Treatment for Acute Graft-Versus-Host Disease - Full Text View

Sponsor:	National Heart, Lung, and Blood Institute (NHLBI)
Collaborators:	National Cancer Institute (NCI) Blood and Marrow Transplant Clinical Trials Network
Information provided by:	National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:	NCT00224874

Purpose

The study is a randomized Phase II, four arm treatment trial. The primary purpose of the study is to define new agents with promising activity against acute graft-versus-host disease (GVHD) suitable for testing against corticosteroids alone in a subsequent Phase III trial.

Condition	Intervention	Phase
Graft vs Host Disease Immune System Disorders	Drug: Etanercept Drug: Mycophenolate Mofetil Drug: Denileukin Diftitox Drug: Pentostatin	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Crossover Assignment, Efficacy Study
Official Title:	Initial Systemic Treatment of Acute GVHD: A Phase II Randomized Trial Evaluating Etanercept, Mycophenolate Mofetil (MMF), Denileukin Diftitox (ONTAK), and Pentostatin in Combination With Corticosteroids (BMT CTN #0302)

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Pentostatin Mycophenolate mofetil hydrochloride Mycophenolate Mofetil Denileukin diftitox Etanercept

U.S. FDA Resources

Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:

Proportion of CR at Day 28 of therapy [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Proportion of partial response, mixed response, and progression [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]
Proportion of treatment failure [ Time Frame: Measured at Day 14 ] [ Designated as safety issue: No ]
Incidence of GVHD flares requiring increasing therapy before Day 90 [ Time Frame: Measured at Day 90 ] [ Designated as safety issue: No ]
Incidence of discontinuation of immune suppression without flare [ Time Frame: Measured at Days 90, 180, and 270 post-treatment ] [ Designated as safety issue: No ]
Incidence of chronic GVHD [ Time Frame: Measured at 9 months ] [ Designated as safety issue: No ]
Overall survival at 6 and 9 months post initiation of therapy [ Time Frame: Measured at 6 and 9 months ] [ Designated as safety issue: No ]
Incidence of systemic infections within 3 months of initiation of therapy [ Time Frame: Measured at 3 months ] [ Designated as safety issue: Yes ]
Incidence of EBV-associated lymphoma [ Time Frame: Measured at 9 months ] [ Designated as safety issue: Yes ]

Enrollment:	180
Study Start Date:	September 2005
Estimated Study Completion Date:	December 2009
Primary Completion Date:	January 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Etanercept	Drug: Etanercept Etanercept [25 mg subcutaneously twice weekly for up to 4 weeks; discontinue if in CR by 4 weeks].
2: Experimental Mycophenolate Mofetil	Drug: Mycophenolate Mofetil Mycophenolate mofetil (MMF) [20 mg/kg (maximum 1 gm) PO or IV BID; continue through prednisone taper, then taper MMF over 4 weeks].
3: Experimental Denileukin Diftitox	Drug: Denileukin Diftitox Denileukin Diftitox (ONTAK®) [9 mcg/kg IV Days 1, 3, 5, 15, 17, 19].
4: Experimental Pentostatin	Drug: Pentostatin Pentostatin [1.5 mg/m2 daily for 3 days; Days 1-3 and repeat Days 15-17

Detailed Description:

BACKGROUND:

Acute graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell (HSC) transplantation. Acute GVHD produces significant morbidity and complicates patient management resulting in organ toxicity, frequent infections, malnutrition, and substantial delay in recovery from transplantation. Corticosteroids have been the primary therapy for acute GVHD for over three decades. Various additional immunosuppressive strategies have been tested as GVHD therapy but neither anti-thymocyte globulin (ATG), CD5-immunotoxins, IL-1 antagonists nor other agents have been demonstrably helpful in either control of GVHD symptoms or improvement in survival. Published response rates of complete response (CR) to acute GVHD therapy with corticosteroids range from 25-41%. These rates will be used as benchmarks for assessing efficacy of promising new agents. New immunosuppressive agents and strategies are required to improve the management of GVHD and decrease the toxicities of the immunosuppressive regimens.

DESIGN NARRATIVE:

In this trial, patients with newly diagnosed acute GVHD will be randomly assigned to receive corticosteroids plus one of four new agents (etanercept, MMF, denileukin diftitox [Ontak], and pentostatin). A control arm of only corticosteroids will not be employed. Each agent will be assessed for safety and efficacy (at least 35% complete remission [CR] rate at Day 28 of therapy can be expected from previously untreated patients).

Eligibility

Ages Eligible for Study:	2 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Prior allogeneic hematopoietic stem cell transplant using either bone marrow, peripheral blood stem cells, or cord blood
De novo acute GVHD diagnosed within 48 hours prior to enrollment; biopsy confirmation of GVHD is strongly recommended but not required; enrollment should not be delayed awaiting biopsy or pathology results; the patient must have had no previous systemic immune suppressive therapy given for treatment of acute GVHD except for a maximum 48 hours of prior corticosteroid therapy (at least 1 mg/kg/day methylprednisolone)
Patients that have undergone a scheduled donor lymphocyte infusion (DLI) as part of their original transplant therapy plan
ANC greater than 500/µL
Clinical status at enrollment to allow tapering of steroids to not less than 1 mg/kg/day methylprednisolone (1.4 mg/kg/day prednisone) at Day 28 of therapy (e.g., persisting malignant disease suggesting the need for accelerated taper of immunosuppression)
Estimated creatinine clearance greater than 30 mL/minute
Assent and educational materials provided to, and reviewed with, patients under the age of 18

Exclusion Criteria:

ONTAK, pentostatin, or etanercept given within 7 days of enrollment
Active uncontrolled infection
Patients that have undergone an unscheduled DLI, or DLI that was not part of their original transplant therapy plan
If any prior steroid therapy (for indication other than GVHD), treatment at doses of at least 0.5 mg/kg/day methylprednisolone within 7 days prior to onset of GVHD
Patients unlikely to be available at the transplant center on Day 28 and 56 of therapy
A clinical syndrome resembling de novo chronic GVHD developing at any time after allotransplantation (see Chapter 2 of the BMT CTN Manual of Procedures for details of de novo chronic GVHD)
Other investigational therapeutics for GVHD within 30 days, including agents used for GVHD prophylaxis
Patients who are pregnant, breast feeding, or if sexually active, unwilling to use effective birth control for the duration of the study
Adults unable to provide informed consent
Patients with a history of intolerance to any of the study drugs

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00224874

Show 27 Study Locations

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

National Cancer Institute (NCI)

Blood and Marrow Transplant Clinical Trials Network

Investigators

Principal Investigator:	Edward Ball, MD	University of California, San Diego
Principal Investigator:	Javier Bolanos-Meade	Johns Hopkins/SKCCC
Principal Investigator:	Joel Brochstein, MD	Hackensack University Medical Center
Principal Investigator:	Nelson Chao, MD	Duke University Medical Center (Adults)
Principal Investigator:	Amin Alousi, MD	University of Texas/MD Anderson CRC
Principal Investigator:	Marcel Devetten, MD	University of Nebraska
Principal Investigator:	John DiPersio, MD, PhD	Washington University/Barnes Jewish Hospital
Principal Investigator:	John Levine, MD	University of Michigan
Principal Investigator:	Pablo Parker, MD	City of Hope National Medical Center
Principal Investigator:	Charles Peters, MD	Children's Mercy Hospital and Clinics
Principal Investigator:	Edward Stadtmauer, MD	University of Pennsylvania
Principal Investigator:	Vincent Ho, MD	DFCI/Brigham & Women's Hospital
Principal Investigator:	Laura Johnston, MD	Stanford Hospital and Clinics
Principal Investigator:	Naynesh Kamani, MD	Children's Research Institute
Principal Investigator:	Joanne Kurtzberg, MD	Duke University Medical Center (Peds)
Principal Investigator:	Hillard Lazarus, MD	University Hospitals of Cleveland/Case Western
Principal Investigator:	Richard Nash, MD	Fred Hutchinson Cancer Research Center
Principal Investigator:	Miguel-Angel Perales, MD	Memorial Sloan-Kettering Cancer Center
Study Chair:	Daniel Weisdorf, MD	University of Minnesota - Clinical and Translational Science Institute
Principal Investigator:	John Wingard, MD	University of Florida College of Medicine (Shands)
Principal Investigator:	George Selby, MD	University of Oklahoma Medical Center
Principal Investigator:	Carlos Bachier, MD	Texas Transplant Institute
Principal Investigator:	Rakesh Goyal, MD	Children's Hospital of Pittsburgh
Principal Investigator:	Jennifer Holter, MD	University of Oklahoma Medical Center
Principal Investigator:	Shalini Shenoy, MD	Washington University/St. Louis Children's Hospital
Principal Investigator:	Eneida Nemecek, MD	Oregon Health and Science University
Principal Investigator:	Amanda Termuhlen, MD	Nationwide Children's Hospital

More Information

No publications provided by National Heart, Lung, and Blood Institute (NHLBI)

Additional publications automatically indexed to this study by National Clinical Trials Identifier (NCT ID):

Alousi AM, Weisdorf DJ, Logan BR, Bolaños-Meade J, Carter S, Difronzo N, Pasquini M, Goldstein SC, Ho VT, Hayes-Lattin B, Wingard JR, Horowitz MM, Levine JE; Blood and Marrow Transplant Clinical Trials Network. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. Blood. 2009 Jul 16;114(3):511-7. Epub 2009 May 14.

Responsible Party:	The EMMES Corporation ( Shelly Carter, ScD )
Study ID Numbers:	285, BMT CTN 0302, U01 HL069294-05
Study First Received:	September 21, 2005
Last Updated:	November 20, 2009
ClinicalTrials.gov Identifier:	NCT00224874 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):

Acute Graft vs Host Disease
GVHD

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Pentostatin
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Mycophenolic Acid
TNFR-Fc fusion protein
Antibiotics, Antineoplastic
Sensory System Agents
Therapeutic Uses
Mycophenolate mofetil
Anti-Inflammatory Agents, Non-Steroidal

Analgesics
Immune System Diseases
Gastrointestinal Agents
Enzyme Inhibitors
Immunosuppressive Agents
Pharmacologic Actions
Interleukin-2
Analgesics, Non-Narcotic
Denileukin diftitox
Graft vs Host Disease
Peripheral Nervous System Agents
Antirheumatic Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on February 08, 2010