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

November 10, 2021 updated by: Jazz Pharmaceuticals

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®)

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

25

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85054
        • Mayo Clinic
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • University of Maryland
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Beth Israel Deaconess Medical Center
      • Boston, Massachusetts, United States, 02215
        • Dana Farber Cancer Institute
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
By CAR-T Day +30

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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
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.
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
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.
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
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.
By CAR-T Day +30
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.
By CAR-T Day +30

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Jazz Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 4, 2019

Primary Completion (Actual)

September 18, 2020

Study Completion (Actual)

September 30, 2020

Study Registration Dates

First Submitted

May 15, 2019

First Submitted That Met QC Criteria

May 15, 2019

First Posted (Actual)

May 17, 2019

Study Record Updates

Last Update Posted (Actual)

December 9, 2021

Last Update Submitted That Met QC Criteria

November 10, 2021

Last Verified

November 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • JZP395-201

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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