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

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ClinicalTrials.gov Identifier: NCT01761968
Recruitment Status : Active, not recruiting
First Posted : January 7, 2013
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
Italfarmaco

Brief Summary:
This is a multicenter, open label, long-term study testing the long-term safety, tolerability and efficacy of Givinostat in patients with Polycythemia Vera, Essential Thrombocythemia, primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis following core protocols in chronic myeloproliferative neoplasms and/or patient-named compassionate use program (if regulated/allowed by the local regulations, e.g. for Italy D.M. 8/5/2003 "Uso terapeutico di medicinale sottoposto a sperimentazione clinica" published on G.U. n. 173 of 28 July 2003, and the following amendments). Patients will continue at their last tolerable dose and treatment schedule of Givinostat monotherapy. If patients previously received Givinostat in combination with other drugs during a core protocol or a compassionate use program (if regulated/allowed by the local regulations, e.g. for Italy D.M. 8/5/2003 "Uso terapeutico di medicinale sottoposto a sperimentazione clinica" published on G.U. n. 173 of 28 July 2003, and the following amendments), they will be treated at the last tolerable dose of the combination. Assessment of safety and efficacy will be performed at each quarterly visit and each visit will also include laboratory tests and ECG examination. During the visits the clinical benefit will be assessed by Investigator according to the revised European LeukemiaNet response criteria (for PV and ET) and EUMNET response criteria (for MF). The dose of Givinostat will be modified for protocol specified toxicities. The treatment may continue up to Marketing Authorization of Givinostat, currently planned in the next 5 years (note: only for Germany, this long-term study is initially limited up to 2 years of treatment). Patients may discontinue study treatment at any time and remain on study therapy as long as they derive clinical benefit. Safety will be monitored at each visit throughout the entire duration of the study. In case the approved label will not cover the whole study population, Givinostat will be provided by the Sponsor to those patients not fulfilling the criteria for the approved label of the drug that are still deriving benefit from Givinostat at the time of its commercial availability.

Condition or disease Intervention/treatment Phase
Chronic Myeloproliferative Neoplasms Drug: Givinostat Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Long-term Study Evaluating the Effect of Givinostat in Patients With JAK2V617F Positive Chronic Myeloproliferative Neoplasms
Study Start Date : March 2013
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: Givinostat

Patients will continue at their last tolerable dose and treatment schedule of Givinostat monotherapy. Givinostat is a histone-deacetylases inhibitor. The product will be supplied as hard gelatine capsules for oral administration at the strength of 50 mg, 75 mg and/or 100 mg each.

If patients previously received Givinostat in combination with other drugs during a core protocol or a compassionate use program, they will be treated at their last tolerable dose of this combination.

Drug: Givinostat

Patients will continue at their last tolerable dose and treatment schedule of Givinostat monotherapy. Givinostat is a histone-deacetylases inhibitor. The product will be supplied as hard gelatine capsules for oral administration at the strength of 50 mg, 75 mg and/or 100 mg each.

If patients previously received Givinostat in combination with other drugs during a core protocol or a compassionate use program, they will be treated at their last tolerable dose of this combination.

Other Name: Givinostat (ITF2357)




Primary Outcome Measures :
  1. Long-term safety and efficacy [ Time Frame: 3 months ]

    To obtain information on the long-term efficacy of Givinostat in patients with chronic myeloproliferative neoplasms following core protocols or compassionate use program:

    • Number of patients experiencing adverse events;
    • Type, incidence, and severity of treatment-related adverse events.

    To determine the long term safety and tolerability of Givinostat in patients with chronic myeloproliferative neoplasms following core protocols or compassionate use program:

    • For Polycythemia Vera and Essential Thrombocythemia, Complete response and partial response rate according to the revised clinico-haematological European LeukemiaNet response criteria;
    • For Myelofibrosis, complete response, major response, moderate response and minor response rate according to European Myelofibrosis Network response criteria.

    Note that these assessment will be repeated periodically (each 3 months) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.



Other Outcome Measures:
  1. Clinical exploratory endpoint [ Time Frame: 1 year ]

    To evaluate the effect of Givinostat on each single response parameter according to the revised European LeukemiaNet (for Polycythemia Vera and Essential Thrombocythemia) and European European Myelofibrosis Network response criteria (for Myelofibrosis).

    Note that this assessment will be repeated periodically (each year) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.


  2. Molecular exploratory endpoint [ Time Frame: 1 year ]

    To evaluate the molecular response (i.e. reduction of the allele burden of the mutated Janus Kinase 2 in the position V617F).

    Note that this assessment will be repeated periodically (each year) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.


  3. Biomolecular exploratory endpoint [ Time Frame: 1 year ]

    To identify potential other markers predictive of clinical benefit of Givinostat (e.g. potential pharmacodynamic markers).

    Note that this assessment will be repeated periodically (each year) during the study. In fact, the treatment will continue up to Marketing Authorisation of Givinostat.




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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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);
  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 with established diagnosis of chronic myeloproliferative neoplasms according to the revised WHO criteria;
  4. Patients must have an Eastern Cooperative Oncology Group performance status < 3;
  5. Acceptable organ function within 7 days of initiating study drug;
  6. Use of an effective means of contraception 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:

  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:

    • Uncontrolled hypertension, myocardial infarction, unstable angina within 6 months from study start;
    • 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;
  6. History of virus infection including human immuno deficiency, hepatitis B virus and hepatitis C virus;
  7. Platelets count < 100 x109/L within 14 days before enrolment (i.e. the receipt of the Patient ID);
  8. Absolute neutrophil count < 1.2 x109/L within 14 days before enrolment (i.e. the receipt of the Patient ID);
  9. Serum creatinine > 2 times the upper normal limit;
  10. Total serum bilirubin > 1.5 times the upper normal limit;
  11. Serum Aspartate aminotransferase/Alanine aminotransferase > 3 times the upper normal limit;
  12. History 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;
  13. Any investigational drug other than Givinostat within 28 days before enrolment (i.e. the receipt of the Patient ID);
  14. Patients with known hypersensitivity to the components of potential study therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01761968


Locations
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France
Hopital Saint Vincent de Paul - GHICL Lille
Lille, Lille Cedex, France, 59020
Germany
Charite Research Organization GmbH
Berlin, Germany, 10117
Universitaetsklinikum Freiburg, Innere Medizin I - Haematologie und Onkologie
Freiburg, Germany, 79106
Italy
Azienda Ospedaliero-Universitaria Policlinico Consorziale, Bari
Bari, BA, Italy, 70124
Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico di Bari
Bari, BA, Italy, 70125
Azienda Ospedaliera Papa Giovanni XXIII
Bergamo, BG, Italy, 24127
Azienda Ospedaliero-Universitaria Careggi, Florence
Florence, FI, Italy, 50134
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico UOS Oncoematologia anziano
Milan, MI, Italy, 20122
Azienda Unità Sanitaria Locale - Presidio Ospedaliero "Spirito Santo", Pescara
Pescara, PE, Italy, 65124
Fondazione I.R.C.C.S.-Policlinico San Matteo, Pavia
Pavia, PV, Italy, 27100
Azienda Ospedaliera "Bianchi-Melacrino-Morelli"
Reggio Calabria, RC, Italy, 89125
Ospedale San Bortolo, Vicenza
Vicenza, VI, Italy, 36100
Azienda Ospedaliera Universitaria Università degli Studi "Federico II", Naple
Naples, Italy, 80131
Università "Campus Bio-Medico", Rome
Rome, Italy, 00128
United Kingdom
Belfast City Hospital
Belfast, United Kingdom, BT9 7BL
Royal Cornwall Hospital
Truro, United Kingdom, TR1 3LJ
Sponsors and Collaborators
Italfarmaco
Investigators
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Principal Investigator: Alessandro Rambaldi, MD Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

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Responsible Party: Italfarmaco
ClinicalTrials.gov Identifier: NCT01761968     History of Changes
Other Study ID Numbers: DSC/11/2357/44
2012-003499-37 ( EudraCT Number )
First Posted: January 7, 2013    Key Record Dates
Last Update Posted: July 16, 2019
Last Verified: July 2019
Keywords provided by Italfarmaco:
chronic myeloproliferative neoplasms
Polycythemia Vera
Essential Thrombocythemia
Primary Myelofibrosis
Post-Polycythemia Vera Myelofibrosis
Post-Essential Thrombocythemia Myelofibrosis
Givinostat
Additional relevant MeSH terms:
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Myeloproliferative Disorders
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action