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Defibrotide TMA Prophylaxis Pilot Trial

Sponsor
University of California, San Francisco (Other)
Overall Status
Completed
CT.gov ID
NCT03384693
Collaborator
(none)
25
Enrollment
1
Location
1
Arm
27
Actual Duration (Months)
0.9
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Thrombotic microangiopathy (TMA) is a common complication in the stem cell transplant population. Certain populations within the hematopoietic stem cell transplant (HSCT) population are at a higher risk than others. Defibrotide is an endothelial stabilizing agent which may prevent the endothelial damage that triggers TMA in HSCT patients. The feasibility, safety, and efficacy of defibrotide prophylaxis in a pediatric transplant population is unknown. Twenty five patients age 0 to 30 years receiving autologous or allogeneic hematopoeitic stem cell transplant who meet TMA high risk criteria will be enrolled. Patients will receive Defibrotide for 28-35 days starting before conditioning, and will be closely monitored for any adverse events up through 6 months post-transplant. The feasibility of administering defibrotide will be evaluated as well as incidence of TMA.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

This is an open-label, single arm pilot study of defibrotide given as prophylaxis to patients receiving a conditioned stem cell transplant for the purpose of preventing post-transplant microangiopathy. The University of California San Francisco Blood and Marrow Transplant program reviewed all cases of non-relapse related death from 2012 through 2015 and identified a complication of endothelial injury known as transplant associated thrombotic microangiopathy (TMA) as the most common cause of transplant related mortality in its patient population. TMA is a multi-system disease in which widespread endothelial injury leads to microangiopathic hemolytic anemia, intravascular platelet activation and formation of thrombi within the microcirculation. Diagnosis of TMA can be difficult as systemic signs and symptoms of TMA are often similar to other common transplant complications, such as medication induced hypertension and cytopenias. The reported prevalence of TMA is varied likely due to diagnostic uncertainty and transplant center expertise, but large retrospective studies have reported it as 10-39%, with the majority of cases occurring in the first 100 days after transplant. Of the patients who develop TMA, approximately half of them will develop severe disease. Outcomes are poor with a reported 30-50% mortality rate and as high as 80% in patients with severe disease. Furthermore, survivors of TMA may have significant morbidity (e.g. renal failure and need for long-term dialysis, heart failure, and significantly prolonged hospital admission). There is no gold standard of treatment for TMA. Supportive care includes renal support, discontinuation of calcineurin inhibitors, and treatment of infections. Treatment options include plasma exchange, complement cascade blockade, and defibrotide. Early treatment is crucial to decrease morbidity and mortality.

Despite the early recognition and treatment of TMA, poor outcomes occur when patients are treated with complement blockade alone. This suggests that complement activation may trigger a complex cascade of parallel inflammatory mediators that lead to end organ damage independent of the complement pathway. The goal is to prevent TMA whenever possible via augmentation of endothelial repair. 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. It is a polydeoxyribonucleotide salt that blocks plasminogen activator inhibitor-1 (PAI-1) and attenuates the effect of tumor necrosis factor. It also increases prostaglandin E2 and prostacyclin levels which alters the platelet activity adhesion and aggregation and relaxes the smooth muscle of blood vessel walls. All of this likely protects the endothelium from damage. It has been shown that patients with TMA who were treated with defibrotide had a 77% response rate.

The use of defibrotide in the context of veno occlusive disease (VOD) treatment and prevention has been studied extensively, including a landmark report showing that defibrotide given to children during stem cell transplant conditioning is safe and effective in the prevention of veno-occlusive disease. Also, defibrotide showed a 67-77% response rate when used as treatment in patients who developed TMA. However, there has not been a prospective study to show that such prophylaxis is effective in the prevention of TMA in pediatric patients undergoing hematopoetic stem cell transplant (HCT).

Patients will receive Defibrotide 6.25mg/kg via two hour intravenous infusions given every 6 hours. Defibrotide will start the day before conditioning is initiated, and will last for 28 to 35 days. During defibrotide administration, participants will have assessments of administration feasibility, hypersensitivity reaction, and bleeding. All hematopoietic stem cell transplant standard of care evaluations will be conducted, including routine clinical evaluations and laboratory assessments.

Patients will be followed for 6 months post-HSCT, or until death, whichever occurs first. All patients will be evaluated for toxicity from the time of their first treatment with the study drug. The study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and modified criteria for hematologic adverse events. Patients removed from study for unacceptable treatment related adverse event(s) will be followed until resolution or stabilization of all treatment-related adverse events to Grade 2 or lower.

Biomarkers indicative of endothelial damage and TMA activity will be drawn to assess subclinical TMA activity as well as risk for subsequent development of TMA while on defibrotide. These include plasma free hemoglobin, suppression of tumorigenicity, angiopoietin 2, and plasminogen activator inhibitor - 1. Study labs will be assessed at 4 time points prior to Day +21, and at diagnosis of TMA.

Study Design

Study Type:
Interventional
Actual Enrollment :
25 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
Defibrotide 6.25mg/kg administered intravenously for 28-35 daysDefibrotide 6.25mg/kg administered intravenously for 28-35 days
Masking:
None (Open Label)
Primary Purpose:
Prevention
Official Title:
A Pilot Trial of Using Pre-Transplant Risk Stratification and Prophylactic Defibrotide to Prevent Serious Thrombotic Microangiopathy in High-Risk Hematopoietic Stem Cell Transplant Patients
Actual Study Start Date :
May 1, 2018
Actual Primary Completion Date :
Jul 31, 2020
Actual Study Completion Date :
Jul 31, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Prophylactic Defibrotide

6.25mg/kg administered intravenously every 6 hours for 28 to 35 days, starting on the day before conditioning is initiated.

Drug: 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.
Other Names:
  • Defitelio

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percent of Total Doses of Defibrotide That Were Missed [Feasibility] [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.

    2. Participants With Reportable Serious Adverse Events [Safety] Per CTACAE v5 Grade 3 or Higher [From first treatment with study drug to 6 months post-transplant]

      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.

    3. Participants With Clinically Significant Bleeding Requiring Discontinuation of Therapy [Safety] [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.

    4. Participants With Hypersensitivity Reaction Requiring Discontinuation of Therapy [Safety] [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.

    Secondary Outcome Measures

    1. Number of Patients With TMA Enrolled on the Study [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

    2. Number of Patients With Severe TMA [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.

    Other Outcome Measures

    1. Incidence of Elevation of Single or Combination of Biomarkers Predictive of Development of TMA [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.

    2. Incidence of TMA [Day 30, day 100 and day 180 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.

    3. Non Relapse Mortality [Day 100 and day 180 post-transplant]

      Deaths which cannot be attributed to disease relapse or progression

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 30 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    Inclusion Criteria

    1. Age 0-30 years of age

    2. Life expectancy > 6 months

    3. Eastern Cooperative Oncology Group or Karnofsky Performance Status >40

    4. Meets minimum organ function requirements per institutional standard of care guiding clearance for autologous or allogeneic stem cell transplantation.

    5. Patients must meet TMA High-Risk criteria 5A or 5B below:

    5A. Patients undergoing tandem autologous transplant with thiotepa in one or more of the conditioning regimens

    OR:

    5B. . Patients with at least 3 of the following characteristics:

    1. 10 years of age

    2. Non-Caucasian race/ Hispanic ethnicity

    3. Undergoing haploidentical transplant

    4. Minor ABO blood group mismatch

    Exclusion Criteria:

    1. Age >30 years

    2. Life expectancy < 6 months

    3. Known bleeding diathesis or bleeding risk deemed by the treating physician to be a contraindication to administration of anticoagulants.

    4. Known hypersensitivity reaction to defibrotide

    5. Any patient not meeting TMA High-Risk criteria

    6. Pregnant women are excluded from this study because they will be receiving teratogenic therapy as part of the stem cell transplant.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Benioff Children's Hospital at UCSF Medical Center San Francisco California United States 94143

    Sponsors and Collaborators

    • University of California, San Francisco

    Investigators

    • Principal Investigator: Christine Higham, MD, University of California, San Francisco

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    University of California, San Francisco
    ClinicalTrials.gov Identifier:
    NCT03384693
    Other Study ID Numbers:
    • 17-23356
    First Posted:
    Dec 27, 2017
    Last Update Posted:
    Sep 16, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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.:
    Yes
    Keywords provided by University of California, San Francisco
    hematopoeitic stem cell transplant
    prophylactic defibrotide
    Additional relevant MeSH terms:
    Thrombotic Microangiopathies
    Defibrotide

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Prophylactic Defibrotide
    Arm/Group Description 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.
    Period Title: Overall Study
    STARTED 25
    COMPLETED 22
    NOT COMPLETED 3

    Baseline Characteristics

    Arm/Group Title Prophylactic Defibrotide
    Arm/Group Description 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 Participants 25
    Age (Count of Participants)
    <=18 years
    22
    88%
    Between 18 and 65 years
    3
    12%
    >=65 years
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    10
    40%
    Male
    15
    60%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    7
    28%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    1
    4%
    White
    15
    60%
    More than one race
    2
    8%
    Unknown or Not Reported
    0
    0%
    Diagnosis (Count of Participants)
    Leukemia
    9
    36%
    Lymphoma
    2
    8%
    Neuroblastoma
    14
    56%
    Recipient CMV (cytomegalovirus) serostatus (Count of Participants)
    Positive
    14
    56%
    Negative
    11
    44%
    Donor type (Count of Participants)
    Unrelated
    1
    4%
    Haploidentical
    10
    40%
    N/A (Autologous)
    14
    56%
    MIBG (Metaiodobenzylguanidine) therapy prior to transplant (Count of Participants)
    Yes
    4
    16%
    No
    21
    84%
    Conditioning backbone (Count of Participants)
    TBI based
    3
    12%
    Melphalan based
    6
    24%
    Busulfan based
    2
    8%
    Other (Autologous)
    14
    56%

    Outcome Measures

    1. Primary Outcome
    Title Percent of Total Doses of Defibrotide That Were Missed [Feasibility]
    Description Feasibility will be determined with regard to administration concurrently with chemotherapy and supportive medications before, during, and after stem cell infusion.
    Time Frame From first treatment with study drug to day +21 post Transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Prophylactic Defibrotide
    Arm/Group Description 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.
    Measure Participants 22
    Median (Full Range) [percentage of missed doses]
    0.7
    2. Primary Outcome
    Title Participants With Reportable Serious Adverse Events [Safety] Per CTACAE v5 Grade 3 or Higher
    Description 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.
    Time Frame From first treatment with study drug to 6 months post-transplant

    Outcome Measure Data

    Analysis Population Description
    all patients having received at least one dose of study drug
    Arm/Group Title Prophylactic Defibrotide
    Arm/Group Description 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.
    Measure Participants 25
    Count of Participants [Participants]
    3
    12%
    3. Primary Outcome
    Title Participants With Clinically Significant Bleeding Requiring Discontinuation of Therapy [Safety]
    Description 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.
    Time Frame From first treatment with study drug to 6 months post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Prophylactic Defibrotide
    Arm/Group Description 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.
    Measure Participants 25
    Count of Participants [Participants]
    3
    12%
    4. Primary Outcome
    Title Participants With Hypersensitivity Reaction Requiring Discontinuation of Therapy [Safety]
    Description 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.
    Time Frame From first treatment with study drug to 6 months post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Prophylactic Defibrotide
    Arm/Group Description 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.
    Measure Participants 25
    Count of Participants [Participants]
    3
    12%
    5. Secondary Outcome
    Title Number of Patients With TMA Enrolled on the Study
    Description 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
    Time Frame 6 months post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Prophylactic Defibrotide
    Arm/Group Description 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.
    Measure Participants 25
    Count of Participants [Participants]
    1
    4%
    6. Secondary Outcome
    Title Number of Patients With Severe TMA
    Description 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.
    Time Frame 6 months post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Prophylactic Defibrotide
    Arm/Group Description 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.
    Measure Participants 25
    Count of Participants [Participants]
    0
    0%
    7. Other Pre-specified Outcome
    Title Incidence of Elevation of Single or Combination of Biomarkers Predictive of Development of TMA
    Description Values will be analyzed to determine whether any one biomarker or a combination of biomarkers may be predictive of TMA development or severity.
    Time Frame 6 months post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Other Pre-specified Outcome
    Title Incidence of TMA
    Description 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.
    Time Frame Day 30, day 100 and day 180 post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Prophylactic Defibrotide
    Arm/Group Description 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.
    Measure Participants 25
    Day 30
    1
    4%
    day 100
    0
    0%
    Day 180
    0
    0%
    9. Other Pre-specified Outcome
    Title Non Relapse Mortality
    Description Deaths which cannot be attributed to disease relapse or progression
    Time Frame Day 100 and day 180 post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame 6 months
    Adverse Event Reporting Description
    Arm/Group Title Prophylactic Defibrotide
    Arm/Group Description 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.
    All Cause Mortality
    Prophylactic Defibrotide
    Affected / at Risk (%) # Events
    Total 0/25 (0%)
    Serious Adverse Events
    Prophylactic Defibrotide
    Affected / at Risk (%) # Events
    Total 3/25 (12%)
    General disorders
    Bleeding 3/25 (12%)
    Other (Not Including Serious) Adverse Events
    Prophylactic Defibrotide
    Affected / at Risk (%) # Events
    Total 0/25 (0%)

    Limitations/Caveats

    Limitations include: Small single institution non-randomized trial. Combination of two separate patient populations at high-risk for TA-TMA allowed for a more robust study, but smaller numbers of patients in each of the groups limits sub-analysis. Some interesting preliminary findings with study biomarkers but the study is too small to draw definitive conclusions regarding utility. No current CLIA-approved lab measuring ANG-2, limiting applicability of this test to the clinical setting.

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Christine Higham
    Organization University of California, San Francisco
    Phone 415-476-2188
    Email christine.higham@ucsf.edu
    Responsible Party:
    University of California, San Francisco
    ClinicalTrials.gov Identifier:
    NCT03384693
    Other Study ID Numbers:
    • 17-23356
    First Posted:
    Dec 27, 2017
    Last Update Posted:
    Sep 16, 2021
    Last Verified:
    Sep 1, 2021