Defibrotide in Treating Patients With Liver Damage Following Peripheral Stem Cell Transplantation
Defibrotide in Treating Patients With Liver Damage Following Peripheral Stem Cell Transplantation
RATIONALE: Giving defibrotide may be an effective treatment for liver damage that may result
 following peripheral stem cell transplantation.

 PURPOSE: This randomized phase II trial is studying defibrotide to see how well it works in
 treating patients with severe liver disease after undergoing peripheral stem cell
 transplantation.
OBJECTIVES:

 -  Determine complete response rate in post-hematopoietic stem cell transplant patients
 with severe veno-occlusive disease of the liver treated with defibrotide.

 -  Determine the minimal effective dose of this drug in these patients.

 -  Assess toxicity and adverse side effects of this drug in these patients.

 OUTLINE: This is a randomized, multicenter study. All patients initially receive the same
 dose of defibrotide IV over 2 hours every 6 hours on day 1. On day 2, patients are randomized
 to 1 of 2 doses of defibrotide.

 -  Arm I: On days 2-14, patients receive a lower dose of defibrotide IV over 2 hours every
 6 hours.

 -  Arm II: On days 2-14, patients receive a higher dose of defibrotide IV over 2 hours
 every 6 hours.

 In both arms, courses repeat every 14 days in the absence of disease progression or
 unacceptable toxicity.

 PROJECTED ACCRUAL: A total of 140 patients (70 per treatment arm) will be accrued for this
 study.
Inclusion Criteria

 -  Clinical diagnosis of VOD defined by:

 -  Jaundice (bilirubin ≥ 2 mg/dL) and 2 or more of the following: ascites, weight
 gain > 5% above baseline weight (see Section 5.2), hepatomegaly, RUQ pain

 -  Patients with jaundice and reversal of flow on Doppler examination of the
 portal vein will be eligible with one of the following: ascites, weight gain
 > 5% above baseline weight, hepatomegaly, RUQ pain

 -  Patients with pre-existing hepatomegaly must have documentation by physical
 exam or imaging that liver size is increased over baseline at admission

 -  Patients who do not meet the criteria in Section 3.1.1 (ie. have two of the major
 criteria but not three) and have biopsy proven VOD are eligible in the presence
 of characteristics consistent with severe disease (see below).

 -  Patients with concurrent, confounding causes of liver dysfunction clinically
 evident or evident on ultrasound or other radiographic imaging (such as evidence
 of biliary ductal dilatation or focal tissue defects) may require biopsy-proven
 VOD and/or elevated wedged trans-hepatic venous pressure gradient measurement (
 ≥10 mm mercury) to be considered eligible. Best medical judgment and further
 imaging studies can be used to clarify the diagnosis and determine confounding
 causes of liver dysfunction.

 -  Severity of VOD defined by:

 -  For patients addressed by the Bearman model (i.e. within 16 days of SCT and
 conditioned with either BU/CY, CY/TBI or CBV), there must be a 30% or greater
 risk of severe VOD (see Appendix B).

 -  For all other patients who are not addressed by the Bearman model (ie. beyond 16
 days of SCT and/or not conditioned with either BU/CY,

 -  CY/TBI or CBV), there must be concomitant multi-organ failure defined as presence
 of one or more of the following :

 -  renal dysfunction: a) creatinine ≥2x value on the date of admission day to
 the BMT unit for conditioning or ≥2x lowest value during conditioning (use
 the lowest value for calculation), or b) creatinine clearance or GFR ≤50% of
 admission value, or c) dialysis dependence"

 -  pulmonary dysfunction: documentation of oxygenation saturation ≤ 90% on room
 air; requirement for positive pressure/ventilator dependence

 ----pulmonary dysfunction must not be attributable to another cause (e.g.
 documented infectious pneumonia)

 -  central nervous dysfunction: documentation of confusion, lethargy, and/or
 delirium ---- central nervous dysfunction must not be attributable to
 another cause (e.g. documented cyclosporin toxicity)

 -  Patients or their parents/guardians or designated proxy must have the ability to
 give voluntary informed consent to the protocol. Where possible, patient assent
 will also be obtained

 -  Patients must be ≥ 12 hours after cessation of heparin

 -  Patient must have an eligible diagnosis of VOD by Day 35 post transplant

 -  Exclusion Criteria

 -  Patients receiving concomitant heparin or other anticoagulants unless being used
 for routine CVL management, fibrinolytic instillation for CVL occlusion,
 intermittent dialysis or ultrafiltration are excluded. Patients who have received
 systemic t-PA (concomitant or prior) are excluded.

 -  Patients with significant uncontrolled acute bleeding, defined as hemorrhage
 requiring > 15 cc/kg of packed red blood cells (ie. a pediatric patient weighing
 20 kg and requiring > 300cc of packed red blood cells /24 hours or an adult
 patient weighing 70 kg and requiring >3 units of packed red blood cells/24 hours)
 to replace blood loss are excluded. These parameters must be reviewed prior to
 enrollment by the PI or his/her designate.

 -  Patients with hemodynamic instability as defined below:

 -  Hemodynamic stability is defined as having no requirement for pressor
 support OR being able to maintain mean arterial pressure within 1 SD of
 age-adjusted levels with pressor support (see Appendix D)

 -  Patients requiring renal dose dopamine alone (2-5 mcg/kg/min) are eligible
 without measurement of mean arterial pressure

 -  Patients with Grade B-D GVHD, graded according to the IBMTR Severity Index (see
 Appendix G). Please note patients with Grade B skin only are eligible.

 -  Patients intubated for documented intrinsic lung disease

 --- Patients intubated secondary to a mechanical barrier to ventilation,
 e.g.pulmonary edema or ascites, will be eligible as long as the PaO2/FiO2 ratio
 is ≥ 300 and/or the oxygen index (OI={MAP x FiO2}÷ PaO2 x 100) is ≤ 25% at the
 time of enrollment

 -  Patients who meet Grade IV common toxicity criteria for neurotoxicity (other than
 Grade IV confusion and/or delirium), i.e. coma, seizures, toxic psychosis

 -  Patients who are currently receiving treatment with another experimental agent.

 -  Please note that an experimental agent in this setting is defined as any drug or
 device used under an IND designation which is associated with systemic effects
 that could influence the outcome in a patient with severe VOD. If the continued
 use of an experimental agent is considered both necessary and appropriate, this
 must be reviewed and approved on a case by case basis by the Overall Study PI,
 Dr. Paul Richardson, or his designate, who will approve the entry of patients
 being concurrently treated with another experimental agent only if there is no
 evidence for a potential adverse pharmacokinetic interaction or overlapping
 toxicity.