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

Primary Purpose

Myeloproliferative Diseases

Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
ITF2357
Sponsored by
Italfarmaco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myeloproliferative Diseases focused on measuring polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Ospedali riuniti
  • IRCCS - Pol. San Matteo

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ITF2357

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.

Full Information

First Posted
January 21, 2008
Last Updated
December 2, 2019
Sponsor
Italfarmaco
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1. Study Identification

Unique Protocol Identification Number
NCT00606307
Brief Title
Phase IIA Study of the HDAC Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases
Official Title
A Phase IIA Study of the Histone-deacetylase Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
December 2007 (undefined)
Primary Completion Date
December 2008 (Actual)
Study Completion Date
December 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Italfarmaco

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myeloproliferative Diseases
Keywords
polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
29 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ITF2357
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
ITF2357
Other Intervention Name(s)
Givinostat
Intervention Description
50 mg b.i.d. PO every day. More precisely, ITF2357 was supplied as 50 mg hard gelatine capsules for oral administration.
Primary Outcome Measure Information:
Title
Number of Patients With Objective Responses (Complete, Major, Moderate or Minor Responses), in Terms of Best Overall Response
Description
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.
Time Frame
Every single week from week 1 to week 24 of treatment
Secondary Outcome Measure Information:
Title
Change in JAK2 Mutated Allele Burden
Description
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.
Time Frame
At screening, at week 12, at week 24, at the end of treatment (EOT) visit
Title
Number of Subject Experiencing an Adverse Event
Description
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.
Time Frame
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
tiziano oldoni, MD
Organizational Affiliation
Italfarmaco
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Alessandro Rambaldi, MD
Organizational Affiliation
A.O. Ospedale Papa Giovanni XXIII
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ospedali riuniti
City
Bergamo
ZIP/Postal Code
24158
Country
Italy
Facility Name
IRCCS - Pol. San Matteo
City
Pavia
ZIP/Postal Code
27100
Country
Italy

12. IPD Sharing Statement

Learn more about this trial

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

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