Long-term Evaluation of Givinostat in JAK2V617F Positive Chronic Myeloproliferative Neoplasms: Safety, Tolerability, and Efficacy Analysis

The primary objective of this study is to determine the long-term **safety** and tolerability of **givinostat** in patients with chronic myeloproliferative neoplasms (cMPN) following core protocols or a compassionate use program. Additionally, the study aims to obtain information on the long-term efficacy of givinostat in these patients. This is clinically relevant as it addresses the need for effective and safe long-term treatment options for individuals with cMPN, a group of disorders characterized by the overproduction of blood cells, which can lead to significant morbidity.

Secondary objectives include evaluating the long-term effect of givinostat on single parameters of the polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) response criteria. The study also aims to assess the long-term molecular response, specifically the JAK2 mutated allele burden, using quantitative Real-Time Polymerase Chain Reaction (qRTPCR). Furthermore, the study seeks to identify potential markers predictive of clinical benefit, such as pharmacodynamic markers, and to evaluate disease parameters related to disease evolution and history, including thrombotic rate and progression-free survival (PFS). These secondary objectives are crucial for understanding the broader impact of givinostat on disease progression and patient outcomes.

The clinical trial involves a total of **5 participants** diagnosed with **chronic myeloproliferative neoplasm** (cMPN). The study population includes adult patients aged 18 years and older, comprising both male and female subjects. Participants were selected based on their completion of givinostat treatment in previous core studies or participation in a compassionate use program, with a requirement of having tolerated the treatment and achieved clinical benefit. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of less than 3 at baseline, indicating a relatively stable health status. Participants are required to have acceptable organ function and must adhere to effective contraception measures if applicable. The study population is characterized by a willingness and capability to comply with study requirements, and it includes a vulnerable population as defined by the trial criteria. The selection process ensures that participants have a confirmed diagnosis of JAK2V617F positive cMPN according to the revised WHO criteria.

The clinical trial is designed to evaluate the long-term safety, tolerability, and efficacy of **givinostat** in patients with JAK2V617F positive chronic myeloproliferative neoplasms (cMPN). This is a phase 4, randomized, double-blind, controlled study. The trial is expected to run until September 2029, with participant recruitment having commenced in March 2013. The study involves the administration of givinostat in capsule form, with dosages of 50 mg, 75 mg, and 100 mg, taken orally. The maximum daily dose is 200 mg, and the treatment period is capped at one year.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as completion of previous givinostat treatment, ability to provide informed consent, and acceptable organ function. Follow-up visits will be scheduled to monitor safety and efficacy, with assessments including adverse event tracking and response rates according to the European LeukemiaNet (ELN) and European Myelofibrosis Network (EUMNET) criteria. The end-of-study visit will conclude the participant's involvement, evaluating long-term outcomes and any residual effects of the treatment.

The expected length of participant involvement is contingent upon the completion of the treatment period and adherence to study protocols. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or non-compliance with study requirements. The primary endpoints focus on the long-term safety and tolerability of givinostat, while secondary endpoints include the reduction of the JAK2v617F allele burden and identification of potential predictive markers of clinical benefit. The trial aims to provide comprehensive data on the long-term impact of givinostat in managing cMPN.

The clinical trial involves the administration of **Givinostat**, an investigational medication, in the form of hard capsules. The study utilizes three different dosages of Givinostat: 50 mg, 75 mg, and 100 mg capsules. Each capsule contains the active substance Givinostat, a chemical compound classified under the ATC codes L01 and M01, indicating its use as an antineoplastic agent and an anti-inflammatory and antirheumatic product. The capsules are manufactured by ITALFARMACO SPA and are intended for **oral use**. The maximum daily dose for participants is set at 200 mg, with the treatment period not exceeding one day. The study aims to evaluate the long-term safety, tolerability, and efficacy of Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as deemed necessary by the study protocol. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve any pediatric formulations, and the investigational product is designated as an orphan drug under the designation number EU/3/09/719. The study is conducted following core protocols or a compassionate use program to gather comprehensive data on the long-term effects of Givinostat in the target patient population.

The efficacy of **givinostat** in the clinical trial will be assessed through several primary and secondary endpoints. For patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET), the primary efficacy endpoints include the complete response (CR) and partial response (PR) rates, evaluated according to the revised clinico-haematological European LeukemiaNet (ELN) response criteria. For patients with Myelofibrosis (MF), the efficacy will be measured by the complete response, major response, moderate response, and minor response rates, as per the European Myelofibrosis Network (EUMNET) response criteria.

Secondary efficacy endpoints will focus on the effect of givinostat on individual response parameters based on the revised ELN and EUMNET criteria. Additionally, the reduction of the JAK2V617F allele burden will be quantified using RT-PCR. The study will also aim to identify potential predictive markers of clinical benefit, such as pharmacodynamic markers, and evaluate parameters indicative of disease evolution and history, including thrombotic rate and progression-free survival (PFS).