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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.

Phase 2
18 Years
Not Enrolling
Myelodysplastic Syndrome

Thank you

Trial Information

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.

Patients who meet eligibility criteria will be administered vorinostat orally at 300mg two
times daily for 7 days as outlined in table 1.1. 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.

Patients will receive 6 cycles unless progression is documented. Patients with a complete
remission (CR), partial remission (PR), or hematological improvement (HI), will be treated
until progression.

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

- 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
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

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

- 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.

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response rate

Outcome Description:

All eligible patients will be treated with Azacitidine and oral vorinostat for 6 cycles of 28 days. The response rate will be evaluated after six cycles, according to IWG 2006. 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.

Outcome Time Frame:

6 month

Safety Issue:


Principal Investigator

Thomas Prebet, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Unité d'Hématologie-Institut Paoli Calmettes,Marseille


France: Agence Nationale de Sécurité du Médicament et des produits de santé

Study ID:

GFM-Aza-Vor 2012-001401-25



Start Date:

March 2013

Completion Date:

March 2016

Related Keywords:

  • Myelodysplastic Syndrome
  • Myelodysplastic Syndromes
  • Preleukemia