A Two-part Study to Assess the Safety and Preliminary Efficacy of Givinostat in Patients With Polycythemia Vera

This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety and tolerability, Maximum Tolerated Dose and preliminary efficacy of Givinostat in patients with JAK2V617F positive Polycythemia Vera. Part A is the dose finding part while Part B is assessing the preliminary efficacy. Patients will be enrolled either in Part A or Part B and transition from one part to the other is not allowed.

Eligible patients for this study will have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria. Only if the enrolment in Part A is slow (i.e. \< 5 patients enrolled in 3 months), eligibility for this part of the study may be expanded to all patients with chronic myeloproliferative neoplasms.

Study therapy will be administered in 28 day cycles (4 weeks of treatment). Disease response will be evaluated according to the European LeukemiaNet criteria after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat for both parts of the study. All phlebotomies performed in the first 3 weeks of treatment will not be counted to assess the clinico-haematological response.

The study will last up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit will be allowed to continue treatment with Givinostat (at the same dose and schedule) in a long-term study.

Safety will be monitored at each visit throughout the entire duration of the study. Treatment will be administered on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalization, the treatment will be continued or interrupted according to the Investigators' decision.

This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety and tolerability, MTD and preliminary efficacy of Givinostat in patients with JAK2V617F positive PV.

Part A is the dose escalation portion of the study and, once the MTD has been established, Part B will commence where the preliminary efficacy of Givinostat in PV patients will be established. Patients will be enrolled either in Part A or Part B and transition from one part to the other is not allowed. Only PV patients from Part A assigned to the dose selected for Part B (MTD) may be counted towards the efficacy assessment in Part B.

Eligible patients for this study will have a confirmed diagnosis of PV according to the revised WHO criteria and the JAK2V617F positivity. Only if the enrolment in Part A is slow (i.e. \< 5 patients enrolled in 3 months), eligibility for this part of the study may be expanded to all patients with cMPN.

After providing informed written consent before undertaking any protocol-related procedure, a unique patient identification code (i.e. patient screening ID which will be a combination of his/her site ID, study part ID and patient screening number, e.g. IT01-A01) will be assigned to each patient and it will identify the patient within his/her enrolment confirmation by Italfarmaco S.p.A. or its designee and never be reused in case of screening failure. After the enrolment confirmation and the assignation of the dose level before the first drug intake, a unique patient identification code (i.e. patient ID which will be a combination of patient screening number ID and dose level ID, e.g. IT01-A01-DL1) will be assigned to each patient and it will identify the patient throughout his/her participation in the study and never be reused in case of premature drop-out.

Study therapy will be administered in 28 day cycles. In fact, the "cycle" is defined as 4 weeks of treatment.

Disease response will be evaluated according to the clinico-haematological ELN criteria after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat for both parts of the study. All phlebotomies performed in the first 3 weeks of treatment will not be counted to assess the clinico-haematological response.

The study will last up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit will be allowed to continue treatment with Givinostat (at the same dose and schedule) in a long-term study (Study N.: DSC/11/2357/44).

Safety will be monitored at each visit throughout the entire duration of the study. Treatment will be administered on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalization, the treatment will be continued or interrupted according to the Investigators' decision.

Eligibility Criteria:
Inclusion Criteria:

1. Patients must be able to provide informed consent and be willing to sign an informed consent form;
2. Patients must have an age ≥18 years;
3. Patients must have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria;
4. Patients must have mutated Janus Kinase 2 (mutation V617F) positive disease;
5. Patients must have an active/not controlled disease defined as

   1. hematocrit ≥ 45% or hematocrit \<45% in need of phlebotomy, and
   2. platelet count \> 400 x109/L, and
   3. white blood cell count \> 10 x109/L;
6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 in Part A, ECOG performance status ≤ 2 in Part B within 7 days of initiating study drug;
7. Female patient of childbearing potential has a negative serum or urine pregnancy test within 72 hours of the first dose of study therapy;
8. Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential;
9. Adequate and acceptable organ function within 7 days of initiating study drug;
10. Willingness and capability to comply with the requirements of the study.

Note that if the enrolment in Part A is slow (i.e. \< 5 patients enrolled in 3 months), eligibility for this part of the study may be expanded to all patients with chronic myeloproliferative neoplasms. In this case, the inclusion criteria 5 will be modified as following only for Part A:

5. Patients must have an active/not controlled disease defined as:

1. Essential Thrombocythemia patients: Platelet count \> 600 x109/L;
2. Myelofibrosis patients: no response according to European Myelofibrosis Network criteria.

Exclusion Criteria:

1. Active bacterial or mycotic infection requiring antimicrobial treatment;
2. Pregnancy or nursing;
3. A clinically significant corrected QT interval prolongation at baseline;
4. Use of concomitant medications known to prolong the corrected QT interval;
5. Clinically significant cardiovascular disease including:

   1. Uncontrolled hypertension despite medical treatment, myocardial infarction, unstable angina within 6 months from study start;
   2. New York Heart Association Grade II or greater congestive heart failure;
   3. History of any cardiac arrhythmia requiring medication (irrespective of its severity);
   4. A history of additional risk factors for torsade de pointes;
6. Known positivity for human immunodeficiency;
7. Known active hepatitis B virus and/or hepatitis C virus infection;
8. Platelet count \< 100 x109/L within 14 days before enrolment;
9. Absolute neutrophil count \< 1.2x109/L within 14 days before enrolment;
10. Serum creatinine \> 2 times the upper limit of normal;
11. Total serum bilirubin \> 1.5 times the upper limit of normal except in case of Gilbert's disease;
12. Serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) \> 3 times the upper limit of normal;
13. History of other diseases (including active tumours), 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;
14. Prior treatment with a Janus Kinase 2 or Histone Deacetylase inhibitor or participation in an interventional clinical trial for chronic myeloproliferative neoplasms;
15. Systemic treatment for chronic myeloproliferative neoplasms other than aspirin/cardio aspirin;
16. Hydroxyurea within 28 days before enrolment;
17. Interferon alpha within 14 days before enrolment;
18. Anagrelide within 7 days before enrolment;
19. Any other investigational drug or device within 28 days before enrolment;
20. Patient with known hypersensitivity to the components of study therapy.