Phase IIA Study of the HDAC Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases

A Phase IIA Study of the Histone-deacetylase Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases

Primary Objective:

To evaluate efficacy and safety of ITF2357 in the treatment of patients with JAK2V617F positive myeloproliferative diseases [Polycythemia Vera (PV), Essential Thrombocytosis (ET), Myelofibrosis (MF)]. Efficacy was evaluated by ad hoc haematological and clinical criteria for PV and ET, and by internationally established response criteria (EUMNET criteria) for MF. Safety was evaluated by number of subjects experiencing an Adverse Event (AE), type, frequency, severity, timing and relatedness of AEs, including changes in vital signs and clinical laboratory results.

Secondary Objective:

To evaluate the JAK2 mutated allele burden by quantitative Real-Time Polymerase Chain Reaction (qRTPCR).

This is a non-randomized, open-label, Phase IIA pilot study testing efficacy and safety of ITF2357 in a population of patients with JAK2V617F positive myeloproliferative diseases. All recruited patients received an initial dose of 50 mg b.i.d. of ITF2357 that was subsequently escalated to 50 mg t.i.d. in case of lack of significant toxicity. Treatment lasted up to a maximum of 24 cumulative weeks of drug administration. The study was carried out in Italy. Enrolled patients were subjects of both genders, with an established diagnosis of polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) according to the revised WHO criteria.

Inclusion Criteria:

• Signed Informed Consent Form
• Male or female, age ≥ 18 years
• Confirmed diagnosis of PV/ET/MF according to the revised World Health Organisation criteria
• JAK-2 V617F positivity
• In need of cytoreductive therapy when hydroxyurea is not indicated (e.g. young patients) or when refractoriness to the drug is documented

Exclusion Criteria:

• Active bacterial or fungal infection requiring antimicrobial treatment on Day 1
• Patients of childbearing potential without a negative pregnancy test prior to initiation of the study drug
• Pregnancy or lactation
• A marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval > 450 ms, according to Bazett's correction formula - see appendix G for the formula)
• The use of concomitant medications that prolong the QT/QTc interval (see appendix F for full list)
• Concomitant acute coronary syndromes; uncontrolled hypertension
• New York Heart Association (NYHA) Grade II or greater congestive heart failure
• History of any cardiac arrhythmia requiring medication (irrespective of its severity)
• A history of additional risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
• Active Epstein Barr Virus (EBV) infection (i.e. positive serology IgM)
• Known HIV infection
• Active hepatitis B and/or C infection
• History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications
• Eastern Cooperative Oncology Group (ECOG) performance status 3 or greater
• Platelets count <100x109/L within 14 days before enrolment
• Absolute neutrophil count <1.2x109/L within 14 days before enrolment
• Percentage of blast cells in peripheral blood >10% within 14 days before enrolment
• Serum creatinine >2xULN (Upper limit of normal)
• Total serum bilirubin >1.5xULN
• Serum AST (aspartate aminotransferase) / ALT (alanine aminotransferase) > 3xULN
• Interferon alpha within 14 days before enrolment
• Hydroxyurea within 14 days before enrolment
• Anagrelide within 7 days before enrolment
• Any other investigational drug within 28 days before enrolment