75276617ALE1001

R/R acute leukemia (P1) or R/R AML per WHO 2022 (P2); molecularly selected (KMT2Ar or NPM1m); ECOG 0–2 (or adolescent PS ≥70)

Each potential participant must satisfy all of the following criteria to be enrolled in the study: 1. ≥18 years of age (participants ≥12 and <18 years of age are only eligible for the Phase 1 adolescent cohort; See Section 4.1.2). 2. Phase 1: R/R acute leukemia and has exhausted, or is ineligible for, available therapeutic options. Phase 2: must have had an initial diagnosis of AML per the WHO 2022 classification criteria. All participants must have R/R disease (with or without hematopoietic stem cell transplantation) as defined below: - Relapsed AML: bone marrow blast burden ≥5% after having initially achieved CR, CRh, or CRi following at least one cycle of initial therapy administered with intent to induce remission. - Refractory AML: bone marrow blast burden ≥5% with never having achieved CR, CRh, or CRi. Participants must have received at least two cycles of initial therapy (eg, intensive chemotherapy, venetoclax-based regimen) administered with intent to induce remission per investigator assessment, or four cycles of monotherapy with a hypomethylating agent. 3. Phase 1: acute leukemia harboring KMT2A (eg, gene rearrangement/translocation), NPM1 (eg, Exon 12 frameshift), or nucleoporin (NUP98 or NUP214; eg, gene rearrangement/translocation) alterations. Phase 2: AML harboring KMT2A-r (gene rearrangement/translocation) or NPM1 mutations only. 4. Pretreatment clinical laboratory values meeting the following criteria: - Hematology: WBC count ≤20 x 10^9/L (hydroxyurea and cytoreductive therapy to lower WBC count may be considered at screening and during study). - Chemistry: AST and ALT ≤2.5 × ULN. - Total serum bilirubin ≤1.5 × ULN (participants with elevated bilirubinemia, such as Gilbert’s syndrome, may enroll if conjugated bilirubin is within clinically acceptable range). - Renal function: estimated or measured glomerular filtration rate ≥50 mL/min per four-variable MDRD equation. 5. ECOG performance status grade of 0, 1, or 2. Note: Adolescent participants only: Performance status ≥70 by Lansky scale (<16 years) or ≥70 Karnofsky scale (≥16 years). 6. A female of childbearing potential must have a negative highly sensitive serum β-human chorionic gonadotropin at screening and within 48 hours prior to first dose. 7. A female of childbearing potential must agree during study and for 6 months after last dose to: - use a barrier method of contraception; - use a highly effective, preferably user-independent method of contraception; - not donate eggs (ova/oocytes) or freeze for assisted reproduction; - not plan pregnancy; - not breast-feed. 8. A male must agree during study and for 90 days after last dose to: - wear a condom during any activity allowing passage of ejaculate to another person; - not donate sperm or freeze sperm for future reproduction; - be advised that female partner should use a highly effective contraceptive method because condoms may break or leak. 9. Must sign informed consent form (participant or legally acceptable representative) before study-specific procedures. Note: In Phase 1 adolescents, assent is required as appropriate; parent(s) or LAR must sign ICF. 10. Willing and able to adhere to protocol prohibitions and restrictions.

Exclude APL/DS-leukemia/JMML, active CNS disease, recent allo-HSCT/GVHD/immunosuppression, prior menin inhibitor (except limited cohorts), major CV/QTc risk, active uncontrolled infection, HIV/HBV/HCV not meeting criteria, GI malabsorption or major confounders.

Any potential participant who meets any of the following criteria will be excluded from participating in the study: 1. Acute promyelocytic leukemia, Down syndrome–associated leukemia, or juvenile myelomonocytic leukemia. 2. Active CNS disease. 3. Prior solid organ transplantation. 4. Cardiovascular disease increasing torsades de pointes risk, or diagnosed within 6 months prior to first dose (eg, severe/unstable angina, myocardial infarction, major thromboembolic events, clinically significant ventricular arrhythmias, NYHA class III–IV heart failure, inflammatory cardiovascular conditions such as pericarditis/myocarditis/endocarditis). 5. QTcF ≥450 ms (males) or ≥470 ms (females), or family history of long QT syndrome. 6. Toxicity from prior anticancer therapy not resolved to baseline or Grade ≤1 (except alopecia, stable peripheral neuropathy, thrombocytopenia, neutropenia, anemia). 7. Pulmonary compromise requiring supplemental oxygen to maintain adequate oxygenation. 8. Reported temperature >100.5°F/38°C within 48 hours prior to first dose. 9. Known allergy/hypersensitivity/intolerance to bleximenib or excipients. 10. Stem cell transplant-related exclusions: - allogeneic bone marrow/stem cell transplant ≤3 months before first dose; - evidence of GVHD; - donor lymphocyte infusion ≤1 month before first dose; - requiring immunosuppressant therapy (exception: prednisone ≤10 mg/day or equivalent for adrenal replacement). 11. Phase 1 and Phase 2 (Cohorts A1/A2): prior treatment with a menin-KMT2A inhibitor (participants with R/R AML and prior menin inhibitor exposure without prior DS may be considered for Phase 1 with sponsor approval and may be enrolled in Phase 2 Cohort B once initiated). 12. Prior cancer immunotherapy (CAR-T, inotuzumab, gemtuzumab ozogamicin) within 4 weeks before enrollment, or blinatumomab within 2 weeks; additional prior cancer therapies within 4 weeks or 5 half-lives (whichever shorter). 13. Live-attenuated vaccine within 4 weeks before first dose or planned during treatment, or investigational vaccine within 2 weeks before first dose (locally approved COVID-19 vaccination within 2 weeks is permitted). 14. Investigational intervention/invasive investigational device within 2 weeks before planned first dose, or currently in another investigational study. 15. Major surgery within 2 weeks before first dose or not recovered; major surgery planned during treatment period. 16. Requires prohibited medication that cannot be discontinued/substituted/temporarily interrupted. 17. HIV positive unless viral load undetectable and CD4 >200 on stable HAART. 18. Active/chronic HBV or HCV infection (per protocol definitions) or clinically active infectious liver disease. 19. Serious underlying medical or psychiatric condition (eg, seizure disorder, substance abuse, dementia, altered mental status) that may interfere with participation. 20. Evidence within 7 days prior to first dose of active or uncontrolled infection. 21. Inability to take oral drug, or GI disorder/prior resection likely to affect absorption (eg, malabsorption syndrome, symptomatic IBD, bowel obstruction, gastric/small bowel resection). 22. Any condition that, in investigator opinion, is not in participant’s best interest or could prevent/limit/confound protocol assessments. 23. Active malignancies (progressing or requiring treatment change in last 24 months) other than disease under study (exception: non-melanoma skin cancers treated within last 24 months and considered cured). 24. Fanconi anemia, Kostmann syndrome, Shwachman-Diamond syndrome, or other known bone marrow failure syndrome.