Defibrotide in Treating Patients With Liver Damage Following Peripheral Stem Cell Transplantation

NCT ID: NCT00003966

Last Updated: 2017-01-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 151 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-04-30
• Study Completion Date: 2006-04-30

Brief Summary

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.

Detailed Description

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.

Conditions

Veno-occlusive Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A Lower dose

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.

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

Group Type: EXPERIMENTAL

defibrotide

Intervention Type: DRUG

Arm B Higher Dose

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 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

Group Type: EXPERIMENTAL

defibrotide

Intervention Type: DRUG

Interventions

defibrotide

Intervention Type: DRUG

Other Intervention Names

Defitelio®

Eligibility Criteria

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.

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Jazz Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Dana-Farber Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Paul G. Richardson, MD

Richardson, Paul MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Paul Richardson, MD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

City of Hope Comprehensive Cancer Center

Duarte, California, United States

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Children's Hospital Boston

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Duke Comprehensive Cancer Center

Durham, North Carolina, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Countries

United States

References

Richardson PG, Soiffer RJ, Antin JH, et al.: Defibrotide (DF) for the treatment of severe veno-occlusive disease (VOD) and multi-system organ failure (MOF) post SCT: final results of a phase II, multicenter, randomized study and preliminary analyses of surrogate markers and ultrasound findings. [Abstract] Blood 104 (11): A-350, 2004.

Reference Type: RESULT

Richardson P, Soiffer RJ, Antin JH, et al.: Defibrotide (DF) is effective in the treatment of severe veno-occlusive disease (VOD) and multi-system organ failure (MOF) post stem cell transplantation (SCT): results of a phase II, multicenter, randomized study. [Abstract] Blood 102 (11): A-674, 2003.

Reference Type: RESULT

Richardson PG, Soiffer R, Antin JH, et al.: Defibrotide (DF) appears effective and safe in a phase II, randomized study of patients (pts) with severe veno-occlusive disease (VOD) and multi-system organ failure (MOF) post stem cell transplantation (SCT). [Abstract] Blood 100 (9): A-414, 2002.

Reference Type: RESULT

Other Identifiers

P30CA015704

Identifier Type: NIH

Identifier Source: secondary_id

View Link

DFCI-1999-P-010076/14

Identifier Type: -

Identifier Source: secondary_id

DUMC-00176-00-2

Identifier Type: -

Identifier Source: secondary_id

FHCRC-1375.00

Identifier Type: -

Identifier Source: secondary_id

NCI-G99-1548

Identifier Type: -

Identifier Source: secondary_id

CHNMC-02118

Identifier Type: -

Identifier Source: secondary_id

MSKCC-03-058

Identifier Type: -

Identifier Source: secondary_id

JHMI-00-06-02-02

Identifier Type: -

Identifier Source: secondary_id

99118

Identifier Type: -

Identifier Source: org_study_id