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出境医 / 临床实验 / A Safety and Efficacy Study of Defibrotide in the Prevention of Chimeric Antigen Receptor-T-cell-associated Neurotoxicity

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

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
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 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
Actual Primary Completion Date : September 18, 2020
Actual Study Completion Date : September 30, 2020
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
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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

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
Tracking Information
First Submitted Date  ICMJE May 15, 2019
First Posted Date  ICMJE May 17, 2019
Last Update Posted Date May 27, 2021
Actual Study Start Date  ICMJE October 4, 2019
Actual Primary Completion Date September 18, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 15, 2019) 		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)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 15, 2019)
  • 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
  • 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
  • Incidence of CRS [ Time Frame: By CAR-T Day +30 ]
    Incidence of CRS (any grade, according to the ASBMT consensus grading system)
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Safety and Efficacy Study of Defibrotide in the Prevention of Chimeric Antigen Receptor-T-cell-associated Neurotoxicity
Official Title  ICMJE 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®)
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • DLBCL
  • Neurotoxicity Syndromes
Intervention  ICMJE 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.
Study Arms  ICMJE 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.

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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: April 16, 2021) 		25
Original Estimated Enrollment  ICMJE
 (submitted: May 15, 2019) 		35
Actual Study Completion Date  ICMJE September 30, 2020
Actual Primary Completion Date September 18, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03954106
Other Study ID Numbers  ICMJE JZP395-201
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jazz Pharmaceuticals
Study Sponsor  ICMJE Jazz Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Jazz Pharmaceuticals
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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