Trial in progress: Efficacy and safety of givinostat versus hydroxyurea in patients with polycythemia vera (GIV-IN-PV)

Abstract Background: Polycythemia vera (PV) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic progenitors in the bone marrow, associated with a dysregulation of JAK2 signaling due to a JAK2V617F gene mutation that is harbored in up to 98% of patients with PV. Patients with PV are at increased risk of thrombotic and hemorrhagic events, progression to myelofibrosis and blast phase. Current treatments include aspirin, phlebotomies, and cytoreductive drugs, most commonly hydroxyurea (HU) (Tefferi A, Am J Hematol. 2023; 98:1465-1487). Givinostat, a histone-deacetylase inhibitor, selectively targets JAK2V617F cell growth, reducing hematopoietic cell proliferation (Rambaldi A, Leukemia 2020; 34: 2234-2237). Givinostat has demonstrated good efficacy and safety in three phase 1/2 studies that included a total of 104 patients with PV, 51 of whom were followed up in the long-term (Rambaldi A, Blood Cancer J. 2021; 11:53). Based on such evidence, this phase 3 trial has been designed and is currently ongoing in EU, Israel, Serbia, UK and US. In April 2025, FDA granted givinostat the Fast Track designation for the treatment of PV. Methods: GIV-IN-PV is an ongoing, international, multicenter, randomized, open-label, phase 3 study to assess the efficacy and safety of givinostat versus HU in high-risk (HR) PV patientswith the JAK2V617F mutation (ClinicalTrials.gov ID: NCT06093672). The trial is planned to randomize 220 patients to either givinostat or HU for 48 weeks. Givinostat and HU are administered orally, with adjusted dosage with the aim of achieving an optimized dose in terms of hematological response and minimize treatment-related toxicities. Eligible patients must have a diagnosis of PV according to the 2016 WHO criteria, with JAK2V617F mutation, meet the definition of high-risk (HR) for thrombosis (patients ≥ 60 years of age and/or with a previous thrombotic event) within 3 years before screening, be in need of treatment and have normalized hematocrit (HCT< 45%) at randomization. Patients will be stratified based on previous treatment, previous history of thromboembolic events (TEs), presence/absence of splenomegaly and JAK2V617F allele burden. The primary objective of the study is to evaluate the proportion of patients achieving a complete response at Week 48 based on HCT < 45% without phlebotomy in the prior 3 months, white blood cell count ≤ 10 × 109/L, platelet count ≤ 400 × 109/L, normal spleen and, absence of progressive disease, major hemorrhagic events and major thrombotic events from week 25 to 48. Secondary objectives include the proportion of patients achieving a complete hematological response (CHR) at Week 48, time from randomization to the first observed CHR, proportion of patients with a normal spleen size at Week 48 and safety and tolerability up to Week 48. In addition, an external independent data monitoring committee (IDMC) is in charge of reviewing safety to protect the ethical and safety interests of patients. Upon completing week 48 of the study, eligible patients will be allowed to transition into a long-term follow-up study to assess sustained efficacy and safety of givinostat. As of June 2025, 95 patients have been randomized in 76 investigational sites worldwide. Countries open for recruitment include Austria, Bulgaria, Croatia, France, Germany, Hungary, Ireland, Israel, Italy, Netherlands, Poland, Serbia, Spain, Turkey, UK, US.