DLBCL, Neurotoxicity Syndromes
Conditions
Keywords
CAR-T
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.
Interventions
DRUGDefibrotide
* 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).
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 4 |
| 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). | 21 |
| Total | 25 |
Baseline characteristics
| Characteristic | Part 1: Safety Lead-In, Defibrotide 2.5 mg/kg/Dose | Phase 2: RP2D, Defibrotide 6.25 mg/kg/Dose | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 14 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 21 Participants | 25 Participants |
| Region of Enrollment United States | 4 participants | 21 participants | 25 participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 14 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 21 |
| other Total, other adverse events | 4 / 4 | 21 / 21 |
| serious Total, serious adverse events | 4 / 4 | 9 / 21 |
Outcome results
Primary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Defibrotide, 6.25 mg/kg/Dose | Incidence of CAR-T-associated Neurotoxicity of Any Grade, Defined by CTCAE v5.0 by CAR-T Day +30 | 50 percentage of participants |
| Stage 2: Defibrotide, 6.25 mg/kg/Dose | Incidence of CAR-T-associated Neurotoxicity of Any Grade, Defined by CTCAE v5.0 by CAR-T Day +30 | 50 percentage of participants |
| Overall: Defibrotide, 6.25 mg/kg/Dose | Incidence of CAR-T-associated Neurotoxicity of Any Grade, Defined by CTCAE v5.0 by CAR-T Day +30 | 51 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Defibrotide, 6.25 mg/kg/Dose | Incidence of CAR-T-Associated Neurotoxicity Grade 3 or Greater Defined by CTCAE v5.0 by CAR-T Day +30 | 80 percentage of participants |
| Stage 2: Defibrotide, 6.25 mg/kg/Dose | Incidence of CAR-T-Associated Neurotoxicity Grade 3 or Greater Defined by CTCAE v5.0 by CAR-T Day +30 | 70 percentage of participants |
| Overall: Defibrotide, 6.25 mg/kg/Dose | Incidence of CAR-T-Associated Neurotoxicity Grade 3 or Greater Defined by CTCAE v5.0 by CAR-T Day +30 | 75 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Defibrotide, 6.25 mg/kg/Dose | 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 |
| Stage 2: Defibrotide, 6.25 mg/kg/Dose | 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 |
| Overall: Defibrotide, 6.25 mg/kg/Dose | 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 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Defibrotide, 6.25 mg/kg/Dose | 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 |
| Stage 2: Defibrotide, 6.25 mg/kg/Dose | Incidence of CAR-T-Associated Neurotoxicity of Grade 3 or Greater According to the ASBMT Consensus Grading System by CAR-T Day +30 | 70 percentage of participants |
| Overall: Defibrotide, 6.25 mg/kg/Dose | Incidence of CAR-T-Associated Neurotoxicity of Grade 3 or Greater According to the ASBMT Consensus Grading System by CAR-T Day +30 | 80 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Defibrotide, 6.25 mg/kg/Dose | 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 |
| Stage 2: Defibrotide, 6.25 mg/kg/Dose | Incidence of Cytokine Release Syndrome (CRS) of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30 | 20 percentage of participants |
| Overall: Defibrotide, 6.25 mg/kg/Dose | Incidence of Cytokine Release Syndrome (CRS) of Any Grade According to the ASBMT Consensus Grading System by CAR-T Day +30 | 15 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1: Defibrotide, 6.25 mg/kg/Dose | Use of High Dose Steroid By CAR-T Day +30 | 45 percentage of participants |