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

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ClinicalTrials.gov Identifier: NCT03954106
Recruitment Status : Recruiting
First Posted : May 17, 2019
Last Update Posted : March 30, 2020
Sponsor:
Information provided by (Responsible Party):
Jazz Pharmaceuticals

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: N/A
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

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Arms and Interventions
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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
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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
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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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03954106


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

Locations
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United States, Arizona
Mayo Clinic Recruiting
Phoenix, Arizona, United States, 85054
United States, Maryland
University of Maryland Recruiting
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
United States, North Carolina
Duke University Medical Center Active, not recruiting
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Jazz Pharmaceuticals
More Information
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Responsible Party: Jazz Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03954106    
Other Study ID Numbers: JZP395-201
First Posted: May 17, 2019    Key Record Dates
Last Update Posted: March 30, 2020
Last Verified: March 2020

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