A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation

Inclusion Criteria:

Participants must have active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts in peripheral blood) as defined by the National Comprehensive Cancer Network (NCCN) in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020), or acute leukemia harboring KMT2A rearrangement, NUP98 rearrangement, or NPM1 mutation that have detectable disease in the bone marrow.

1. Phase 1:

• Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers orfluconazole.

• Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, orvoriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis.

• Arm C: Participants receiving revumenib in combination with cobicistat.

• Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor).

• Arm E: Participants not receiving any weak, moderate, or strong CYP3A4inhibitors/inducers.

• Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) forantifungal prophylaxis.

2. Phase 2: Documented R/R active acute leukemia (bone marrow blasts ≥5% or reappearance ofblasts in peripheral blood) as defined by the NCCN Guidelines® for AcuteLymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020).

• Cohort 2A: Documented R/R ALL/MPAL with KMT2A rearrangement.

• Cohort 2B: Documented R/R AML with KMT2A rearrangement.

• Cohort 2C: Documented R/R AML with NPM1m.

3. White blood cell count below 25,000/ microliter at time of enrollment. Participantsmay receive cytoreduction prior to enrollment per protocol-specified criteria.

4. Male or female participants aged ≥30 days old.

5. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 orKarnofsky/Lansky score ≥50.

6. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment,with the exception of ≤Grade 2 neuropathy or alopecia.

7. Radiation Therapy: At least 60 days from prior total body irradiation (TBI),craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14 days fromlocal palliative radiation therapy (small port).

8. Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stem celltransplant and at least 4 weeks must have elapsed from donor lymphocyte infusion.

9. Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines,and at least 21 days since receipt of chimeric antigen receptor therapy or othermodified T or NK cell therapy.

10. Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, sincethe completion of antileukemic therapy.

11. Hematopoietic Growth Factors: At least 7 days since the completion of therapy withshort-acting hematopoietic growth factors and 14 days with long-acting growthfactors.

12. Biologics: At least 90 days, or 5 half-lives, whichever is shorter, since thecompletion of therapy with an antineoplastic biologic agent.

13. Steroids: At least 7 days since systemic glucocorticoid therapy, unless receivingphysiologic dosing or cytoreductive therapy.

14. Adequate organ function.

15. If of childbearing potential, willing to use a highly effective method ofcontraception or double barrier method from the time of enrollment through 120 daysfollowing the last study drug dose.

Exclusion Criteria:

Participants meeting any of the following criteria are not eligible for study participation:

1. Diagnosis of active acute promyelocytic leukemia.

2. Isolated extramedullary relapse (Phase 2 only).

3. Active central nervous system disease (cytologic, such as any blasts on cytospin, orradiographic).

4. Detectable human immunodeficiency virus (HIV) viral load within the previous 6months. Participants with a known history of HIV 1/2 antibodies must have viral loadtesting prior to study enrollment.

5. Hepatitis B or C.

6. Pregnant or nursing women.

7. Cardiac Disease:

• Any of the following within the 6 months prior to study entry: myocardialinfarction, uncontrolled/unstable angina, congestive heart failure (New YorkHeart Association Classification Class ≥II), life-threatening, uncontrolledarrhythmia, cerebrovascular accident, or transient ischemic attack.

• Corrected QT interval (QTc) >450 milliseconds.

8. Gastrointestinal Disease:

• any gastrointestinal issue of the upper GI tract that might affect oral drugabsorption or ingestion (that is, gastric bypass, gastroparesis, etc).

• Cirrhosis with a Child-Pugh score of B or C.

9. Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD >Grade 0 within 4 weeks of enrollment. All transplant participants must have been off allsystemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeksprior to enrollment. Participants may be on physiological doses of steroids.

10. Concurrent malignancy in the previous 2 years with the exception of basal cellcarcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (for example, breast carcinoma, cervical cancer in situ, melanoma in situ) treatedwith potentially curative therapy, or concurrent low-grade lymphoma, that isasymptomatic and lacks bulky disease and shows no evidence of progression, and forwhich the participant is not receiving any systemic therapy or radiation.

11. In Phase 1 and Phase 2: Participants requiring the concurrent use of medicationsknown or suspected to prolong the QT/QTc interval, with the exception of drugs withlow risk of QT/QTc prolongation that are used as standard supportive therapies (forexample, diphenhydramine, famotidine, ondansetron, Bactrim) and the azoles permittedin the relevant arms of Phase 1 and in Phase 2.