Phase II Study of GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Polycythemia Vera

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.

This is a multicentre, randomized, open-label, phase II study testing GIVINOSTAT (ITF2357) in combination with hydroxyurea in a population of patients with JAK2V617F positive Polycythemia Vera non-responders to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months.

Recruited patients will be randomly assigned to one of the following treatment groups:

* group A: 50 mg o.d. of oral GIVINOSTAT (ITF2357) in combination with the maximum tolerated dose of hydroxyurea monotherapy already in use before admission to the study;
* group B: 50 mg b.i.d. of oral GIVINOSTAT (ITF2357) in combination with the maximum tolerated dose of hydroxyurea monotherapy already in use before admission to the study.

The two groups will be balanced for number and for Centre in order to provide valuable information on both treatment regimens.

In both groups assigned doses shall remain stable until week 12, which is when the primary endpoint is assessed, unless specific tolerability issues arise which impose dose reduction.

After the primary endpoint assessment at week 12, one of the following treatment schedules will be chosen case by case on the basis of the achieved clinical response and continued for up to 12 further weeks:

* Partial or Complete Response at week 12:
* group A: continue 50 mg o.d.;
* group B: continue 50 mg b.i.d.;
* No Response at week 12:
* group A: increase to 50 mg b.i.d.;
* group B: increase to 50 mg t.i.d.. At any time during study course, if toxicity is observed, GIVINOSTAT (ITF2357) treatment will be discontinued until recovery and then restarted at a reduced dose level. The drug will be definitively withdrawn in case of reappearance of toxicity even at a reduced daily dose. Overall, the treatment will last up to a maximum of 24 cumulative weeks of drug administration.

The study will recruit subjects of both genders with an established diagnosis of JAK2V617F positive Polycythemia Vera according to the revised WHO criteria, in need of cytoreductive therapy, non-responders to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months.

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.