| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Chronic myeloproliferative neoplasm
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| E.1.1.1 | Medical condition in easily understood language |
| A group of diseases of the bone marrow in which excess 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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028578 |
| E.1.2 | Term | Myeloproliferative disorders (excl leukaemias) |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10005329 |
| E.1.2 | Term | Blood and lymphatic system disorders |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To determine the long-term safety and tolerability of givinostat in patients with cMPN following core protocols or compassionate use program.
• To obtain information on the long-term efficacy of givinostat in patients with cMPN following core protocols or compassionate use program.
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the long-term effect of givinostat on single parameters of the PV, ET and MF response criteria
• To evaluate the long-term molecular response (JAK2 mutated allele burden) by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR)
• To identify potential other markers predictive of clinical benefit of givinostat (e.g. potential pharmacodynamics – PD – markers)
• To evaluate the disease parameters related to disease evolution and history (e.g. thrombotic rate, progression free survival (PFS) etc.).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must have completed Givinostat treatment on at least one core study in cMPN (i.e. Study DSC/07/2357/28, DSC/08/2357/38 and/ or any future core protocols in cMPN), 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)
2. Patients must be able to provide informed consent and be willing to sign an informed consent form
3. Adult patients (age ≥18 years), of both genders, and with established diagnosis of JAK2V617F positive cMPN according to the revised WHO criteria
4. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status <3 at baseline
5. Acceptable organ function within 7 days of initiating study drug
6. Use of an effective means of contraception from the 28 days before first dose of study drug through 3 months after the last dose of study drug for women of childbearing potential and men with partners of childbearing potential
7. Willingness and capability to comply with the requirements of the study.
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| E.4 | Principal exclusion criteria |
1. 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) an until the termination of gestation;
2. A clinically significant QTc prolongation at baseline (e.g. repeated demonstration of a QTc interval ≥ 450 msec); Of note, a repeated demonstration of a QTc interval >450 msec means that, if the first ECG evaluation demonstrates a prolonged QTc interval (i.e. a QTc interval ≥ 450 msec), two additional ECG evaluations over a brief period of time (i.e. 5 minutes between each recording) must be performed. The averaged value of these three ECG evaluations has to be used for the evaluation of the QTc interval. In the eCRF all the performed ECG evaluations have to be entered as well as the average value of multiple ECG evaluation, if necessary
3. Use of drugs concomitant medications known to prolong the QTc interval
4. Clinically significant cardiovascular disease including:
- Uncontrolled hypertension, myocardial infarction, unstable angina within 6 months of study start;
- New York Heart Association (NYHA) grade II or greater congestive heart failure
- History of any cardiac arrhythmia requiring medication (regardless of severity)
- A history of additional risk factors for TdP (eg, heart failure, hypokalemia, family history of long QTc syndrome)
5. Active virus infection including HIV, HBV and HCV
6. Platelets count <100 x109/L within 14 days before enrolment
7. Absolute neutrophil count < 1.2 x109/L within 14 days before enrolment
8. Total serum bilirubin >1.5xULN except in case of Gilbert's disease or pattern consistent with Gilbert's disease
9. Serum asparatate aminotransferase / alanine aminotransferase AST/ALT >3xULN
10. 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 exclusion criterion).
11. Uncontrolled hypertriglyceridemia at baseline, i.e. triglycerides >1.5xULN in fasting state.
12. 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 contraindicated use of an investigational drug or that might affect interpretation of the results of the study or might render the patient at high risk from treatment complications or significantly alter the absorption of the study drug
13. Any investigational drug other than givinostat within 28 days before enrolment. Notably . the use of such medicaitons 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.
14. Use of concomitant medications known to inhibit Pgp
15. Patients with known hypersensitivity to the components of potential study therapy
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Long term safety and tolerability
• Number of patients experience 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).
Long term efficacy
• For PV and ET: Complete response (CR) and partial response (PR) rate according to the revised clinicl-haematological European LeukemiaNet (ELN) response criteria
• For MF: complete response, major response, moderate response and minor response rate according to European Myelofibrosis Network (EUMNET) response criteria
If the response as per ELN/EUMNET criteria is not evaluable, due to missing or not done evaluations, the missing evaluations should be repeated within one week from the visit in order to calculate the response as per ELN/EUMNET response criteria. Of note, since this is a long-term Study, at each quarterly visit the Investigator should include in their clinical evaluation the patient's benefit-risk assessment, taking into account both the clinical course of the patient in the Study until the visit time (i.e. the "clinical benefit") and any possible treatment option available at the time when the visit is performed. In all cases, the medical judgment of the Investigator is taken into account. In particular, if the Investigator's clinical response assessment - which takes into account the overall medical judgement of the specific patients's case- is not in agreement with the exact application of the revised clinico-haematological ELN response criteria for PV/ET patients and EUMNET response criteria for MF patients, the Investigator's assessment will supersede the "mathematical" application of these criteria. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be assessed at each quarterly visit and patients deriving clinical benefit from participating in the study will be allowed to continue study medication. |
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| E.5.2 | Secondary end point(s) |
• The long-term effect of givinostat on each single response parameter according to the revised ELN (For PV and ET) and EUMNET response criteria (for MF)
• Long-term reduction of the JAK2 v617F allele burden by quantitative RT-PCR
• Identification of potential other markers predictive of clinical benefit of givinostat (e.g. potential PD markers). Evaluation of the parameters that allows to evaluate the disease evolution and history (e.g. thrombotic rate, PFC etc.)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoint will be assessed at each quarterly visit. |
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 4 |
| 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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| The end of the study (last visit of the last patient) will take place after all patients in the study have completed the final assessment under the Protocol. |
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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 | 12 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 12 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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