Inclusion Criteria:
* Diagnosis of AML or higher-risk MDS (HR-MDS) according to the World Health Organization (WHO) 5th Edition or International Consensus Classification (ICC) 2022 criteria.
* HR-MDS is defined as:
* IPSS-R (score \> 3.5) or IPSS-M (score \> 0.5) OR
* ≥ 10% bone marrow blasts
* At least one of the following demonstrated on standard of care testing:
* A pathogenic or likely pathogenic TP53 mutation with a VAF ≥10%
* A TP53 or chromosome 17p deletion detected in ≥10% of cells by a cytogenetic assay
* \>20% p53-positive cells by immunohistochemistry
* Meeting R/R disease criteria for AML or HR-MDS:
* Patients with R/R AML must have received at least 1 prior AML-directed treatment regimen appropriate for their disease and fitness. Patients with FLT3, IDH1, IDH2, or NPM1 mutations must also have previously received, or been deemed ineligible for, an approved targeted therapy directed against the relevant mutation. In addition, patients must meet at least one of the following criteria:
* Disease progression during treatment with, or failure to achieve CR, CRh, or CRi after ≥ 2 cycles of a hypomethylating agent (HMA) plus venetoclax.
* Disease progression during treatment with, or failure to achieve CR, CRh, or CRi after ≥ 4 cycles of HMA-based therapy when venetoclax was contraindicated, not tolerated, or otherwise considered clinically inappropriate.
* First relapse with an initial remission duration \< 12 months
* First relapse following failed salvage chemotherapy
* Relapse after allogeneic hematopoietic cell transplant
* Second or subsequent relapse
* Patients with R/R HR-MDS must have received at least 1 prior MDS-directed treatment regimen appropriate for their disease and fitness. Patients with IDH1 mutations must also have previously received, or been deemed ineligible for, an approved targeted therapy directed against the relevant mutation. Patients must meet at least one of the following criteria:
* Disease progression during treatment with, or failure to achieve CR, CRh, or CRi after ≥ 4 cycles of HMA-based therapy or 2 cycles of HMA in combination with another agent, including an investigational agent as part of a clinical trial or in routine clinical care.
* Relapse after allogeneic hematopoietic cell transplant
* Second or subsequent relapse
* At least 18 years of age.
* ECOG performance status ≤ 2
* Adequate organ function within 28 days prior to the first dose of mosipasertib as defined below:
* Total bilirubin ≤ 2.0 x IULN; patients with known or suspected Gilbert's syndrome may have total bilirubin ≤ 3 x IULN
* AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
* Creatinine clearance ≥ 45 mL/min/1.73 m\^2 by Cockcroft-Gault formula
* The effects of mosipasertib and decitabine on the developing human fetus are unknown. For this reason, people of childbearing potential and people able to father a child must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 6 months after the last dose of mosipasertib or decitabine on study (whichever is later) for people of childbearing potential and 3 monthsafter the last dose of mosipasertib or decitabine on study (whichever is later) for people able to father a child.
* Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Exclusion Criteria:
* Active CNS involvement by AML requiring therapeutic intervention.
* Active graft-versus-host disease (GVHD) requiring systemic immunosuppressive therapy except for low-dose steroids (prednisone ≤ 10 mg per day or other steroid equivalent)
* Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
* Currently receiving any other investigational agents.
* Concomitant systemic treatment with inhibitors of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, or MATE2-K. Patients may be eligible after a washout period of at least 7 days or 5 half-lives, whichever is longer, prior to the first dose of ATRN-119.
* Concomitant systemic treatment with strong inhibitors or inducers of CYP enzymes. Patients may be eligible after a washout period of 5 half-lives or 14 days (whichever is longer) before PK Run-In Day 1 or C1D1 (whichever is applicable) for strong inducers, and 5 half-lives or 7 days (whichever is longer) before PK Run-In Day 1 or C1D1 (whichever is applicable) for strong inhibitors.
* A history of allergic reactions attributed to or known hypersensitivity to compounds of similar chemical or biologic composition to mosipasertib, decitabine, or other agents used in the study.
* Persistent corrected QT interval using Fridericia's formula (QTcF) \>480 msec (CTCAE v6.0 ≥ grade 2), except in patients with bundle branch block and/or ventricular paced rhythm for whom QTc cannot be reliably assessed using standard correction methods.
* Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, clinically significant autoimmune disease requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, or clinically significant or uncontrolled cardiac arrhythmia. Patients with a known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Function Classification; to be eligible for this trial, patients should be a class 2B or better.
* Conditions that may impair oral drug administration or absorption, including inability to swallow oral medications, malabsorption syndromes, or other clinically significant gastrointestinal disorders.
* Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of PK Run-In Day 1/Cycle 1 Day 1.
* HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing is not required in the absence of known history of infection.
* Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load by PCR on suppressive therapy are eligible. HBV testing is not required in the absence of known history of infection.
* History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing is not required in the absence of known history of infection.
