DLBCLPhase 2NCT03954106

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

A Phase 2 study testing Defibrotide in people with DLBCL and Neurotoxicity Syndromes, run by Jazz Pharmaceuticals at 5 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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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. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: DLBCL, Neurotoxicity Syndromes
What is being tested?: Defibrotide
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 25 participants
Where: 5 sitesUnited States
Study dates: 4 Oct 2019to 30 Sep 2020
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.

Who cannot join

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.

Show all 9Show fewer

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.

Trial locations and contacts

5 sites in 1 country.

City, postcode or hospital

5 sites in 1 country

United States5 sites

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

Other trials in United States

About this study

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®)

Conditions: DLBCL, Neurotoxicity Syndromes
Being tested: Defibrotide
Keywords: CAR-T
Medical subject headings: Neurotoxicity Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

DefibrotideDrug
- 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).

Study groups in NCT03954106
Study group	Role	What they receive
Defibrotide	Experimental	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. Receives: Drug: Defibrotide

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: By CAR-T Day +30

Secondary outcomes (5)

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: By CAR-T Day +30

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

4 Oct 201930 Sep 2020

First posted17 May 2019
Study start4 Oct 2019
Primary completion18 Sep 2020
Study completion30 Sep 2020

Why it stopped: Primary endpoint would unlikely to be met based on the unplanned interim assessment on the first 20 efficacy evaluable patients.

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for DLBCLStudies of the same condition, open and under way.
More trials run by Jazz PharmaceuticalsThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Sequential
Masking: None (open label)
Enrolment: 25 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03954106
Sponsor's protocol ID: JZP395-201
Status last verified: Nov 2021
First submitted: 15 May 2019
Last updated: 9 Dec 2021
Results posted: Yes, on ClinicalTrials.gov
FDA-regulated drug: Yes
FDA-regulated device: No

Publications

Jacobson CA, Rosenthal AC, Arnason J, Agarwal S, Zhang P, Wu W, Amber V, Yared JA. A phase 2 trial of defibrotide for the prevention of chimeric antigen receptor T-cell-associated neurotoxicity syndrome. Blood Adv. 2023 Nov 14;7(21):6790-6799. doi: 10.1182/bloodadvances.2023009961.
PubMed 37399456
Danish H, Santomasso BD. Neurotoxicity Biology and Management. Cancer J. 2021 Mar-Apr 01;27(2):126-133. doi: 10.1097/PPO.0000000000000507.
PubMed 33750072

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Not yet recruitingPhase 2
The CARDIOPROTECT Trial
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RecruitingPhase 2
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RecruitingPhase 1/2
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All DLBCL trials

Study at a glance

From the registry record, last updated by the sponsor on 9 Dec 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

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®)
ClinicalTrials.gov ID: NCT03954106
Acronym / sponsor ID: JZP395-201
Conditions: DLBCL, Neurotoxicity Syndromes
Keywords: CAR-T
Phase: Phase 2
Study type: Interventional
Recruitment status: TerminatedReason stopped: Primary endpoint would unlikely to be met based on the unplanned interim assessment on the first 20 efficacy evaluable patients.
Enrolment: 25 participants (actual)
Lead sponsor: Jazz PharmaceuticalsIndustry (pharma, biotech, devices)
Study start: 4 Oct 2019 (actual)
Primary completion: 18 Sep 2020 (actual)
Study completion: 30 Sep 2020 (actual)
First posted: 17 May 2019 (actual)
Results: Posted 9 Dec 2021

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Sequential
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
Defibrotide	Experimental	Drug: DefibrotidePart 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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (4 listed)

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.

Key exclusion criteria (9 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
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).	Drug	Defibrotide

Primary outcome

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.

5 secondary outcomes

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
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
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
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
Use of High Dose Steroid By CAR-T Day +30
Time frame: By CAR-T Day +30

Results and safety

Results posted to the registry on 9 Dec 2021, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose	4	4
Phase 2: RP2D, Defibrotide 6.25 mg/kg/Dose	0	0

Primary outcome: 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. Number (90% Confidence Interval). Unit: percentage of participants

Measure	Stage 1: Defibrotide, 6.25 mg/kg/Dose n = 10	Stage 2: Defibrotide, 6.25 mg/kg/Dose n = 10	Overall: Defibrotide, 6.25 mg/kg/Dose n = 20
Value	50 (NA to NA)	50 (NA to NA)	51 (36 to 66)

Population analysed: The Efficacy Evaluable Analysis Set consisted of all participants in the Enrolled (RP2D) Analysis Set who received at least 18 doses (of all 35) of defibrotide and either developed CAR-T-associated neurotoxicity on or before CAR-T Day +30; OR completed the CAR-T Day +30 neurological assessment and discontinued defibrotide due to CAR-T-associated neurotoxicity before receiving 18 doses of defibrotide. Yescarta infusion must NOT have been delayed by more than 2 days from the original schedule.

5 secondary outcomes are reported in the full results.

Adverse events

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).. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose	4 of 4 (100%)	4 of 4 (100%)	0 of 4
Phase 2: RP2D, 6.25 mg/kg/Dose	9 of 21 (42.9%)	21 of 21 (100%)	0 of 21

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 9 Dec 2021.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 37399456Jacobson CA, Rosenthal AC, Arnason J, Agarwal S, Zhang P, Wu W, Amber V, Yared JA. A phase 2 trial of defibrotide for the prevention of chimeric antigen receptor T-cell-associated neurotoxicity syndrome. Blood Adv. 2023 Nov 14;7(21):6790-6799. doi: 10.1182/bloodadvances.2023009961.
Derived from this study: PubMed 33750072Danish H, Santomasso BD. Neurotoxicity Biology and Management. Cancer J. 2021 Mar-Apr 01;27(2):126-133. doi: 10.1097/PPO.0000000000000507.

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Study of Oral MRT-2359 in Selected Cancer Patients
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Active, not recruitingEarly Phase 1
Iomab-ACT: A Pilot Study of 131-I Apamistamab Followed by CD19-Targeted CAR T-Cell Therapy for Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma
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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

5 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Defibrotide in people with DLBCL and Neurotoxicity Syndromes, run by Jazz Pharmaceuticals at 5 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 9 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Dec 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03954106, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Dec 2021.