Trial Outcomes & Findings for A Safety and Efficacy Study of Defibrotide in the Prevention of Chimeric Antigen Receptor-T-cell-associated Neurotoxicity (NCT NCT03954106)

Last Updated: 2021-12-09

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

25 participants

Primary outcome timeframe

By CAR-T Day +30

Results posted on

2021-12-09

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose 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).	Phase 2: RP2D, Defibrotide 6.25 mg/kg/Dose 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).
Part 1: Safety Lead In Phase STARTED	4	0
Part 1: Safety Lead In Phase COMPLETED	4	0
Part 1: Safety Lead In Phase NOT COMPLETED	0	0
Phase 2: Treatment at RP2D STARTED	0	21
Phase 2: Treatment at RP2D COMPLETED	0	21
Phase 2: Treatment at RP2D NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose n=4 Participants 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).	Phase 2: RP2D, Defibrotide 6.25 mg/kg/Dose n=21 Participants 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 n=25 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	2 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	14 Participants n=7 Participants	16 Participants n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	7 Participants n=7 Participants	8 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	14 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	4 Participants n=5 Participants	21 Participants n=7 Participants	25 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	4 participants n=5 Participants	21 participants n=7 Participants	25 participants n=5 Participants

PRIMARY outcome

Timeframe: By CAR-T Day +30

Population: 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.

Outcome measures

Outcome measures
Measure	Stage 1: Defibrotide, 6.25 mg/kg/Dose n=10 Participants 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.	Stage 2: Defibrotide, 6.25 mg/kg/Dose n=10 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.	Overall: Defibrotide, 6.25 mg/kg/Dose n=20 Participants 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.
Incidence of CAR-T-associated Neurotoxicity of Any Grade, Defined by CTCAE v5.0 by CAR-T Day +30	50 percentage of participants As per the Statistical Analysis Plan, confidence intervals (CIs) were not calculated for the primary outcome for Stage 1 or Stage 2. CIs were only calculated for the Overall: Defibrotide 6.25 mg/kg/dose group.	50 percentage of participants As per the Statistical Analysis Plan, confidence intervals (CIs) were not calculated for the primary outcome for Stage 1 or Stage 2. CIs were only calculated for the Overall: Defibrotide 6.25 mg/kg/dose group.	51 percentage of participants Interval 36.0 to 66.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Stage 1: Defibrotide, 6.25 mg/kg/Dose n=10 Participants 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.	Stage 2: Defibrotide, 6.25 mg/kg/Dose n=10 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.	Overall: Defibrotide, 6.25 mg/kg/Dose n=20 Participants 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.
Incidence of CAR-T-Associated Neurotoxicity Grade 3 or Greater Defined by CTCAE v5.0 by CAR-T Day +30	80 percentage of participants	70 percentage of participants	75 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Stage 1: Defibrotide, 6.25 mg/kg/Dose n=10 Participants 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.	Stage 2: Defibrotide, 6.25 mg/kg/Dose n=10 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.	Overall: Defibrotide, 6.25 mg/kg/Dose n=20 Participants 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.
Incidence of CAR-T-Associated Neurotoxicity of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30	0 percentage of participants	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Stage 1: Defibrotide, 6.25 mg/kg/Dose n=10 Participants 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.	Stage 2: Defibrotide, 6.25 mg/kg/Dose n=10 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.	Overall: Defibrotide, 6.25 mg/kg/Dose n=20 Participants 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.
Incidence of CAR-T-Associated Neurotoxicity of Grade 3 or Greater According to the ASBMT Consensus Grading System by CAR-T Day +30	90 percentage of participants	70 percentage of participants	80 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Stage 1: Defibrotide, 6.25 mg/kg/Dose n=10 Participants 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.	Stage 2: Defibrotide, 6.25 mg/kg/Dose n=10 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.	Overall: Defibrotide, 6.25 mg/kg/Dose n=20 Participants 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.
Incidence of Cytokine Release Syndrome (CRS) of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30	10 percentage of participants	20 percentage of participants	15 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Stage 1: Defibrotide, 6.25 mg/kg/Dose n=20 Participants 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.	Stage 2: Defibrotide, 6.25 mg/kg/Dose 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.	Overall: Defibrotide, 6.25 mg/kg/Dose 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.
Use of High Dose Steroid By CAR-T Day +30	45 percentage of participants	—	—

Adverse Events

Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose

Serious events: 4 serious events

Other events: 4 other events

Deaths: 0 deaths

Phase 2: RP2D, 6.25 mg/kg/Dose

Serious events: 9 serious events

Other events: 21 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Director, Clinical Trial Disclosure & Transparency

Jazz Pharmaceuticals

Phone: 2158709177

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose n=4 participants at risk 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).	Phase 2: RP2D, 6.25 mg/kg/Dose n=21 participants at risk 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).
Blood and lymphatic system disorders Febrile neutropenia	25.0% 1/4 • Number of events 2 • 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 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.	4.8% 1/21 • Number of events 1 • 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 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.
Cardiac disorders Atrial fibrillation	25.0% 1/4 • Number of events 1 • 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 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.	0.00% 0/21 • 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 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.
Cardiac disorders Myocardial infarction	25.0% 1/4 • Number of events 1 • 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 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.	0.00% 0/21 • 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 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.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/4 • 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 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.	4.8% 1/21 • Number of events 1 • 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 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.
General disorders Asthenia	0.00% 0/4 • 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 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.	4.8% 1/21 • Number of events 1 • 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 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.
General disorders Pyrexia	25.0% 1/4 • Number of events 1 • 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 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.	0.00% 0/21 • 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 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.
Immune system disorders Cytokine release syndrome	25.0% 1/4 • Number of events 1 • 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 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.	9.5% 2/21 • Number of events 2 • 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 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.
Infections and infestations Clostridium difficile colitis	0.00% 0/4 • 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 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.	4.8% 1/21 • Number of events 1 • 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 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.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/4 • 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 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.	4.8% 1/21 • Number of events 1 • 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 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.
Metabolism and nutrition disorders Tumour lysis syndrome	0.00% 0/4 • 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 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.	4.8% 1/21 • Number of events 1 • 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 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.
Nervous system disorders Neurotoxicity	0.00% 0/4 • 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 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.	9.5% 2/21 • Number of events 3 • 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 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.
Nervous system disorders Presyncope	0.00% 0/4 • 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 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.	4.8% 1/21 • Number of events 1 • 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 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.
Nervous system disorders Transient ischaemic attack	0.00% 0/4 • 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 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.	4.8% 1/21 • Number of events 1 • 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 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.
Psychiatric disorders Confusional state	25.0% 1/4 • Number of events 1 • 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 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.	0.00% 0/21 • 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 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.
Respiratory, thoracic and mediastinal disorders Pleural effusion	25.0% 1/4 • Number of events 1 • 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 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.	0.00% 0/21 • 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 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.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	25.0% 1/4 • Number of events 1 • 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 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.	0.00% 0/21 • 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 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.
Vascular disorders Hypotension	0.00% 0/4 • 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 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.	9.5% 2/21 • Number of events 2 • 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 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.