Givinostat vs Hydroxyurea for Polycythemia Vera

(GIV-IN-PV Trial)

Recruiting at 83 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments, givinostat and hydroxyurea, for individuals with polycythemia vera, a blood disorder that increases red blood cells. Researchers aim to determine which treatment is more effective and safer for those with the JAK2V617F genetic mutation, who also face a high risk of blood clots. Candidates should have a diagnosis of polycythemia vera and require treatment due to high blood counts or recent medical procedures to manage the condition. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that givinostat is safe for people with polycythemia vera. Previous studies indicate that most people can use givinostat long-term without serious side effects. One study confirmed that even the highest dose of givinostat is safe for patients.

Hydroxyurea, the other treatment in this trial, is a common therapy for polycythemia vera. Its long history of use reassures doctors about its safety. While it can cause side effects, most people tolerate it well.

Both treatments have strong safety records, but discussing any concerns with a doctor before joining a trial is always important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for polycythemia vera?

Givinostat is unique because it targets polycythemia vera by inhibiting histone deacetylases, which can help control the overproduction of blood cells. This mechanism of action is different from the standard treatment, hydroxyurea, which works by suppressing bone marrow activity. Researchers are excited about Givinostat because it offers a novel approach that could potentially manage the symptoms more effectively and improve patients' quality of life.

What evidence suggests that this trial's treatments could be effective for polycythemia vera?

Research shows that givinostat, a treatment under study in this trial, may help treat polycythemia vera. Studies have found it safe and effective. Givinostat controls the growth of excess cells, reducing symptoms and improving long-term health for patients. Long-term research supports its continued use, demonstrating its safety and effectiveness in managing the condition. This trial compares givinostat to hydroxyurea, another treatment option, to determine which works better. ^{1 2 4 5 6}

Are You a Good Fit for This Trial?

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.

Uncontrolled hypertriglyceridemia at screening, i.e., triglycerides ˃ 1.5 × ULN

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Givinostat - Core phase Experimental Treatment 1 Intervention

Givinostat 50 mg BID from baseline till week 48

Group II: Hydroxyurea - Core phase Active Control 1 Intervention

HU 500 mg BID from baseline till week 48

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+

PPD Development, LP

Industry Sponsor

Published Research Related to This Trial

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 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]

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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06093672

NCT06093672 | Study on Efficacy and Safety of Givinostat ... 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.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7936975/

Long-term safety and efficacy of givinostat in polycythemia ... In conclusion, givinostat demonstrated a good safety and efficacy profile in patients with PV, data supporting long-term use in this population.

3. synapse.patsnap.com synapse.patsnap.com/article/what-clinical-trials-have-been-conducted-for-givinostat-hydrochloride

What clinical trials have been conducted for Givinostat ... ... Polycythemia Vera ... data consistently indicate that givinostat exhibits a favorable safety profile with promising efficacy outcomes.

4. cancernetwork.com cancernetwork.com/view/fda-gives-fast-track-designation-to-givinostat-for-polycythemia-vera

FDA Gives Fast Track Designation to Givinostat for ... Givinostat may control excessive cell proliferation, reduce disease burden, alleviate symptoms, and improve long-term outcomes for patients with ...

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2024/217865Orig1s000IntegratedR.pdf

217865Orig1s000 INTEGRATED REVIEW - accessdata.fda.gov ... efficacy of the maximum tolerated dose of givinostat in polycythemia vera: a two-part Phase Ib/II study,. Leukemia, 34(8):2234-2237 ...

6. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT01761968?term=givinostat&draw=2&rank=2

Long-term Study Evaluating the Effect of Givinostat in ... This is a multicenter, open label, long-term study testing the long-term safety, tolerability and efficacy of givinostat in patients with Polycythemia Vera, ...