The goal of Phase 1 is to find the recommended dose of ziftomenib and olutasidenib in patients with relapsed/refractory AML that has a mutation in the NPM1 and IDH1 genes.

The goal of Phase 1b is to learn if the recommended dose of ziftomenib and olutasidenib found in Phase 1 can help to control the disease.

The safety and effects of this combination will also be studied in both parts.

Primary Objectives:

• Phase 1: To determine the safety and tolerability and recommended phase 2 dose (RP2D)) of ziftomenib and olutasidenib in adult patients with R/R NPM1 and IDH1 co-mutated AML
• Phase 1b: To determine the preliminary efficacy of combination treatment as reflected by the composite remission rate (CRc=CR+ CRi +CRh) of ziftomenib and olutasidenib in adult patients with R/R NPM1 and IDH1 co-mutated AML

Secondary Objectives:

• To determine the overall response rate (ORR) including composite remission rate (CRc), partial remission (PR), and morphologic leukemia free state (MLFS) following therapy
• To determine the duration of response (DOR), event-free survival (EFS), relapse-free survival (RFS), time to CRc, and overall survival (OS) following therapy
• To determine the occurrence of minimal residual disease (MRD) negative response (CR/CRi) as assessed by multiparameter flow cytometry and NPM1m qPCR following therapy
• To determine the time to achieve CR/CRi following initiation of therapy
• To determine the rate of transfusion independence (TI) achieved by patients on therapy
• To determine the proportion of patients that undergo allogeneic stem cell transplantation (alloSCT) following study therapy
• To monitor longitudinal changes in IDH1m VAF in patients following treatment

Exploratory Objective:

• To perform detailed bulk and single cell multi-omics (DNA sequencing, RNA sequencing, global gene expression profiles, DNA methylation profiles), and other potential prognostic marker assays on longitudinally collected samples over the course of therapy to explore potential predictors of anti-tumor activity and/or resistance to treatment

Inclusion Criteria:

1. Age > 18 years
2. Diagnosis of relapsed or refractory AML (including biphenotypic or bilineage leukemia) as defined by ≥ 5% marrow blasts; patients with isolated extramedullary AML without marrow involvement are not eligible
3. AML disease must be characterized by IDH1 and NPM1 co-mutations as determined by local molecular testing (next generation sequencing, PCR)
4. Eastern Cooperative Oncology Group (ECOG) Performance Status </=2
5. Adequate renal function with CrCl ≥30 ml/min to be calculated using Cockroft Gault formula
6. Adequate hepatic function (total bilirubin < 3.0x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement, and AST and/or ALT < 3x ULN unless considered due to leukemic involvement, in which case total bilirubin < 5x ULN or AST and/or ALT < 5x ULN will be considered eligible
7. Baseline QTcF ≤ 480 msec
8. In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation of study therapy will be 14 days from last cytotoxic or non-cytotoxic (immunotherapy agent(s), or an interval of 5 half- lives of the prior therapy whichever is shorter. Cytarabine (up to 2 gm/m2), leukapheresis, and oral hydroxyurea are permitted in patients with rapidly proliferative disease before the start of study therapy for clinical benefit as needed. Hydroxyurea can also be administered during cycles 1-2 of study therapy for cytoreduction as deemed necessary by the treating physician and after discussion with the PI. Concurrent intrathecal therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted.
9. Female patients of childbearing potential must agree to use a highly effective method of contraception as well as a double-barrier method (e.g., condom with spermicide) and refrain from egg donation from screening visit until 180 days following the last dose of study intervention. Male patients capable of having intercourse with females of childbearing potential and who have not had vasectomies must agree to abstain from heterosexual intercourse or use a double-barrier method of contraception and have their partner use a highly effective method of contraception from the screening visit until 90 days following the last dose of study intervention. They must also refrain from sperm donation from the screening visit until 90 days following the last dose of study intervention. Please refer to NIH Contraception Guidance (https://rsc.niaid.nih.gov/sites/default/files/trpguidancereproriskfinal.pdf) for additional recommendations.
10. Willing and able to provide informed consent

Exclusion Criteria:

1. Patients with t (15;17) karyotypic abnormality or acute promyelocytic leukemia (French American- British [FAB] class M3-AML).
2. Patients with any concurrent uncontrolled clinically significant medical condition including life- threatening severe infection, or psychiatric illness, which could place the patient at unacceptable risk of study treatment or be unable to consent or comply with protocol therapy. Patients with controlled infections are allowed. Other prior or concurrent malignancies will be considered after discussion with the PI.
3. Patients with active, uncontrolled, leukemia involvement of the CNS
4. Patients with grade II-IV active or extensive chronic graft-versus-host disease (cGHVD) status post stem cell transplant requiring topical therapy. Patients must have discontinued calcineurin inhibitors at least 2 weeks prior to the start of the study therapy.
5. Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
6. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known HIV infection.
7. Subject has a white blood cell count > 20 x 10⁹/L. (Note: Hydroxyurea, leukapheresis, and cytarabine is permitted to meet this criterion- see above Inclusion criteria #8.)
8. Prior treatment with ziftomenib or olutasidenib
9. Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception. Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, IUD, and double barrier methods (for example, a condom in combination with a spermicide).
10. Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drugs including medical, psychological, familial, social or geographical consideration
11. Receiving treatment with moderate or strong CYP3A inducer within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study drug (see Appendix A for examples).