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

• Sponsor: Jazz Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03954106
• Collaborator: (none)
• Enrollment: 25
• Locations: 5
• Arm: 1
• Actual Duration (Months): 11.9
• Patients Per Site: 5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
DLBCL; Neurotoxicity Syndromes	Drug: Defibrotide	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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®)
• Actual Study Start Date: Oct 4, 2019
• Actual Primary Completion Date: Sep 18, 2020
• Actual Study Completion Date: Sep 30, 2020

Arms and Interventions

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).

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

1. Incidence of CAR-T-Associated Neurotoxicity Grade 3 or Greater Defined by CTCAE v5.0 by CAR-T Day +30 [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.

2. Incidence of CAR-T-Associated Neurotoxicity of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30 [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.

3. Incidence of CAR-T-Associated Neurotoxicity of Grade 3 or Greater According to the ASBMT Consensus Grading System by CAR-T Day +30 [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.

4. Incidence of Cytokine Release Syndrome (CRS) of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30 [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.

5. Use of High Dose Steroid By CAR-T Day +30 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Phoenix	Arizona	United States	85054
2	University of Maryland	Baltimore	Maryland	United States	21201
3	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
4	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
5	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Jazz Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 9, 2019
• Statistical Analysis Plan - Jan 21, 2021

More Information

Publications

None provided.

• Responsible Party: Jazz Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03954106
• Other Study ID Numbers: JZP395-201
• First Posted: May 17, 2019
• Last Update Posted: Dec 9, 2021
• Last Verified: Nov 1, 2021

• 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
• Keywords provided by Jazz Pharmaceuticals: CAR-T
• Additional relevant MeSH terms: Neurotoxicity Syndromes; Defibrotide

Study Results

Participant Flow

Pre-assignment Detail	Patient disposition was assessed in the Safety Analysis Set (N=25) which was comprised of the Part 1: Defibrotide 2.5 mg/kg/dose (n=4) and the combined Part 1: Defibrotide 6.25 mg/kg/dose and Phase 2: RP2D 6.25 mg/kg/dose (n=21). The patient disposition is reported in this format as per the Statistical Analysis Plan.

Arm/Group Title	Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose	Phase 2: RP2D, Defibrotide 6.25 mg/kg/Dose
Arm/Group Description	Participants who received the safety (lead in) dose of 2.5 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7).	Participants who received the recommended phase 2 dose of 6.25 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7).
Period Title: Part 1: Safety Lead In Phase
STARTED	4	0
COMPLETED	4	0
NOT COMPLETED	0	0
Period Title: Part 1: Safety Lead In Phase
STARTED	0	21
COMPLETED	0	21
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose	Phase 2: RP2D, Defibrotide 6.25 mg/kg/Dose	Total
Arm/Group Description	Participants who received the safety (lead in) dose of 2.5 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7).	Participants who received the recommended phase 2 dose of 6.25 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7).	Total of all reporting groups
Overall Participants	4	21	25
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	2 50%	7 33.3%	9 36%
>=65 years	2 50%	14 66.7%	16 64%
Sex: Female, Male (Count of Participants)
Female	1 25%	7 33.3%	8 32%
Male	3 75%	14 66.7%	17 68%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	4 100%	21 100%	25 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%	21 100%	25 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of CAR-T-associated Neurotoxicity of Any Grade, Defined by CTCAE v5.0 by CAR-T Day +30
Description	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.
Time Frame	By CAR-T Day +30

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Stage 1: Defibrotide, 6.25 mg/kg/Dose	Stage 2: Defibrotide, 6.25 mg/kg/Dose	Overall: Defibrotide, 6.25 mg/kg/Dose
Arm/Group Description	Participants who either received the safety (lead in) dose of 6.25 mg/kg/dose defibrotide in Part 1 (n=4) or received the RP2D of 6.25 mg/kg/dose defibrotide in Part 2 (n=6) once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). Stage 1 participants are the first 10 efficacy evaluable participants.	Participants who received the RP2D of 6.25 mg/kg/dose defibrotide in Part 2 (n=10) once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). Stage 2 participants include the additional efficacy evaluable participants enrolled after the completion of Stage 1.	All participants who received 6.25 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7) in Stage 1 and Stage 2.
Measure Participants	10	10	20
Number (90% Confidence Interval) [percentage of participants]	50 1250%	50 238.1%	51 204%

2. Secondary Outcome

Title	Incidence of CAR-T-Associated Neurotoxicity Grade 3 or Greater Defined by CTCAE v5.0 by CAR-T Day +30
Description	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.
Time Frame	By CAR-T Day +30

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Stage 1: Defibrotide, 6.25 mg/kg/Dose	Stage 2: Defibrotide, 6.25 mg/kg/Dose	Overall: Defibrotide, 6.25 mg/kg/Dose
Arm/Group Description	Participants who either received the safety (lead in) dose of 6.25 mg/kg/dose defibrotide in Part 1 (n=4) or received the RP2D of 6.25 mg/kg/dose defibrotide in Part 2 (n=6) once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). Stage 1 participants are the first 10 efficacy evaluable participants.	Participants who received the RP2D of 6.25 mg/kg/dose defibrotide in Part 2 (n=10) once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). Stage 2 participants include the additional efficacy evaluable participants enrolled after the completion of Stage 1.	All participants who received 6.25 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7) in Stage 1 and Stage 2.
Measure Participants	10	10	20
Number [percentage of participants]	80 2000%	70 333.3%	75 300%

3. Secondary Outcome

Title	Incidence of CAR-T-Associated Neurotoxicity of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30
Description	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.
Time Frame	By CAR-T Day +30

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Stage 1: Defibrotide, 6.25 mg/kg/Dose	Stage 2: Defibrotide, 6.25 mg/kg/Dose	Overall: Defibrotide, 6.25 mg/kg/Dose
Arm/Group Description	Participants who either received the safety (lead in) dose of 6.25 mg/kg/dose defibrotide in Part 1 (n=4) or received the RP2D of 6.25 mg/kg/dose defibrotide in Part 2 (n=6) once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). Stage 1 participants are the first 10 efficacy evaluable participants.	Participants who received the RP2D of 6.25 mg/kg/dose defibrotide in Part 2 (n=10) once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). Stage 2 participants include the additional efficacy evaluable participants enrolled after the completion of Stage 1.	All participants who received 6.25 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7) in Stage 1 and Stage 2.
Measure Participants	10	10	20
Number [percentage of participants]	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	Incidence of CAR-T-Associated Neurotoxicity of Grade 3 or Greater According to the ASBMT Consensus Grading System by CAR-T Day +30
Description	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.
Time Frame	By CAR-T Day +30

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Stage 1: Defibrotide, 6.25 mg/kg/Dose	Stage 2: Defibrotide, 6.25 mg/kg/Dose	Overall: Defibrotide, 6.25 mg/kg/Dose
Arm/Group Description	Participants who either received the safety (lead in) dose of 6.25 mg/kg/dose defibrotide in Part 1 (n=4) or received the RP2D of 6.25 mg/kg/dose defibrotide in Part 2 (n=6) once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). Stage 1 participants are the first 10 efficacy evaluable participants.	Participants who received the RP2D of 6.25 mg/kg/dose defibrotide in Part 2 (n=10) once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). Stage 2 participants include the additional efficacy evaluable participants enrolled after the completion of Stage 1.	All participants who received 6.25 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7) in Stage 1 and Stage 2.
Measure Participants	10	10	20
Number [percentage of participants]	90 2250%	70 333.3%	80 320%

5. Secondary Outcome

Title	Incidence of Cytokine Release Syndrome (CRS) of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30
Description	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.
Time Frame	By CAR-T Day +30

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Stage 1: Defibrotide, 6.25 mg/kg/Dose	Stage 2: Defibrotide, 6.25 mg/kg/Dose	Overall: Defibrotide, 6.25 mg/kg/Dose
Arm/Group Description	Participants who either received the safety (lead in) dose of 6.25 mg/kg/dose defibrotide in Part 1 (n=4) or received the RP2D of 6.25 mg/kg/dose defibrotide in Part 2 (n=6) once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). Stage 1 participants are the first 10 efficacy evaluable participants.	Participants who received the RP2D of 6.25 mg/kg/dose defibrotide in Part 2 (n=10) once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7). Stage 2 participants include the additional efficacy evaluable participants enrolled after the completion of Stage 1.	All participants who received 6.25 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7) in Stage 1 and Stage 2.
Measure Participants	10	10	20
Number [percentage of participants]	10 250%	20 95.2%	15 60%

6. Secondary Outcome

Title	Use of High Dose Steroid By CAR-T Day +30
Description	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.
Time Frame	By CAR-T Day +30

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Overall: Defibrotide, 6.25 mg/kg/Dose
Arm/Group Description	All participants who received 6.25 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7) in Stage 1 and Stage 2.
Measure Participants	20
Number [percentage of participants]	45 1125%

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).
Adverse Event Reporting Description	Adverse events (AEs), SAEs, and all-cause mortality were assessed in the Safety Analysis Set (N=25) which comprised of the Part 1: Defibrotide 2.5 mg/kg/dose (n=4) and the combined Part 1: Defibrotide 6.25 mg/kg/dose and Phase 2: RP2D 6.25 mg/kg/dose (n=21). The safety data are reported in this format as per the Statistical Analysis Plan.
Arm/Group Title	Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose		Phase 2: RP2D, 6.25 mg/kg/Dose
Arm/Group Description	Participants who received the safety (lead in) dose of 2.5 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7).		Participants who received the recommended phase 2 dose of 6.25 mg/kg/dose defibrotide once daily as a single dose on CAR-T Day -5, -4, and -3 prior to lymphodepletion and then every 6 hours daily for 8 days (CAR-T Day 0 to Day 7).
All Cause Mortality
	Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose		Phase 2: RP2D, 6.25 mg/kg/Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/21 (0%)
Serious Adverse Events
	Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose		Phase 2: RP2D, 6.25 mg/kg/Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		9/21 (42.9%)
Blood and lymphatic system disorders
Febrile neutropenia	1/4 (25%)	2	1/21 (4.8%)	1
Cardiac disorders
Atrial fibrillation	1/4 (25%)	1	0/21 (0%)	0
Myocardial infarction	1/4 (25%)	1	0/21 (0%)	0
Gastrointestinal disorders
Small intestinal obstruction	0/4 (0%)	0	1/21 (4.8%)	1
General disorders
Asthenia	0/4 (0%)	0	1/21 (4.8%)	1
Pyrexia	1/4 (25%)	1	0/21 (0%)	0
Immune system disorders
Cytokine release syndrome	1/4 (25%)	1	2/21 (9.5%)	2
Infections and infestations
Clostridium difficile colitis	0/4 (0%)	0	1/21 (4.8%)	1
Metabolism and nutrition disorders
Decreased appetite	0/4 (0%)	0	1/21 (4.8%)	1
Tumour lysis syndrome	0/4 (0%)	0	1/21 (4.8%)	1
Nervous system disorders
Neurotoxicity	0/4 (0%)	0	2/21 (9.5%)	3
Presyncope	0/4 (0%)	0	1/21 (4.8%)	1
Transient ischaemic attack	0/4 (0%)	0	1/21 (4.8%)	1
Psychiatric disorders
Confusional state	1/4 (25%)	1	0/21 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/4 (25%)	1	0/21 (0%)	0
Pulmonary embolism	1/4 (25%)	1	0/21 (0%)	0
Vascular disorders
Hypotension	0/4 (0%)	0	2/21 (9.5%)	2
Other (Not Including Serious) Adverse Events
	Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose		Phase 2: RP2D, 6.25 mg/kg/Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		21/21 (100%)
Blood and lymphatic system disorders
Anemia	1/4 (25%)	1	6/21 (28.6%)	9
Disseminated intravascular coagulation	1/4 (25%)	1	0/21 (0%)	0
Febrile neutropenia	0/4 (0%)	0	6/21 (28.6%)	8
Neutropenia	1/4 (25%)	1	10/21 (47.6%)	25
Thrombocytopenia	1/4 (25%)	1	3/21 (14.3%)	8
Cardiac disorders
Bradycardia	0/4 (0%)	0	2/21 (9.5%)	3
Pericardial effusion	0/4 (0%)	0	1/21 (4.8%)	1
Sinus bradycardia	0/4 (0%)	0	2/21 (9.5%)	3
Sinus Tachycardia	0/4 (0%)	0	6/21 (28.6%)	6
Tachycardia	0/4 (0%)	0	4/21 (19%)	4
Ventricular tachycardia	0/4 (0%)	0	2/21 (9.5%)	2
Eye disorders
Eye irritation	1/4 (25%)	1	0/21 (0%)	0
Gastrointestinal disorders
Abdominal distension	0/4 (0%)	0	1/21 (4.8%)	1
Abdominal pain	1/4 (25%)	2	4/21 (19%)	6
Anal incontinence	0/4 (0%)	0	2/21 (9.5%)	2
Anorectal discomfort	1/4 (25%)	1	0/21 (0%)	0
Constipation	2/4 (50%)	2	11/21 (52.4%)	16
Diarrhoea	3/4 (75%)	5	12/21 (57.1%)	14
Flatulence	0/4 (0%)	0	1/21 (4.8%)	1
Haematochezia	0/4 (0%)	0	2/21 (9.5%)	3
Nausea	3/4 (75%)	4	14/21 (66.7%)	14
Vommiting	1/4 (25%)	1	5/21 (23.8%)	5
General disorders
Asthenia	1/4 (25%)	1	1/21 (4.8%)	1
Chest pain	1/4 (25%)	1	0/21 (0%)	0
Chills	2/4 (50%)	2	10/21 (47.6%)	13
Fatigue	1/4 (25%)	1	12/21 (57.1%)	13
Gait disturbance	0/4 (0%)	0	4/21 (19%)	4
Generalized oedema	1/4 (25%)	1	0/21 (0%)	0
Localized oedema	1/4 (25%)	1	2/21 (9.5%)	2
Oedema peripheral	1/4 (25%)	1	5/21 (23.8%)	6
Pain	0/4 (0%)	0	2/21 (9.5%)	2
Pyrexia	3/4 (75%)	7	17/21 (81%)	48
Immune system disorders
Cytokine release syndrome	3/4 (75%)	4	15/21 (71.4%)	27
Infections and infestations
Candida infection	0/4 (0%)	0	3/21 (14.3%)	4
Lung infection	0/4 (0%)	0	1/21 (4.8%)	1
Urinary tract infection	1/4 (25%)	1	4/21 (19%)	4
Injury, poisoning and procedural complications
Fall	0/4 (0%)	0	1/21 (4.8%)	1
Incision site pain	0/4 (0%)	0	1/21 (4.8%)	1
Investigations
Blood bilirubin increased	1/4 (25%)	1	0/21 (0%)	0
Blood creatinine increased	0/4 (0%)	0	1/21 (4.8%)	1
Blood fibrinogen decreased	1/4 (25%)	1	0/21 (0%)	0
Blood glucose increased	1/4 (25%)	1	0/21 (0%)	0
Blood potassium decreased	1/4 (25%)	1	3/21 (14.3%)	3
Blood sodium decrreased	0/4 (0%)	0	2/21 (9.5%)	2
Blood thyroid stimulating hormone decreased	0/4 (0%)	0	1/21 (4.8%)	1
Blood urea decreased	1/4 (25%)	1	0/21 (0%)	0
C-reactive protein increased	0/4 (0%)	0	2/21 (9.5%)	2
Clostridium test	1/4 (25%)	1	0/21 (0%)	0
Clostridium test positive	1/4 (25%)	1	0/21 (0%)	0
International normalised ratio increased	1/4 (25%)	1	0/21 (0%)	0
Neutrophil count decreased	1/4 (25%)	5	1/21 (4.8%)	2
Transaminases increased	0/4 (0%)	0	1/21 (4.8%)	1
Metabolism and nutrition disorders
Acidosis	1/4 (25%)	1	0/21 (0%)	0
Decreased appetite	1/4 (25%)	3	7/21 (33.3%)	8
Fluid overload	1/4 (25%)	1	0/21 (0%)	0
Hypocalcaemia	1/4 (25%)	4	6/21 (28.6%)	11
Hypokalemia	0/4 (0%)	0	4/21 (19%)	12
Hypomagnesaemia	0/4 (0%)	0	6/21 (28.6%)	16
Hyponatraemia	1/4 (25%)	2	1/21 (4.8%)	2
Hypophagia	1/4 (25%)	1	3/21 (14.3%)	4
Hypophosphataemia	2/4 (50%)	2	5/21 (23.8%)	6
Vitamin D deficiency	0/4 (0%)	0	3/21 (14.3%)	3
Musculoskeletal and connective tissue disorders
Arthalgia	0/4 (0%)	0	3/21 (14.3%)	3
Back pain	0/4 (0%)	0	5/21 (23.8%)	5
Muscle Spasma	0/4 (0%)	0	3/21 (14.3%)	3
Muscular weakness	0/4 (0%)	0	3/21 (14.3%)	3
Myalgia	0/4 (0%)	0	3/21 (14.3%)	5
Neck pain	1/4 (25%)	1	0/21 (0%)	0
Pain in extremity	1/4 (25%)	1	4/21 (19%)	6
Nervous system disorders
Aphasia	1/4 (25%)	1	4/21 (19%)	6
Atazia	0/4 (0%)	0	1/21 (4.8%)	1
Cognative disorder	0/4 (0%)	0	1/21 (4.8%)	1
Depressed level of consciousness	1/4 (25%)	1	2/21 (9.5%)	2
Dizziness	1/4 (25%)	1	6/21 (28.6%)	8
Dysarthria	1/4 (25%)	1	3/21 (14.3%)	4
Headache	2/4 (50%)	2	10/21 (47.6%)	15
Hypoaesthesia	0/4 (0%)	0	2/21 (9.5%)	2
Neurotoxicity	0/4 (0%)	0	7/21 (33.3%)	16
Presyncope	1/4 (25%)	1	2/21 (9.5%)	4
Tremor	1/4 (25%)	2	11/21 (52.4%)	17
Psychiatric disorders
Agitation	1/4 (25%)	3	1/21 (4.8%)	1
Anxiety	0/4 (0%)	0	3/21 (14.3%)	3
Confusional state	2/4 (50%)	3	7/21 (33.3%)	24
Delirium	0/4 (0%)	0	3/21 (14.3%)	3
Dysphemia	0/4 (0%)	0	1/21 (4.8%)	1
Insomnia	1/4 (25%)	1	3/21 (14.3%)	3
Renal and urinary disorders
Acute kidney injury	0/4 (0%)	0	3/21 (14.3%)	3
Incontinence	1/4 (25%)	1	0/21 (0%)	0
Micturition urgency	1/4 (25%)	1	0/21 (0%)	0
Stress unrinary incontinence	0/4 (0%)	0	1/21 (4.8%)	1
Urinary incontinence	1/4 (25%)	1	5/21 (23.8%)	5
Urinary retention	0/4 (0%)	0	1/21 (4.8%)	1
Reproductive system and breast disorders
Penile haemorrhage	0/4 (0%)	0	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
Cough	0/4 (0%)	0	2/21 (9.5%)	2
Dyspnoes	2/4 (50%)	2	2/21 (9.5%)	3
Hiccups	1/4 (25%)	1	1/21 (4.8%)	1
Hypoxia	2/4 (50%)	2	7/21 (33.3%)	10
Laryngeal haemorrage	1/4 (25%)	1	0/21 (0%)	0
Nasal Congestion	1/4 (25%)	1	1/21 (4.8%)	1
Oropharyngeal pain	0/4 (0%)	0	5/21 (23.8%)	5
Pleural effusion	1/4 (25%)	1	1/21 (4.8%)	1
Tachypnoes	1/4 (25%)	1	2/21 (9.5%)	2
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/4 (0%)	0	3/21 (14.3%)	5
Night sweats	0/4 (0%)	0	2/21 (9.5%)	3
Rash generalised	1/4 (25%)	1	0/21 (0%)	0
Rash maculo-papular	0/4 (0%)	0	2/21 (9.5%)	2
Vascular disorders
Hypotension	2/4 (50%)	6	14/21 (66.7%)	29

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can review trial results communications prior to public release and can embargo such communications for a period of at least 60 days from the time submitted to sponsor for review. If requested by sponsor, the PI will withhold publication for up to an additional 30 days. Furthermore, the first publication of study results must be a joint publication of all study sites unless a joint manuscript has not been submitted for publication within 12 months of completion of the study.