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

• ClinicalTrials.gov Identifier: NCT03954106
• Recruitment Status: Recruiting
• First Posted: May 17, 2019
• Last Update Posted: December 9, 2019
• Sponsor: Jazz Pharmaceuticals
• Information provided by (Responsible Party): Jazz Pharmaceuticals

Study Description

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.

Condition or disease	Intervention/treatment	Phase
DLBCL; Neurotoxicity Syndromes	Drug: Defibrotide	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 35 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prospective, Multicenter, Open-Label, Single Arm, Phase 2 Study to Evaluate the Safety and Efficacy of Defibrotide in the Prevention of Chimeric Antigen Receptor-T-cell-associated Neurotoxicity in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma Receiving Axicabtagene Ciloleucel (Yescarta®)
• Actual Study Start Date: October 4, 2019
• Estimated Primary Completion Date: April 2021
• Estimated Study Completion Date: May 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Defibrotide; 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; Once daily on CAR-T Day -5, -4, -3 before lymphodepletion and also every 6 hours daily on CAR-T Day 0-7.

Outcome Measures

Primary Outcome Measures :

1. Incidence of CAR-T-associated neurotoxicity [ Time Frame: By CAR-T Day +30 ]
   Incidence of CAR-T-associated neurotoxicity (any grade, defined by CTCAE v5.0)

Secondary Outcome Measures :

1. Incidence of CAR-T-associated neurotoxicity of Grade 3 or greater [ Time Frame: By CAR-T Day +30 ]
   CAR-T-associated neurotoxicity of Grade 3 or greater defined by CTCAE v5.0
2. Incidence of CAR-T-associated neurotoxicity of any grade and Grade 3 or greater [ Time Frame: By CAR-T Day +30 ]
   CAR-T-associated neurotoxicity (any grade and Grade 3 or greater) according to the ASBMT consensus grading system
3. Incidence of CRS [ Time Frame: By CAR-T Day +30 ]
   Incidence of CRS (any grade, according to the ASBMT consensus grading system)
4. Use of high dose steroid by CAR-T Day +30 [ Time Frame: By CAR-T Day +30 ]
   The use of high dose steroids is defined as a dose of dexamethasone of at least 7.5 mg/day or equivalent

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Subject must be ≥ 18 years of age at signing of informed consent.
2. 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.
3. 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.
4. Subject must be able to understand and sign written informed consent.

Exclusion Criteria:

1. Subject is currently receiving dialysis or expected to receive dialysis.
2. 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.
3. Subject has previously been treated with CAR-T therapy.
4. Hemodynamic instability requiring vasopressors or uncontrolled hypertension with persistent systolic blood pressure > 180.
5. Subject has clinically significant active bleeding, history of intracranial bleeding, or is at risk for intracranial bleeding as determined by the Investigator.
6. Subject plans to use any medication that increases the risk of bleeding.
7. Subject is pregnant or lactating and does not agree to stop breastfeeding.
8. Subject has a known history of hypersensitivity to defibrotide or any of the excipients.
9. Subject has primary CNS lymphoma.

Contacts and Locations

Contacts

Contact: Director Clinical Trial Disclosure & Transparency; 2159707145; ClinicalTrialDisclosure@JazzPharma.com

Locations

United States, Maryland

University of Maryland; Recruiting

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Beth Israel Deaconess Medical Center; Active, not recruiting

Boston, Massachusetts, United States, 02215

Dana Farber Cancer Institute; Active, not recruiting

Boston, Massachusetts, United States, 02215

United States, North Carolina

Duke University Medical Center; Recruiting

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Jazz Pharmaceuticals

More Information

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03954106
• Other Study ID Numbers: JZP395-201
• First Posted: May 17, 2019
• Last Update Posted: December 9, 2019
• Last Verified: December 2019

• 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.: No

Keywords provided by Jazz Pharmaceuticals:

CAR-T

Additional relevant MeSH terms:

Neurotoxicity Syndromes; Nervous System Diseases; Poisoning; Chemically-Induced Disorders; Defibrotide; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors