∙ 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.

• Phase 1:

‣ Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or fluconazole.

⁃ Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or voriconazole (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 CYP3A4 inhibitors/inducers.

⁃ Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis.

• Phase 2:

• Documented R/R active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts in peripheral blood) as defined by the NCCN Guidelines® for Acute Lymphoblastic 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.

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

• Male or female participants aged ≥30 days old.

• Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or Karnofsky/Lansky score ≥50.

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

• 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 from local palliative radiation therapy (small port).

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

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

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

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

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

⁃ Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing or cytoreductive therapy.

⁃ Adequate organ function.

⁃ If of childbearing potential, willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose.