FHD-286 with Decitabine and Venetoclax for the Treatment of Newly Diagnosed or Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria

• Newly diagnosed adverse risk AML, including myelodysplastic syndrome (MDS)/AML, per the 2022 European Leukemia Network (ELN) criteria, with a histopathologic diagnosis confirmed by hematopathology review OR AML that has progressed after 1 prior line of therapy with ≥ 5% blasts
• NEWLY DIAGNOSED AML: 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: * Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or 3 * Cardiac history of congestive heart failure requiring treatment, or ejection fraction ≤ 50%, or chronic stable angina pectoris * Diffusing capacity of the lung for carbon monoxide ≤ 65% or forced expiratory volume in 1 second ≤ 65% * Creatinine clearance ≥ 30 mL/min to < 45 mL/min * Moderate hepatic impairment with total bilirubin >1.5 to ≤ 3.0 × upper limit of normal (ULN) * Any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy
• NEWLY DIAGNOSED AML: Bone marrow blasts ≥ 10%
• NEWLY DIAGNOSED AML: Have not received an hypomethylating agent (HMA) or VEN for their disease under study
• No other disease-directed therapy, except hydroxyurea or cytarabine, and including experimental or investigational drug therapy, for at least 14 days before study entry
• ECOG PS * Newly diagnosed AML: ** ≥ 75 years: ≤ 2 ** ≥ 18 years to < 75 years: ≤ 3 * AML that has progressed after 1 prior line of therapy (Any age): ** ≤ 3 if relapsed/refractory (R/R) AML
• Life expectancy ≥ 3 months
• 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
• Prothrombin time ≤ 1.5 × ULN or international normalized ratio ≤ 1.4
• 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
• No known portal vein thrombosis
• 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)
• Adequate cardiovascular, respiratory, and immune system function as evidenced by the below criterion and in the opinion of the investigator: * Left ventricular ejection fraction (LVEF) of ≥ 40% by echocardiogram (ECHO)
• White blood cell (WBC) count ≤ 20 × 10^9/L (treatment with hydroxyurea or cytarabine ≤ 1 g/m^2 to achieve this count is allowed before the start of study treatment and for up to 28 days after the start of study treatment)
• Agree to abide by dietary and other considerations required during the study
• Ability to understand and willingness to sign a written informed consent form (ICF) and complete study-related procedures

Exclusion Criteria

• Acute promyelocytic leukemia
• Core binding factor AML who is a candidate for intensive chemotherapy
• Eligible for and willing to receive standard HMA/VEN therapy (only applicable for individuals with newly diagnosed AML)
• Evidence (or suspicion) of central nervous system (CNS) involvement
• Prior treatment with AZA, 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
• 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].)
• Planning to become pregnant within 1 year after start of study treatment
• Uncontrolled intercurrent illness that could limit life expectancy or ability to complete study correlates. This includes, but is not limited to: * Ongoing or active infection. Because patients with myeloid malignancies are prone to infections, if patients are actively being treated with appropriate antibiotics or antifungal agents with clinical evidence of infection control, they may be considered eligible for study with principal investigator (PI) approval. 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. * Uncontrolled concurrent malignancy * 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 enrolled with approval from PI. * Congestive heart failure of New York Heart Association class III/IV. Patients with compensated heart failure are permitted. * Unstable angina pectoris * New or unstable cardiac arrhythmia. Stable or controlled arrhythmias may be permitted with approval from PI. * Decompensated liver cirrhosis (Child-Pugh score ≥ 12 or a Model for EndStage Liver Disease [MELD] score ≥ 21) * Psychiatric illness/social situation that would limit compliance with study requirements * 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
• Unable to tolerate administration of oral medication or has gastrointestinal dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of FHD286
• Taking medications classified as: * 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 treatment. 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). * 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 treatment. * Sensitive CYP3A substrates with narrow therapeutic indices
• Taking proton pump inhibitors (PPIs). Administration of PPIs must be stopped or switched to another acid-reducing agent (eg, antacids or H2 blockers) at least 7 days before study entry
• WOCBP sexually active with male partners and fertile males sexually active with WOCBP unwilling to agree to use dual contraceptive measures (ie, 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. Male participants must agree to refrain from donating sperm from the screening visit through 90 days after the last dose of FHD-286
• 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 CD4 count > 200 cells/µL, and on a stable regimen of antiretroviral therapy would be eligible
• 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
• Known allergy or hypersensitivity to any component of DAC, VEN, or FHD-286 formulations