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

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

Eligibility Criteria:
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