This is a Phase 1, uncontrolled, single-arm, open-label, nonrandomized, dose escalation, study of Decitabine (DAC)+Venetoclax (VEN)+FHD-286 in participants with newly diagnosed Acute Myeloid Leukemia (AML) classified as adverse risk per the 2022 European Leukemia Net (ELN) criteria or AML that has progressed after one prior line of therapy.

This study evaluates the addition of FHD-286, which has a distinct mechanism of action and clinical activity in AML, to a modification of the current standard of care regimen (DAC/VEN) that has been shown to be more tolerable than and have similar clinical activity as the more intensive regimen evaluated in the VIALE-A study (see References section).

Total duration of trial intervention for each participant will vary. Participants are anticipated to remain on treatment for at least 12 weeks (induction period). As long as they are receiving benefit from treatment, participants may remain on treatment until they experience a reason for treatment discontinuation or study withdrawal. Participants may remain on study as long as they are receiving DAC and VEN, even if FHD-286 is on hold or discontinued due to toxicity.

After written informed consent is obtained from a participant, they will undergo screening evaluations within 28 days before the first dose of study treatment. Results from assessments conducted within 28 days before the first dose of study treatment may be used to fulfill screening requirements, even if they occurred before written informed consent was obtained. The first 3 to 6 participants will participate in the safety run-in portion of the study. During this portion, if ≥3 of the participants develop AEs meeting the stopping criterion during the DLT evaluation period, the study will be terminated. Thereafter, interim safety analyses will be conducted after the enrollment of every 3 participants. The first 12 weeks of treatment (cycles 1-3) are an induction period intended to produce a relatively rapid reduction in tumor burden, to a level that will permit more functional hematopoiesis, alleviating cytopenias and permitting bone marrow recovery. During the induction period, dose modifications and holds are discouraged, except in the case of severe toxicity from severe, non-hematologic adverse events. Additionally, if treatment-related myelosuppression is suspected, dose holds or reductions may be implemented, upon agreement with the principal investigator (PI). If the participant is receiving clinical benefit (at minimum, stable disease) after 12 weeks of treatment, they will have the option of continuing their treatment regimen during the long-term treatment period. The goal of the long-term treatment period is to continue to provide clinical benefit via disease control and hematopoietic improvement. Each participant may continue treatment until they experience a reason for treatment discontinuation. Upon discontinuation of treatment, each participant will be asked to undergo an end-of-treatment evaluation. Thirty days after discontinuation of study treatment, each participant will be asked to undergo a safety follow-up evaluation. Participants will then be contacted approximately every 2 months for long-term follow-up to assess survival status, receipt and type of subsequent anticancer therapy, and disease status.

Dose-limiting toxicities will be assessed during the first cycle (first 28 days) of treatment.

Inclusion Criteria:

1. Newly diagnosed adverse risk AML, including Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), per the 2022 ELN criteria, with a histopathologic diagnosis confirmed by hematopathology review OR AML that has progressed after 1 prior line of therapy with ≥5% blasts

   Inclusion Criteria 2 to 4 apply only for patients who are individuals with newly diagnosed AML:

2. Aged ≥75 years, or aged 18-74 years and either refuse to receive intensive induction chemotherapy or are not a candidate for intensive induction chemotherapy due to one or more of the following comorbidities:

   1. Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or 3
   2. Cardiac history of congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina pectoris
   3. Diffusing capacity of the lung for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%
   4. Creatinine clearance ≥30 mL/min to <45 mL/min
   5. Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0×upper limit of normal (ULN)
   6. Any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy

3. Bone marrow blasts ≥10%

4. Have not received a hypomethylating agent (HMA) or VEN for their disease under study

5. No other disease-directed therapy, except hydroxyurea or cytarabine, and including experimental or investigational drug therapy, for at least 14 days before study entry

6. ECOG PS:

   1. New diagnosed AML:

      • 75 years: ≤2
      • 18 years to <75 years: ≤3

   2. AML that has progressed after 1 prior line of therapy (Any age):

      • 3 if R/R AML

7. Life expectancy ≥3 months

8. Adequate end organ function, defined as:

   1. Adequate hepatic function, including:

      • Serum total bilirubin ≤3.0×ULN, unless considered due to advanced hematologic malignancy involvement or documented Gilbert syndrome with direct bilirubin ≤1.5×ULN
      • Aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤3.0×ULN, unless considered due to advanced hematologic malignancy involvement

   2. Prothrombin time ≤1.5×ULN or international normalized ratio ≤1.4

   3. Activated partial thromboplastin time ≤1.5×ULN Note: Individuals who have been receiving a stable dose of anticoagulation therapy without bleeding episodes for ≥12 weeks may be considered for the study

   4. No known portal vein thrombosis

   5. Glomerular filtration rate (GFR) ≥30 mL/min (based on a contemporary, widely accepted, and clinically applicable equation that estimates GFR or a measure of GFR)

9. Adequate cardiovascular, respiratory, and immune system function as evidenced by the below criterion and in the opinion of the investigator:

   a. Left ventricular ejection fraction (LVEF) of ≥40% by echocardiogram (ECHO)

10. White blood cell count ≤20×10^9/L (treatment with hydroxyurea or cytarabine ≤1 g/m2 to achieve this count is allowed before the start of study treatment and for up to 28 days after the start of study treatment)

11. Agree to abide by dietary and other considerations required during the study

12. Ability to understand and willingness to sign a written informed consent form and complete study-related procedures

Exclusion Criteria:

1. Acute promyelocytic leukemia

2. Core binding factor AML who is a candidate for intensive chemotherapy

3. Eligible for and willing to receive standard HMA/VEN therapy (only applicable for individuals with newly diagnosed AML)

4. Evidence (or suspicion) of central nervous system (CNS) involvement

5. Prior treatment with azacitidine, DAC, VEN, or FHD-286. For individuals with AML that has progressed after 1 prior line of therapy, prior treatment with Azacitidine, Decitabine and VEN is allowed

6. Currently pregnant or breast-feeding. Women of child-bearing potential (WOCBP) must have negative serum pregnancy test within 72 hours before treatment start. (NOTE: WOCBP is any biological female, regardless of sexual or gender orientation, having undergone tubal ligation, or remaining celibate by choice, who has not undergone a documented hysterectomy or bilateral oophorectomy or has had a menses any time in the preceding 12 months [therefore not naturally post-menopausal for >12 months].)

7. Planning to become pregnant within 1 year after start of study treatment

8. Uncontrolled intercurrent illness that could limit life expectancy or ability to complete study correlates. This includes, but is not limited to:

   1. Ongoing or active infection. Because patients with myeloid malignancies are prone to infections, if individuals are actively being treated with appropriate antibiotics or antifungal agents with clinical evidence of infection control, they may be considered for the study. If treatment with a triazole antifungal agent is indicated, isavuconazonium sulfate should be used preferentially. If isavuconazonium sulfate cannot be used, a different triazole antifungal agent may be used. Refer to Exclusion Criterion 10a regarding strong Cytochrome P450, family 3, subfamily A (CYP3A) inhibitors
   2. Uncontrolled concurrent malignancy
   3. Heart rate-corrected QT interval (QTc) by Fridericia method (QTcF) >470 milliseconds (ms) or other factors that increase the risk of QTc prolongation. Participants with QTcF >470 ms and bundle branch block and/or pacemaker rhythm may be considered for the study
   4. Congestive heart failure of New York Heart Association class III/IV. Individuals with compensated heart failure are permitted
   5. Unstable angina pectoris
   6. New or unstable cardiac arrhythmia. Patients with stable or controlled arrhythmias may be considered for the study.
   7. Decompensated liver cirrhosis (Child-Pugh score ≥12 or a Model for End-Stage Liver Disease (MELD) score ≥21)
   8. Psychiatric illness/social situation that would limit compliance with study requirements
   9. Any other prior or ongoing condition that, in the opinion of the investigator, could adversely affect the safety of the individual or impair the assessment of study results

9. Unable to tolerate administration of oral medication or has gastrointestinal dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of FHD-286.

10. Taking medications classified as:

    1. Strong CYP3A inhibitors. Individuals must have stopped treatment with strong CYP3A inhibitors at least 1 week or 5 half-lives, whichever is longer, before the first dose of study drug. Strong CYP3A inhibitors may be permitted; however, the FHD-286 dose should be reduced to 1.5 mg QD when a strong CYP3A inhibitor is in use, and for at least 1 week or 5 half-lives of the strong CYP3A inhibitor, whichever is longer, after the end of treatment with the strong CYP3A inhibitor. The venetoclax dose should be reduced as per the United States Prescribing Information (USPI)
    2. Strong CYP3A inducers. Individuals must have stopped treatment with strong CYP3A inducers at least 2 weeks or 5 half-lives, whichever is longer, before the first dose of study drug
    3. Sensitive CYP3A substrates with narrow therapeutic indices

11. Taking proton pump inhibitors (PPIs). Administration of PPIs must be stopped or switched to another acid-reducing agent (e.g., antacids or H2 blockers) at least 7 days before study entry

12. WOCBP sexually active with male partners and fertile males sexually active with WOCBP unwilling to agree to use dual contraceptive measures (i.e., hormonal or barrier method of birth control, abstinence, condom), beginning at the screening visit and continuing until 4 weeks after taking the last dose of DAC/VEN and 90 days after taking the last dose of FHD-286. Participants must agree to refrain from donating sperm/Ova from the screening visit through 90 days after the last dose of FHD-286

13. Uncontrolled active HIV infection, as this will further increase the risk for opportunistic infections. However, individuals with HIV with undetectable viral load by polymerase chain reaction, without opportunistic infection, with Cluster of Differentiation 4 count (CD4) count >200 cells/µL, and on a stable regimen of antiretroviral therapy would be eligible

14. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, unless the individual has a sustained viral response to HCV treatment or immunity to prior HBV infection

15. Known allergy or hypersensitivity to any component of DAC, VEN, or FHD-286 formulations