Long-term Study Evaluating the Effect of Givinostat in Patients With Chronic Myeloproliferative Neoplasms

Prior treatment

• Any investigational drug other than givinostat within 28 days before enrolment. Notably, the use of such medications within 28 days or 6 half-lives - whichever is longer - prior to the first dose of study drugs (i.e. Day 1) and during the study through all the study conduct (including any safety follow-up \[FU\] visit) is prohibited;
• Use of concomitant medications known to inhibit Pgp;

Other illness

• Clinically significant cardiovascular disease including:
  • Uncontrolled hypertension, myocardial infarction, unstable angina at screening;
  • New York Heart Association 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 Point;
• Active virus infection including human HIV, HBV and HCV;
• Patients with known hypersensitivity to the components of potential study therapy.

Lab values

• Pregnancy or nursing (lactating) women, where pregnancy is defined as the state of a female after conception, confirmed by a positive human Chorionic Gonadotropin (hCG) laboratory test (i.e. \> 5 mIU/mL) and until the termination of gestation;
• A clinically significant corrected QT interval prolongation at baseline;
• Use of concomitant medications known to prolong the corrected QT interval;
• Platelets count \< 100 x109/L within 14 days before enrolment (i.e. the receipt of the Patient ID);
• Absolute neutrophil count \< 1.2 x109/L within 14 days before enrolment (i.e. the receipt of the Patient ID);
• Total serum bilirubin \> 1.5 1.5 x ULN except in case of Gilbert's disease or pattern consistent with Gilbert's disease;
• Serum Aspartate aminotransferase/Alanine aminotransferase (AST/ALT) \> 3 times the upper normal limit;
• Serum Cystatin C \> 2 x ULN for two subsequent evaluations (i.e. if the value of serum Cystatin C is \>2 x ULN, the test will be repeated once, and if the value is again \> 2 x ULN, this becomes an exclusioncriterion);
• Uncontrolled hypertriglyceridemia at baseline, i.e. triglycerides ˃ 1.5 x ULN in fasting state.
• History and/or presence 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 patient at high risk from treatment complications or significantly alter the absorption of the study drug;

• Patients must have completed givinostat treatment on at least one core study in chronic myeloproliferative neoplasms, or patients must be participating in a compassionate use program with givinostat AND Patients must have tolerated previous givinostat treatment and achieved a clinical benefit at the end of core protocols or compassionate use program with givinostat, assessed by the Investigator according to the revised clinico-haematological ELN response criteria (for PV and ET) and EUMNET response criteria (for MF);
• Patients must be able to provide informed consent and be willing to sign an informed consent form;
• Adult patients (age ≥ 18 years) of both genders with established diagnosis of chronic myeloproliferative neoplasms according to the revised WHO criteria;
• Patients must have an Eastern Cooperative Oncology Group performance status \< 3 at baseline;
• Acceptable organ function within 7 days of initiating study drug;
• 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.