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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Myeloproliferative Diseases

Intervention / Treatment
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* Drug: ITF2357


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ITF2357<br>Initial dose of 50 mg b.i.d. that was subsequently escalated to 50 mg t.i.d in case of lack of significant toxicity. | Drug: ITF2357<br>* 50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.<br>* Other names: Givinostat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response | Patients with Objective Response were defined as those patients achieving a complete, major, moderate or minor (only for Myelofibrosis patients) response during the experimental treatment course. The best response is reported hereunder by intensity of response. | Every single week from week 1 to week 24 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in JAK2 Mutated Allele Burden | This outcome was assessed by quantitative real time Polymerase Chain Reaction (RT PCR). At each time point, the number of patients is the following: Screening: N=29 Week 12: N=20 Week 24: N=18 EOT: N=24. End of treatment corresponds to the last visit performed before treatment discontinuation. | At screening, at week 12, at week 24, at the end of treatment (EOT) visit | 
| Number of Subject Experiencing an Adverse Event | An adverse event (AE) is any untoward occurrence in a patient or clinical investigation subject administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The adverse events must to be followed to the end of study (28 days after the last study drug intake). A serious AE (SAE) is defined as an untoward (unfavourable) medical occurrence that at any dose results in death, or is life-threatening or requires inpatient hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect. | At weekly visits (Days 8, 15, 22, 36, 43, 50, 64, 71, 78, 99, 127, 155); At monthly visits (Days 29, 57, 85 113, 141,169); at end of treatment visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF)