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NCT03954106

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

Terminated Phase 2 Results posted Last updated 9 December 2021
What this trial tests

Phase 2 trial testing Defibrotide in DLBCL in 25 participants. Terminated before completion.

Timeline
4 October 2019
Primary endpoint
18 September 2020
30 September 2020

Quick facts

Lead sponsorJazz Pharmaceuticals
PhasePhase 2
StatusTerminated
Study typeINTERVENTIONAL
Allocationna
Designsequential
Maskingnone
Primary purposetreatment
Enrollment25
Start date4 October 2019
Primary completion18 September 2020
Estimated completion30 September 2020
Sites5 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Jazz Pharmaceuticals — full company profile →

Who can join

18 and older, any sex, with DLBCL or Neurotoxicity Syndromes. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Incidence of CAR-T-associated Neurotoxicity of Any Grade, Defined by CTCAE v5.0 by CAR-T Day +30 Primary · 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.

GroupValue95% CI
Stage 1: Defibrotide, 6.25 mg/kg/Dose50NA – NA
Stage 2: Defibrotide, 6.25 mg/kg/Dose50NA – NA
Overall: Defibrotide, 6.25 mg/kg/Dose5136 – 66
Incidence of CAR-T-Associated Neurotoxicity Grade 3 or Greater Defined by CTCAE v5.0 by CAR-T Day +30 Secondary · 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.

GroupValue95% CI
Stage 1: Defibrotide, 6.25 mg/kg/Dose80
Stage 2: Defibrotide, 6.25 mg/kg/Dose70
Overall: Defibrotide, 6.25 mg/kg/Dose75
Incidence of CAR-T-Associated Neurotoxicity of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30 Secondary · 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.

GroupValue95% CI
Stage 1: Defibrotide, 6.25 mg/kg/Dose0
Stage 2: Defibrotide, 6.25 mg/kg/Dose0
Overall: Defibrotide, 6.25 mg/kg/Dose0
Incidence of CAR-T-Associated Neurotoxicity of Grade 3 or Greater According to the ASBMT Consensus Grading System by CAR-T Day +30 Secondary · 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.

GroupValue95% CI
Stage 1: Defibrotide, 6.25 mg/kg/Dose90
Stage 2: Defibrotide, 6.25 mg/kg/Dose70
Overall: Defibrotide, 6.25 mg/kg/Dose80
Incidence of Cytokine Release Syndrome (CRS) of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30 Secondary · 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.

GroupValue95% CI
Stage 1: Defibrotide, 6.25 mg/kg/Dose10
Stage 2: Defibrotide, 6.25 mg/kg/Dose20
Overall: Defibrotide, 6.25 mg/kg/Dose15
Use of High Dose Steroid By CAR-T Day +30 Secondary · 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.

GroupValue95% CI
Overall: Defibrotide, 6.25 mg/kg/Dose45

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse Events (AEs) and Serious Adverse Events (SAEs) were recorded from the time the subject signed informed consent until the final study visit or Early Termination (ET).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose
Serious: 4/4 (100%)
Deaths: 0/4
Phase 2: RP2D, 6.25 mg/kg/Dose
Serious: 9/21 (43%)
Deaths: 0/21

Serious adverse events (17 terms)

ReactionSystemPart 1: Safety Lead-In, De…Phase 2: RP2D, 6.25 mg/kg/…
Cytokine release syndromeImmune system disorders
NeurotoxicityNervous system disorders
HypotensionVascular disorders
Febrile neutropeniaBlood and lymphatic system disorders
Atrial fibrillationCardiac disorders
Myocardial infarctionCardiac disorders
Small intestinal obstructionGastrointestinal disorders
AstheniaGeneral disorders
PyrexiaGeneral disorders
Clostridium difficile colitisInfections and infestations
Decreased appetiteMetabolism and nutrition disorders
Tumour lysis syndromeMetabolism and nutrition disorders
PresyncopeNervous system disorders
Transient ischaemic attackNervous system disorders
Confusional statePsychiatric disorders
Pleural effusionRespiratory, thoracic and mediastinal disorders
Pulmonary embolismRespiratory, thoracic and mediastinal disorders
Other adverse events (107 terms — click to expand)

ReactionSystemPart 1: Safety Lead-In, De…Phase 2: RP2D, 6.25 mg/kg/…
PyrexiaGeneral disorders
Cytokine release syndromeImmune system disorders
NauseaGastrointestinal disorders
HypotensionVascular disorders
DiarrhoeaGastrointestinal disorders
FatigueGeneral disorders
ConstipationGastrointestinal disorders
TremorNervous system disorders
NeutropeniaBlood and lymphatic system disorders
ChillsGeneral disorders
HeadacheNervous system disorders
Decreased appetiteMetabolism and nutrition disorders
NeurotoxicityNervous system disorders
Confusional statePsychiatric disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
AnemiaBlood and lymphatic system disorders
Febrile neutropeniaBlood and lymphatic system disorders
Sinus TachycardiaCardiac disorders
HypocalcaemiaMetabolism and nutrition disorders
HypomagnesaemiaMetabolism and nutrition disorders
DizzinessNervous system disorders
VommitingGastrointestinal disorders
Oedema peripheralGeneral disorders
HypophosphataemiaMetabolism and nutrition disorders
Back painMusculoskeletal and connective tissue disorders
Urinary incontinenceRenal and urinary disorders
Oropharyngeal painRespiratory, thoracic and mediastinal disorders
TachycardiaCardiac disorders
Abdominal painGastrointestinal disorders
Gait disturbanceGeneral disorders
Urinary tract infectionInfections and infestations
HypokalemiaMetabolism and nutrition disorders
Pain in extremityMusculoskeletal and connective tissue disorders
AphasiaNervous system disorders
ThrombocytopeniaBlood and lymphatic system disorders
Candida infectionInfections and infestations
Blood potassium decreasedInvestigations
HypophagiaMetabolism and nutrition disorders
Vitamin D deficiencyMetabolism and nutrition disorders
ArthalgiaMusculoskeletal and connective tissue disorders

Most-reported serious reactions: Cytokine release syndrome, Neurotoxicity, Hypotension, Febrile neutropenia, Atrial fibrillation, Myocardial infarction, Small intestinal obstruction, Asthenia.

Data from ClinicalTrials.gov NCT03954106 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies.
    Siegler EL, Kenderian SS. · · 2020 · cited 204× · PMID 32983132 · DOI 10.3389/fimmu.2020.01973
  2. Cytokines in CAR T Cell-Associated Neurotoxicity.
    Gust J, Ponce R, Liles WC, Garden GA, et al · · 2020 · cited 191× · PMID 33391257 · DOI 10.3389/fimmu.2020.577027
  3. A deep insight into CRISPR/Cas9 application in CAR-T cell-based tumor immunotherapies.
    Razeghian E, Nasution MKM, Rahman HS, Gardanova ZR, et al · · 2021 · cited 80× · PMID 34321099 · DOI 10.1186/s13287-021-02510-7
  4. Chimeric Antigen Receptor T-Cells: An Overview of Concepts, Applications, Limitations, and Proposed Solutions.
    Alnefaie A, Albogami S, Asiri Y, Ahmad T, et al · · 2022 · cited 77× · PMID 35814023 · DOI 10.3389/fbioe.2022.797440
  5. Endothelial cell function and endothelial-related disorders following haematopoietic cell transplantation.
    Hildebrandt GC, Chao N. · · 2020 · cited 64× · PMID 32319084 · DOI 10.1111/bjh.16621
  6. Enhancing the safety of CAR-T cell therapy: Synthetic genetic switch for spatiotemporal control.
    Lu L, Xie M, Yang B, Zhao WB, et al · · 2024 · cited 52× · PMID 38394207 · DOI 10.1126/sciadv.adj6251
  7. The pathogenesis, diagnosis, prevention, and treatment of CAR-T cell therapy-related adverse reactions.
    Li Y, Ming Y, Fu R, Li C, et al · · 2022 · cited 37× · PMID 36313336 · DOI 10.3389/fphar.2022.950923
  8. Mechanisms and management of CAR T toxicity.
    Ferreri CJ, Bhutani M. · · 2024 · cited 27× · PMID 38835382 · DOI 10.3389/fonc.2024.1396490

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Other trials of Defibrotide

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