A Biomarker-Directed Phase 2 Trial of Tamibarotene (SY-1425) in Participants With Acute Myeloid Leukemia or Myelodysplastic Syndrome

Key Inclusion Criteria

• Must have:
• Relapsed and/or refractory non-APL AML that has failed to achieve a complete remission (CR) or partial remission (PR) following standard induction therapy, or has relapsed after any duration of CR or PR i. Must have measurable disease with bone marrow blasts ≥5%at screening
• Relapsed and/or refractory HR-MDS (High / Very High Risk, as defined by the Revised International Prognostic Scoring System (IPSS-R)) that has failed to achieve a CR or PR, or any hematologic improvement (HI, per IWG 2006 criteria) after standard therapy with hypomethylating agents (e.g., azacitidine, decitabine), or has relapsed after any duration of CR or PR or HI i. Must have measurable disease with bone marrow blasts >5% at screening
• Newly diagnosed, treatment-naïve non-APL AML in participants who, at the time of study entry are unlikely to tolerate standard intensive chemotherapy due to age, performance status, or comorbidities based on at least one of the following criteria:
• i. Age ≥ 75 years old
• ii. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 3
• iii. Cardiac history of congestive heart failure (CHF) or documented ejection fraction (EF) ≤ 50%
• iv. Pulmonary disease with diffusing capacity of lung for carbon monoxide ≤ 65% or Forced Expiratory Volume in 1 Second ≤ 65%
• v. Creatinine clearance ≥ 30 milliliter (mL)/minute (min) to 1.5 to ≤ 3.0 x upper limit of normal (ULN)
• vii. Any other comorbidity that the Investigator judges to be incompatible with intensive chemotherapy, and reviewed and approved by the Sponsor prior to enrollment
• Transfusion-dependent LR-MDS without the del 5q abnormality, in participants refractory to erythropoietin treatment or unlikely to respond to erythropoietin treatment (EPO >500).
• i. LR-MDS: Very Low /Low / Intermediate Risk, as defined by IPSS-R.
• ii.Red blood cell (RBC) transfusion-dependent anemia defined as no eight consecutive weeks without RBC transfusions within the 16 weeks prior to study entry, or ≥4 RBC transfusions within the 8 weeks prior to study entry.
• iii.Refractory to or ineligible for erythropoiesis-stimulating agents (ESAs) is defined as RBC-Transfusion Dependence despite ESA treatment of ≥40,000 units/week recombinant human erythropoietin for 8 weeks or an equivalent dose of darbepoetin (150 µg/week) or serum EPO level >500 milliunits (mU)/mL in participants not previously treated with ESAs.
• Participants must be evaluated for the RARA super-enhancer associated biomarker or RARA pathway associated biomarker at the time of study screening.

a. Participants treated with tamibarotene monotherapy and in combination with daratumumab, and R/R AML participants treated with tamibarotene in combination with azacitidine must be positive as defined by a pre-determined cut-off

• Must be amenable to serial bone marrow aspirates and peripheral blood sampling during the study.
• ECOG Performance Status (PS) of 0, 1 or 2. For newly diagnosed AML participants 1000 mg/dL (CTCAE Grade 4).
• Participants with clinically significant cardiac disease including one of the following currently or in the previous 6 months: myocardial infarction, unstable cardiac function due to unstable angina or congestive heart failure, congenital long QT syndrome, torsades de pointes or significant ventricular arrhythmias.
• Participants with known active uncontrolled central nervous system (CNS) leukemia.
• Participants taking Vitamin A supplements (>10, 000 IU/d) unless discontinued prior to first dose of study drug, or having hypervitaminosis.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.