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

Study Overview
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Brief Summary
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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.

Official Title
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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®)

Conditions
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DLBCL, Neurotoxicity Syndromes

Intervention / Treatment
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* Drug: Defibrotide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be ≥ 18 years of age at signing of informed consent. 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. 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. Subject must be able to understand and sign written informed consent. Exclusion Criteria: Subject is currently receiving dialysis or expected to receive dialysis. 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. Subject has previously been treated with CAR-T therapy. Hemodynamic instability requiring vasopressors or uncontrolled hypertension with persistent systolic blood pressure > 180. Subject has clinically significant active bleeding, history of intracranial bleeding, or is at risk for intracranial bleeding as determined by the Investigator. Subject plans to use any medication that increases the risk of bleeding. Subject is pregnant or lactating and does not agree to stop breastfeeding. Subject has a known history of hypersensitivity to defibrotide or any of the excipients. Subject has primary CNS lymphoma.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Defibrotide<br>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<br>* 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).<br>|

What is the study measuring?
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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 | 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 | 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 | 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 | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR-T