Trial Outcomes & Findings for Defibrotide TMA Prophylaxis Pilot Trial (NCT NCT03384693)

Last Updated: 2021-09-16

Results Overview

Feasibility will be determined with regard to administration concurrently with chemotherapy and supportive medications before, during, and after stem cell infusion.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

25 participants

Primary outcome timeframe

From first treatment with study drug to day +21 post Transplant

Results posted on

2021-09-16

Participant Flow

Participant milestones

Participant milestones
Measure	Prophylactic Defibrotide 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Overall Study STARTED	25
Overall Study COMPLETED	22
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Prophylactic Defibrotide 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Overall Study Adverse Event	3

Baseline Characteristics

Defibrotide TMA Prophylaxis Pilot Trial

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Prophylactic Defibrotide n=25 Participants 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Age, Categorical <=18 years	22 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	7 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants
Race (NIH/OMB) White	15 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Diagnosis Leukemia	9 Participants n=5 Participants
Diagnosis Lymphoma	2 Participants n=5 Participants
Diagnosis Neuroblastoma	14 Participants n=5 Participants
Recipient CMV (cytomegalovirus) serostatus Positive	14 Participants n=5 Participants
Recipient CMV (cytomegalovirus) serostatus Negative	11 Participants n=5 Participants
Donor type Unrelated	1 Participants n=5 Participants
Donor type Haploidentical	10 Participants n=5 Participants
Donor type N/A (Autologous)	14 Participants n=5 Participants
MIBG (Metaiodobenzylguanidine) therapy prior to transplant Yes	4 Participants n=5 Participants
MIBG (Metaiodobenzylguanidine) therapy prior to transplant No	21 Participants n=5 Participants
Conditioning backbone TBI based	3 Participants n=5 Participants
Conditioning backbone Melphalan based	6 Participants n=5 Participants
Conditioning backbone Busulfan based	2 Participants n=5 Participants
Conditioning backbone Other (Autologous)	14 Participants n=5 Participants

PRIMARY outcome

Timeframe: From first treatment with study drug to day +21 post Transplant

Feasibility will be determined with regard to administration concurrently with chemotherapy and supportive medications before, during, and after stem cell infusion.

Outcome measures

Outcome measures
Measure	Prophylactic Defibrotide n=22 Participants 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Percent of Total Doses of Defibrotide That Were Missed [Feasibility]	0.7 percentage of missed doses Interval 0.5 to 2.0

PRIMARY outcome

Timeframe: From first treatment with study drug to 6 months post-transplant

Population: all patients having received at least one dose of study drug

Safety was assessed by evaluating drug-related Serious Adverse Events per CTACAE v5 that occur after prophylactic administration of defibrotide. Analyses will be performed for all patients having received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Prophylactic Defibrotide n=25 Participants 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Participants With Reportable Serious Adverse Events [Safety] Per CTACAE v5 Grade 3 or Higher	3 Participants

PRIMARY outcome

Timeframe: From first treatment with study drug to 6 months post-transplant

Bleeding was assessed using Common Toxicity Criteria for Adverse Events version 4.03. (CTCAE). Study drug was permanently discontinued at grade 3 bleeding or higher. Analyses will be performed for all patients having received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Prophylactic Defibrotide n=25 Participants 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Participants With Clinically Significant Bleeding Requiring Discontinuation of Therapy [Safety]	3 Participants

PRIMARY outcome

Timeframe: From first treatment with study drug to 6 months post-transplant

Hypersensitivity reaction will be assessed using Common Toxicity Criteria for Adverse Events version 4.03. For grade 2 hypersensitivity reaction, study drug will be held until it resolves to grade 1 or lower. Study drug will be permanently discontinued at grade 3 hypersensitivity reaction or higher. Analyses will be performed for all patients having received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Prophylactic Defibrotide n=25 Participants 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Participants With Hypersensitivity Reaction Requiring Discontinuation of Therapy [Safety]	3 Participants

SECONDARY outcome

Timeframe: 6 months post-transplant

Evidence of microangiopathy, with either clinical markers/organ dysfunction or presence of biomarkers, or one of the following: 1) presence of schistocytes in peripheral blood; 2) Histologic evidence of microangiopathy on a tissue specimen; 3) Undetectable haptoglobin with increased reticulocyte counts. If there is no evidence of microangiopathy but at least one clinical marker or at least 3 biomarkers, the participant will meet the criteria for TMA incidence. Based on prior analysis at our center, we anticipated an incidence of TA-TMA of 28.2% (95 CI, 17.8-38.6%) in the high-risk patients undergoing allogeneic transplants and 40% (95% CI, 13.9-69.5%) in the neuroblastoma patients undergoing planned tandem HSCT

Outcome measures

Outcome measures
Measure	Prophylactic Defibrotide n=25 Participants 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Number of Patients With TMA Enrolled on the Study	1 Participants

SECONDARY outcome

Timeframe: 6 months post-transplant

Severe TMA is defined as any TMA meeting the criteria in Objective 2 with the following complications: renal dysfunction requiring dialysis, pleural or pericardial effusion requiring any medical or surgical intervention, central nervous system dysfunction including seizure or posterior reversible encephalopathy syndrome, or death.

Outcome measures

Outcome measures
Measure	Prophylactic Defibrotide n=25 Participants 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Number of Patients With Severe TMA	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months post-transplant

Values will be analyzed to determine whether any one biomarker or a combination of biomarkers may be predictive of TMA development or severity.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 30, day 100 and day 180 post-transplant

Outcome measures

Outcome measures
Measure	Prophylactic Defibrotide n=25 Participants 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
Incidence of TMA Day 30	1 Participants
Incidence of TMA day 100	0 Participants
Incidence of TMA Day 180	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 100 and day 180 post-transplant

Deaths which cannot be attributed to disease relapse or progression

Outcome measures

Outcome data not reported

Adverse Events

Prophylactic Defibrotide

Serious events: 3 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Prophylactic Defibrotide n=25 participants at risk 6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated. Defibrotide: Defibrotide is an anticoagulant and fibrinolytic agent that has been shown to be an effective treatment in other endothelial disorders such as hepatic veno-occlusive disease.
General disorders Bleeding	12.0% 3/25 • 6 months

Other adverse events

Adverse event data not reported

Additional Information

Dr. Christine Higham

University of California, San Francisco

Phone: 415-476-2188

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place