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

Sponsor:	Italfarmaco
Information provided by:	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 The drug will be definitively withdrawn in case of reappearance of toxicity even at a reduced daily dose.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:	Treatment, Randomized, Open Label, Uncontrolled, Parallel Assignment, Safety/Efficacy Study
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:

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 ]

Estimated Enrollment:	44
Study Start Date:	June 2009
Estimated Study Completion Date:	December 2010
Estimated Primary Completion Date:	June 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
GIVINOSTAT + MTD Hydroxyurea_1: Experimental 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
GIVINOSTAT + MTD Hydroxyurea_2: Experimental 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

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 angina;
- 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

Contacts

Contact: Tiziano Oldoni, MD

+39 02 6443 2540

t.oldoni@italfarmaco.com

Locations

Italy
Azienda Ospedaliera Ospedali Riuniti di Bergamo	Recruiting
Bergamo, Italy, 24100
Contact: Alessandro Rambaldi, MD +39 035 269492 arambaldi@ospedaliriuniti.bergamo.it
Sub-Investigator: Giovanni Barosi, MD
Sub-Investigator: Alessandro M. Vannucchi, MD
Sub-Investigator: Giorgina Specchia, MD
Sub-Investigator: Enrico M. Pogliani, MD
Sub-Investigator: Francesco Rodeghiero, MD
Sub-Investigator: Andrea Gallamini, MD
Sub-Investigator: Brunangelo Falini, MD
Sub-Investigator: Corrado Tarella, MD

Sponsors and Collaborators

Italfarmaco

Investigators

Principal Investigator:

Alessandro Rambaldi, MD

Azienda Ospedaliera Ospedali Riuniti di Bergamo

More Information

No publications provided

Responsible Party:	Dr. Tiziano Oldoni ( Italfarmaco S.p.A. )
Study ID Numbers:	DSC/08/2357/38
Study First Received:	June 25, 2009
Last Updated:	October 13, 2009
ClinicalTrials.gov Identifier:	NCT00928707 History of Changes
Health Authority:	Italy: Ministry of Health

Keywords provided by Italfarmaco:

Polycythemia Vera
GIVINOSTAT
ITF2357

Additional relevant MeSH terms:

Polycythemia
Polycythemia Vera
Antisickling Agents
Molecular Mechanisms of Pharmacological Action
Hematologic Diseases
Hydroxyurea
Antineoplastic Agents

Hematologic Agents
Myeloproliferative Disorders
Enzyme Inhibitors
Pharmacologic Actions
Therapeutic Uses
Bone Marrow Diseases
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on November 20, 2009