Phase II Study of GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Polycythemia Vera
Condition: Polycythemia Vera
MeSH terms: Polycythemia Vera; Polycythemia
Intervention: GIVINOSTAT (ITF2357) 50 mg o.d. + MTD Hydroxyurea; GIVINOSTAT (ITF2357) 50 mg b.i.d. + MTD Hydroxyurea
Intervention description: 50 mg o.d. of GIVINOSTAT + MTD of HU monotherapy; 50 mg b.i.d. of GIVINOSTAT + MTD HU monotherapy
Intervention MeSH terms: Hydroxyurea; Givinostat hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 45.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Polycythemia Vera; GIVINOSTAT; ITF2357

Summary:

      The primary objective of the study was to evaluate the efficacy of Givinostat in combination
      with hydroxyurea in patients with JAK2V617F-positive Polycythemia Vera (PV) non-responders to
      the maximum tolerated dose of hydroxyurea monotherapy.

      The secondary objectives of this study were:

        -  To evaluate the safety and tolerability of Givinostat in combination with hydroxyurea in
           patients with JAK2V617Fpositive PV non-responders to the maximum tolerated dose of
           hydroxyurea monotherapy;

        -  To explore the impact in terms of efficacy and tolerability of Givinostat 50 mg dose
           escalation in patients not achieving at least a partial response at the time when the
           primary endpoint was assessed (week 12);

        -  To evaluate the molecular response (JAK2 mutated allele burden) by quantitative Real
           Time-Polymerase Chain Reaction (RT-PCR);

        -  To evaluate the reduction of the fraction of JAK2V617F positive clonogenic progenitors.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written Informed Consent.

          -  Age ≥18 years.

          -  Confirmed diagnosis of Polycythemia Vera according to the revised World Health
             Organization (WHO) criteria.

          -  JAK2V617F positivity.

          -  Non-response to the maximum tolerated dose of hydroxyurea monotherapy for at least 3
             months.

          -  ECOG (Eastern Cooperative Oncology Group) performance status <3.

          -  Use of an effective means of contraception for women of childbearing potential and men
             with partners of childbearing potential.

          -  Willingness and capability to comply with the requirements of the study.

        Exclusion Criteria:

          -  Active bacterial or mycotic infection requiring antimicrobial treatment.

          -  Pregnancy or lactation.

          -  A marked baseline prolongation of QT/QTc (corrected) interval (e.g. repeated
             demonstration of a QTc interval > 450 ms, according to Bazett's correction formula).

          -  Use of concomitant medications that prolong the QT/QTc interval.

          -  Clinically significant cardiovascular disease including:

               -  Uncontrolled hypertension, myocardial infarction, unstable angin, within 6 months
                  from study start;

               -  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 (TdP) (e.g., heart
                  failure, hypokalemia, family history of Long QT Syndrome).

          -  Positive blood test for HIV (Human Immunodeficiency Virus)

          -  Active HBV (Hepatitis B Virus) and/or HCV (Hepatitis C Virus) infection.

          -  Platelets count <100x109/L within 14 days before enrolment.

          -  Absolute neutrophil count <1.2x109/L within 14 days before enrolment.

          -  Serum creatinine >2xULN (upper limit of normal).

          -  Total serum bilirubin >1.5xULN.

          -  Serum aspartate aminotransferase (AST) / alanine aminotransferase (ALT) > 3xULN.

          -  History of other diseases, metabolic dysfunctions, physical examination findings, or
             clinical laboratory findings 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.

          -  Interferon alpha within 14 days before enrolment.

          -  Anagrelide within 7 days before enrolment.

          -  Any other investigational drug within 28 days before enrolment.