: Subjects with Gilbert's Syndrome may have a total bilirubin > 1.5 × ULN per discussion with the Sponsor-Investigator

• Resolution of adverse reactions to prior drug therapy (such as hydroxyurea) to ≤grade 1

• Eligible for intensive cytarabine/daunorubicin (7+3) chemotherapy based on theopinion of the treating physician.

• Male subjects must agree to refrain from unprotected sex and sperm donation frominitial study drug administration until 90 days after the last dose of study drug.

• Females of childbearing potential (i.e., not postmenopausal for at least 1 year ornot surgically sterile) must have negative results by a serum or urine pregnancytest performed within 7 days of day 1.

• Ability to understand and the willingness to sign a written informed consentdocument. (Providing consents in as many languages as possible is encouraged)

• Consolidation should occur between 1-4 weeks following count recovery afterinduction and remission (must be confirmed by labs to document maximal response) isestablished. Subjects will receive medium intensity cytarabine -based consolidationin combination with midostaurin and revumenib if the following criteria arefulfilled.

• an induction response < 5% blasts in the bone marrow and ANC >1000 and PLT >75000 for whom documented path report is submitted.

• sufficiently fit (performance status <3)

• resolution of any adverse reactions to no greater than grade 1 severity

Exclusion Criteria:

• Subject has acute promyelocytic leukemia, inversion (16), t(8;21) AML as describedbelow. Contact Sponsor-Investigator with questions. Inversion 16 and t(8;21): CBFchromosomal abnormalities may be assessed by molecular (PCR), metaphasecytogenetics, or FISH.

• Subject has known active CNS involvement with AML.

• Subject has received a strong CYP3A4 inducer (APPENDIX C) within 7 days prior to theinitiation of study treatment

• Strong CYP3A4 inhibitors (APPENDIX C) are contraindicated except strong CYP3A4inhibitor antifungal azole medications (systemic itraconazole, ketoconazole,posaconazole, voriconazole). For strong CYP3A4 inhibitor antifungal azolemedications, the starting dose of revumenib has to be adjusted (Table 1).

• QTc using Fridericia's correction [QTcF]) > 450 msec. Drugs that prolong QTc shouldbe avoided if possible. A list of common QTc prolonging drugs and alternatives thatare not QTc prolonging can be found in APPENDIX D.

• Subject has tested positive for HIV (due to potential drug-drug interaction betweenantiretroviral medications and Midostaurin/revumenib). Note: HIV testing is notrequired.

• Subject is known to be positive for hepatitis B or C infection with the exception ofthose with an undetectable viral load within 3 months. (Hepatitis B or C testing isnot required). Subjects with serologic evidence of prior vaccination to HBV [i.e.,HBs Ag-, and antiHBs+] are allowed.

• Subject has consumed grapefruit, grapefruit products, Seville oranges (includingmarmalade containing Seville oranges) or Star fruit within 3 days prior to theinitiation of study treatment.

• Subject has a cardiovascular disability status of New York Heart Association Class ≥

2. Class 2 is defined as cardiac disease in which patients are comfortable at restbut ordinary physical activity results in fatigue, palpitations, dyspnea, or anginalpain.

• Subject has a significant history of renal, neurologic, psychiatric, endocrinologic,metabolic, immunologic, hepatic, cardiovascular disease, or any other medicalcondition that in the opinion of the investigator would adversely affect his/herparticipating in this study.

• Subject has chronic respiratory disease that requires continuous oxygen use.

• Subject has a malabsorption syndrome or other condition that precludes enteral routeof administration.

• Subject exhibits evidence of other clinically significant uncontrolled condition(s)including, but not limited to uncontrolled systemic infection.

• Subject has a history of other malignancies prior to study entry, with the exceptionof:

• Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situof breast;

• Basal cell carcinoma of the skin or localized squamous cell carcinoma of theskin;

• Previous malignancy confined and surgically resected (or treated with othermodalities) with curative intent.

• Prior malignancies treated with (surgery+/- chemotherapy+/- radiation) thathave remained disease free for at least two years after completion of therapy

• Subject treated with any form of chemotherapy, immunotherapy, or investigative agentwithin 1 month of enrollment.

• Patients who have had prior exposure to a menin inhibitor.