Addition of Vorinostat to Azacitidine in Higher Risk MDS a Phase II add-on Study in Patients With Azacitidine Failure
Condition: Myelodysplastic Syndrome
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: Azacitidine and oral vorinostat
Intervention description: 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.
Intervention MeSH terms: Azacitidine; Vorinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Azacytidine (AZA) is the current standard of care for frontline patient treated with
      high-risk MDS and is clinically active in all type of MDS, however, 50% of the patients will
      never respond. Vorinostat is an orally available HDAC inhibitor with clinical activity in MDS
      and proven in vitro synergy with AZA. Patient treated upfront with a combination of this
      agents have shown more responses based on phase I/II data. In the present study, we will use
      the combination of these two drugs to try to create a synergetic effect and generate a
      response for patients who experienced treatment failure after AZA.

      All eligible patients will be treated with Azacitidine and oral vorinostat for 6 cycles of 28
      days. Study Design
    

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.