Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA

Inclusion criteria

• Voluntary written informed consent
• Histologically or cytologically documented diagnosis of MDS (any French-American-British classification [FAB] subtype)
• Bone marrow blasts >5% and <30% and a peripheral white blood cell (WBC) count of <20,000 /µL
• Bone marrow biopsy, aspirates, and peripheral blood smears within 28 days of first study treatment
• Group 1:

Primary failures: Progression after their most recent HMA therapy according to IWG criteria after receiving single agent azacitidine and/or single agent decitabine, or has worsening cytopenias (increased transfusion requirement), increased BM blasts, progression to a higher FAB type, or develops additional clinically significant cytogenetic abnormalities; Secondary failures: Relapse after any initial CR, PR, HI, or development of clinically significant cytogenetic abnormalities at any time according to IWG criteria after receiving single agent azacitidine or decitabine

Group 2:

Failure to achieve a response (any CR, PR or HI) according to IWG criteria definition of stable disease after the most recent HMA therapy (at least 6 cycles of azacitidine or 4 cycles of decitabine)

• Must have demonstrated tolerability to single agent HMA
• Able to start combination therapy within 3 months of the last single agent HMA dose with no other therapy for disease under study received during this interval
• Not a candidate for hematopoietic stem cell transplant within 4 months of screening
• ECOG performance status of 0, 1, or 2
• Adequate organ function as evidenced by:

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x the upper limit of normal (ULN)
• Total bilirubin ≤1.5 x ULN or total bilirubin of ≤2 mg/dL, whichever is higher
• Serum creatinine <2 mg/dL, or creatinine clearance ≥60 mL/min
• QTcF interval ≤470 msec
• Female or male patients ≥18 years-of-age
• Male patients with female partners are required to use two forms of acceptable contraception; Female patients of childbearing potential must have a negative pregnancy test ≤7 days before first study treatment.
• Willingness and ability to understand the nature of this trial and to comply

Exclusion criteria

• Received any of the following within the specified time frame after the last single agent HMA dose until the first administration of study medication:

• Any therapy for malignancy between the time of single agent HMA and first on-study treatment
• Hydroxyurea within 48 hours prior to first study treatment
• Hematopoietic growth factors: erythropoietin, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), or thrombopoietin receptor agonists within 7 days (14 days for Aranesp) prior to first study treatment
• Major surgery within 28 days of study day 1
• Patients who are candidates for aggressive chemotherapy (e.g. typical AML induction therapy)
• Cardiopulmonary function criteria:

• Current unstable arrhythmia requiring treatment
• History of symptomatic congestive heart failure (New York Heart Association Class III or IV)
• History of myocardial infarction within 6 months of enrollment
• Current unstable angina
• Concomitant treatment with agents that have activity against HDAC inhibitors is not permitted
• Clinical evidence of CNS involvement
• Patients with gastrointestinal (GI) tract disease, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)
• Active infection with human immunodeficiency virus or chronic hepatitis B or C
• Life-threatening illness unrelated to cancer or any serious medical or psychiatric illness that could potentially interfere with participation in this study
• Presence of a malignant disease within the last 12 months, with the exception of adequately treated in-situ carcinomas, basal or squamous cell carcinoma, or non-melanomatous skin cancer and other concurrent malignancies will be considered on a case by case basis
• Inability or unwillingness (including psychological, familial, sociological, or geographical conditions) to comply