Assessing PI3K Gamma Inhibition With Azacitidine, Venetoclax and Eganelisib in Patients With Acute Myeloid Leukemia

Inclusion Criteria: * Subjects must have histologically confirmed AML that meets one of these categories of disease: * Group A: Relapsed or Refractory: Subjects with relapsed or refractory AML or relapsed/refractory AML, who are not recommended for any approved targeted therapy must meet any one of the following criteria: (1) morphologic relapse (at least 5% blasts), or (2) refractory to intensive chemotherapy (at least one cycle of cytarabine and anthracycline-based intensive regimen) or at least 2 cycles of prior HMA/venetoclax-based therapy (without CR/CRh/CRi). No limit to prior lines of AML therapy. OR * (Expansion only) Group B: Untreated AML with ELN 2022 adverse risk disease: Subjects with newly diagnosed or previously untreated AML must be ineligible for intensive chemotherapy based on Ferrara criteria (age ≥75 years or presence of co- morbidity). * Evidence of marrow involved AML. * Age 18-90 years. Because no dosing or adverse event data are currently available on the use of eganelisib in participants \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. * Eastern Cooperative Oncology Group performance status ≤ 3 if 18 to 74 years of age or ECOG 0-2 if ≥ 75 years of age. * Subjects must meet the following organ and marrow function as defined below: * total serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) or ≤ 3 x ULN in case of Gilbert's disease * AST(SGOT)/ALT(SGPT) ≤ 2.5 x × institutional ULN * Creatinine clearance (CrCl) ≥ 30 L/min (Cockcroft-Gault formula) * Prior history of CNS leukemia that has been treated, asymptomatic and controlled are eligible. CNS evaluation is not required for screening if asymptomatic. * Subjects with a prior or concurrent malignancy (other than MDS, MPN, MDS/MPN, or AML) whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Treatment must be at least 12 months from last dose of chemotherapy or immunotherapy (except no window is required for palliative radiation or supportive or hormonal therapies). Concurrent malignancy must be considered not active or requiring therapy. * Male subjects and female subjects/women of childbearing potential (WCBP) must agree to the following: The effects of eganelisib on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. When eganelisib is being used alone, the duration of contraception after the last dose should be 3 months for both males and females of childbearing potential. When eganelisib is being used with azacitidine + venetoclax, according to the USPI for azacitidine, females of reproductive potential should use effective contraception during treatment with azacitidine and for 6 months after the last dose and males with female partners of reproductive potential should use effective contraception during treatment with azacitidine and for 3 months after the last dose. WCBP must have negative serum beta human chorionic gonadotropin test measured within 7 days prior to the first dose of eganelisib and consent to ongoing pregnancy testing during the study. * Willingness to practice adequate sun protection (i.e. use of sunscreen or sun-protective clothing, limitation of sun and artificial ultraviolet \[UV\] exposure) for the study duration and for 30 days after the last dose of eganelisib. * Agree to the protocol-required bone marrow biopsies. * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Prior systemic cancer therapy is allowed as long as \>14 days prior to study treatment start. Hormonal therapy may be allowed if approved by Sponsor-Investigator. * Major surgery within 28 days prior to study treatment start. * Allogeneic stem cell transplant within 100 days prior to study treatment start. * Active graft-versus-host disease (GVHD) after allogeneic stem cell transplantation or chronic GVHD requiring systemic steroid administration. Topical therapies are allowed for controlled GVHD. * Receiving systemic immunosuppressive therapy such as steroids or calcineurin inhibitors. * Participants who have not recovered from adverse events due to prior anti-cancer therapy with the exception of alopecia. * Participants who are receiving any other investigational AML directed-agents for this condition. * White blood cell count \> 25x109/L prior to first dose of study treatment. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to eganelisib, venetoclax, or azacitidine. * Participants receiving any medications or substances within 14 days prior to first dose of study drug and for duration of the study: * Moderate or strong inhibitors or inducers of CYP2C8 and CYP3A4, including grapefruit, grapefruit juice, Seville oranges, St. John's wort and herbal supplements, except for antibiotics, antifungals, or antivirals that are moderate or strong inhibitors of CYP3A (preference for moderate CYP3A inhibitors if antifungal therapy is recommended when clinically acceptable). * P-glycoprotein (P-gp) inhibitors except for azole antifungals. * Breast cancer resistance protein (BCRP) inhibitors. * Administration of any of the following as of Cycle 1 Day 1 and for the study duration: Substrates with a narrow therapeutic index for P-gp, or Warfarin, phenytoin, or other substrates with a narrow therapeutic index for CYP2C8 or CYP2C9 * Pregnant women are excluded from this study because eganelisib is an agent without known fertility and developmental toxicity studies. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with eganelisib, breastfeeding should be discontinued if the mother is treated with eganelisib. These potential risks may also apply to other agents used in this study. * History or current evidence of any acute or chronic condition, therapy, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or might confound the results of the trial, interfere with participation for the full duration of the trial, or render trial participation not compatible with the participant's best interest, in the opinion of the Investigator. * Participant must be able to swallow pills and not have any known gastrointestinal abnormality that would affect drug absorption (examples include gastric bypass, gastrectomy, chronic diarrhea).