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

NCT01901432 | Completed Phase 1 Results

• 2 other identifiers: DSC/12/2357/452013-000860-27
• Study Type: interventional
• Target: 48
• Locations: 5 countries
• Sites: 25

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.

Conditions

Polycythemia Vera

Keywords

chronic myeloproliferative neoplasms; Polycythemia Vera; Essential Thrombocythemia; Primary Myelofibrosis; Post-Polycythemia Vera Myelofibrosis; Post-Essential Thrombocythemia Myelofibrosis; Givinostat

Outcome Measures

Primary Outcomes (4)

• Number of Patients Experiencing Treatment-emergent Adverse Events (TEAEs) in Part A of the Study

  Evaluations were performed on the type, incidence and severity of TEAEs, graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03, following administration of givinostat for up to 6 cycles of treatment in Part A. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / treatment-emergent serious adverse event (TESAE) corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment.

  168 days (up to Cycle 6 Day 28 in Part A).

• Number of Dose Limiting Toxicities (DLTs) After 1 Cycle in Part A of the Study

  The MTD of givinostat was based only on Cycle 1 DLTs. A DLT was defined as the following drug-related toxicity: * Grade 4 hematological toxicity, or * Grade 3 febrile neutropenia, or * Grade ≥3 non-hematological toxicity (with the exception Grade 3 diarrhea without adequate supportive care lasting less than 3 days, and Grade 3 nausea or vomiting without adequate supportive care lasting less than 3 days), or * Any drug-related serious AE, or * Any toxicity clearly not related to disease progression or intercurrent illness requiring interruption of dosing for more than 3 days during first cycle. At end of Cycle 1, for the third patient in each DL, the safety of the 3 patients treated for 1 cycle was reviewed and it was decided if the dose should be escalated or not. Results are reported as the number of patients with DLT events for Cycle 1 in Part A.

  28 days (up to Cycle 1 Day 28 in Part A).

• Number of Patients Experiencing TEAEs After 3 Cycles in Part B of the Study

  Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 3 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment.

  84 days (up to Cycle 3 Day 28 in Part B).

• Overall Response Rate (ORR) (i.e. Complete Response [CR] and Partial Response [PR]) After 3 Cycles in Part B of the Study

  ORR, CR and PR following administration of givinostat at MTD for 3 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological European LeukemiaNet (ELN) response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. CR defined as: 1. Hematocrit (HCT) \<45% without phlebotomy, and 2. Platelets ≤400 x10\^9/litre (L), and 3. White Blood Cell count ≤10 x10\^9/L, and 4. Normal spleen size, and 5. No disease-related systemic symptoms (i.e. pruritus, headache, microvascular disturbances). PR defined as: Patients not fulfilling CR and 1. HCT \<45% without phlebotomy, or 2. Response in ≥3 other criteria.

  84 days (up to cycle 3 Day 28 in Part B).

Secondary Outcomes (13)

• ORR After 3 Cycles and After 6 Cycles in Part A of the Study

  84 and 168 days (up to Cycle 3 Day 28 and Cycle 6 Day 28 in Part A).

• ORR After 6 Cycles in Part B of the Study

  168 days (up to Cycle 6 Day 28 in Part B).

• Number of Patients Experiencing TEAEs After 6 Cycles in Part B of the Study

  168 days (up to Cycle 6 Day 28 in Part B).

• Assessment of Maximum Plasma Concentration (Cmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

  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.

• Assessment of Time to Maximum Plasma Concentration (Tmax) of Givinostat and Metabolites (ITF2374 and ITF2375) in Part A of the Study

  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.

Study Arms (1)

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 mg, 75 mg and/or 100 mg each.

Drug: Givinostat

Interventions

Givinostat DRUG

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 mg, 75 mg and/or 100 mg each.

Also known as: Givinostat (ITF2357)

Givinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must be able to provide informed consent and be willing to sign an informed consent form;
• Patients must have an age ≥18 years;
• Patients must have a confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization criteria;
• Patients must have mutated Janus Kinase 2 (mutation V617F) positive disease;
• Patients must have an active/not controlled disease defined as
• hematocrit ≥ 45% or hematocrit \<45% in need of phlebotomy, and
• platelet count \> 400 x109/L, and
• white blood cell count \> 10 x109/L;
• 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;
• Female patient of childbearing potential has a negative serum or urine pregnancy test within 72 hours of the first dose of study therapy;
• Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential;
• Adequate and acceptable organ function within 7 days of initiating study drug;
• Willingness and capability to comply with the requirements of the study.
• \. Patients must have an active/not controlled disease defined as:
• Essential Thrombocythemia patients: Platelet count \> 600 x109/L;

You may not qualify if:

• Active bacterial or mycotic infection requiring antimicrobial treatment;
• Pregnancy or nursing;
• A clinically significant corrected QT interval prolongation at baseline;
• Use of concomitant medications known to prolong the corrected QT interval;
• Clinically significant cardiovascular disease including:
• Uncontrolled hypertension despite medical treatment, 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 pointes;
• Known positivity for human immunodeficiency;
• Known active hepatitis B virus and/or hepatitis C virus infection;
• Platelet count \< 100 x109/L within 14 days before enrolment;
• Absolute neutrophil count \< 1.2x109/L within 14 days before enrolment;
• Serum creatinine \> 2 times the upper limit of normal;
• Total serum bilirubin \> 1.5 times the upper limit of normal except in case of Gilbert's disease;

Sponsors & Collaborators

• Italfarmaco: lead

Study Sites (25)

CHU Amiens - Hôpital Sud

Amiens, 80054, France

Location

Hôpital Morvan - CHRU de Brest

Brest, 29609, France

Location

Hopital Saint Vincent de Paul - GHICL Lille

Lille, 59020, France

Location

Hôpital Saint-Louis (AP-HP), Centre Investigations Cliniques

Paris, 75475, France

Location

Charite Research Organisation GmbH

Berlin, 10117, Germany

Location

Universitaetsklinikum Koeln

Cologne, 50937, Germany

Location

Universitaetsklinikum Carl Gustav Carus TU Dresden

Dresden, 01307, Germany

Location

Universitaetsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Azienda ospedaliero universitaria Consorziale Policlinico di Bari

Bari, BA, 70124, Italy

Location

Azienda Ospedaliera Papa Giovanni XXIII

Bergamo, BG, 24127, Italy

Location

Azienda Ospedaliero-Universitaria Careggi, Florence

Florence, FI, 50134, Italy

Location

Fondazione IRCCS Policlinico San Matteo

Pavia, PV, 27100, Italy

Location

Istituto Tumori Giovanni Paolo II - IRCCS Ospedale Oncologico di Bari

Bari, 70124, Italy

Location

Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico

Milan, Italy

Location

Università degli Studi di Napoli Federico II, Facoltà di Medicina e Chirurgia

Napoli, 80131, Italy

Location

Ospedale Civile dello Spirito Santo

Pescara, Italy

Location

Azienda Ospedaliero Universitaria Pisana

Pisa, 56126, Italy

Location

Azienda Ospedaliera "Bianchi-Melacrino-Morelli"

Reggio Calabria, 89125, Italy

Location

Università Campus Bio-Medico di Roma

Rome, Italy

Location

Ospedale San Bortolo di Vicenza

Vicenza, 36100, Italy

Location

SP ZOZ Zespol Szpitali Miejskich w Chorzowie

Chorzów, 41-500, Poland

Location

Uniwersyteckie Centrum Kliniczne

Gdansk, 80-952, Poland

Location

Belfast City Hospital

Belfast, BT9 7BL, United Kingdom

Location

Royal London Hospital

London, E1 1BB, United Kingdom

Location

Royal Cornwall Hospital

Truro, TR1 3LJ, United Kingdom

Location

MeSH Terms

Conditions

Polycythemia Vera; Myeloproliferative Disorders; Thrombocythemia, Essential; Primary Myelofibrosis

Interventions

givinostat; givinostat hydrochloride

Condition Hierarchy (Ancestors)

Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Blood Coagulation Disorders; Thrombocytosis; Blood Platelet Disorders; Hemorrhagic Disorders

Results Point of Contact

• Title: Medical Expert
• Organization: ITALFARMACO S.p.A.

p.bettica@italfarmaco.com

+39 026443 258

Study Officials

• Paolo Bettica, MD

  Italfarmaco S.p.A.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 10, 2013
• First Posted: July 17, 2013
• Study Start: October 1, 2013
• Primary Completion: June 26, 2017
• Study Completion: September 25, 2017
• Last Updated: July 30, 2019
• Results First Posted: June 20, 2019

Record last verified: 2019-07

Locations

FR (4); PL (2); DE (4); GB (3); IT (12)