Intervention: Azacitidine
Trial phase: Phase 2
ATC code: L01BC07
SMILES: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 21
Group description: Patients who meet eligibility criteria will be administered vorinostat orally at 300mg two times daily for 7 days. AZA will be administered SC at 75 mg/m2/day x 7 consecutive days or at maximum tolerated dose if a dose reduction of AZA was needed before entering the trial with a minimum dose of 50mg/m2/d for 7 consecutive days.

Each cycle will last 28 days with AZA starting on day 1 of each cycle and vorinostat starting on day 3.

Azacitidine and oral vorinostat: In patients still responding after six cycles, the drugs will continue to be supplied, and follow up until death or unacceptable tolerance will be continued in all patients.
Eligibility criteria:
Inclusion Criteria:

Myelodysplastic syndrome (WHO and FAB classified) including: RA, RARS, RCMD, RCMD-RS RAEB , RAEB-t and CMML with WBC < 13000/mm3)
IPSS score 1.5 or higher (IPSS intermediate-2 and high risk categories) at the beginning of azacitidine,
Absence of response (CR, PR, marrow CR or HI according to IWG 2006) after a minimum of 6 cycles of azacitidine single agent at 75 mg/m²/d for 7 days per cycle. Patients with a previous dose reduction of AZA may be eligible if the maximum tolerated dose was equal to or above 350mg/m2/cycle (i.e. 50 mg/m²/d for 7 days or 75mg/m2/d for 5 days).
Age more or egal to 18 years
ECOG performance status ≤ 2 (cf. appendix 2);
Patient must have adequate organ function as indicated by the following laboratory values

Renal Serum creatinine or calculated creatinine clearancea < 2 mg/dl OR ≥ 60 mL/min for patients with creatinine levels > 1.5 X institutional ULN Hepatic

Serum total bilirubin ≤ 2.5 X ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels ≥ 2 mg/dL.

AST (SGOT) and ALT (SGPT) ≤ 2.5 times ULN Alkaline Phosphatase ≤ 5 X ULN If > 2.5 X ULN, then liver fraction should be ≤ 2.5 X ULN a Creatinine clearance should be calculated per institutional standard.

Patient is known to not be refractory to platelet transfusions.
Patient ineligible for allogeneic hematopoietic stem cell transplantation at the time of inclusion in the study
Adherence to the study visit schedule;
Women of childbearing potential must:

Agree to use effective contraception without interruption throughout the study and for a further 3 months after the end of treatment;

- Men must: Agree to not conceive during the treatment and to use effective contraception during the treatment period (including periods of dose reduction or temporary suspension) and for a further 3 months after the end of treatment if their partner is of childbearing potential.

Agree to learn about the procedures for preservation of sperm.

Exclusion Criteria:

Patient had prior treatment with an HDAC inhibitor (e.g., depsipeptide or NSC-630176, MS 275, LAQ-824, PXD-101, LBH589, MGCD0103, CRA024781, etc). Patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study. Patients who have received such compounds for other indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout period.
Severe infection or any other uncontrolled severe condition.
Last dose of AZA was given more than 3 months before entering the trial.
Patient already enrolled in another therapeutic trial of an investigational drug
HIV infection or active hepatitis B or C.
Patient has a known allergy or hypersensitivity to any component of vorinostat or azacitidine.
Active cancer, or cancer during the year prior to trial entry other than basal cell carcinoma or carcinoma in situ of the cervix or breast.
Less than 30 days since prior treatment with growth factors (EPO, G-CSF) or non-cytotoxic agents (including low-dose oral chemotherapy); in the event of prior treatment with cytotoxic or demethylating agents, an interval of 3 months is required;
Patient is on any systemic steroids that have not been stabilized to the equivalent of ≤ 10 mg/day prednisone during the 4 weeks prior to the start of the study drugs.
Patients with clinical evidence of CNS leukemia.
Patient has a history of GI surgery or other procedures that might interfere with the absorption or swallowing of the study drugs.
Women who are or could become pregnant, or who are currently breastfeeding
Patient eligible for allotransplantation at the time of inclusion.