E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
JAK2V617F positive Polycythemia Vera |
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E.1.1.1 | Medical condition in easily understood language |
Disorder of the bone marrow in which excess blood cells are produced |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036061 |
E.1.2 | Term | Polycythemia vera |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part A
• To characterize the safety, tolerability and MTD of Givinostat in patients with PV.
Part B
• To evaluate the preliminary efficacy of Givinostat at the MTD after 3 cycles according to the clinico-haematological European LeukemiaNet (ELN) response criteria.
• To determine the safety and tolerability of Givinostat at the MTD after 3 cycles.
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E.2.2 | Secondary objectives of the trial |
Part A
• To evaluate the preliminary efficacy of Givinostat after 3 and 6 cycles of treatment according to the clinico-haematological European LeukemiaNet (ELN) response criteria.
• To characterize PK.
Part B
• To evaluate the preliminary efficacy of Givinostat at the MTD after 6 cycles according to the clinico-haematological European LeukemiaNet (ELN) response criteria.
• To determine the safety and tolerability of Givinostat at the MTD after 6 cycles.
• To characterize PK.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 PV according to the revised WHO criteria;
4. Patients must have JAK2V617F positive disease;
5. Patients must have an active/not controlled disease defined as
a) HCT ≥ 45% or HCT <45% in need of phlebotomy, and
b) PLT counts > 400 x109/L, and
c) WBC > 10 x109/L;
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 cMPN. 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:
a) ET patients: PLT counts > 600 x109/L;
b) MF patients: no response according to EUMNET criteria.
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; please note that a borderline urine pregnancy test must be followed with a serum pregnancy test;
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.
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E.4 | Principal exclusion criteria |
1. Active bacterial or mycotic infection requiring antimicrobial treatment;
2. Pregnancy or nursing;
3. A clinically significant QTc prolongation at baseline (e.g. repeated demonstration of a QTc interval ≥ 450 msec);
4. Use of concomitant medications known to prolong the QT/QTc interval;
5. Clinically significant cardiovascular disease including:
a) Uncontrolled hypertension despite medical treatment, myocardial infarction, unstable angina within 6 months from study start;
b) New York Heart Association (NYHA) Grade II or greater congestive heart failure;
c) History of any cardiac arrhythmia requiring medication (irrespective of its severity);
d) A history of additional risk factors for TdP (e.g. heart failure, hypokalemia, family history of Long QT Syndrome);
6. Known positivity for HIV;
7. Known active HBV and/or HCV infection;
8. Platelet count < 100 x109/L within 14 days before enrolment (i.e. the receipt of the Patient ID);
9. Absolute neutrophil count < 1.2x109/L within 14 days before enrolment (i.e. the receipt of the Patient ID);
10. Serum creatinine > 2 xULN;
11. Total serum bilirubin > 1.5 xULN except in case of Gilbert’s disease;
12. Serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) > 3 x ULN;
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 JAK2 or HDAC inhibitor or participation in an interventional clinical trial for cMPN, including PV, ET or MF;
15. Systemic treatment for cMPN other than aspirin/cardio aspirin;
16. Hydroxyurea within 28 days before enrolment (i.e. the receipt of the Patient ID);
17. Interferon alpha within 14 days before enrolment (i.e. the receipt of the Patient ID);
18. Anagrelide within 7 days before enrolment (i.e. the receipt of the Patient ID);
19. Any other investigational drug or device within 28 days before enrolment (i.e. the receipt of the Patient ID);
20. Patient with known hypersensitivity to the components of study therapy.
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A
• Safety and tolerability evaluated as following:
- Number of patients experiencing adverse events;
- Type, incidence, and severity of treatment-related adverse events, graded according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.03, 14th June 2010).
• Determination of the MTD of Givinostat based on cycle 1 DLT’s.
Part B
• Overall response rate - i.e. Complete Response (CR) and Partial Response (PR) - of Givinostat at the MTD after 3 cycles; the response will be evaluated according to the clinico-haematological European LeukemiaNet (ELN) response criteria.
• Safety and tolerability of Givinostat at the MTD after 3 cycles evaluated as following:
- Number of patients experiencing adverse events;
- Type, incidence, and severity of treatment-related adverse events, graded according to CTCAE v. 4.03.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A
Safety - ongoing
MTD - cycle 1
Part B
After 3 cycles |
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E.5.2 | Secondary end point(s) |
Part A
• Overall response rate - i.e. Complete Response (CR) and Partial Response (PR) - of Givinostat at the MTD after 3 and 6 cycles; the response will be evaluated according to the clinico-haematological ELN response criteria.
• Individual Givinostat concentrations tabulated by dose cohort along with descriptive statistics.
Part B
• Overall response rate - i.e. Complete Response (CR) and Partial Response (PR) - of Givinostat at the MTD after 6 cycles; the response will be evaluated according to the clinico-haematological ELN response criteria.
• Safety and tolerability of Givinostat at the MTD after 6 cycles evaluated as following:
- Number of patients experiencing adverse events;
- Type, incidence, and severity of treatment-related adverse events, graded according to CTCAE v. 4.03.
• Individual Givinostat concentrations tabulated with descriptive statistics.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A
cycle 3 and cycle 6
Part B
Cycle 6 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |