Defibrotide Prophylaxis of Transplant Associated-Thrombotic Microangiopathy for Neuroblastoma

Defibrotide Prophylaxis of Transplant Associated-Thrombotic Microangiopathy in Patients With High-Risk Neuroblastoma Receiving Tandem Transplants

This phase II trial tests how well defibrotide works in preventing transplant-associated thrombotic microangiopathy (TA-TMA) in patients with high-risk neuroblastoma undergoing tandem transplants (hematopoietic stem cell transplant [HSCT]). TMA is a potential life-threatening complication of stem cell transplant. TMA is a possible side effect of the chemotherapy (conditioning regimen) patients receive to help treat high-risk neuroblastoma, because these medicines can sometimes damage the blood vessel walls in the body. This damage leads to formation of tiny blood clots in organs, especially the kidney. This then causes organ damage and leads to problems with how they function. This study may help researchers learn how defibrotide may help prevent TMA before it starts, or help treat it once it starts among patients with high-risk neuroblastoma undergoing tandem transplants.

Study Overview

• Status: Withdrawn
• Conditions: Thrombotic Microangiopathies; Neuroblastoma; High-risk Neuroblastoma; Transplant-Associated Thrombotic Microangiopathy
• Intervention / Treatment: Drug: Defibrotide

Detailed Description

PRIMARY OBJECTIVE:

I. To determine if administration of prophylactic defibrotide sodium (defibrotide) will prevent the development of TA-TMA in participants with high-risk neuroblastoma receiving tandem transplants compared to historic controls.

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of defibrotide in the prevention of severe TA-TMA, as defined by any TA-TMA with one or more of the following complications:

Ia. Renal failure requiring dialysis; Ib. Pleural or pericardial effusion requiring any surgical intervention; Ic. Central nervous system dysfunction, including seizure, posterior reversible encephalopathy syndrome (PRES); Id. Pulmonary hypertension; Ie. Biopsy-proven gastrointestinal involvement with bleeding; If. Death not related to relapse of underlying neuroblastoma; II. To determine the incidence of grade ≥ 3 hemorrhage (per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0) in participants on prophylactic defibrotide (grade 3 hemorrhage = transfusion indicated; invasive intervention indicated; hospitalization).

EXPLORATORY OBJECTIVES:

I. To evaluate the incidence of hepatic sinusoidal obstructive syndrome (SOS) grade >= 2 (per Cairo criteria) with first and second HSCT.

II. To evaluate the percentage of patients who go on to second transplant compared to historic controls.

III. To evaluate median time in days to start of subsequent therapy (radiation and immunotherapy) and percent of patients who have delays compared to historic controls.

OUTLINE:

Participants receive defibrotide intravenously (IV) over 2 hours every 6 hours (Q6H) on days -8 to +21 during their first and second HSCT in the absence of unacceptable toxicity. After completion of study treatment, participants are followed until day +42 after second transplant and then every 2 weeks until 6 months after first HSCT.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age: 1 - < 18 years old.
2. Participants must have high-risk neuroblastoma according to Children's Oncology Group (COG) risk classification at the time of initial diagnosis. Participants who were initially considered low or intermediate risk, but then reclassified as high risk are also eligible.

3. Participants may have had salvage therapies (i.e., meta-iodobenzylguanidine (MIBG), dinutuximab) after induction but cannot have progressive disease at start of 4.

   Planned tandem transplants with conditioning with cyclophosphamide-thiotepa and carboplatin-etoposide-melphalan on, or as per, NCT03126916 (ANBL1531) or other tandem-containing COG high-risk neuroblastoma trials.

4. Participants may be enrolled in upfront neuroblastoma protocol, but this is not required.
5. Upfront MIBG or other therapies is not a contraindication.
6. Organ function per institutional standard of care (SOC) guiding clearance for autologous HSCT.
7. Written informed consent (and assent when applicable) obtained from participant or participant's legal representative and ability for subject to comply with the requirements of the study.

Exclusion Criteria:

1. Life expectancy < 6 months.
2. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
3. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
4. Known bleeding diathesis or bleeding risk deemed by the treating physician to be a contraindication to administration of defibrotide or on concomitant therapeutic anticoagulation. Administration of heparin and/or alteplase for central line maintenance is allowed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Supportive Care (defibrotide); Participants receive defibrotide IV over 2 hours every six hours on days -8 to +21 during the first and second rounds of Hematopoietic stem-cell transplantation (HSCT).	Drug: Defibrotide; Given intravenously (IV); Other Names: Noravid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of transplant-associated thrombotic microangiopathy (TA-TMA)	The cumulative incidence of TA-TMA in participants will be compared to historical controls. The historic controls will be participants with high-risk neuroblastoma who underwent planned tandem transplant at University of California San Francisco (UCSF) between 2017 and 2023.	Up to1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of severe TA-TMA	The cumulative incidence of severe TA-TMA in the patients enrolled on study compared to historical controls.	Up to 1 year

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Jazz Pharmaceuticals
• Investigators: Principal Investigator: Christine Higham, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2024
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): May 31, 2027

Study Registration Dates

• First Submitted: December 13, 2023
• First Submitted That Met QC Criteria: December 13, 2023
• First Posted (Actual): December 26, 2023

Study Record Updates

• Last Update Posted (Actual): August 7, 2024
• Last Update Submitted That Met QC Criteria: August 5, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Hematologic Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Thrombocytopenia; Blood Platelet Disorders; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Cytopenia; Vascular Diseases; Thrombotic Microangiopathies; Neuroblastoma; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Defibrotide
• Other Study ID Numbers: 230822; NCI-2023-10277 (Registry Identifier: NCI Clinical Trials Reporting Program (CTRP))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes