Study of R289 in Patients With Lower-risk Myelodysplastic Syndromes (LR MDS)

Inclusion Criteria:

• Patient must be ≥ 18 years of age at the time of signing the informed consent.

• Must have definitive diagnosis of MDS with very low, low, or intermediate-1 risk (International Prognostic Scoring System (IPSS)-R ≤ 3.5) and ≤5% bone marrowmyeloblasts.

• Must be relapsed, refractory/resistant, intolerant, or have inadequate response totherapies with known clinical benefits for MDS, such as EPOs, luspatercept, andHMAs(i.e., azacytidine or decitabine). Patients with del (5q) must have failed priorlenalidomide therapy.

• Symptomatic anemia untransfused with hemoglobin < 9.0 g/dL and no RBC transfusionwithin 16 of registration or

• RBC transfusion dependent defined as receiving ≥ 2 units of packed red blood cells (PRBCs) within 8 weeks in the preceding 16 weeks for a hemoglobin <9.0 g/dL.

• Exploratory Phase 1B Cohort:

1. Transfusion-dependent LR-MDS who are refractory or intolerant to, or areineligible for ESAs.

2. No prior therapy with any approved or investigational therapies for MDS

3. No del 5q cytogenetic abnormality

4. RBC transfusion dependent defined as receiving ≥ 2 units of PRBCs within 8weeks in the preceding 16 weeks for a hemoglobin <9.0 g/dL

• All participants must have documented marrow iron stores. If marrow iron stain isnot available, the transferrin saturation must be >20% or a serum ferritin > 100ng/100mL

• Must have Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 atscreening.

• Must have adequate organ function, defined as:

1. Hepatic function:

• aspartate amino transferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 × upper limit of normal (ULN)
• total bilirubin ≤ 1.5 × ULN

2. Renal function defined as creatinine clearance > 60 mL/min (usingCockcroft-Gault), or blood creatine < 1.5 mg/dL

Exclusion Criteria:

• Prior treatment for MDS (i.e., TPOs, EPOs, luspatercept, HMAs) concluded < 4 weeksprior to study treatment

• Clinically significant anemia resulting from iron, B12 or folate deficiencies,autoimmune or hereditary hemolysis, or GI bleeding.

• MDS secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy formalignant or autoimmune diseases.

• Diagnosis of chronic myelomonocytic leukemia.

• History of uncontrolled seizures.

• Uncontrolled bacterial or viral infection (i.e., documented HIV, hepatitis B orhepatitis C).

• History of an active malignancy within the past 2 years prior to study entry, withthe exception of:

1. Adequately treated in situ carcinoma of the cervix uteri

2. Adequately treated basal cell carcinoma or localized squamous cell carcinoma ofthe skin, or

3. Low grade, early-stage prostate cancer (Gleason score 6 or below, stage 1 or 2)with no requirement for therapy at any time prior to the study, or previouslyresected.

• History of or active, clinically significant, cardiovascular, respiratory, GI,renal, hepatic, neurological, psychiatric, musculoskeletal, genitourinary,dermatological, or other disorder that, in the Investigator's opinion, could affectthe conduct of the study or the absorption, metabolism or excretion of the studytreatment.

• Prior history of autologous or allogeneic stem cell transplantation

• Marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of aQTc interval > 480 milliseconds [msec]) (Common Terminology Criteria for AdverseEvents [CTCAE] Grade 1) using Fridericia's QT correction formula.

• History of additional risk factors for TdP (e.g., symptomatic heart failure withleft ventricular ejection fraction [LVEF] <40%, hypokalemia, family history of LongQT Syndrome).

• Receiving any other concurrent chemotherapy, radiotherapy, or immunotherapy (within 2 weeks of initiating study treatment), or the toxicity of the relevant priortreatment has not been resolved yet.

• Use of concomitant medications that prolong the QT/QTc interval during studytreatment

• Use of concomitant medications that are strong CYP3A or CYP2B6 inhibitors orinducers during study treatment