Givinostat vs Hydroxyurea for Polycythemia Vera
(GIV-IN PV Trial)
Recruiting in Palo Alto (17 mi)
+75 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Italfarmaco
Must not be taking: JAK2 inhibitors, HDAC inhibitors
Disqualifiers: Cardiovascular disease, Liver/renal dysfunction, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?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.
Do I need to stop my current medications to join the trial?
The trial information does not specify if you need to stop taking your current medications. However, if you are currently being treated with an investigational agent or have participated in another clinical study recently, you may not be eligible.
What data supports the effectiveness of the drug Givinostat in combination with Hydroxyurea for treating polycythemia vera?
Research shows that Givinostat, when combined with Hydroxyurea, is effective in treating patients with polycythemia vera who do not respond to Hydroxyurea alone. In a study, 55% of patients had a complete or partial response, and the combination was well tolerated with manageable side effects.
12345Is Givinostat combined with Hydroxyurea safe for treating polycythemia vera?
Givinostat combined with Hydroxyurea has been shown to be generally safe and well-tolerated in patients with polycythemia vera, with only a small percentage experiencing severe side effects. Long-term studies also support its safety, with no severe treatment-related adverse events reported.
12356How does the drug combination of Givinostat and Hydroxyurea differ from other treatments for polycythemia vera?
The combination of Givinostat and Hydroxyurea is unique because Givinostat is a histone-deacetylase inhibitor that specifically targets cells with the JAK2 V617F mutation, which is common in polycythemia vera. This combination has shown to be effective in patients who do not respond to Hydroxyurea alone, offering a new option for those with resistant forms of the disease.
12456Eligibility Criteria
This trial is for people over 60 years old or those who've had a blood clot, diagnosed with Polycythemia Vera (PV) within the last 3 years. They must have high white blood cell or platelet counts and test positive for JAK2V617F mutation. Their hematocrit levels should be normalized before joining.Inclusion Criteria
My condition is JAK2V617F-positive.
I need treatment and have had a phlebotomy, or my blood counts are high.
Patients must have normalized HCT (i.e., HCT < 45%) at randomization
+2 more
Exclusion Criteria
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
My liver or kidney function is not normal.
I have a history of not responding well or being intolerant to hydroxyurea, as per ELN criteria.
+7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive either givinostat or hydroxyurea to assess efficacy and safety
48 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study compares two treatments for PV: Givinostat Hydrochloride and Hydroxyurea, focusing on their effectiveness and safety in patients with a specific genetic marker (JAK2V617F) associated with higher risk of the disease.
2Treatment groups
Experimental Treatment
Active Control
Group I: GivinostatExperimental Treatment1 Intervention
Group II: HydroxyureaActive Control1 Intervention
Givinostat is already approved in United States for the following indications:
🇺🇸 Approved in United States as Duvyzat for:
- Duchenne muscular dystrophy (DMD) in patients 6 years of age and older
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
VA Puget Sound Health Care System - NAVREF - PPDSSeattle, WA
University of Utah - Huntsman Cancer Institute - PPDSSalt Lake City, UT
The Cleveland Clinic FoundationCleveland, OH
MD Anderson Cancer CenterHouston, TX
More Trial Locations
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Who Is Running the Clinical Trial?
ItalfarmacoLead Sponsor
References
A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. [2023]Givinostat, a histone-deacetylase inhibitor (HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms (MPN). In this multicentre, open-label, phase II study, 44 patients with polycythaemia vera (PV), unresponsive to the maximum tolerated doses (MTD) of hydroxycarbamide (HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukaemiaNet response criteria were used to assess the primary endpoint after 12 weeks of treatment. Complete or partial response was observed in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, respectively. Control of pruritus was observed in 64% and 67% of patients in the 50 and 100 mg groups, respectively. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4·5%) in each treatment arm. The combined use of Givinostat and HC was safe and clinically effective in HC-unresponsive PV patients.
Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2(V617F) myeloproliferative neoplasm patients. [2014]We investigated whether clinically achievable concentrations of the histone deacetylase (HDAC) inhibitors givinostat and hydroxyurea induce synergistic cytotoxicity in Jak2(V617F) cells in vitro and through which possible mechanism. Givinostat and hydroxyurea at low doses potentiated the pro-apoptotic effects of each other in the Jak2(V617F) HEL and UKE1 cell lines. Givinostat induced 6.8%-20.8% and hydroxyurea (HU) 20.4%-42.4% cell death alone and 35.8%-75.3% in combination. The effect was statistically significant using the median effect Chou-Talalay method, resulting in a combination index less than 1, indicating synergy. Givinostat alone induced cell cycle arrest of the cell lines in G0/G1 and hydroxyurea in S phase, whereas both drugs together led to a G1 block. At the molecular level, hydroxyurea counteracted the induction of p21CDKN1A by Givinostat and potentiated caspase 3 activation, explaining at least in part the increased apoptosis observed in presence of both compounds. We also verified the effect of the same drugs in colony assays of freshly isolated Jak2(V617F) polycythemia vera cells. In this case, low doses of the compounds were additive to each other. These results suggest that combined treatment with givinostat and hydroxyurea is a potential strategy for the management of Jak2(V617F) myeloproliferative neoplasms.
[Treatment of polycythemia vera with hydroxyurea or pipobroman. Efficacy and toxicity analysed from a protocol of 96 patients under 65 years of age. Le Groupe d'Etude des Polyglobulies]. [2016]Between 1980 and 1991, 96 patients with documented polycythemia vera were treated by hydroxyurea or pipobroman, according to a protocol including randomization, and maintenance therapy. Complete remission was induced in all cases. Two cases treated with hydroxy-urea had a very severe granulothrombocytopenia during the initial phase. Maintenance was generally satisfactory on pipobroman, but the platelet count often remained high (400 to 900.10(9)/l) on low-dosage hydroxy-urea, with a risk of vascular events. Progressive resistance to these drugs was observed in 5 cases. Digestive and cutaneous troubles were more frequent on pipobroman maintenance, sometimes enough to legitimate a therapeutic change. It may be concluded that such a treatment is less easy to use and to follow than is currently accepted. In the present series (397/years/patients follow-up, median 5-3 years), only one leukemia and one cancer were observed, which however only demonstrates the absence of any carcinogenic risk at short- but not at long-term.
[Treatment of polycythemia. II.--Comparison of hydroxyurea with pipobroman in 294 patients less than 65 years of age]. [2013]To compare by a prospective study in low risk polycythemia vera (PV) patients alone two drugs: hydroxyurea and pipobroman. Toxicity, efficiency, and leukemogenic potential were studied.
Givinostat: an emerging treatment for polycythemia vera. [2022]Label="INTRODUCTION" NlmCategory="BACKGROUND">Polycythemia vera (PV), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by panmyelosis, pancytosis, and a JAK2 mutation. Patients are at increased risk of thrombohemorrhagic events, and progression to myelofibrosis or acute leukemia. Current treatments include aspirin, phlebotomy, and cytoreductive drugs (most commonly hydroxyurea). Givinostat is a potent, class I/II histone deacetylase (HDAC) inhibitor that is in phase I/II clinical trials in PV. Givinostat was well tolerated and yielded promising clinico-hematological responses. A phase III study of givinostat versus hydroxyurea in high-risk PV patients is planned.
Long-term safety and efficacy of givinostat in polycythemia vera: 4-year mean follow up of three phase 1/2 studies and a compassionate use program. [2022]Polycythemia vera (PV) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow, mainly due to a Janus kinase 2 gene mutation (JAK2V617F). Givinostat, a histone-deacetylase inhibitor that selectively targets JAK2V617F cell growth, has demonstrated good efficacy and safety in three phase 1/2 studies in patients with PV. This manuscript focuses on the 4-year mean (2.8 year median) follow-up of an open-label, long-term study that enrolled 51 patients with PV (out of a total of 54 with MPN) who received clinical benefit from givinostat in these previous studies or on compassionate use, and who continued to receive givinostat at the last effective and tolerated dose. The primary objectives are to determine givinostat's long-term safety and tolerability, and efficacy evaluated by the investigators according to internationally recognized response criteria. During follow-up, only 10% of PV patients reported Grade 3 treatment-related adverse events (AEs), while none had Grade 4 or 5 treatment-related AEs. The overall response rate for the duration of follow-up was always greater than 80% in patients with PV. In conclusion, givinostat demonstrated a good safety and efficacy profile in patients with PV, data supporting long-term use in this population.