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

PV is a cMPN mainly driven by JAK2V617F mutation. The disease has an increased risk of thromboembolic complications, a predisposition to evolve into myelofibrosis (MF) and transformation into acute myeloid leukemia.

Patients ≥ 60 years of age and/or with a previous thrombotic event (TE) are considered at High Risk (HR) for thrombosis. The association of absolute values of circulating neutrophil, lymphocyte and monocyte and the high value of JAK2V617F allele burden are additional risk factors for the occurrence of thrombosis and for progression to MF, respectively.

Overall, most patients treated with HU are not adequately under control for both symptoms and long-term risks.

In recent years, data have shown that histone deacetylase (HDACs) inhibitors induce growth arrest, differentiation, and/or apoptosis in neoplastic cells. Givinostat has demonstrated preliminary signs of clinical activity and an acceptable safety profile in patients with JAK2V617F-positive cMPNs in three phase 2 studies.

The core treatment phase (pivotal phase 3 study) is designed to demonstrate the superiority of givinostat versus HU on efficacy, in JAK2V617F-positive, HR PV patients.

The extended treatment phase will allow eligible patients to receive givinostat in the long-term, with the objective of collecting long-term safety and efficacy data.

• Givinostat (Drug), also known as ITF2357: Oral. The dosage must be modified, according to the manifestation of toxicities or lack of efficacy, with the aim to achieve an optimized dose.
• Hydroxyurea (Drug), also known as ITF2357: Oral. The dosage must be modified, according to the manifestation of toxicities or lack of efficacy, with the aim to achieve an optimized dose.

Primary outcomes

• Proportion of patients achieving a response at Week 48. [week 25 - week 48]: Response assessment based on: * Hematocrit < 45% without phlebotomy in the prior 3 months, and * White blood cell (WBC) count ≤ 10 × 109/L, and * Platelet count ≤ 400 × 109/L, and * Normal spleen size as measured by imaging (normal spleen size is defined as: a longitudinal diameter ≤ 12 cm for female and ≤ 13 cm for male) and * During Part 2 (Week 25 to 48), absence of progressive disease, major hemorrhagic events and major thrombotic events.

Secondary outcomes

• Proportion of patients achieving a complete hematological response (CHR) at Week 48. [week 48]: CHR based on: * Hematocrit < 45% without phlebotomy in the prior 3 months, and * White blood cell (WBC) count ≤ 10 × 109/L, and * Platelet count ≤ 400 × 109/L
• Time from randomization to the first observed CHR [Randomization - week 48]
• Proportion of patients with a normal spleen size at Week 48. [week 48]
• Safety and tolerability up to Week 48. [Randomization - week 48]

Sex: All, ages: 18 Years to any

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