Study on Efficacy and Safety of Givinostat Versus Hydroxyurea in Patients With Polycythemia Vera

Core Treatment - Inclusion Criteria:

• Patients must have been diagnosed with PV according to the 2016 WHO criteria before randomization

• Patients must have JAK2V617F-positive disease

• Patients with PV must meet the definition of HR for thrombosis (i.e., HR) within 3 years before screening as follows:

• Age ≥ 60 years, and/or

• Prior thrombosis.

• Patients must be in need of treatment at screening, defined by the presence of at least one of the following:

• HCT ≥ 45% or HCT < 45% with at least 1 phlebotomy performed in the 3 months before screening, or

• WBC count > 10 × 109/L, or

• PLT count > 400 × 109/L.

• Patients must have normalized HCT (i.e., HCT < 45%) at randomization

Extended Treatment - Inclusion Criteria

• Patients must have completed the Week 48 visit of the DSC/08/2357/32 core treatment phase and:

1. if the patient received givinostat, a complete hematological response (CHR) at Week 48 shall be achieved

2. if the patient received HU, did not achieve a CHR (see above for the definition) at Week 48

Core Treatment phase - Exclusion Criteria

• Patients pre-treated with HU with a documented history of resistance or intolerance to HU defined by the original ELN criteria

• Patients with a QTcF value of > 450 msec for males and > 460 msec for females at the Screening visit (as the mean of 3 consecutive readings 5 minutes apart in the event a first ECG demonstrates a prolonged QTcF interval); congenital or acquired history of QTc prolongation or ventricular arrhythmias, at the Screening visit

• Splanchnic thrombosis and/or thrombosis of the cerebral venous sinuses and/or splenectomy in the medical history

• Patients with clinically significant cardiovascular disease

• Patients with myocardial infarction, stroke or unstable angina within the 6 months prior to screening.

• Patients with inadequate liver or renal function at screening

• Uncontrolled hypertriglyceridemia at screening, i.e., triglycerides ˃ 1.5 × ULN

• Previous treatment with a JAK2 or HDAC inhibitor or 32-phosphorus (radioactive isotope) therapy.

• Patients being treated concurrently with any investigational agent or prior participation in an interventional clinical study within the 30 days prior to screening or within 5 half-lives of the investigational product, whichever is longer.

• Pregnant or nursing women

Extended treatment phase - Exclusion criteria

• For patients randomized to givinostat in the core treatment phase - Patients with a QTcF value at Week 48 of > 500 msec

• For patients randomized to HU in the core treatment phase:

• PLT count ≤ 150 × 109/L at Week 48

• ANC < 1.2 × 109/L at Week 48

• Uncontrolled hypertriglyceridemia at Week 48

• Patients with a QTcF value at Week 48 of > 450 msec for males and > 460 msec for female