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

DLBCL Clinical Trial

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®)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03954106
• Other study ID #: JZP395-201
• Status: Terminated
• Phase: Phase 2
• Start date: October 4, 2019
• Est. completion date: September 30, 2020

Study information

• Verified date: November 2021
• Source: Jazz Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 25
• Est. completion date: September 30, 2020
• Est. primary completion date: September 18, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• DLBCL
• Neurotoxicity Syndromes

Intervention

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).

Locations

Country	Name	City	State
United States	University of Maryland	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Duke University Medical Center	Durham	North Carolina
United States	Mayo Clinic	Phoenix	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Jazz Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of CAR-T-associated Neurotoxicity of Any Grade, Defined by CTCAE v5.0 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	Incidence of CAR-T-Associated Neurotoxicity Grade 3 or Greater Defined by CTCAE v5.0 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
Secondary	Incidence of CAR-T-Associated Neurotoxicity of Any Grade According to the ASBMT Consensus Grading System 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
Secondary	Incidence of CAR-T-Associated Neurotoxicity of Grade 3 or Greater According to the ASBMT Consensus Grading System 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
Secondary	Incidence of Cytokine Release Syndrome (CRS) of Any Grade According to the ASBMT Consensus Grading System 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
Secondary	Use of High Dose Steroid 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