Clinical trial NCT01901432: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Polycythemia Vera
Keywords: chronic myeloproliferative neoplasms
Polycythemia Vera
Essential Thrombocythemia
Primary Myelofibrosis
Post-Polycythemia Vera Myelofibrosis
Post-Essential Thrombocythemia Myelofibrosis
Givinostat
Lead sponsor: Italfarmaco
Sponsor class: INDUSTRY
First posted: 2013-07-17
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Primary outcomes:
measure: Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study
timeFrame: 168 days (up to Cycle 6 Day 28 in Part A).
measure: Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study
timeFrame: 28 days (up to Cycle 1 Day 28 in Part A).
measure: Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study
timeFrame: 84 days (up to Cycle 3 Day 28 in Part B).
measure: Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study
timeFrame: 84 days (up to cycle 3 Day 28 in Part B).
Secondary outcomes:
measure: ORR After 3 Cycles and After 6 Cycles in Part A of the Study
timeFrame: 84 and 168 days (up to Cycle 3 Day 28 and Cycle 6 Day 28 in Part A).
measure: ORR After 6 Cycles in Part B of the Study
timeFrame: 168 days (up to Cycle 6 Day 28 in Part B).
measure: Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study
timeFrame: 168 days (up to Cycle 6 Day 28 in Part B).
measure: Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study
timeFrame: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
measure: Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study
timeFrame: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
measure: Assessment of Time of the Last Detectable Concentration (Tlast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study
timeFrame: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
measure: Assessment of Area Under Plasma Concentration Versus the Time Curve up to the Last Detectable Concentration (AUClast) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study
timeFrame: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
measure: Assessment of Area Under Plasma Concentration Versus the Time Curve in the Dosing Interval (0-12 Hours) (AUC0-12) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study
timeFrame: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
measure: Assessment of Cmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study
timeFrame: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
measure: Assessment of Tmax of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study
timeFrame: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
measure: Assessment of Tlast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study
timeFrame: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
measure: Assessment of AUClast of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study
timeFrame: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
measure: Assessment of AUC0-12 of Givinostat and Metabolites (ITF2374 and ITF2375) in Part B of the Study
timeFrame: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
Other outcomes:
Locations:
city: Amiens Cedex 1
country: France
facility: CHU Amiens - Hôpital Sud
city: Brest Cedex
country: France
facility: Hôpital Morvan - CHRU de Brest
city: Lille cedex
country: France
facility: Hopital Saint Vincent de Paul - GHICL Lille
city: Paris Cedex 10
country: France
facility: Hôpital Saint-Louis (AP-HP), Centre Investigations Cliniques
city: Berlin
country: Germany
facility: Charite Research Organisation GmbH
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus TU Dresden
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln
city: Bari
country: Italy
facility: Azienda ospedaliero universitaria Consorziale Policlinico di Bari
state: BA
city: Bergamo
country: Italy
facility: Azienda Ospedaliera Papa Giovanni XXIII
state: BG
city: Florence
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi, Florence
state: FI
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
state: PV
city: Bari
country: Italy
facility: Istituto Tumori Giovanni Paolo II - IRCCS Ospedale Oncologico di Bari
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico
city: Napoli
country: Italy
facility: Università degli Studi di Napoli Federico II, Facoltà di Medicina e Chirurgia
city: Pescara
country: Italy
facility: Ospedale Civile dello Spirito Santo
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Reggio Calabria
country: Italy
facility: Azienda Ospedaliera "Bianchi-Melacrino-Morelli"
city: Rome
country: Italy
facility: Università Campus Bio-Medico di Roma
city: Vicenza
country: Italy
facility: Ospedale San Bortolo di Vicenza
city: Chorzow
country: Poland
facility: SP ZOZ Zespol Szpitali Miejskich w Chorzowie
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: London
country: United Kingdom
facility: Royal London Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
Study officials:
affiliation: Italfarmaco S.p.A.
name: Paolo Bettica, MD
role: STUDY_DIRECTOR
References: