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Trial record 1 of 1 for:    NCT03954106
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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 : Terminated (Primary endpoint would unlikely to be met based on the unplanned interim assessment on the first 20 efficacy evaluable patients.)
First Posted : May 17, 2019
Results First Posted : December 9, 2021
Last Update Posted : December 9, 2021
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)
Actual Enrollment : 25 participants
Allocation: N/A
Intervention Model: Sequential 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
Actual Primary Completion Date : September 18, 2020
Actual Study Completion Date : September 30, 2020

Resource links provided by the National Library of Medicine


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
  • 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).


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of CAR-T-associated Neurotoxicity of Any Grade, Defined by CTCAE v5.0 by CAR-T Day +30 [ Time Frame: 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.


Secondary Outcome Measures :
  1. Incidence of CAR-T-Associated Neurotoxicity Grade 3 or Greater Defined by CTCAE v5.0 by CAR-T Day +30 [ Time Frame: By CAR-T Day +30 ]
    The secondary efficacy endpoint was the incidence of CAR-T-associated neurotoxicity Grade 3 or greater defined by CTCAE v5.0 by CAR-T Day +30. The results report the estimated percentage of participants with no CAR-T-associated neurotoxicity (Grade 3 or greater defined by CTCAE v5.0) by CAR-T Day +30.

  2. Incidence of CAR-T-Associated Neurotoxicity of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30 [ Time Frame: By CAR-T Day +30 ]
    The secondary efficacy endpoint was the incidence of CAR-T-associated neurotoxicity of any grade according to ASBMT consensus grading system by CAR-T Day +30. The results report the estimated percentage of participants with no CAR-T-associated neurotoxicity by CAR-T Day +30 summarized descriptively by any grade according to the ASBMT consensus grading system.

  3. Incidence of CAR-T-Associated Neurotoxicity of Grade 3 or Greater According to the ASBMT Consensus Grading System by CAR-T Day +30 [ Time Frame: By CAR-T Day +30 ]
    The secondary efficacy endpoint was the incidence of CAR-T-associated neurotoxicity grade 3 or greater according to ASBMT consensus grading system by CAR-T Day +30. The results report the estimated percentage of participants with no CAR-T-associated neurotoxicity by CAR-T Day +30 summarized descriptively by grade 3 or greater according to the ASBMT consensus grading system.

  4. Incidence of Cytokine Release Syndrome (CRS) of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30 [ Time Frame: By CAR-T Day +30 ]
    The secondary efficacy endpoint was the incidence of cytokine release syndrome (CRS) of any grade according to ASBMT consensus grading system by CAR-T Day +30. The results report the estimated percentage of participants with no CRS any grade according to ASBMT criteria and was summarized descriptively using the ASBMT consensus grading system by CAR-T Day +30.

  5. Use of High Dose Steroid By CAR-T Day +30 [ Time Frame: By CAR-T Day +30 ]
    The percentage of participants using high dose steroids was summarized descriptively. The use of high dose steroids was defined as a dose of dexamethasone of at least 7.5 mg/day or equivalent. Only the Overall Defibrotide: 6.25 mg/kg/dose group was analyzed for this outcome.


Eligibility Criteria
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Information from the National Library of Medicine

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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


Locations
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United States, Arizona
Mayo Clinic
Phoenix, Arizona, United States, 85054
United States, Maryland
University of Maryland
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Jazz Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Jazz Pharmaceuticals:
Study Protocol  [PDF] February 9, 2019
Statistical Analysis Plan  [PDF] January 21, 2021

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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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
Results First Posted: December 9, 2021
Last Update Posted: December 9, 2021
Last Verified: November 2021

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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