Phase II Study of GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Polycythemia Vera - Full Text View

Sponsor:	Italfarmaco
Information provided by (Responsible Party):	Italfarmaco
ClinicalTrials.gov Identifier:	NCT00928707

Purpose

This is a multicentre, randomized, open-label, phase II study testing GIVINOSTAT (ITF2357) in combination with hydroxyurea in a population of patients with JAK2V617F positive Polycythemia Vera non-responders to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months.

Recruited patients will be randomly assigned to one of the following treatment groups:

group A: 50 mg o.d. of oral GIVINOSTAT (ITF2357) in combination with the maximum tolerated dose of hydroxyurea monotherapy already in use before admission to the study;
group B: 50 mg b.i.d. of oral GIVINOSTAT (ITF2357) in combination with the maximum tolerated dose of hydroxyurea monotherapy already in use before admission to the study.

The two groups will be balanced for number and for Centre in order to provide valuable information on both treatment regimens.

In both groups assigned doses shall remain stable until week 12, which is when the primary endpoint is assessed, unless specific tolerability issues arise which impose dose reduction.

After the primary endpoint assessment at week 12, one of the following treatment schedules will be chosen case by case on the basis of the achieved clinical response and continued for up to 12 further weeks:

Partial or Complete Response at week 12:
group A: continue 50 mg o.d.;
group B: continue 50 mg b.i.d.;
No Response at week 12:
group A: increase to 50 mg b.i.d.;
group B: increase to 50 mg t.i.d.. At any time during study course, if toxicity is observed, GIVINOSTAT (ITF2357) treatment will be discontinued until recovery and then restarted at a reduced dose level. The drug will be definitively withdrawn in case of reappearance of toxicity even at a reduced daily dose. Overall, the treatment will last up to a maximum of 24 cumulative weeks of drug administration.

The study will recruit subjects of both genders with an established diagnosis of JAK2V617F positive Polycythemia Vera according to the revised WHO criteria, in need of cytoreductive therapy, non-responders to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months.

Condition	Intervention	Phase
Polycythemia Vera	Drug: GIVINOSTAT (ITF2357) 50 mg o.d. + MTD Hydroxyurea Drug: GIVINOSTAT (ITF2357) 50 mg b.i.d. + MTD Hydroxyurea	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase II Study of the Histone-deacetylase Inhibitor GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Patients With JAK2V617F Positive Polycythemia Vera Non-responder to Hydroxyurea Monotherapy.

Resource links provided by NLM:

Genetics Home Reference related topics: polycythemia vera

Drug Information available for: Hydroxyurea

U.S. FDA Resources

Further study details as provided by Italfarmaco:

Primary Outcome Measures:

To evaluate the efficacy of GIVINOSTAT (ITF2357) in combination with hydroxyurea in patients with JAK2V617F positive Polycythemia Vera non-responders to the maximum tolerated dose of hydroxyurea monotherapy. [ Time Frame: after 12 weeks of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

To evaluate the safety and tolerability of GIVINOSTAT-HU combination in patients with JAK2V617F positive PV NR to the MTD of HU monotherapy; to evaluate the molecular response. [ Time Frame: after 24 weeks of treatment ] [ Designated as safety issue: Yes ]

Enrollment:	45
Study Start Date:	June 2009
Study Completion Date:	October 2011
Primary Completion Date:	July 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: GIVINOSTAT + MTD Hydroxyurea_1 50 mg o.d. of GIVINOSTAT + MTD of HU monotherapy	Drug: GIVINOSTAT (ITF2357) 50 mg o.d. + MTD Hydroxyurea 50 mg o.d. of GIVINOSTAT + MTD of HU monotherapy Other Names: GIVINOSTAT (ITF2357) ONCOCARBIDE (HYDROXYUREA)
Experimental: GIVINOSTAT + MTD Hydroxyurea_2 50 mg b.i.d. of GIVINOSTAT + MTD of HU monotherapy	Drug: GIVINOSTAT (ITF2357) 50 mg b.i.d. + MTD Hydroxyurea 50 mg b.i.d. of GIVINOSTAT + MTD HU monotherapy Other Names: GIVINOSTAT (ITF2357) ONCOCARBIDE (HYDROXYUREA)

Eligibility

Ages Eligible for Study:	18 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Written Informed Consent.
Age ≥18 years.
Confirmed diagnosis of Polycythemia Vera according to the revised WHO criteria.
JAK2V617F positivity.
Non-response to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months.
ECOG performance status <3.
Use of an effective means of contraception for women of childbearing potential and men with partners of childbearing potential.
Willingness and capability to comply with the requirements of the study.

Exclusion Criteria:

Active bacterial or mycotic infection requiring antimicrobial treatment.
Pregnancy or lactation.
A marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval > 450 ms, according to Bazett's correction formula).
Use of concomitant medications that prolong the QT/QTc interval.
Clinically significant cardiovascular disease including:
- Uncontrolled hypertension, myocardial infarction, unstable angin,within 6 months from study start; ;
- New York Heart Association (NYHA) 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 TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
Positive blood test for HIV.
Active HBV and/or HCV infection.
Platelets count <100x109/L within 14 days before enrolment.
Absolute neutrophil count <1.2x109/L within 14 days before enrolment.
Serum creatinine >2xULN.
Total serum bilirubin >1.5xULN.
Serum AST/ALT > 3xULN.
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 subject at high risk from treatment complications.
Interferon alpha within 14 days before enrolment.
Anagrelide within 7 days before enrolment.
Any other investigational drug within 28 days before enrolment.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00928707

Locations

Italy
Azienda Ospedaliero-Universitaria Policlinico Consorziale di Bari
Bari, BA, Italy, 70124
Azienda Ospedaliera Santa Croce e Carle di Cuneo
Cuneo, CN, Italy, 12100
Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Garibaldi di Catania
Catania, CT, Italy, 95126
Fondazione I. R. C. C. S. - Casa sollievo della sofferenza di San Giovanni Rotondo
San Giovanni Rotondo, FG, Italy, 71013
Azienda Ospedaliero-Universitaria Careggi di Firenze
Florence, FI, Italy, 50134
Azienda Ospedaliera San Gerardo di Monza
Monza, MB, Italy, 20052
Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino" di Messina
Messina, ME, Italy, 98125
Azienda Ospedaliera Ospedali Riuniti "Villa Sofia - Cervello" di Palermo
Palermo, PA, Italy, 90146
Azienda Unità Sanitaria Locale di Pescara, Presidio Ospedaliero "Spirito Santo"
Pescara, PE, Italy, 65124
Azienda Ospedaliera Santa Maria della Misericordia di Perugia
Perugia, PG, Italy, 06156
Azienda Ospedaliera Universitaria Pisana
Pisa, PI, Italy, 56126
Azienda Ospedaliera Ospedale San Carlo di Potenza
Potenza, PT, Italy, 85100
Fondazione I.R.C.C.S.-Policlinico San Matteo, Pavia
Pavia, PV, Italy, 27100
Azienda Ospedaliera "Bianchi-Melacrino-Morelli"
Reggio di Calabria, RC, Italy, 891225
Azienda Ospedaliera Universitaria S. Luigi Gonzaga di Orbassano
Orbassano, TO, Italy, 10043
Ospedale Mauriziano Umberto I
Torino, TO, Italy, 10128
Azienda Ospedaliero-Universitaria San Giovanni Battista("Le Molinette") di Torino
Torino, TO, Italy, 10126
Ospedale San Bortolo di Vicenza
Vicenza, VI, Italy, 36100
Azienda Ospedaliera Ospedali Riuniti di Bergamo
Bergamo, Italy, 24100
Azienda Ospedaliera Universitaria Università degli Studi di Napoli Federico II
Napoli, Italy, 80131
Università "Campus Bio-Medico", Rome
Rome, Italy, 00128
Policlinico Universitario Agostino Gemelli di Roma
Rome, Italy, 00168

Sponsors and Collaborators

Italfarmaco

Investigators

Principal Investigator:

Alessandro Rambaldi, MD

Azienda Ospedaliera Ospedali Riuniti di Bergamo

More Information

No publications provided

Responsible Party:	Italfarmaco
ClinicalTrials.gov Identifier:	NCT00928707 History of Changes
Other Study ID Numbers:	DSC/08/2357/38
Study First Received:	June 25, 2009
Last Updated:	January 31, 2012
Health Authority:	Italy: Ministry of Health

Keywords provided by Italfarmaco:

Polycythemia Vera
GIVINOSTAT
ITF2357

Additional relevant MeSH terms:

Polycythemia
Polycythemia Vera
Hematologic Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hydroxyurea
Histone Deacetylase Inhibitors
Antineoplastic Agents

Therapeutic Uses
Pharmacologic Actions
Antisickling Agents
Hematologic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on February 09, 2012