This is a prospective, single-arm phase 2 pilot study to assess the response rate of IDH1 mutated relapsed/refractory acute myeloid leukemia (AML) patients who receive olutasidenib after progressing on venetoclax based regimens. Each cycle will last for 28 days. Patients will receive olutasidenib 150 mg orally twice daily Day 1 through Day 28. After 3 cycles of olutasidenib, azacitidine 75 mg/m2 given on Day 1 through Day 7 may be added at the discretion of the treating investigator if the patient has not achieved a complete remission. Subjects with at least a PR after 6 cycles of treatment will continue treatment as previously described. Subjects without at least a partial response (PR) after 6 cycles of treatment will move to long term follow up.

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

2. Age ≥ 18 years at the time of consent.

3. ECOG Performance Status of ≤ 2 within 28 days prior to registration.

4. Must have histologically or cytologically documented relapsed and/or refractory Acute Myeloid Leukemia (Refractory is defined as failure to achieve a CR after induction chemotherapy or a minimum of two cycles of HMA plus venetoclax)

5. Acute Myeloid Leukemia with a documented IDH1 mutation.

6. No more than 2 lines of prior therapy. NOTE: One line of therapy must have contained venetoclax.

7. Persisting, non-hematologic and non-infectious toxicities from prior treatment must be Grade ≤ 2. NOTE: Documentation of these criteria is required at screening.

8. Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 14 days prior to registration.

   • Renal
   • Calculated creatinine clearance (Cockcroft-Gault formula will be used to calculate creatinine clearance) ≥ 30 mL/min
   • Hepatic
   • Total bilirubin2 ≤ 2× upper limit of normal (ULN); ≤ 3 times ULN in patients with Gilbert Syndrome
   • Aspartate aminotransferase (AST) ≤ 5 × ULN
   • Alanine aminotransferase (ALT) ≤ 5× ULN

9. Participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation of treatment.

10. Participants of childbearing potential who are having penile-vaginal intercourse with a person able to father a child must be willing to abstain from penile-vaginal intercourse or must use an effective method(s) of contraception. A participant able to father a child who is having penile-vaginal intercourse with a person of childbearing potential must be willing to abstain from penile-vaginal intercourse or use an effective method(s) of contraception.

11. Subjects with known HIV infection may be eligible if they are on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration. Testing is not required at screening.

12. Subjects with known chronic hepatitis B virus (HBV) infection may be eligible if they have an undetectable HBV viral load on suppressive therapy, if indicated. Subjects with a history of hepatitis C virus (HCV) infection may be eligible if they have been treated and cured. Subjects with an HCV infection who are currently on treatment must have an undetectable HCV viral load to be eligible for this trial. Testing is not required at screening.

13. As determined by the investigator or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria:

1. Previous exposure to ivosidenib or any IDH1 inhibitor.
2. Active infection requiring IV systemic therapy. NOTE: Subjects receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
3. Known CNS involvement with AML.
4. Previous allogeneic stem cell transplant within 60 days prior to registration.
5. Treatment with any investigational drug within 21 days or 2 half-life's prior to registration.
6. History of severe allergic anaphylactic reactions to olutasidenib or any of their excipients.
7. Pregnant or breastfeeding. NOTE: breast milk cannot be stored for future use while the subject is being treated on study.
8. Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen, per treating physician discretion.
9. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olutasidenib is 2 weeks or 5 half-lives (whichever is longer) prior to initiation of treatment.
10. Concomitant use of known sensitive CYP3A substrates (e.g. Midazolam, simvastatin, fluticasone, budesonide). The required washout period prior to starting olutasidenib is 2 weeks or 5 half-lives (whichever is longer) prior to initiation of treatment.