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

Study Description

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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

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Study Design

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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 2020
Estimated Study Completion Date :	December 2020

Arms and Interventions

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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)

Outcome Measures

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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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
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.

Contacts and Locations

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Contacts

Contact: Paolo Bettica, MD, PhD	+390264432584	p.bettica@italfarmaco.com
Contact: Silvia Di Tollo, PhD	+390264432523	s.ditollo@italfarmaco.com

Locations

France
Hopital Saint Vincent de Paul - GHICL Lille	Recruiting
Lille, Lille Cedex, France, 59020
Contact: Nathalie Cambier, MD +33320874532 cambier.nathalie@ghicl.net
Principal Investigator: Nathalie Cambier, MD
Germany
Charite Research Organization GmbH	Recruiting
Berlin, Germany, 10117
Contact: Antonio Pezzutto, Prof. antonio.pezzutto@charite.de
Principal Investigator: Antonio Pezzutto, Prof.
Universitaetsklinikum Freiburg, Innere Medizin I - Haematologie und Onkologie	Recruiting
Freiburg, Germany, 79106
Contact: Nikolas von Bubnoff, MD nikolas.bubnoff@uniklinik-freiburg.de
Principal Investigator: Nikolas von Bubnoff, MD
Italy
Azienda Ospedaliero-Universitaria Policlinico Consorziale, Bari	Recruiting
Bari, BA, Italy, 70124
Contact: Giorgina Specchia, MD
Principal Investigator: Giorgina Specchia, MD
Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico di Bari	Recruiting
Bari, BA, Italy, 70125
Contact: Attilio Guarini, MD attilioguarini@oncologico.bari.it
Azienda Ospedaliera Papa Giovanni XXIII	Recruiting
Bergamo, BG, Italy, 24127
Contact: Alessandro Rambaldi, MD arambaldi@hpg23.it
Principal Investigator: Alessandro Rambaldi, MD
Azienda Ospedaliero-Universitaria Careggi, Florence	Recruiting
Florence, FI, Italy, 50134
Contact: Alessandro M Vannucchi, MD
Principal Investigator: Alessandro M Vannucchi, MD
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico UOS Oncoematologia anziano	Recruiting
Milan, MI, Italy, 20122
Contact: Alessandra Iurlo, Prof aiurlo@policlinico.mi.it
Azienda Unità Sanitaria Locale - Presidio Ospedaliero "Spirito Santo", Pescara	Recruiting
Pescara, PE, Italy, 65124
Contact: Paolo Di Bartolomeo, MD
Principal Investigator: Paolo Di Bartolomeo, MD
Fondazione I.R.C.C.S.-Policlinico San Matteo, Pavia	Recruiting
Pavia, PV, Italy, 27100
Contact: Vittorio Rosti, MD
Principal Investigator: Vittorio Rosti, MD
Azienda Ospedaliera "Bianchi-Melacrino-Morelli"	Recruiting
Reggio Calabria, RC, Italy, 89125
Contact: Bruno Martino, MD
Principal Investigator: Bruno Martino, MD
Ospedale San Bortolo, Vicenza	Recruiting
Vicenza, VI, Italy, 36100
Contact: Marco Ruggeri, MD
Principal Investigator: Marco Ruggeri, MD
Azienda Ospedaliera Universitaria Università degli Studi "Federico II", Naple	Recruiting
Naples, Italy, 80131
Contact: Vincenzo Martinelli, MD
Principal Investigator: Vincenzo Martinelli, MD
Università "Campus Bio-Medico", Rome	Recruiting
Rome, Italy, 00128
Contact: Giuseppe Avvisati, MD
Principal Investigator: Giuseppe Avvisati, MD
United Kingdom
Belfast City Hospital	Recruiting
Belfast, United Kingdom, BT9 7BL
Contact: Mary Frances McMullin, MD m.mcmullin@qub.ac.uk
Principal Investigator: Mary Frances McMullin, MD
Royal Cornwall Hospital	Recruiting
Truro, United Kingdom, TR1 3LJ
Contact: Richard Noble, MD richard.noble@rcht.cornwall.nhs.uk
Principal Investigator: Richard Noble, MD

Sponsors and Collaborators

Italfarmaco

Investigators

Principal Investigator:	Alessandro Rambaldi, MD	Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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
Last Update Posted:	September 21, 2017
Last Verified:	August 2017

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:

Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases	Histone Deacetylase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action