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A Phase I/II Study of Vorinostat in Combination With Low Dose Ara-C for Patients With Intermediate-2 or High Risk Myelodysplastic Syndromes

Phase 1/Phase 2
18 Years
Not Enrolling
Myelodysplastic Syndromes

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Trial Information

A Phase I/II Study of Vorinostat in Combination With Low Dose Ara-C for Patients With Intermediate-2 or High Risk Myelodysplastic Syndromes

This is a multi-center, open-label, non-randomized, Phase I/II study. Patients will be
treated either with arm A or B dosing schedules which contain increasing durations of
exposure to vorinostat. LD Ara-C will be administered once daily, subcutaneously(SC), at
10 mg/m² in Cycle 1 and escalated to 20 mg/m² daily in Cycle 2 and above for 14 out of 28
days. Oral vorinostat will be administered as 400 mg, once daily either sequentially(Arm A)
or concurrently (Arm B) with LD Ara-C in Dose Level #1 for 7 days, Dose Level #2 for 10
days, or Dose Level #3 for 14 days out of each 28-day cycle. Patients who do not have
disease progression and who continue to meet eligibility criteria may receive up to 3
additional 28-day cycles of treatment.

Inclusion Criteria:

- Patients must meet all of the following criteria to participate in the study:

1. Patient has MDS including the following FAB sub-types: refractory anemia with
blast excess (RAEB) ,transformed refractory anemia with blast excess (RAEB-t)
and non proliferative Chronic MyeloMonocytic Leukemias (WBC below 13G/l).

2. Patient has a IPSS score > 1. 5 (INT-2 and high risk categories).

3. Patient must have been previously treated with demethylating agents (including
Azacitidine and Decitabine) and :

1. failed to respond or

2. progress after treatment.

4. Patient is male or female, and ≥ 18 years of age on day of signing informed

5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
(See Appendix 6.1).

6. Patient has recovered from toxicities due to prior therapy (less than grade 2)
except for cytopenia

7. Patient must have adequate organ function as indicated by the following
laboratory values: serum creatinine <2mg/dl; total bilirubin <2,5ULN;

8. Patient is known to not be refractory to platelet transfusions.

9. Female patient of childbearing potential has a negative serum pregnancy test
(β-hCG) within 72 hours prior to receiving the first dose of vorinostat and or
Ara-C . Female patient is not actively breastfeeding at the time of study entry.

10. Female patient is either post-menopausal, free from menses for > 2 years,
surgically sterilized or willing to use 2 adequate barrier methods of
contraception to prevent pregnancy or agrees to abstain from becoming pregnant
throughout the study, starting with Visit 1.

11. Male patient agrees to use an adequate method of contraception for the duration
of the study. Men should be advised not to father a child while receiving
vorinostat and for 1 month post study.

12. Patient is available for periodic blood sampling, study related assessments, and
appropriate clinical management at the treating institution for the duration of
the study.

13. Patient has the ability to understand and willingness to sign an informed
consent form indicating the investigational nature of the study.

14. Patient is able to swallow capsules.

Exclusion Criteria:

1. 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.

2. Patient has been previously treated with low dose (20 mg/m2 SC daily) Ara-C for MDS
within 3 months of beginning this study.

3. Patient has active and uncontrolled infection

4. Patient has uncontrolled intercurrent illness or circumstances that could limit
compliance with the study, including but not limited to the following: symptomatic
congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia,
pancreatitis, or psychiatric or social conditions that may interfere with patient

5. Patient is currently participating or has participated in a study with an
investigational compound or device within 30 days of initial dosing with study drug.

6. Patient has known human immunodeficiency virus (HIV) infection or HIV-related

7. Patient has clinically active hepatitis B or hepatitis C infection.

8. Patient has a known allergy or hypersensitivity to any component of vorinostat or

9. Patient with a "currently active" second malignancy, other than nonmelanoma skin
cancer and carcinoma in situ of the cervix, should not be enrolled. Patients are not
considered to have a "currently active" malignancy if they have completed therapy for
a prior malignancy, are disease free from prior malignancies for >5 years or are
considered by their physician to be at less than 30% risk of relapse.

10. Patient has received growth factors such as epoetin alfa (EPO) or granulocyte
colony-stimulating factor (G-CSF) or has received non cytotoxic agents (including low
dose oral chemotherapy) in the 30 days before inclusion. In case of previous
cytotoxic treatment, an interval of 3 months is required.

11. 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

12. Patients with clinical evidence of CNS leukemia.

13. Patient has a history of GI surgery or other procedures that might interfere with the
absorption or swallowing of the study drugs.

14. Patient is unable to take and/or tolerate oral medications on a continuous basis.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the Maximum tolerated dose of the association

Outcome Time Frame:

After 1 cycle of treatment

Safety Issue:


Principal Investigator


Investigator Role:

Principal Investigator

Investigator Affiliation:

Groupe Francophone des Myelodysplasies


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:

GFM VOR 2007-01



Start Date:

May 2008

Completion Date:

November 2011

Related Keywords:

  • Myelodysplastic Syndromes
  • Epigenetic
  • Myelodysplasia
  • Cytarabine
  • Myelodysplastic Syndromes
  • Preleukemia