Addition of Suberoylanilide Hydroxamic Acid (Vorinostat) to Azacitidine in Patients With Higher Risk Myelodysplastic Syndromes (MDS): a Phase II add-on Study in Patients With Azacitidine Failure.
- 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
- 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
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
- 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
Agree to learn about the procedures for preservation of sperm.
- 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
- 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
- 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.