Study on Efficacy and Safety of Givinostat Versus Hydroxyurea in Patients With Polycythemia Vera

Official title

Randomized, Open-label, Multicenter Phase 3 Study to Assess the Efficacy and Safety of GIVinostat Versus Hydroxyurea IN JAK2V617F-positive High-risk Polycythemia Vera Patients: the GIV-IN PV TRIAL

Overview

The goal of this clinical trial is to compare the efficacy and safety of givinostat to hydroxyurea in Jak2V617F-positive high risk polycythemia vera patients.

Detailed description

PV is a cMPN mainly driven by JAK2V617F mutation. The disease has an increased risk of thromboembolic complications, a predisposition to evolve into myelofibrosis (MF) and transformation into acute myeloid leukemia.

Patients ≥ 60 years of age and/or with a previous thrombotic event (TE) are considered at High Risk (HR) for thrombosis. The association of absolute values of circulating neutrophil, lymphocyte and monocyte and the high value of JAK2V617F allele burden are additional risk factors for the occurrence of thrombosis and for progression to MF, respectively.

Overall, most patients treated with HU are not adequately under control for both symptoms and long-term risks.

In recent years, data have shown that histone deacetylase (HDACs) inhibitors induce growth arrest, differentiation, and/or apoptosis in neoplastic cells. Givinostat has demonstrated preliminary signs of clinical activity and an acceptable safety profile in patients with JAK2V617F-positive cMPNs in three phase 2 studies.

The core treatment phase (pivotal phase 3 study) is designed to demonstrate the superiority of givinostat versus HU on efficacy, in JAK2V617F-positive, HR PV patients.

The extended treatment phase will allow eligible patients to receive givinostat in the long-term, with the objective of collecting long-term safety and efficacy data.

Interventions

• Drug Givinostat
  Oral. The dosage must be modified, according to the manifestation of toxicities or lack of efficacy, with the aim to achieve an optimized dose.
• Drug Hydroxyurea
  Oral. The dosage must be modified, according to the manifestation of toxicities or lack of efficacy, with the aim to achieve an optimized dose.

Primary outcome measures

• Proportion of patients achieving a response at Week 48. [Time frame: week 25 - week 48]

Secondary outcome measures (4)

• Proportion of patients achieving a complete hematological response (CHR) at Week 48. [Time frame: week 48]
• Time from randomization to the first observed CHR [Time frame: Randomization - week 48]
• Proportion of patients with a normal spleen size at Week 48. [Time frame: week 48]
• Safety and tolerability up to Week 48. [Time frame: Randomization - week 48]

Eligibility criteria

Core Treatment - Inclusion Criteria:

• Patients must have been diagnosed with PV according to the 2016 WHO criteria before randomization
• Patients must have JAK2V617F-positive disease
• Patients with PV must meet the definition of HR for thrombosis (i.e., HR) within 3 years before screening as follows:

• Age ≥ 60 years, and/or
• Prior thrombosis.
• Patients must be in need of treatment at screening, defined by the presence of at least one of the following:

• HCT ≥ 45% or HCT < 45% with at least 1 phlebotomy performed in the 3 months before screening, or
• WBC count > 10 × 109/L, or
• PLT count > 400 × 109/L.
• Patients must have normalized HCT (i.e., HCT < 45%) at randomization

Extended Treatment - Inclusion Criteria

• Patients must have completed the Week 48 visit of the DSC/08/2357/32 core treatment phase and:

• if the patient received givinostat, a complete hematological response (CHR) at Week 48 shall be achieved
• if the patient received HU, did not achieve a CHR (see above for the definition) at Week 48

Core Treatment phase - Exclusion Criteria

• Patients pre-treated with HU with a documented history of resistance or intolerance to HU defined by the original ELN criteria
• Patients with a QTcF value of > 450 msec for males and > 460 msec for females at the Screening visit (as the mean of 3 consecutive readings 5 minutes apart in the event a first ECG demonstrates a prolonged QTcF interval); congenital or acquired history of QTc prolongation or ventricular arrhythmias, at the Screening visit
• Splanchnic thrombosis and/or thrombosis of the cerebral venous sinuses and/or splenectomy in the medical history
• Patients with clinically significant cardiovascular disease
• Patients with myocardial infarction, stroke or unstable angina within the 6 months prior to screening.
• Patients with inadequate liver or renal function at screening
• Uncontrolled hypertriglyceridemia at screening, i.e., triglycerides ˃ 1.5 × ULN
• Previous treatment with a JAK2 or HDAC inhibitor or 32-phosphorus (radioactive isotope) therapy.
• Patients being treated concurrently with any investigational agent or prior participation in an interventional clinical study within the 30 days prior to screening or within 5 half-lives of the investigational product, whichever is longer.
• Pregnant or nursing women

Extended treatment phase - Exclusion criteria

• For patients randomized to givinostat in the core treatment phase - Patients with a QTcF value at Week 48 of > 500 msec
• For patients randomized to HU in the core treatment phase:

• PLT count ≤ 150 × 109/L at Week 48
• ANC < 1.2 × 109/L at Week 48
• Uncontrolled hypertriglyceridemia at Week 48
• Patients with a QTcF value at Week 48 of > 450 msec for males and > 460 msec for female

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Italy · 16 centers

• Istituto Tumori "Giovanni Paolo II" I.R.C.C.S. — Bari
• Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli — Reggio Calabria
• Azienda Ospedaliero-Universitaria Di Bologna IRCCS Istituto Di Ricerca E Di Cura A Caratte — Bologna
• Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST S.r.l — Meldola
• Azienda USL IRCCS di Reggio Emilia — Reggio Emilia
• Azienda Sanitaria Universitaria Friuli Centrale — Udine
• Fondazione Policlinico Universitario Campus Bio-Medico di Roma — Rome
• Azienda Ospedaliera Papa Giovanni XXIII — Bergamo
• … and 8 more centers

United States · 14 centers

• University of Alabama at Birmingham — Birmingham
• Emad Ibrahim, MD, Inc — Redlands
• US Oncology Inc — Englewood
• American Oncology Partners of Maryland, PA — Bethesda
• Icahn School of Medicine at Mount Sinai — New York
• University of North Carolina at Chapel Hill — Chapel Hill
• The Cleveland Clinic Foundation — Cleveland
• Oncology Associates of Oregon, P.C. — Eugene
• … and 6 more centers

France · 9 centers

• Centre Hospitalier de Saint-Quentin — Saint-Quentin
• CHU de Nice — Nice
• Centre Hospitalier de Troyes — Troyes
• Hôpital Bretonneau — Tours
• CHU Nantes — Nantes
• CHU Angers — Angers
• CHU Amiens Hôpital Sud — Amiens
• Hôpital Saint Louis — Paris
• … and 1 more center

United Kingdom · 6 centers

Center list to be confirmed — check the primary protocol.

Serbia · 5 centers

• Clinical Hospital Center Bezanijska Kosa — Belgrade
• Clinical Hospital Center Zemun — Belgrade
• University Clinical Center of Serbia — Belgrade
• University Clinical Center Nis — Niš
• Clinical Center of Vojvodina — Novi Sad

Spain · 5 centers

• ICO Badalona-H.U. Germans Trias i Pujol — Badalona
• Hospital General Universitario Dr. Balmis — Alicante
• Hospital Universitario Ramon y Cajal — Madrid
• Hospital Universitario Virgen de la Victoria — Málaga
• Hospital Universitari i Politecnic La Fe de Valencia — Valencia

Austria · 4 centers

• Landesklinikum Wiener Neustadt — Wiener Neustadt
• Medizinische Universitat Wien (Medical University of Vienna) — Vienna
• Ordensklinikum Linz GmbH Elisabethinen — Linz
• Klinikum Wels-Grieskirchen GmbH — Wels

Croatia · 4 centers

• Clinical Hospital Dubrava — Zagreb
• Clinical Hospital Center Rijeka - PPDS — Rijeka
• Clinical Hospital Center Rijeka — Rijeka
• General Hospital Sibenik — Šibenik

Germany · 4 centers

• Medizinische Fakultät Mannheim der Universität Heidelberg, Universitätsmedizin Mannheim — Mannheim
• Gemeinschaftspraxis Hämatologie - Onkologie — Dresden
• Universitätsmedizin Halle, Universitätsklinikum Halle, Klinik für Innere Medizin IV — Halle
• OncoResearch Lerchenfeld GmbH — Hamburg

Israel · 4 centers

• Hadassah Medical Center - PPDS — Jerusalem
• Assuta Medical Center — Tel Aviv
• Bnai Zion Medical Center — Haifa
• Carmel Medical Center — Haifa

Turkey (Türkiye) · 4 centers

Center list to be confirmed — check the primary protocol.

Bulgaria · 3 centers

• Acibadem City Clinic Multiprofile Hospital for Active Treatment Tokuda — Sofia
• University Multiprofile Hospital for Active Treatment Sveti Georgi EAD — Plovdiv
• University Multiprofile Hospital for Active Treatment - Prof. Dr. Stoyan Kirkovich AD — Stara Zagora

Hungary · 3 centers

• Gyor-Moson-Sopron Vármegyei Petz Aladár Egyetemi Oktató Kórház — Győr
• Szabolcs-Szatmár-Bereg Vármegyei Oktatókórház — Nyíregyháza
• Tolna Vármegyei Megyei Balassa János Kórház — Szekszárd

Ireland · 3 centers

• Cork University Hospital — Cork
• Connolly Hospital Blanchardstown — Dublin
• Mater Misericordiae University Hospital — Dublin

Netherlands · 3 centers

• Spaarne Gasthuis — Hoofddorp
• Medisch Spectrum Twente — Enschede
• Albert Schweitzer Ziekenhuis — Dordrecht

Poland · 3 centers

• Indywidualna Specjalistyczna Praktyka Lekarska Tomasz Woźny — Poznan
• Specjalistyczny Szpital im. dra Alfreda Sokołowskiego — Wałbrzych
• Uniwersytecki Szpital Kliniczny im. Jana Mikulicza- Radeckiego we Wrocławiu — Wroclaw

Identifiers

NCT: NCT06093672 · DSC/08/2357/32 · 2022-502276-23-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗