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 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.