Defribrotide Jazz 15-007

Principal Investigator: David Shyr
Keywords: Defibrotide , Hepatic Veno-Occlusive Disease , Hematopoietic Stem Cell Transplant Department: Pediatric Hematology/Oncology
IRB Number: 00096430 Co Investigator:  
Specialty: Pediatric Hematology and Oncology, Pediatrics, General
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Luke Stone
Luke.Stone@hsc.utah.edu
801-213-3395

Brief Summary

The primary objective of the study is to compare the efficacy of defibrotide prophylaxis in addition to BSC (DP arm) vs BSC alone (BSC arm) for the prevention of VOD as measured by VOD-free survival by Day +30 post-HSCT in patients who are at high risk or very high risk for developing VOD.

The key secondary objective of the study is to compare the efficacy of defibrotide prophylaxis in addition to BSC (DP arm) vs BSC alone (BSC arm) for the prevention of VOD as measured by VOD-free survival by Day +100 post-HSCT in patients who are at high risk or very high risk for developing VOD.

Other secondary objectives of the study are as follows:

To further compare the efficacy of defibrotide prophylaxis in addition to BSC (DP arm) vs BSC alone (BSC arm) on additional variables, as follows:

  • Incidence of VOD by Day +30 post-HSCT
  • VOD-free survival by Day +180 post-HSCT
  • Non-relapse mortality (NRM) by Day +100 and by Day +180 post-HSCT - Incidence of VOD-associated multi-organ dysfunction (MOD) (i.e., severe VOD) by Day +30 and by Day +100 post-HSCT (in those patients who develop VOD)
  • Proportion of patients who have resolution of VOD by Day +180 post-HSCT and time to resolution of VOD (in those patients who develop VOD)
  • - Incidence of VOD after Day +30 post-HSCT, by Day +100, and by Day +180 post-HSCT
  • To compare the health-related quality of life using the following questionnaires:
  • 5-Level EuroQol-5D (EQ-5D-5L) (adults only)
  • EuroQol-5D for Youth (EQ-5D-Y), proxy version 1 (pediatric patients 4 to 7 years of age) - EQ-5D-Y, self-report version 1 (pediatric patients 8 to 18 <16 years of age)
  • To characterize the pharmacokinetics of defibrotide  To compare the overall safety of defibrotide in addition to BSC vs BSC alone, including AE profile, SAE profile, laboratory abnormalities, and vital signs (including peri-infusional vital signs for patients who receive defibrotide)
  • To compare the overall safety of defibrotide in addition to BSC vs BSC alone by comparing the incidence of grades 2, 3, and 4 acute GvHD by Day +30, Day +100, and Day +180 post-HSCT, and the incidence of chronic GvHD at Day +180 post-HSCT
  • To compare graft failure and time to neutrophil and platelet engraftment

Exploratory Objectives
The exploratory objectives of this study are as follows:

  • To compare the hospital resource utilization for defibrotide prophylaxis and BSC patients
  • To evaluate plasma concentration of potential predictive or prognostic VOD biomarkers (which may include but will not be limited to vascular cell adhesion molecule 1 [VCAM1], von Willebrand factor [vWF], L-fFicolin, plasminogen activator inhibitor [PAI-1], thrombomodulin, C-reactive protein [CRP], angiopoietin 2 [ANG2]) and/or GvHD biomarkers (which may include but will not be limited to tumor necrosis factor receptor 1 [TNFR1], interleukin-1 receptor-like-1 [IL1RL1, also known as ST2]), and regenerating islet-derived 3-alpha [REG3α])
  • To evaluate potential formation of anti-drug binding and neutralizing antibodies in patients who receive defibrotide for treatment or prophylaxis

Inclusion Criteria

Each patient must meet the following criteria to be enrolled in this study. Study treatment is defined as defibrotide prophylaxis in addition to BSC or BSC alone.

  1. Patient must be above the age of 1 month as of the start date of study treatment.
  2. Patient must be scheduled to undergo allogeneic (adults or pediatric patients) or autologous HSCT (pediatric patients only) and be at high risk or very high risk of developing VOD.
    1. High-risk patients must meet both of the following criteria:
      1. Patient must be scheduled to receive myeloablative conditioning, defined as either of the following:
        1. At least 2 alkylating agents (e.g., cyclophosphamide, busulfan, melphalan); the investigator must document in the medical chart that the conditioning regimen is considered to be myeloablative or
        2. TBI (single dose of ≥5 Gy, or ≥8 Gy fractionated dose) and at least 1 alkylating agent, and
    2. Patient must meet at least 1 of the following criteria (a or b): a. Have Has at least 1 hepatic-related risk factor, as defined by the European Society for Blood and Marrow Transplantation (EBMT) position statement (adapted and modified from Mohty et al. 2015), atduring screening as follows:  Transaminase level >2.5 times the upper limit of normal (ULN) during screening or within 14 days prior to screening on a non-screening test if the test was performed as part of patient’s routine standard of care  Serum total bilirubin level >1.5 times the ULN during screening or within 14 days prior to screening on a non-screening test if the test was performed as part of patient’s routine standard of care
  3. Prior history of Ccirrhosis (with biopsy evidence)
  4. Hepatic Prior history of hepatic fibrosis (by histology or other diagnostic scoring system per institutional guidelines)  Known Prior history of active viral hepatitis within 1 year before the start of study treatment as indicated by a positive test for any of the following: – Hepatitis A virus (HAV) immunoglobulin M (IgM) (anti-HAV IgM)
  5. Hepatitis B virus (HBV) core immunoglobulin G (IgG) or IgM (anti-HBc IgG or anti-HBc IgM) – HBV surface antigen (HBsAg) – HBV DNA by polymerase chain reaction (PCR) or nucleic acid amplification testing (NAAT) – Hepatitis C virus (HCV) antibody (anti-HCV) and HCV RNA by PCR or NAAT,
  6. Any prior hepatic irradiation, including abdominal irradiation covering the hepatic area
    1. Documented diagnosis of iron overload (serum ferritin >2000 ng/mL; Armand et al. 2007) or liver iron content ≥5.0 mg/gdw as estimated by magnetic resonance imaging T2* (Armand et al. 2011) within 3 months prior to screening.
    2. Has advanced-stage neuroblastoma requiring myeloablative conditioning. Note: if the patient is scheduled to receive a tandem transplant, then enrollment may only occur following the first transplant and prior to second transplant
  7. Very high-risk patients must meet one 1 of the following criteria:
    1. Osteopetrosis and undergoing myeloablative conditioning
    2. Primary HLH, Griscelli II Chediak-Higashi syndrome, Hermansky-Pudiak II, X-linked lymphoproliferative disorders, X-linked severe combined immunodeficiency, X-linked hypogammaglobulinemia, or familial HLH 1-5 and undergoing myeloablative conditioning (Weitzman 2011, Naithani et al. 2013)
    3. Prior treatment with an ozogamicin-containing monoclonal antibody using the minimum dose and schedule, according to the patient prescribing information; examples include the following:  Gemtuzumab ozogamicin, at least 9 mg/m2 total dose (Wadleigh et al. 2003) per dose
    4. Inotuzumab ozogamicin, at least 1.5 mg/mg2 over 28 daysClass III, high-risk thalassemia (i.e., patients who are ≥7 years old and have a liver size ≥5 cm at the time of screening [Mathews et al. 2007])
  8. Female patients (and female partners of male patients) of childbearing potential who are sexually active must agree to use a highly effective medically acceptable method of contraception with their partners during exposure to defibrotidethroughout the entire study period and for 4 1 weeks after the last dose of defibrotidestudy drug; male patients with female partners of childbearing potential must agree to use a medically acceptable method of contraception for 6 months after the last dose of study drug. Highly effective Medically acceptable methods of contraception that may be used by the patient and/or partner include abstinence (when this is in line with the preferred and usual lifestyle of the patient [periodic abstinence, e.g., calendar, post-ovulation, symptothermal methods, and withdrawal are not acceptable methods]), combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (i.e., birth control pills, patches, vaginal ring), progestogen-only hormonal contraception associated with inhibition of ovulation (i.e., progestin implant or injection), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), diaphragm and spermicide, condom and vaginal spermicide, surgical sterilization, and vasectomy (>6 months before Study Day 1), and progestin implant or injection. Post-menopausal women (i.e., women with >2 years of amenorrhea) do not need to use contraception. 4. Adult patients must be able to understand and sign a written informed consent. For minor patients, the parentPatient and/or the /legal guardian or representative must be able to understand and sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria

 

  1. Patient has hemodynamic instability within 24 hours before the start of study treatment.
  2. Patient has acute bleeding that is clinically significant within 24 hours before the start of study treatment, defined as either of the following (a or b):
    1. hemorrhage requiring >15 cc/kg of packed red blood cells (e.g., pediatric patient weighing 20 kg and requiring 300 cc packed red blood cells/24 hours, or an adult weighing >70 kg and requiring 3 units of packed red blood cells/24 hours) to replace blood loss, or
    2. bleeding from a site which, in the investigator’s opinion, constitutes a potential life-threatening source (e.g., pulmonary hemorrhage or central nervous system bleeding), irrespective of amount of blood loss
  3. Patient used any medication that increases the risk of bleeding within 24 hours before the start of study treatment, including, but not limited to, systemic heparin, low molecular weight heparin, heparin analogs, alteplase (tPA), streptokinase, urokinase, antithrombin III (ATIII), and oral anticoagulants including warfarin, and other agents that increase the risk of bleeding. Patients may receive heparin or other anticoagulants for routine central venous line management and intermittent dialysis or ultrafiltration. Fibrinolytic instillation for central venous line occlusion is also permitted. Note: Heparin use used to keep catheters open will be allowed in both treatment arms (up to a maximum of 100 U/kg/day).
  4. Patient is using or plans to use an investigational agent for the prevention or treatment of VOD.
  5. Patient, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
  6. Patient or parent/legal guardian or representative has a psychiatric illness that would prevent the patient or parent/legal guardian or representative from giving informed consent and/or assent.
  7. Patient has a serious active disease or co-morbid medical condition, as judged by the investigator, which would interfere with the conduct of this study.
  8. Patient is pregnant or lactating and does not agree to stop breastfeeding.
  9. Patient has a known history of hypersensitivity to defibrotide or any of the excipients.
  10. Patient or parent/legal guardian or representative lacks the full mental capacity to understand and sign a written informed consent.
  11. Patient is receiving or plans to receive other investigational therapy during study.