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

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

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).

Study Overview

• Status: Completed
• Conditions: Myeloproliferative Diseases
• Intervention / Treatment: Drug: ITF2357

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Bergamo, Italy, 24158
    • Ospedali Riuniti
  • Pavia, Italy, 27100
    • IRCCS - Pol. San Matteo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ITF2357; 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; 50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.; Other Names: Givinostat

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Italfarmaco
• Investigators: Study Director: tiziano oldoni, MD, Italfarmaco

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: January 21, 2008
• First Submitted That Met QC Criteria: January 21, 2008
• First Posted (Estimate): February 1, 2008

Study Record Updates

• Last Update Posted (Actual): December 3, 2019
• Last Update Submitted That Met QC Criteria: December 2, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: myelofibrosis (MF); polycythemia vera (PV); essential thrombocythemia (ET)
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Givinostat hydrochloride
• Other Study ID Numbers: DSC/07/2357/28