Clinical Trials /

A Two-part Study to Assess the Safety and Preliminary Efficacy of Givinostat in Patients With Polycythemia Vera

NCT01901432

Description:

This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety and tolerability, Maximum Tolerated Dose and preliminary efficacy of Givinostat in patients with JAK2V617F positive Polycythemia Vera. Part A is the dose finding part while Part B is assessing the preliminary efficacy. Patients will be enrolled either in Part A or Part B and transition from one part to the other is not allowed. Eligible patients for this study will have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria. Only 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 chronic myeloproliferative neoplasms. Study therapy will be administered in 28 day cycles (4 weeks of treatment). Disease response will be evaluated according to the European LeukemiaNet criteria after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat for both parts of the study. All phlebotomies performed in the first 3 weeks of treatment will not be counted to assess the clinico-haematological response. The study will last up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit will be allowed to continue treatment with Givinostat (at the same dose and schedule) in a long-term study. Safety will be monitored at each visit throughout the entire duration of the study. Treatment will be administered on an outpatient basis and patients will be followed regularly with physical and laboratory tests, as specified in the protocol; in case of hospitalization, the treatment will be continued or interrupted according to the Investigators' decision.

Related Conditions:
  • Essential Thrombocythemia
  • Polycythemia Vera
  • Primary Myelofibrosis
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

A Two-part Study to Assess the Safety and Preliminary Efficacy of <span class="go-doc-concept go-doc-intervention">Givinostat</span> in Patients With Polycythemia Vera

Title

  • Brief Title: A Two-part Study to Assess the Safety and Preliminary Efficacy of Givinostat in Patients With Polycythemia Vera
  • Official Title: A Two-part Study Top Assess the Safety and Preliminary Efficacy of Givinostat in Patients With JAK2V617F Positive Polycythemia Vera
  • Clinical Trial IDs

    NCT ID: NCT01901432

    ORG ID: DSC/12/2357/45

    NCI ID: 2013-000860-27

    Trial Conditions

    Polycythemia Vera

    Trial Interventions

    Drug Synonyms Arms
    Givinostat Givinostat (ITF2357) Givinostat

    Trial Purpose

    This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the
    safety and tolerability, Maximum Tolerated Dose and preliminary efficacy of Givinostat in
    patients with JAK2V617F positive Polycythemia Vera. Part A is the dose finding part while
    Part B is assessing the preliminary efficacy. Patients will be enrolled either in Part A or
    Part B and transition from one part to the other is not allowed.

    Eligible patients for this study will have a confirmed diagnosis of Polycythemia Vera
    according to the revised World Health Organization criteria. Only 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 chronic myeloproliferative neoplasms.

    Study therapy will be administered in 28 day cycles (4 weeks of treatment). Disease response
    will be evaluated according to the European LeukemiaNet criteria after 3 and 6 cycles (i.e.
    at weeks 12 and 24, respectively) of treatment with Givinostat for both parts of the study.
    All phlebotomies performed in the first 3 weeks of treatment will not be counted to assess
    the clinico-haematological response.

    The study will last up to a maximum of 24 weeks of treatment. However, after completion of
    the trial, all patients achieving clinical benefit will be allowed to continue treatment
    with Givinostat (at the same dose and schedule) in a long-term study.

    Safety will be monitored at each visit throughout the entire duration of the study.
    Treatment will be administered on an outpatient basis and patients will be followed
    regularly with physical and laboratory tests, as specified in the protocol; in case of
    hospitalization, the treatment will be continued or interrupted according to the
    Investigators' decision.

    Detailed Description

    This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the
    safety and tolerability, MTD and preliminary efficacy of Givinostat in patients with
    JAK2V617F positive PV.

    Part A is the dose escalation portion of the study and, once the MTD has been established,
    Part B will commence where the preliminary efficacy of Givinostat in PV patients will be
    established. Patients will be enrolled either in Part A or Part B and transition from one
    part to the other is not allowed. Only PV patients from Part A assigned to the dose selected
    for Part B (MTD) may be counted towards the efficacy assessment in Part B.

    Eligible patients for this study will have a confirmed diagnosis of PV according to the
    revised WHO criteria and the JAK2V617F positivity. Only 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.

    After providing informed written consent before undertaking any protocol-related procedure,
    a unique patient identification code (i.e. patient screening ID which will be a combination
    of his/her site ID, study part ID and patient screening number, e.g. IT01-A01) will be
    assigned to each patient and it will identify the patient within his/her enrolment
    confirmation by Italfarmaco S.p.A. or its designee and never be reused in case of screening
    failure. After the enrolment confirmation and the assignation of the dose level before the
    first drug intake, a unique patient identification code (i.e. patient ID which will be a
    combination of patient screening number ID and dose level ID, e.g. IT01-A01-DL1) will be
    assigned to each patient and it will identify the patient throughout his/her participation
    in the study and never be reused in case of premature drop-out.

    Study therapy will be administered in 28 day cycles. In fact, the "cycle" is defined as 4
    weeks of treatment.

    Disease response will be evaluated according to the clinico-haematological ELN criteria
    after 3 and 6 cycles (i.e. at weeks 12 and 24, respectively) of treatment with Givinostat
    for both parts of the study. All phlebotomies performed in the first 3 weeks of treatment
    will not be counted to assess the clinico-haematological response.

    The study will last up to a maximum of 24 weeks of treatment. However, after completion of
    the trial, all patients achieving clinical benefit will be allowed to continue treatment
    with Givinostat (at the same dose and schedule) in a long-term study (Study N.:
    DSC/11/2357/44).

    Safety will be monitored at each visit throughout the entire duration of the study.
    Treatment will be administered on an outpatient basis and patients will be followed
    regularly with physical and laboratory tests, as specified in the protocol; in case of
    hospitalization, the treatment will be continued or interrupted according to the
    Investigators' decision.

    Trial Arms

    Name Type Description Interventions
    Givinostat Experimental In Part A patients will treated in dose levels at the following daily doses of Givinostat: 50 mg b.i.d., 100 mg b.i.d.; 150 mg b.i.d., 200 mg b.i.d.; 150 mg t.i.d.; 200 mg t.i.d.. Intermediate dose levels and, consequently, additionally dose levels may be used to establish the Maximum Tolerated Dose. In Part B patients will be treated at the Maximum Tolerated Dose established in Part A. The product will be supplied as hard gelatine capsules for oral administration at the strength of 50 and/or 100 mg each. Givinostat

    Eligibility Criteria

    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 Polycythemia Vera according to the
    revised World Health Organization criteria;

    4. Patients must have mutated Janus Kinase 2 (mutation V617F) positive disease;

    5. Patients must have an active/not controlled disease defined as

    1. hematocrit 45% or hematocrit <45% in need of phlebotomy, and

    2. platelet count > 400 x109/L, and

    3. white blood cell count > 10 x109/L;

    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;

    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.

    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 chronic
    myeloproliferative neoplasms. 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:

    1. Essential Thrombocythemia patients: Platelet count > 600 x109/L;

    2. Myelofibrosis patients: no response according to European Myelofibrosis Network
    criteria.

    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:

    1. Uncontrolled hypertension despite medical treatment, myocardial infarction,
    unstable angina within 6 months from study start;

    2. New York Heart Association Grade II or greater congestive heart failure;

    3. History of any cardiac arrhythmia requiring medication (irrespective of its
    severity);

    4. A history of additional risk factors for torsade de pointes;

    6. Known positivity for human immunodeficiency;

    7. Known active hepatitis B virus and/or hepatitis C virus infection;

    8. Platelet count < 100 x109/L within 14 days before enrolment;

    9. Absolute neutrophil count < 1.2x109/L within 14 days before enrolment;

    10. Serum creatinine > 2 times the upper limit of normal;

    11. Total serum bilirubin > 1.5 times the upper limit of normal except in case of
    Gilbert's disease;

    12. Serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) > 3 times the
    upper limit of normal;

    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 Janus Kinase 2 or Histone Deacetylase inhibitor or
    participation in an interventional clinical trial for chronic myeloproliferative
    neoplasms;

    15. Systemic treatment for chronic myeloproliferative neoplasms other than aspirin/cardio
    aspirin;

    16. Hydroxyurea within 28 days before enrolment;

    17. Interferon alpha within 14 days before enrolment;

    18. Anagrelide within 7 days before enrolment;

    19. Any other investigational drug or device within 28 days before enrolment;

    20. Patient with known hypersensitivity to the components of study therapy.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Part A: Maximum Tolerated Dose

    Part B: Preliminary efficacy after 3 cycles of treatment

    Part A: Safety and tolerability

    Part B: Safety and tolerability after 3 cycles of treatment

    Secondary Outcome Measures

    Part A: characterization of pharmacokinetic

    Part B: characterization of pharmacokinetic

    Part A: preliminary efficacy after 3 and 6 cycles of treatment

    Part B: preliminary efficacy of Givinostat at the Maximum Tolerated Dose after 6 cycles.

    Part B: safety and tolerability after 6 cycles

    Trial Keywords

    chronic myeloproliferative neoplasms

    Polycythemia Vera

    Essential Thrombocythemia

    Primary Myelofibrosis

    Post-Polycythemia Vera Myelofibrosis

    Post-Essential Thrombocythemia Myelofibrosis

    Givinostat