PhII 5-Azacytidine Plus Valproic Acid and Eventually Atra in Intermediate II and High Risk MDS

Inclusion Criteria:

• Have a diagnosis of refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-t) according to the French-American-British classification system for MDS with an International Prognostic Scoring System score of INT-2 or High or diagnosis of Myelodysplastic CMMoL per a modified FAB criteria and a relatively high risk of AML transformation;

  • Age ≥18 years;
  • life expectancy ≥3 months;
  • Be unlikely to proceed to bone marrow or stem cell transplantation therapy following remission;
  • Signed written informed consent according to IGH/EU/GCP and national local laws;
  • Eastern Cooperative Oncology Group Performance Status Grade of 0-2 (Appendix D);
  • Serum bilirubin levels ≤1.5 x the upper limit of the normal (ULN) range for the laboratory; higher levels are acceptable if these can be attributed to active hemolysis (as indicated by positive direct Coombs' testing, decreased haptoglobin level, elevated indirect bilirubin and/or lactate dehydrogenase), or ineffective erythropoiesis (as indicated by bone marrow findings);
  • Serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) or serum glutamic-pyruvic transaminase (alanine aminotransferase) levels ≤2 x ULN;
  • Women of childbearing potential may participate, providing they meet the following conditions:
• Must not start a pregnancy throughout the study and for 6 months following the date of the last dose of study medications;

• Must have a negative serum pregnancy test obtained within 48 hours prior to Day 1.

  • Males with female partner of childbearing potential must avoid fathering throughout the study and for 6 months following the date of the last dose of study medication.

Exclusion criteria:

• acute myeloid leukaemia (i.e. bone marrow blasts >30%);
• concurrent malignancy diagnosed in the past 12 months (with the exception of skin basalioma);
• severe renal impairment (creatinine clearance <30 ml/min);
• pregnant or lactating, or are potentially fertile (both males and females) and have not agreed to avoid pregnancy during the trial period;
• they have liver disease characterized by AST and ALT level >2X ULN and total bilirubin > 1.5X ULN (unless due to active hemolysis or ineffective erythropoiesis;
• HIV infection;
• active, uncontrolled HCV or HBV infections or liver cirrhosis;
• clinically relevant neurological diseases;
• psychiatric illness that would prevent granting of informed consent;
• hypersensitivity (known or suspected) to Azacytidine or Mannitol
• prior Treatments: Prior investigational drugs (within 30 days) Radiation therapy, chemotherapy, or cytotoxic therapy for non- MDS conditions within the previous 6 months Growth factors (EPO, G-CSF or GM-CSF) during the previous 21 days Androgenic hormones during the previous 14 days Prior transplantation or cytotoxic therapy, including azacitidine and chemotherapy, administered to treat MDS.