PhII 5-Azacytidine Plus Valproic Acid and Eventually Atra in Intermediate II and High Risk MDS
Condition: Myelodysplastic Syndromes
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: 5-Azacytidine; Valproic Acid; ATRA
Intervention MeSH terms: Azacitidine; Valproic Acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 62.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: MDS; 5-Azacytidine; valproic acid; atra; intermediate or high risk; Age ≥18 yearsAge

Summary:

      The primary objective of the trial is to assess the activity of the combined use of Valproic
      Acid (VPA)in combination with 5-Azacytidine (5-Aza C) in the treatment of MDS.

      Activity will be evaluated as percentage of patients achieving complete or partial remission.
    

Eligibility criteria:

        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.