Treatment of Anemia in Patients With Very Low, Low or Intermediate Risk Myelodysplastic Syndromes With CA-4948

Anemia in non-transfusion dependent (NTD) or transfusion dependent (low or high transfusion burden, LTB/HTB) patients with very low, low or intermediate risk myelodysplastic syndromes

Inclusion Criteria:

Diagnosis of de novo myelodysplastic syndrome (MDS) OR de novo myelodysplastic/myeloproliferative neoplasias (MDS/MPN) including MDS/MPN-RS-T, MDS/MPNu, aCML or CMML
Very low/low/intermediate risk disease: IPSS-R up to 3.5 for MDS; MDS/MPN < 10% bone marrow blasts; for CMML low or intermediate risk according to CPSS-Score Symptomatic anemia (based on valid and complete hemoglobin and transfusion history): NTD (non transfusion dependent): < 3 RBC transfusions and mean hemoglobin level <10 g/dl within the last 16 weeks LTB (low transfusion burden): 3-7 RBC transfusions within the last 16 weeks in at least two transfusion episodes, maximum 3 in 8 weeks HTB (high transfusion burden): ≥ 8 RBC transfusions within the last 16 weeks, ≥ 4 in 8 weeks Defined transfusion strategy No available option of an approved MDS therapy and classification of prior erythropoiesis-stimulating agent (ESA) treatment as follows: Cohort A: ESA exposed (and refractory or intolerant) Cohort B: ESA naive AND serum erythropoietin level >200 U/L

Exclusion Criteria:

Compliance with major study procedures

Inability to swallow and retain oral medications (> 10 pills)
Patient does not accept bone marrow sampling during screening and after the treatment
Patient does not accept up to weekly peripheral blood sampling during screening and treatment

Safety

ECOG performance status ≥ 3

Inacceptable organ function

Serum creatinine > 2 × ULN or calculated creatinine clearance < 30 ml/min AST > 2 × ULN or ALT > 2 × ULN
total bilirubin > 2 × ULN (exception >3 × ULN in patients with documented Gilbert’s syndrome)

Interfering treatments

Prior treatment with azacitidine or decitabine
Treatment with erythropoiesis stimulating agent (ESA), G-CSF, GM-CSF, lenalidomide, luspatercept and/or another investigational drug or device up to 14 days before registration
Treatment with iron chelation therapy 56 days before registration, except for subjects on a stable or decreasing dose for at least eight weeks prior to inclusion and during study treatment
Major surgery within 28 days prior to registration

Concomitant diseases

Known human immunodeficiency virus infection (HIV)
Active infectious hepatitis (HBV or HCV)
Hepatitis virus detectable within 6 months before registration in patients with a history of hepatitis
History of other invasive malignancy, unless definitively treated with curative intent, provided it is deemed to be at low risk for recurrence by the treating physician
Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy that has not resolved to Grade ≤ 1 (except anemia and alopecia)
Known allergy or hypersensitivity to any component of the formulation of CA-494824
Severe cardiovascular disease (e.g. myocardial infarction within 6 months registration, unstable angina within 6 months registration, NYHA Class III or greater congestive heart failure, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, known QTc abnormality > 450 msec on ECG

Formal requirements

Positive serum pregnancy test in women of childbearing potential
Women of childbearing potential and men who partner with a woman of childbearing potential unwilling to use highly effective contraceptive methods for the duration of the study and for 90 days after the last dose of CA-4948
Age under 18 years at registration
Inability to provide written informed consent
Simultaneous participation in another interventional clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 28 days prior registration