Olutasidenib, Venetoclax, and Azacitidine in IDH1 Mutated Newly Diagnosed Acute Myeloid Leukemia Patients Eligible for Intensive Induction Chemotherapy

Inclusion Criteria:

1. Participant is an adult male or female participant aged 18-75 years consideredeligible to undergo intensive induction chemotherapy at the time of signing theinformed consent form (ICF).

2. Eastern Cooperative Oncology Group (ECOG) performance status ≤2

3. Confirmed diagnosis of:

4. Newly diagnosed AML Isocitrate dehydrogenase 1 (IDH1) R132 mutated disease asassessed locally. Note: historical results from within 30 days of informedconsent will be accepted if the participant did not receive systemic treatmentafter collection.

5. Secondary AML, including prior hypomethylating agents (HMA) exposure formyelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), or MDS/MPNis allowed.

6. Participant must have adequate organ function, defined by the following:

7. Aspartate transaminase (AST) and alanine aminotransferase (ALT) values ≤3 ×upper limit of normal (ULN) or ≤5 × ULN for participants with leukemicinvolvement.

8. Bilirubin ≤2 ULN (≤3 × ULN in participants with Gilbert Syndrome) or ≤3 × ULNfor participants with leukemic involvement.

9. Creatinine clearance ≥30 mL/min (using Cockcroft-Gault), or serum creatinine ≤1.5 × ULN.

10. The interval from prior treatment for an antecedent hematologic disorder to thefirst dose of study treatment (C1D1) will be at least 7 days for cytotoxic ornon-cytotoxic (immunotherapy) agents. In addition, the following will be allowed:

11. Intrathecal chemotherapy for prophylactic use or for controlled central nervoussystem (CNS) leukemia.

12. Use of hydroxyurea for participants with rapidly proliferative disease isallowed before the start of study therapy and for the first 4 weeks on studytreatment.

13. Recovery from non-hematologic toxic effects of prior treatment to Grade ≤1, orbaseline value according to National Cancer Institute (NCI) Common TerminologyCriteria for Adverse Events (CTCAE) version 5.0 classification (excludinginfertility, alopecia, or Grade 1 neuropathy).

14. Baseline QT interval corrected using the Fridericia equation (QTcF) ≤ 480 msec.Note: This criterion does not apply to participants with a bundle branch block (BBB); for participants with BBB, a cardiology consult is recommended to ensure thatQTcF is not prolonged.

15. Female participants who are women of childbearing potential (WOCBP) must have anegative serum or urine (beta-human chorionic gonadotropin (βhCG)) pregnancy test atscreening and negative serum or urine test documented within the 24-hour periodprior to the first dose of study drug. WOCBP are defined as sexually mature womenwithout prior hysterectomy or who have had any evidence of menses in the past 12months. However, women who have been amenorrheic for 12 or more months are stillconsidered to be of childbearing potential if the amenorrhea is possibly due toprior chemotherapy, anti-estrogens, or ovarian suppression (Section 4.8.1).

16. Sexually active female participants who are WOCBP and male participants who aresexually active partners of WOCBP must agree to use a highly effective method ofcontraception during the course of the study from the date of informed consent andfor at least 3 months after their last dose of study drug. Effective birth controlmethods include the following:

17. Intrauterine device (IUD) plus one barrier method.

18. Stable doses of hormonal contraception for at least 3 months (eg, oral,injectable, implant, transdermal).

19. 2 barrier methods; effective barrier methods are male or female condoms,diaphragms, and spermicides (creams or gels that contain a chemical to killsperm).

20. A vasectomized partner (where vasectomy was done at least 4 months prior tofirst dose of study treatment).

21. True abstinence (ie, abstinence that is in line with the preferred and usuallifestyle of the participant).

22. Female and male participants must agree to refrain from egg/ova retrieval either fortheir own use or donation or from sperm donation, respectively, from the date ofinformed consent until 3 months after the last dose of study treatment.

23. Participant is willing and able to participate and comply with all studyrequirements and to provide signed and dated written informed consent prior toinitiation of any study procedures.

Exclusion Criteria:

1. Relapsed/Refractory AML.

2. ELN (2022) favorable risk AML, except for nucleophosmin 1 (NPM1) mutated AML, whichis allowed.

3. Acute promyelocytic leukemia (APL).

4. Positive Fms related receptor tyrosine kinase 3-Internal tandem duplication (FLT3-ITD) mutation.

5. Active CNS involvement by leukemia (other extramedullary disease is allowed).

6. Participants <18 years or >75 years of age.

7. Female participant who is pregnant or breastfeeding.

8. Participant plans to become pregnant or father a child (including ova or spermdonation) while enrolled in this study or within 3 months after last dose of studytreatment (Section 4.8).

9. Participant has a known allergy or history of hypersensitivity to study drugs ortheir excipients.

10. Previous therapy with olutasidenib (or ivosidenib or other IDH1 inhibitor) orvenetoclax (or another B cell lymphoma 2 (BCL-2) inhibitor).

11. Participant has active evidence of clinically significant unstable medical conditionsuch as uncontrolled infection, severe metabolic abnormality, poorly controlledpsychiatric illness, or symptomatic coronary artery disease (other than stableangina), which could place the participant at unacceptable risk of study treatment,per the Investigator's judgement.

12. Participants receiving treatment with strong Cytochrome P450, family 3, subfamily A (CYP3A) inhibitors within 7 to 14 days or 5 half-lives (whichever is longer) priorto the first dose of study medication. Azoles are allowed with appropriatevenetoclax dose reductions. Please note that participants receiving thesemedications would qualify for this study after undergoing a washout period of 7 to 14 days or 5 half-lives, whatever is longer for the inhibitor/inducer.

13. Participants receiving treatment with strong CYP3A inducers within 7 to 14 days or 5half-lives (whichever is longer) prior to the first dose of study medication. Pleasenote that participants receiving these medications would qualify for this studyafter undergoing a washout period of 7 to 14 days or 5 half-lives, whatever islonger for the inhibitor/inducer.

14. History of allogeneic hematopoietic stem cell transplant (HSCT) for a diagnosisother than AML if there is clinically significant active graft-versus-host disease (GVHD) or ongoing immunosuppressive therapy is required beyond prednisone 10 mgdaily or equivalent. Otherwise, prior allogeneic HSCT is allowed.

15. Participants with a concurrent active malignancy under treatment.

16. Known history of active hepatitis B (HBV) or hepatitis C (HCV) infection or humanimmunodeficiency virus (HIV) infection (clinically detectable viral load).

17. Major surgery within 28 days prior to the first dose. Participants must haverecovered from surgery and be without current complications.

18. Participants with impaired decision-making capacity.