Danvatirsen Monotherapy Followed by Combination With Venetoclax in Relapsed/Refractory MDS & AML

Inclusion Criteria: * Subjects must be at least 18 years of age at the time of signing the Informed Consent Form (ICF); must voluntarily sign an ICF; and be able to meet all study requirements * Morphologically confirmed diagnosis of AML or MDS in accordance with World Health Organization (WHO) diagnostic criteria * Subjects with relapsed/refractory AML who are refractory or relapsed to all conventional therapy and do not have any FDA approved or standard therapeutic options \& subjects with intermediated/high/very high IPSS-R MDS who are refractory or relapsed to at least 2 cycles of hypomethylating agent based therapy (azacitidine / decitabine based) OR patients with rapid progression of disease regardless of number of cycles of therapy * Subjects with MDS/MPN overlap features by NCCN version 3.2026 will also be eligible for the study after they are relapsed or refractory to at least 2 cycles of hypomethylating agent based therapy OR patients with rapid progression of disease regardless of number of cycles of therapy * At least 3 months from Allogenic stem cell transplantation and no clinical sign of active graft vs host disease (GVHD) * WBC must be \<25,000 cells/uL and may be reduced with hydroxyurea to reach this goal prior to study start. Hydroxyurea can be administered on trial with an increase in WBC counts at the discretion of the PI * A bone marrow biopsy must be performed within the screening window (day-28-day-1) and tissue collected for correlative analysis for entrance to this trial. Correlative sample collection is essential for this study * Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 * Recovery to ≤ Grade 1 or baseline for any toxicities considered to be due to prior systemic treatments, excluding alopecia * Must have adequate hepatic and renal function as follows: ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN) or ≤ 5x ULN if considered to be leukemia related; Direct bilirubin ≤ 1.5 x ULN or ≤ 3x ULN (in patients with known Gilberts syndrome or if considered to be leukemia related) * Serum creatinine clearance ≥ 45 mL/min/1.73 m2 either measured or calculated using standard Cockroft-Gault formula * Subjects enrolled within childbearing ages of 18-50 years should use 2 forms of contraception while on study Exclusion Criteria: * Acute Promyelocytic Leukemia * Low or very low risk MDS by IPSS-R after failure/progression of first line therapy with hypomethylating agents * Active, uncontrolled infection. Patients with infection under active treatment and controlled with antibiotics are eligible. Use of prophylactic anti-microbials per institutional standards is allowed * Active documented central nervous system (CNS) leukemia. Patients with a known history of CNS leukemia will be eligible if they have at least two most recent consecutive LPs showing clearance of CNS disease and no active/progressive symptoms thought to be related to the CNS disease * Concurrent treatment with a non-permitted concomitant medication * Concurrent anticancer treatment, major surgery, or the use of any investigational drug within 14 days before the start of trial treatment * Other malignancy currently being treated or likely to need treatment in next 6 months with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ, surgically removed malignancies or malignancies definitively treated with chemotherapy, XRT and/or surgery with no evidence of active malignancy or not anticipated to need treatment in next 6 months or malignancies on maintenance therapy (e.g. tamoxifen for breast cancer) will be allowed after discussion and approval by both MPIs * Pregnant or breastfeeding females * Known current alcohol or drug abuse * Clinically significant cardiovascular disease within the past 6 months (e.g. percutaneous intervention, coronary artery bypass graft, documented NYHA class III/IV cardiac heart failure, unstable angina or MI, poorly controlled atrial or ventricular arrhythmia) as determined by the investigator * Any psychiatric condition that would prohibit the understanding or rendering of informed consent * Legal incapacity or limited legal capacity to sign consent and/or participate in the trial * Any condition deemed by the investigator to make the patient a poor candidate for clinical trial and/or treatment with investigational agents * Previous exposure to the investigational agent (danvatirsen)