LBH589 in Refractory Myelodysplastic Syndromes (MDS)

A Phase II Trial of LBH589 in Refractory Myelodysplastic Syndromes (MDS) Patients

This will be a single arm Phase II study.

LBH589 (20 mg PO) will be administered three times a week on Monday, Wednesday and Friday. Treatment will be given over 21 days followed by a 7 day rest period and repeated every 28 days. Patients will be assessed for toxicity on an ongoing basis and disease assessment will be determined every 2 treatment cycles (8 weeks). Patients will be allowed to continue on treatment for a maximum of eight four week treatment cycles. Treatment will be discontinued if there is evidence of disease progression, unacceptable toxicity and/or at the discretion of the investigator.

Inclusion Criteria:

• Histologically or cytological documented diagnosis of myelodysplastic syndrome (MDS).
• Male or female patients aged >= 18 years old.
• MDS patients who have failed hypomethylating (azacitidine or decitabine) therapy.
• Patients with 5q-cytogenic abnormalities must also have progressed on or been intolerant to lenalidomide.
• Patients with up to and including 30% blasts (FAB RAEB-T) will be eligible to enroll.
• CMML with >= 5% blasts will be eligible to enroll.
• ECOG PS 0, 1 or 2.
• Laboratory values must be as follows:

Bilirubin <= 1.5 mg/dL AST/SGOT <= 2.5 x ULN ALT/SGPT Creatinine <= 2.0 mg/dL or 24-hour Creatinine Clearance >= 50 ml/min Albumin >= 3 g/dL Potassium >= lower limit normal (LLN) Phosphorous >= LLN Calcium >= LLN Magnesium >= LLN

• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to start of treatment.
• Life expectancy >= 12 weeks.

Exclusion Criteria:

• Prior treatment with an HDAC inhibitor.
• Prior intensive chemotherapy or high dose ara-C (>= 1 gm/m2)
• More than one prior single agent chemotherapy regimen. Prior hydroxyurea for cytoreduction will be permitted however.
• Impaired cardiac function
• Active CNS disease, including leptomeningeal metastases.
• Unresolved diarrhea > CTCAE grade 1.
• Chemotherapy, investigational drug therapy, major surgery < 4 weeks prior to starting study drug or patients that have not recovered from side effects of previous therapy.
• Patient is < 5 years free of another primary malignancy except if the other primary malignancy is not currently clinically significant or requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed.
• Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and 3 months after the end of treatment. One of these methods of contraception must be a barrier method.
• Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom.
• Patients with gastrointestinal (GI) tract disease, causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).
• Other concurrent severe, uncontrolled systemic fungal, bacterial, viral or other infection or intercurrent illness, including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with uncontrolled coagulopathy.
• Abnormal thyroid function (TSH or free T4) detected at screening. Patients with known hypothyroidism who are stable on thyroid replacement are eligible.