A Safety and Efficacy Study of Defibrotide in the Prevention of Chimeric Antigen Receptor-T-cell-associated Neurotoxicity

NCT03954106 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: JZP395-201
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 5

Brief Summary

This is a prospective, open-label, single-arm study evaluating the safety and efficacy of defibrotide for the prevention of CAR-T-associated neurotoxicity in subjects with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) receiving Yescarta.

Conditions

DLBCL; Neurotoxicity Syndromes

Keywords

CAR-T

Outcome Measures

Primary Outcomes (1)

• Incidence of CAR-T-associated Neurotoxicity of Any Grade, Defined by CTCAE v5.0 by CAR-T Day +30

  The primary efficacy endpoint was the incidence of CAR-T-associated neurotoxicity of any grade defined by CTCAE v5.0 by CAR-T Day +30. The results report the estimated percentage of participants with no CAR-T-associated neurotoxicity of any grade, defined by CTCAE v5.0, which incorporated the 2 stage design.

  By CAR-T Day +30

Secondary Outcomes (5)

• Incidence of CAR-T-Associated Neurotoxicity Grade 3 or Greater Defined by CTCAE v5.0 by CAR-T Day +30

  By CAR-T Day +30

• Incidence of CAR-T-Associated Neurotoxicity of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30

  By CAR-T Day +30

• Incidence of CAR-T-Associated Neurotoxicity of Grade 3 or Greater According to the ASBMT Consensus Grading System by CAR-T Day +30

  By CAR-T Day +30

• Incidence of Cytokine Release Syndrome (CRS) of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30

  By CAR-T Day +30

• Use of High Dose Steroid By CAR-T Day +30

  By CAR-T Day +30

Study Arms (1)

Defibrotide

EXPERIMENTAL

Part 1 (lead-in phase) will evaluate a 2.5 mg/kg/dose regimen before escalating to a 6.25 mg/kg/dose regimen. After the Safety Assessment Committee establishes the recommended phase 2 dose based on dose-limiting toxicities during Part 1, Part 2 will enroll subjects at the recommended phase 2 dose.

Drug: Defibrotide

Interventions

Defibrotide DRUG

* Part 1: Defibrotide 2.5 mg/kg/dose or 6.25 mg/kg/dose once daily as a single dose on CAR-T Day -5, -4, and -3 before lymphodepletion, then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). * Part 2 Recommended Phase 2 Dose: Defibrotide 6.25 mg/kg/dose once daily as a single dose on CAR-T Day -5, -4, and -3 before lymphodepletion, then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7).

Defibrotide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must be ≥ 18 years of age at signing of informed consent.
• Subject must be diagnosed with relapsed or refractory DLBCL (including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma) and scheduled to receive treatment with Yescarta.
• Female subjects of childbearing potential who are sexually active and male subjects who are sexually active and have female partners of childbearing potential must agree to use a highly effective method of contraception with their partners during exposure to defibrotide and for 30 days after the last dose of defibrotide.
• Subject must be able to understand and sign written informed consent.

You may not qualify if:

• Subject is currently receiving dialysis or expected to receive dialysis.
• Subject has used any investigational anticancer agent within 3 weeks prior to the first dose of defibrotide, or is using or plans to use any investigational agent during the study.
• Subject has previously been treated with CAR-T therapy.
• Hemodynamic instability requiring vasopressors or uncontrolled hypertension with persistent systolic blood pressure \> 180.
• Subject has clinically significant active bleeding, history of intracranial bleeding, or is at risk for intracranial bleeding as determined by the Investigator.
• Subject plans to use any medication that increases the risk of bleeding.
• Subject is pregnant or lactating and does not agree to stop breastfeeding.
• Subject has a known history of hypersensitivity to defibrotide or any of the excipients.
• Subject has primary CNS lymphoma.

Sponsors & Collaborators

• Jazz Pharmaceuticals: lead

Study Sites (5)

Mayo Clinic

Phoenix, Arizona, 85054, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Publications (2)

• Jacobson CA, Rosenthal AC, Arnason J, Agarwal S, Zhang P, Wu W, Amber V, Yared JA. A phase 2 trial of defibrotide for the prevention of chimeric antigen receptor T-cell-associated neurotoxicity syndrome. Blood Adv. 2023 Nov 14;7(21):6790-6799. doi: 10.1182/bloodadvances.2023009961.

  PMID: 37399456 DERIVED

• Danish H, Santomasso BD. Neurotoxicity Biology and Management. Cancer J. 2021 Mar-Apr 01;27(2):126-133. doi: 10.1097/PPO.0000000000000507.

  PMID: 33750072 DERIVED

MeSH Terms

Conditions

Neurotoxicity Syndromes

Interventions

defibrotide

Condition Hierarchy (Ancestors)

Nervous System Diseases; Poisoning; Chemically-Induced Disorders

Results Point of Contact

• Title: Director, Clinical Trial Disclosure & Transparency
• Organization: Jazz Pharmaceuticals

ClinicalTrialDisclosure@JazzPharma.com

2158709177

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2019
• First Posted: May 17, 2019
• Study Start: October 4, 2019
• Primary Completion: September 18, 2020
• Study Completion: September 30, 2020
• Last Updated: December 9, 2021
• Results First Posted: December 9, 2021

Record last verified: 2021-11

Locations

US (5)