Defibrotide for Veno-occlusive Disease

Overseen By Mitchell S Cairo, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: New York Medical College

Must be taking: Defibrotide

Must not be taking: Systemic anticoagulants

Disqualifiers: No HCT, Active bleeding, Anaphylaxis, others

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

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 16 days

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests defibrotide, a drug designed to treat veno-occlusive disease, a blockage in the liver's veins that can occur after stem cell transplants. The trial aims to determine the safety and optimal dosage for patients whose condition hasn't improved with standard defibrotide doses. Suitable candidates have undergone a stem cell transplant and continue to experience veno-occlusive disease affecting their kidneys or lungs, despite previous defibrotide treatments being insufficient. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on systemic anticoagulation (blood thinners).

Is there any evidence suggesting that defibrotide is likely to be safe for humans?

Research has shown that defibrotide is generally safe and manageable. It reduces symptoms and the risk of death from veno-occlusive disease (VOD) and is usually well-tolerated by patients. However, it increases the risk of bleeding, so careful monitoring during treatment is important. The FDA has already approved defibrotide for treating VOD with kidney or lung issues after a specific type of transplant, which adds confidence in its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Defibrotide is unique because it offers a dose-escalation strategy to potentially enhance effectiveness for patients with severe veno-occlusive disease (VOD). While standard treatments often include a fixed dose, this approach allows for increasing the dosage up to 100mg/kg/day to achieve better patient outcomes. Researchers are excited because this flexibility might improve response rates, especially in patients with more severe cases or who don't fully respond to standard doses.

What evidence suggests that defibrotide might be an effective treatment for veno-occlusive disease?

This trial will evaluate the effectiveness of defibrotide for treating veno-occlusive disease (VOD), especially in patients with liver involvement and complications affecting the kidneys or lungs. Studies have shown that defibrotide effectively treats VOD, with patients receiving it experiencing better recovery outcomes than those who did not. Real-world data from hospitals also support its effectiveness and safety. Specifically, defibrotide helps patients who develop multiple organ problems after a stem cell transplant. The treatment is approved for use in these cases, demonstrating confidence in its ability to aid those with severe forms of this disease. ^{6 7 8 9 10}

Who Is on the Research Team?

Mitchell S Cairo, MD

Principal Investigator

New York Medical College

Are You a Good Fit for This Trial?

This trial is for patients aged 1 month to 75 years who have had a stem cell transplant and are suffering from sinusoidal obstructive syndrome (SOS)/veno-occlusive disease (VOD) with kidney or lung problems. It's specifically for those not fully responding to standard defibrotide treatment or whose condition has worsened.

Inclusion Criteria

I have received a stem cell transplant.

I am between 1 month and 75 years old.

I have been diagnosed with SOS/VOD with kidney or lung issues.

Exclusion Criteria

I have not undergone a stem cell transplant.

I am currently experiencing significant bleeding.

History of development of Grade III/IV anaphylaxis probably or directly secondary to defibrotide

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo intra-patient dose escalation of defibrotide every 4 days until a complete response is obtained or the highest dose level is reached

Up to 16 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

100 days

What Are the Treatments Tested in This Trial?

Interventions

• Defibrotide

Trial Overview The study tests the safety of increasing doses of defibrotide in patients with SOS/VOD after a hematopoietic cell transplantation (HCT). The goal is to see if higher doses can be tolerated and more effective when standard treatments fail.

How Is the Trial Designed?

Group I: Defibrotide Experimental Treatment 1 Intervention

7.1.1 HCT recipients with SOS/VOD and renal and/or pulmonary dysfunction with either PR after 21 days of standard doses of defibrotide (25mg/kg/day) or SD, after 14 days of standard doses of defibrotide (25mg/kg/day) progressive disease after 7 days on defibrotide (25mg/kg/day) will undergo intra-patient dose escalation every 4 days until a complete response is obtained up until the highest dose level of 100mg/kg/day at which point an endpoint of CR, PR or SD will be sought (see 7.2 for definition of response) (Maximum of 4 dose levels) (7.1.2):

Defibrotide is already approved in United States, European Union for the following indications:

Approved in United States as Defitelio for:

• Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT)

Approved in European Union as Defitelio for:

• Severe hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT)

Who Is Running the Clinical Trial?

New York Medical College

Lead Sponsor

Trials

73

Recruited

8,700+

Published Research Related to This Trial

Intravenous defibrotide prophylaxis resulted in a low overall incidence of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) at 5%, with similar rates in adults and higher rates in pediatric patients (8%).

Defibrotide significantly reduced the risk of developing VOD/SOS compared to control groups (risk ratio of 0.30), indicating it is an effective preventive treatment for patients at high risk of this condition after hematopoietic cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review and Meta-Analysis of Studies of Defibrotide Prophylaxis for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome. Corbacioglu, S., Topaloglu, O., Aggarwal, S.[2022]

In a study of 23 patients undergoing hematopoietic stem cell transplantation, defibrotide was effective in treating sinusoidal obstruction syndrome (SOS/VOD), with 14 patients showing a positive response to the therapy.

Patients treated with defibrotide experienced significant improvements in symptoms and biochemical markers, including a decrease in bilirubin levels and weight, and a 70% survival rate at 100 days post-transplant, indicating its potential as a key treatment option for SOS/VOD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defibrotide for the treatment of sinusoidal obstruction syndrome: evaluation of response to therapy and patient outcomes. Coutsouvelis, J., Avery, S., Dooley, M., et al.[2021]

Defibrotide has been approved in the EU for treating severe hepatic veno-occlusive disease (VOD) in patients undergoing hematopoietic stem cell transplantation (HSCT), showing a significantly higher complete response rate and lower mortality at day +100 compared to historical controls.

The treatment was generally well tolerated, with no increased risk of hemorrhagic adverse events, making it a safe option for patients with severe hepatic VOD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defibrotide: a review of its use in severe hepatic veno-occlusive disease following haematopoietic stem cell transplantation. Keating, GM.[2021]

Defibrotide (DF) has shown promising efficacy in treating severe hepatic veno-occlusive disease (VOD), with complete response rates between 30-60% and survival rates past day 100 ranging from 32-50% in Phase II studies.

DF may also serve as a preventive treatment for VOD in high-risk patients, highlighting its potential role in both treatment and prophylaxis for this serious complication following high-dose chemotherapy and stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of defibrotide in the treatment and prevention of veno-occlusive disease. Richardson, P., Linden, E., Revta, C., et al.[2013]

In a study of 511 stem cell transplant patients, only 1.7% developed hepatic veno-occlusive disease (VOD), and all patients treated with a low fixed dose of defibrotide (200mg twice daily for adults) experienced complete resolution of VOD without any bleeding complications.

The use of a lower dose of defibrotide was effective and safe, suggesting that it could be a viable treatment option in resource-limited settings, although further prospective studies are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low, fixed dose defibrotide in management of hepatic veno-occlusive disease post stem cell transplantation. Bagal, B., Chandrasekharan, A., Chougle, A., et al.[2018]

Citations

1. nature.com nature.com/articles/s41409-022-01900-6

Real-world use of defibrotide for veno-occlusive disease ... The DEFIFrance study collected real-world data on the usage, effectiveness, and safety of defibrotide from 53 French HCT centres.

2. defitelio.com defitelio.com/about-defitelio/clinical-data

Defitelio® (defibrotide sodium) | Clinical Data Read about the efficacy of Defitelio® (defibrotide sodium) in the treatment of VOD/SOS with renal or pulmonary dysfunction post HSCT.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6032999/

Final results from a defibrotide treatment‐IND study for ... Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [ie, multi‐organ dysfunction (MOD)] after HSCT in the United ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2666636725014848

Real-world treatment outcome of defibrotide for ... Hepatic sinusoidal obstruction syndrome or veno-occlusive disease (VOD/SOS) is a rare but severe complication occurring after hematopoietic cell ...

5. ashpublications.org ashpublications.org/blood/article/132/Supplement%201/4702/262322/Cost-Effectiveness-of-Defibrotide-for-the

Cost-Effectiveness of Defibrotide for the Treatment of Veno ... Hospital costs were calculated by taking the difference in time to CR in each arm in order to estimate the expected difference in hospital days ...

6. defitelio.com defitelio.com/about-defitelio/safety-profile

Defitelio® (defibrotide sodium) | Safety Profile Learn about the safety profile for Defitelio® (defibrotide sodium) in the treatment of VOD/SOS with renal or pulmonary dysfunction post HSCT.

7. defitelio.com defitelio.com/

Defitelio® (defibrotide sodium) | VOD/SOS Learn about the first and only FDA-approved treatment of VOD/SOS with renal or pulmonary dysfunction post HSCT.

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2016/208114Orig1s000CrossR.pdf

208114Orig1s000 - accessdata.fda.gov Defibrotide sodium appears to have reasonable safety profile when assessed in the context of the treatment of a life-threatening disease with no ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6171967/

Defibrotide for the treatment of hepatic veno-occlusive disease ... Defibrotide has demonstrated significant reduction in VOD/SOS-related mortality and resolved VOD/SOS-related symptoms, with a manageable safety profile.

10. mdanderson.cloud-cme.com mdanderson.cloud-cme.com/assets/mdanderson/pdf/VOD%20Clinical%20Guide.pdf

VOD Clinical Guide IMPORTANT SAFETY INFORMATION. Warnings and Precautions. Hemorrhage—Defitelio may increase the risk of bleeding in patients with VOD after HSCT. Do not.