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

A Phase II, Open-Label, Multicenter Study of Orally Administered CA-4948 for the Treatment of Anemia in Patients With Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS)

Anemia in LR-MDS patients

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:

1. 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

2. 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

3. 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

4. Defined transfusion strategy

5. 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

  1. Serum creatinine > 2 × ULN or calculated creatinine clearance < 30 ml/min
  2. AST > 2 × ULN or ALT > 2 × ULN
  3. 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