Long-term study evaluating the effect of givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Italfarmaco S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

8 Mar 2013 → ongoing

Decision date (initial)

2024-06-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

ITALFARMACO S.p.A

External identifiers

EU CT number

2024-512413-40-00

EudraCT number

2012-003499-37

ClinicalTrials.gov

NCT01761968

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

1. To determine the long-term safety and tolerability of givinostat in patients with cMPN following core protocols or compassionate use program.
2. To obtain information on the long-term efficacy of givinostat in patients with cMPN following core protocols or compassionate use program

Secondary objectives 4

1. To evaluate the long-term effect of givinostat on single parameters of the PV, ET and MF response criteria
2. To evaluate the long-term molecular response (JAK2 mutated allele burden) by quantitative Real-Time Polymerase Chain Reaction (qRTPCR)
3. To identify potential other markers predictive of clinical benefit of givinostat (e.g. potential pharmacodynamics – PD – markers)
4. To evaluate the disease parameters related to disease evolution and history (e.g. thrombotic rate, progression free survival (PFS) etc.)

Conditions and MedDRA coding

Chronic myeloproliferative neoplasm

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Patients must have completed givinostat treatment on at least one core study in cMPN (i.e. Study DSC/07/2357/28, Study DSC/08/2357/38, Study DSC/12/2357/45 and/or any further 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 benefitat the end of core protocols or compassionate use program with givinostat, assessed bythe 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

Exclusion criteria 13

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) and 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. Clinically significant cardiovascular disease including: • Uncontrolled hypertension, myocardial infarction, unstable angina at screening • 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)
4. Active virus infection including HIV, HBV and HCV
5. Platelets count <100 x109/L within 14 days before enrolment
6. Absolute neutrophil count < 1.2 x109/L within 14 days before enrolment
7. Total serum bilirubin >1.5xULN except in case of Gilbert's disease or pattern consistent with Gilbert's disease
8. Serum aspartate aminotransferase/alanine aminotransferase AST/ALT >3xULN
9. 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)
10. Uncontrolled hypertriglyceridemia at baseline, i.e. triglycerides >1.5xULN in fasting state.
11. 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 migh render the patient at high risk from treatment complications or significantly alter the absorption of the study drug
12. Any investigational drug other than givinostat within 28 days before enrolment.Notably, the use of such medications within 28 days or 6 halflives - 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
13. Patients with known hypersensitivity to the components of potential study therapy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Long term safety and tolerability • Number of patients experience adverse events • Type, incidence, and severity of treatment-related adverse events, graded according to the latest available version of Common Terminology Criteria for Adverse Events (CTCAE).
2. 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. Please refer to the protocol for the full details

Secondary endpoints 4

1. The effect of givinostat on each single response parameter according to the revised ELN (For PV and ET) and EUMNET response criteria (for MF)
2. Reduction of the JAK2v617F allele burden by quantitative RT-PCR
3. Identification of potential other markers predictive of clinical benefit of givinostat (e.g. potential PD markers).
4. Evaluation of the parameters that allows to evaluate the disease evolution and history (e.g. thrombotic rate, PFS etc.).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Italfarmaco S.p.A.

Sponsor organisation

Italfarmaco S.p.A.

Address

Via Dei Lavoratori 54

City

Cinisello Balsamo

Postcode

20092

Country

Italy

Scientific contact point

Organisation

Italfarmaco S.p.A.

Contact name

Maurizio Caserini

Public contact point

Organisation

Italfarmaco S.p.A.

Contact name

Paolo Bettica

Third parties 5

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications