Back to resultsPhase II Study of GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Polycythemia Vera (PV)
Primary Purpose
Polycythemia Vera
Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
GIVINOSTAT (ITF2357) 50 mg o.d. + MTD Hydroxyurea
GIVINOSTAT (ITF2357) 50 mg b.i.d. + MTD Hydroxyurea
Sponsored by
About this trial
This is an interventional treatment trial for Polycythemia Vera focused on measuring Polycythemia Vera, GIVINOSTAT, ITF2357
Eligibility Criteria
Inclusion Criteria:
- Written Informed Consent.
- Age ≥18 years.
- Confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization (WHO) criteria.
- JAK2V617F positivity.
- Non-response to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months.
- ECOG (Eastern Cooperative Oncology Group) 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 (corrected) 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 torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
- Positive blood test for HIV (Human Immunodeficiency Virus)
- Active HBV (Hepatitis B Virus) and/or HCV (Hepatitis C Virus) infection.
- Platelets count <100x109/L within 14 days before enrolment.
- Absolute neutrophil count <1.2x109/L within 14 days before enrolment.
- Serum creatinine >2xULN (upper limit of normal).
- Total serum bilirubin >1.5xULN.
- Serum aspartate aminotransferase (AST) / alanine aminotransferase (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.
Sites / Locations
- Azienda Ospedaliero-Universitaria Policlinico Consorziale di Bari
- Azienda Ospedaliera Santa Croce e Carle di Cuneo
- Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Garibaldi di Catania
- Fondazione I. R. C. C. S. - Casa sollievo della sofferenza di San Giovanni Rotondo
- Azienda Ospedaliero-Universitaria Careggi di Firenze
- Azienda Ospedaliera San Gerardo di Monza
- Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino" di Messina
- Azienda Ospedaliera Ospedali Riuniti "Villa Sofia - Cervello" di Palermo
- Azienda Unità Sanitaria Locale di Pescara, Presidio Ospedaliero "Spirito Santo"
- Azienda Ospedaliera Santa Maria della Misericordia di Perugia
- Azienda Ospedaliera Universitaria Pisana
- Azienda Ospedaliera Ospedale San Carlo di Potenza
- Fondazione I.R.C.C.S.-Policlinico San Matteo, Pavia
- Azienda Ospedaliera "Bianchi-Melacrino-Morelli"
- Azienda Ospedaliera Universitaria S. Luigi Gonzaga di Orbassano
- Azienda Ospedaliero-Universitaria San Giovanni Battista("Le Molinette") di Torino
- Ospedale Mauriziano Umberto I
- Ospedale San Bortolo di Vicenza
- Azienda Ospedaliera Ospedali Riuniti di Bergamo
- Azienda Ospedaliera Universitaria Università degli Studi di Napoli Federico II
- Università "Campus Bio-Medico", Rome
- Policlinico Universitario Agostino Gemelli di Roma
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
GIVINOSTAT + MTD Hydroxyurea (HU)_1
GIVINOSTAT + MTD Hydroxyurea (HU)_2
Arm Description
50 mg o.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy
50 mg b.i.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy
Outcomes
Primary Outcome Measures
Percentage of Patients With Overall Haematological Response at Week 12.
The percentage of patients with overall (complete or partial) response at week 12 were assessed. · Complete response: 1. HCT (Hematocrit) < 45% without phlebotomy, and 2. platelets ≤ 400 x109/L, and 3. WBC (white blood cell) ≤ 10 x 109/L, and 4. no splenomegaly, and 5. no disease related systemic symptoms (microvascular disturbances, pruritus, headache); · Partial response: 1. HCT < 45% without phlebotomy, or 2. fulfilment of at least 3 of the other above mentioned criteria; · No response: any response that did not satisfy the criteria set for partial response.
Secondary Outcome Measures
Percentage of Patients With Overall Haematological Response at Week 24 by Dose Escalation After Week 12.
Haematological response after a 50 mg increase of the initial Givinostat dose in non-responder patients at the time when the primary endpoint was assessed (week 12).
Complete response:
HCT< 45% without phlebotomy, and
platelets ≤ 400 x109/L, and
WBC ≤ 10 x 109/L, and
no splenomegaly, and
no disease related systemic symptoms (microvascular disturbances, pruritus, headache);
Partial response:
HCT < 45% without phlebotomy, or
fulfilment of at least 3 of the other above mentioned criteria;
No response:
any response that did not satisfy the criteria set for partial response.
Change From Baseline of the JAK2V617F Allele Burden by Quantitative RT-PCR
To determine JAK2V617F mutational status, a quantitative RT-PCR (Real Time-Polymerase Chain Reaction) is executed on peripheral blood granulocyte and haematopoietic colonies (with and without hepatocyte growth factors - HGFs).
Percentage of Patients With a Reduction of the Fraction of JAK2V617F Positive Clonogenic Progenitor by Timepoints
JAK2V617F genotyping and quantification were performed on gradient-separated mononuclear cells during the pre-treatment evaluations (baseline), halfway through the study (12th weeks) and at the end of the study period (24th weeks).
Baseline: n=22 (50 mg od); 22 (50 mg bid) Week 12: n=20 (50 mg od); 19 (50 mg bid) Week 24: n=18 (50 mg od); 18 (50 mg bid)
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00928707
Brief Title
Phase II Study of GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Polycythemia Vera
Acronym
PV
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.
Study Type
Interventional
2. Study Status
Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
June 2009 (undefined)
Primary Completion Date
July 2011 (Actual)
Study Completion Date
October 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Italfarmaco
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The primary objective of the study was to evaluate the efficacy of Givinostat in combination with hydroxyurea in patients with JAK2V617F-positive Polycythemia Vera (PV) non-responders to the maximum tolerated dose of hydroxyurea monotherapy.
The secondary objectives of this study were:
To evaluate the safety and tolerability of Givinostat in combination with hydroxyurea in patients with JAK2V617Fpositive PV non-responders to the maximum tolerated dose of hydroxyurea monotherapy;
To explore the impact in terms of efficacy and tolerability of Givinostat 50 mg dose escalation in patients not achieving at least a partial response at the time when the primary endpoint was assessed (week 12);
To evaluate the molecular response (JAK2 mutated allele burden) by quantitative Real Time-Polymerase Chain Reaction (RT-PCR);
To evaluate the reduction of the fraction of JAK2V617F positive clonogenic progenitors.
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polycythemia Vera
Keywords
Polycythemia Vera, GIVINOSTAT, ITF2357
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
45 (Actual)
8. Arms, Groups, and Interventions
Arm Title
GIVINOSTAT + MTD Hydroxyurea (HU)_1
Arm Type
Experimental
Arm Description
50 mg o.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy
Arm Title
GIVINOSTAT + MTD Hydroxyurea (HU)_2
Arm Type
Experimental
Arm Description
50 mg b.i.d. of GIVINOSTAT + maximum tolerated dose (MTD) of Hydroxyurea (HU) monotherapy
Intervention Type
Drug
Intervention Name(s)
GIVINOSTAT (ITF2357) 50 mg o.d. + MTD Hydroxyurea
Other Intervention Name(s)
GIVINOSTAT (ITF2357), ONCOCARBIDE (HYDROXYUREA)
Intervention Description
50 mg o.d. of GIVINOSTAT + MTD of HU monotherapy
Intervention Type
Drug
Intervention Name(s)
GIVINOSTAT (ITF2357) 50 mg b.i.d. + MTD Hydroxyurea
Other Intervention Name(s)
GIVINOSTAT (ITF2357), ONCOCARBIDE (HYDROXYUREA)
Intervention Description
50 mg b.i.d. of GIVINOSTAT + MTD HU monotherapy
Primary Outcome Measure Information:
Title
Percentage of Patients With Overall Haematological Response at Week 12.
Description
The percentage of patients with overall (complete or partial) response at week 12 were assessed. · Complete response: 1. HCT (Hematocrit) < 45% without phlebotomy, and 2. platelets ≤ 400 x109/L, and 3. WBC (white blood cell) ≤ 10 x 109/L, and 4. no splenomegaly, and 5. no disease related systemic symptoms (microvascular disturbances, pruritus, headache); · Partial response: 1. HCT < 45% without phlebotomy, or 2. fulfilment of at least 3 of the other above mentioned criteria; · No response: any response that did not satisfy the criteria set for partial response.
Time Frame
At week 12 of treatment
Secondary Outcome Measure Information:
Title
Percentage of Patients With Overall Haematological Response at Week 24 by Dose Escalation After Week 12.
Description
Haematological response after a 50 mg increase of the initial Givinostat dose in non-responder patients at the time when the primary endpoint was assessed (week 12).
Complete response:
HCT< 45% without phlebotomy, and
platelets ≤ 400 x109/L, and
WBC ≤ 10 x 109/L, and
no splenomegaly, and
no disease related systemic symptoms (microvascular disturbances, pruritus, headache);
Partial response:
HCT < 45% without phlebotomy, or
fulfilment of at least 3 of the other above mentioned criteria;
No response:
any response that did not satisfy the criteria set for partial response.
Time Frame
At week 24 of treatment
Title
Change From Baseline of the JAK2V617F Allele Burden by Quantitative RT-PCR
Description
To determine JAK2V617F mutational status, a quantitative RT-PCR (Real Time-Polymerase Chain Reaction) is executed on peripheral blood granulocyte and haematopoietic colonies (with and without hepatocyte growth factors - HGFs).
Time Frame
At weeks 12, 24, at "drop out visit" and at "End of Study" (EOS). EOS stays for 7 days after last drug intake if patient is withdrawn from the study before week 24.
Title
Percentage of Patients With a Reduction of the Fraction of JAK2V617F Positive Clonogenic Progenitor by Timepoints
Description
JAK2V617F genotyping and quantification were performed on gradient-separated mononuclear cells during the pre-treatment evaluations (baseline), halfway through the study (12th weeks) and at the end of the study period (24th weeks).
Baseline: n=22 (50 mg od); 22 (50 mg bid) Week 12: n=20 (50 mg od); 19 (50 mg bid) Week 24: n=18 (50 mg od); 18 (50 mg bid)
Time Frame
Baseline, at weeks 12 and 24
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Written Informed Consent.
Age ≥18 years.
Confirmed diagnosis of Polycythemia Vera according to the revised World Health Organization (WHO) criteria.
JAK2V617F positivity.
Non-response to the maximum tolerated dose of hydroxyurea monotherapy for at least 3 months.
ECOG (Eastern Cooperative Oncology Group) 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 (corrected) 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 torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
Positive blood test for HIV (Human Immunodeficiency Virus)
Active HBV (Hepatitis B Virus) and/or HCV (Hepatitis C Virus) infection.
Platelets count <100x109/L within 14 days before enrolment.
Absolute neutrophil count <1.2x109/L within 14 days before enrolment.
Serum creatinine >2xULN (upper limit of normal).
Total serum bilirubin >1.5xULN.
Serum aspartate aminotransferase (AST) / alanine aminotransferase (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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alessandro Rambaldi, MD
Organizational Affiliation
Azienda Ospedaliera Ospedali Riuniti di Bergamo
Official's Role
Principal Investigator
Facility Information:
Facility Name
Azienda Ospedaliero-Universitaria Policlinico Consorziale di Bari
City
Bari
State/Province
BA
ZIP/Postal Code
70124
Country
Italy
Facility Name
Azienda Ospedaliera Santa Croce e Carle di Cuneo
City
Cuneo
State/Province
CN
ZIP/Postal Code
12100
Country
Italy
Facility Name
Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Garibaldi di Catania
City
Catania
State/Province
CT
ZIP/Postal Code
95126
Country
Italy
Facility Name
Fondazione I. R. C. C. S. - Casa sollievo della sofferenza di San Giovanni Rotondo
City
San Giovanni Rotondo
State/Province
FG
ZIP/Postal Code
71013
Country
Italy
Facility Name
Azienda Ospedaliero-Universitaria Careggi di Firenze
City
Florence
State/Province
FI
ZIP/Postal Code
50134
Country
Italy
Facility Name
Azienda Ospedaliera San Gerardo di Monza
City
Monza
State/Province
MB
ZIP/Postal Code
20052
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino" di Messina
City
Messina
State/Province
ME
ZIP/Postal Code
98125
Country
Italy
Facility Name
Azienda Ospedaliera Ospedali Riuniti "Villa Sofia - Cervello" di Palermo
City
Palermo
State/Province
PA
ZIP/Postal Code
90146
Country
Italy
Facility Name
Azienda Unità Sanitaria Locale di Pescara, Presidio Ospedaliero "Spirito Santo"
City
Pescara
State/Province
PE
ZIP/Postal Code
65124
Country
Italy
Facility Name
Azienda Ospedaliera Santa Maria della Misericordia di Perugia
City
Perugia
State/Province
PG
ZIP/Postal Code
06156
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria Pisana
City
Pisa
State/Province
PI
ZIP/Postal Code
56126
Country
Italy
Facility Name
Azienda Ospedaliera Ospedale San Carlo di Potenza
City
Potenza
State/Province
Point
ZIP/Postal Code
85100
Country
Italy
Facility Name
Fondazione I.R.C.C.S.-Policlinico San Matteo, Pavia
City
Pavia
State/Province
PV
ZIP/Postal Code
27100
Country
Italy
Facility Name
Azienda Ospedaliera "Bianchi-Melacrino-Morelli"
City
Reggio di Calabria
State/Province
RC
ZIP/Postal Code
891225
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria S. Luigi Gonzaga di Orbassano
City
Orbassano
State/Province
TO
ZIP/Postal Code
10043
Country
Italy
Facility Name
Azienda Ospedaliero-Universitaria San Giovanni Battista("Le Molinette") di Torino
City
Torino
State/Province
TO
ZIP/Postal Code
10126
Country
Italy
Facility Name
Ospedale Mauriziano Umberto I
City
Torino
State/Province
TO
ZIP/Postal Code
10128
Country
Italy
Facility Name
Ospedale San Bortolo di Vicenza
City
Vicenza
State/Province
VI
ZIP/Postal Code
36100
Country
Italy
Facility Name
Azienda Ospedaliera Ospedali Riuniti di Bergamo
City
Bergamo
ZIP/Postal Code
24100
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria Università degli Studi di Napoli Federico II
City
Napoli
ZIP/Postal Code
80131
Country
Italy
Facility Name
Università "Campus Bio-Medico", Rome
City
Rome
ZIP/Postal Code
00128
Country
Italy
Facility Name
Policlinico Universitario Agostino Gemelli di Roma
City
Rome
ZIP/Postal Code
00168
Country
Italy
12. IPD Sharing Statement
Learn more about this trial
Phase II Study of GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Polycythemia Vera
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