A Study to Investigate BAY2402234, a Dihydroorotate Dehydrogenase (DHODH) Inhibitor, in Myeloid Malignancies

An Open-label, Multicenter Phase 1 Study to Characterize the Safety, Tolerability, Preliminary Antileukemic Activity, Pharmacokinetics, and Maximum Tolerated Dose or Pharmacological Active Dose of BAY2402234 in Patients With Advanced Myeloid Malignancies

The primary objective is to determine the safety, tolerability, pharmacokinetics, maximum tolerated dose (MTD), or pharmacological active dose (PAD) of BAY2402234 in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML).

The secondary objective is to evaluate evidence of clinical efficacy associated with BAY2402234 in patients with AML (defined as Complete remission, Complete remission with partial hematologic recovery), and MDS (defined as hematological improvement).

Inclusion Criteria:

• Patients with relapsed or refractory AML. Relapsed AML is defined as relapse after achieving a response to initial therapy and refractory AML is defined as failure to achieve a response after one previous line of therapy. Response is defined as per IWG criteria (CR, CRi or CRp). Patients who are not candidates to receive or who decline standard of care therapy are also eligible.
• Patients with intermediate-1 or higher risk MDS who have failed therapy with a hypomethylating agent, or have failed lenalidomide therapy if harboring a 5q-chromosomal deletion.
• Patients with relapsed/refractory CMML.
• Estimated glomerular filtration rate (eGFR) > 40 mL per 1.73 m^2
• Patients must have adequate coagulation (international normalized ratio [INR] ≤ 1.5; activated partial thromboplastin time [aPTT] ≤1.5 X the upper limit of normal [ULN]; patients on chronic anticoagulation therapy at investigator's discretion; patients on chronic use of direct-acting oral anticoagulants who have acceptable benefit-risk ratio at investigator's discretion)
• Adequate liver function (total bilirubin ≤1.5 X ULN (or ≤3 X ULN in patients with documented Gilbert's syndrome or for patients with hyperbilirubinemia considered due to myeloid disease), alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≤3 X ULN (or ≤5 X ULN for patients with liver involvement of their myeloid disease)

Exclusion Criteria:

• Patients eligible for hematopoietic stem cell transplantation
• Clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia
• Human immunodeficiency virus (HIV) infection
• Chronic or active hepatitis B or C if not controlled by antiviral therapy
• History of organ allograft (allogeneic bone marrow or stem cell transplant) within 3 months prior to first dose of study drug
• Serious, uncontrolled infection requiring systemic antibiotic, antifungal or antiviral therapy. Prophylactic antibiotic, antifungal and/or antiviral therapy is permitted
• Left ventricular ejection fraction (LVEF) <40%