ATRN-119 in Combination With Decitabine in Patients With TP53-Mutated AML or Higher-Risk MDS

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 ii.≥ 10% bone marrow blasts
• Dose Escalation ONLY - One of the following:

• Previously untreated AML with ELN 2022 adverse-risk genetic features based on local testing, in patients who are ineligible for intensive induction chemotherapy (cytarabine plus an anthracycline) due to age, comorbidities, or performance status.
• Previously untreated HR-MDS
• Relapsed or refractory AML or HR-MDS meeting one or more of the following criteria: Failure to achieve CR, CRh, or CRi after ≥ 4 cycles of a hypomethylating agent (HMA); Failure to achieve CR, CRh, or CRi after ≥ 2 cycles of a HMA plus venetoclax; Overt disease progression during HMA-based therapy; 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
• Dose Expansion ONLY - Both of the following:

• AML or HR-MDS with a TP53 alteration, defined by the presence of any of the following features on local testing: Pathogenic or likely pathogenic TP53 mutation detected by molecular testing (with a minimum 2% VAF); Cytogenetic and/or FISH evidence of 17p deletion involving TP53 (with a minimum 2% cell involvement or the lower limit of detection of the assay); Increased hematopoietic p53 protein expression by immunohistochemistry (defined as >20% p53-positive cells). Patients enrolled during the dose expansion phase on the basis of increased p53 protein expression who are subsequently found not to harbor a TP53 mutation on molecular testing may continue study treatment.
• No prior therapy for a myeloid neoplasm, with the exception of permitted treatments
• At least 18 years of age.
• ECOG performance status ≤ 2
• Adequate organ function within 28 days prior to the first dose of ATRN-119 as defined below:

• Total bilirubin ≤ 2.0 x IULN; patients with known or suspected Gilbert's syndrome may have total bilirubin ≤ 5 mg/dL
• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
• Estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 or creatinine clearance ≥ 30 mL/min/1.73 m2 by Cockcroft-Gault formula or creatinine ≤ 2.0 x IULN
• The effects of ATRN-119 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 ATRN-119 or decitabine on study (whichever is later) for people of childbearing potential and 3 months 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

• Dose Expansion ONLY - Prior therapy for AML, HR-MDS, antecedent MDS, or antecedent myeloproliferative neoplasm (MPN) with the exception of erythropoiesis-stimulating agents, hematopoietic growth factors (e.g., G-CSF, thrombopoietin receptor agonists), hydroxyurea, luspatercept, imetelstat, all-trans retinoic acid (ATRA), and leukapheresis.
• 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 strong inhibitors or inducers of CYP3A4. Patients may be eligible after a washout period of 5 half-lives or 28 days (whichever is shorter).
• A history of allergic reactions attributed to or known hypersensitivity to compounds of similar chemical or biologic composition to ATRN-119, decitabine, or other agents used in the study.
• 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 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.