Clinical trial NCT00224874: Treatment for Acute Graft-Versus-Host Disease (BMT CTN 0302)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Graft vs Host Disease
Immune System Disorders
Keywords: Acute Graft vs Host Disease
GVHD
Lead sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Sponsor class: NIH
Collaborators: name: National Cancer Institute (NCI)
name: Blood and Marrow Transplant Clinical Trials Network
First posted: 2005-09-23
Enrollment: 180
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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
* Absolute neutrophil count (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

Primary outcomes:
measure: Number of Complete Response (CR) at Day 28 of Therapy
timeFrame: Measured at Day 28
Secondary outcomes:
measure: Number of Partial Response (PR), Mixed Response (MR), and Progression
timeFrame: Measured at Day 28
measure: Proportion of Treatment Failure
timeFrame: Measured at Day 56
measure: Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90
timeFrame: Measured at Day 90
measure: Number of Patients Discontinuing Immune Suppression Without Flare
timeFrame: Measured at Days 90, 180, and 270 post-treatment
measure: Number of Patients With Chronic Graft-versus-host Disease (GVHD)
timeFrame: Measured at 9 months
measure: Number of Patients Surviving at 6 and 9 Months Post Randomization
timeFrame: Measured at 6 and 9 months
measure: Cumulative Incidence of Systemic Infections
timeFrame: Measured at Day 270
measure: Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma
timeFrame: Measured at 9 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: San Diego
country: United States
facility: University of California
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Gainesville
country: United States
facility: University of Florida College of Medicine (Shands)
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins/SKCCC
state: Maryland
city: Boston
country: United States
facility: DFCI/Brigham & Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University/Barnes Jewish Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center (Peds)
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals of Cleveland/Case Western
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas/MD Anderson CRC
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Center for International Blood and Marrow Transplant Research
name: Mary Horowitz, MD
role: STUDY_DIRECTOR
References:
citation: Alousi AM, Weisdorf DJ, Logan BR, Bolanos-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. doi: 10.1182/blood-2009-03-212290. Epub 2009 May 14.
citation: Jacobson PA, Huang J, Wu J, Kim M, Logan B, Alousi A, Grimley M, Bolanos-Meade J, Ho V, Levine JE, Weisdorf D. Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network. Biol Blood Marrow Transplant. 2010 Mar;16(3):421-9. doi: 10.1016/j.bbmt.2009.11.010.
citation: Levine JE, Logan B, Wu J, Alousi AM, Ho V, Bolanos-Meade J, Weisdorf D; Blood and Marrow Transplant Clinical Trials Network. Graft-versus-host disease treatment: predictors of survival. Biol Blood Marrow Transplant. 2010 Dec;16(12):1693-9. doi: 10.1016/j.bbmt.2010.05.019. Epub 2010 Jun 9.
citation: Levine JE, Logan BR, Wu J, Alousi AM, Bolanos-Meade J, Ferrara JL, Ho VT, Weisdorf DJ, Paczesny S. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood. 2012 Apr 19;119(16):3854-60. doi: 10.1182/blood-2012-01-403063. Epub 2012 Mar 1.