Vorinostat and Low Dose Cytarabine for High Risk Myelodysplasia

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:

• 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).
• Patient has a IPSS score > 1. 5 (INT-2 and high risk categories).
• Patient must have been previously treated with demethylating agents (including Azacitidine and Decitabine) and :

• failed to respond or
• progress after treatment.
• Patient is male or female, and ≥ 18 years of age on day of signing informed consent.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (See Appendix 6.1).
• Patient has recovered from toxicities due to prior therapy (less than grade 2) except for cytopenia
• Patient must have adequate organ function as indicated by the following laboratory values: serum creatinine <2mg/dl; total bilirubin <2,5ULN; AST<2,5ULN, ALT<2,5ULN, PAL<5ULN
• Patient is known to not be refractory to platelet transfusions.
• 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.
• 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.
• 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.
• Patient is available for periodic blood sampling, study related assessments, and appropriate clinical management at the treating institution for the duration of the study.
• Patient has the ability to understand and willingness to sign an informed consent form indicating the investigational nature of the study.
• Patient is able to swallow capsules.

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.
• Patient has been previously treated with low dose (20 mg/m2 SC daily) Ara-C for MDS within 3 months of beginning this study.
• Patient has active and uncontrolled infection
• 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 compliance.
• 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.
• Patient has known human immunodeficiency virus (HIV) infection or HIV-related malignancy.
• Patient has clinically active hepatitis B or hepatitis C infection.
• Patient has a known allergy or hypersensitivity to any component of vorinostat or Ara-C.
• 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.
• 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.
• 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.
• Patient is unable to take and/or tolerate oral medications on a continuous basis.