Givinostat vs Hydroxyurea for Polycythemia Vera

(GIV-IN PV Trial)

Recruiting at 75 trial locations

Overseen By Maurizio Caserini

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Italfarmaco

Must not be taking: JAK2 inhibitors, HDAC inhibitors

Disqualifiers: Cardiovascular disease, Liver/renal dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 48 weeks

220 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 2 3 5 6}

How 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. ^{1 2 4 5 6}

Eligibility 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

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.

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

Treatment Details

Interventions

• Givinostat
• Hydroxy Urea

Trial Overview 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.

Participant Groups

Group I: Givinostat Experimental Treatment 1 Intervention

Group II: Hydroxyurea Active Control 1 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

Who Is Running the Clinical Trial?

Italfarmaco

Lead Sponsor

Trials

36

Recruited

4,500+

Findings from Research

In a phase II study involving 44 patients with polycythaemia vera who did not respond to hydroxycarbamide, Givinostat combined with hydroxycarbamide showed a complete or partial response in 55% of patients taking 50 mg and 50% of those taking 100 mg.

The treatment was well tolerated, with only 18% of patients discontinuing due to adverse effects, and serious side effects were rare, indicating that Givinostat is both safe and effective for patients unresponsive to standard therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. Finazzi, G., Vannucchi, AM., Martinelli, V., et al.[2023]

The combination of the HDAC inhibitor givinostat and hydroxyurea showed significant synergistic cytotoxicity in Jak2(V617F) cells, with cell death rates increasing from 20.4%-42.4% for hydroxyurea alone to 35.8%-75.3% when both drugs were used together.

Mechanistically, the combination treatment led to a G1 cell cycle block and enhanced apoptosis through increased caspase 3 activation, suggesting that this drug pairing could be an effective strategy for treating Jak2(V617F) myeloproliferative neoplasms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2(V617F) myeloproliferative neoplasm patients. Amaru Calzada, A., Pedrini, O., Finazzi, G., et al.[2014]

In a study of 96 patients with polycythemia vera treated with hydroxyurea or pipobroman, complete remission was achieved in all cases, but hydroxyurea caused severe granulothrombocytopenia in two patients during initial treatment.

While pipobroman maintenance therapy was generally satisfactory, it was associated with more frequent digestive and skin issues, and there was a risk of high platelet counts with hydroxyurea, which could lead to vascular events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[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]. Najean, Y.[2016]

In a study of 294 low-risk polycythemia vera patients, both hydroxyurea and pipobroman showed higher-than-expected hematologic toxicity, necessitating close monitoring and leading to treatment changes in 10% of cases.

Both drugs were found to have a leukemogenic potential with a 15% risk of developing leukemia by year 15, and hydroxyurea was associated with a significant risk of skin cancer, indicating that their long-term safety profiles are concerning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of polycythemia. II.--Comparison of hydroxyurea with pipobroman in 294 patients less than 65 years of age]. Najean, Y., Rain, JD., Lejeune, F., et al.[2013]

Givinostat, a histone deacetylase (HDAC) inhibitor, has shown promising results in treating polycythemia vera (PV) with good tolerance and clinico-hematological responses, indicating its potential as a new treatment option.

A phase III clinical trial comparing givinostat to hydroxyurea in high-risk PV patients is planned, which could lead to a shift in treatment guidelines if givinostat proves to be more effective or safer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Givinostat: an emerging treatment for polycythemia vera. Chifotides, HT., Bose, P., Verstovsek, S.[2022]

In a long-term study of 51 patients with polycythemia vera (PV), givinostat showed a strong safety profile, with only 10% reporting Grade 3 treatment-related adverse events and no severe (Grade 4 or 5) adverse events.

Givinostat also demonstrated high efficacy, maintaining an overall response rate greater than 80% over a mean follow-up of 4 years, supporting its long-term use in treating PV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Rambaldi, A., Iurlo, A., Vannucchi, AM., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2(V617F) myeloproliferative neoplasm patients. [2014]

3. France pubmed.ncbi.nlm.nih.gov

[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]

4. France pubmed.ncbi.nlm.nih.gov

[Treatment of polycythemia. II.--Comparison of hydroxyurea with pipobroman in 294 patients less than 65 years of age]. [2013]

5. England pubmed.ncbi.nlm.nih.gov

Givinostat: an emerging treatment for polycythemia vera. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

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]