IMetelstat and Azacitidine With or Without Venetoclax GIveN in rElapsed Acute Myeloid Leukemia (IMAGINE Trial)

Inclusion Criteria In order to be eligible for participation in this trial, * Participants must be ≥18 years of age at time of signing the Informed Consent Form (ICF). * Participants must voluntarily sign an ICF. * Participants must have WHO-confirmed non-APL AML who have not responded to or relapsed after at least one prior therapy and for whom no standard therapy that may provide clinical benefit is available. o Participants with isolated extramedullary disease (EMD), including leukemia cutis, are included but not those with active known CNS disease. * Participants must have a life expectancy of at least 12 weeks per investigator. * ECOG performance status ≤ 3. * Women of child bearing potential (WOCBP), defined as a sexually mature woman not surgically sterilized or post-menopausal for at least 24 consecutive months if ≤55 years or 12 months if \>55 years, must have a negative serum pregnancy test at screening and cycle 1 day 1 and must agree to use highly effective methods of birth control starting with the first dose of study therapy through 6 months after the last dose of study therapy. Highly effective methods of contraception include double-barrier methods (diaphragm with spermicidal gel and condoms with spermicide), partner vasectomy, and total abstinence * Male participants should agree to use a highly effective method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy. 8. Must have adequate organ function as demonstrated by the following: * Serum total bilirubin ≤ 2.0 x upper limit of normal (ULN) unless considered due to leukemic organ involvement or Gilbert's syndrome. * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN. * Creatinine clearance (CrCl) ≥ 30 mL/min (measured or estimated by Cockcroft-Gault formula). * Ability to adhere to the study visit schedule and all protocol requirements. * Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria The participant must be excluded from participating in the trial if the participant: * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 2 weeks or within 5 half-lives of the prior investigational agent, whichever is shorter, of the first dose of treatment. * Known clinically active central nervous system (CNS) leukemia. a. Prior CNS leukemia will be allowed if the most recent cerebral spinal fluid sample is negative prior to study initiation and there is no clinical suspicion for active CNS disease. * Has a white blood cell count \> 25 x 109/L (hydroxyurea and/or continuous cytarabine ≤1 g/m2 is permitted to meet this criterion). * Active Graft Versus Host Disease (GVHD), or any GVHD requiring treatment with immunosuppression, with the exception of topical steroids and systemic steroids at a dose equivalent to prednisone 10mg or less. Any GVHD treatment (including calcineurin inhibitors) must be discontinued at least 28 days prior to Day 1 of study treatment. * Participants with a history of other cancers must not be receiving active treatment (with radiation or chemotherapy) and must be free of disease for 2 years prior to the Screening Visit with the exception of localized prostate cancer treated with hormone therapy, breast cancer treated with hormone therapy, localized basal cell carcinoma, non-melanoma skin cancer, cervical carcinoma in situ, concurrent low-grade lymphoma, that is asymptomatic and lacks bulky disease and shows no evidence of progression, and for which the participant is not receiving any systemic therapy or radiation * Myocardial infarction or unstable angina within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification. * Presence of active serious infection. a. If a participant is identified to have COVID-19 during the screening period, participants may be considered eligible if in the opinion of the investigator there are no COVID-19 sequelae that may place the participant at a higher risk of receiving investigational treatment * Any serious, unstable medical or psychiatric condition that would prevent, (as judged by the Investigator) the participant from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. * Known history of uncontrolled human immunodeficiency virus (HIV) * Active known systemic hepatitis A, B, or C infection requiring therapy or known cirrhosis. * Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or pharmaceutical sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific participant. * Organ transplant recipients other than bone marrow transplant. * Women who are pregnant or lactating. * Participants with known gastrointestinal (GI) disease or prior GI procedure that could interfere with the oral absorption or tolerance of venetoclax, including difficulty swallowing, are not eligible (Part B only).