Treatment for Acute Graft-Versus-Host Disease (BMT CTN 0302)

Graft vs Host Disease Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00224874
• Other study ID #: BMTCTN0302
• Secondary ID: BMT CTN 0302U01H
• Status: Completed
• Phase: Phase 2
• Start date: September 2005
• Est. completion date: June 2012

Study information

• Verified date: August 2017
• Source: National Heart, Lung, and Blood Institute (NHLBI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Other known NCT identifiers

• NCT00253656
• NCT00474149

Recruitment information / eligibility

• Status: Completed
• Enrollment: 180
• Est. completion date: June 2012
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Graft vs Host Disease
• Immune System Diseases
• Immune System Disorders

Intervention

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

Locations

Country	Name	City	State
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Johns Hopkins/SKCCC	Baltimore	Maryland
United States	DFCI/Brigham & Women's Hospital	Boston	Massachusetts
United States	University Hospitals of Cleveland/Case Western	Cleveland	Ohio
United States	City of Hope National Medical Center	Duarte	California
United States	Duke University Medical Center (Peds)	Durham	North Carolina
United States	University of Florida College of Medicine (Shands)	Gainesville	Florida
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	University of Texas/MD Anderson CRC	Houston	Texas
United States	University of Minnesota	Minneapolis	Minnesota
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Pennsylvania Cancer Center	Philadelphia	Pennsylvania
United States	Oregon Health Sciences University	Portland	Oregon
United States	Washington University/Barnes Jewish Hospital	Saint Louis	Missouri
United States	Texas Transplant Institute	San Antonio	Texas
United States	University of California	San Diego	California
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Stanford Hospital and Clinics	Stanford	California

Sponsors (3)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)	Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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 pe — View Citation

Jacobson PA, Huang J, Wu J, Kim M, Logan B, Alousi A, Grimley M, Bolaños-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 C — View Citation

Levine JE, Logan B, Wu J, Alousi AM, Ho V, Bolaños-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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Complete Response (CR) at Day 28 of Therapy	Complete response at day 28 after randomization. CR was defined as resolution of all signs and symptoms of Graft-Versus-Host Disease (GVHD) in all evaluable organs in comparison to Day 1 scoring.	Measured at Day 28
Secondary	Number of Partial Response (PR), Mixed Response (MR), and Progression	Partial response, mixed response, and progression at Day 28 after randomization. Partial response was defined as improvement in one or more organs involved with Graft-Versus-Host Disease (GVHD) symptoms without progression in others. Mixed response was defined as improvement in one or more organs with deterioration in another organ manifesting symptoms of GVHD or development of symptoms of GVHD in a new organ. Progression was defined as deterioration in at least one organ without any improvement in others.	Measured at Day 28
Secondary	Proportion of Treatment Failure		Measured at Day 56
Secondary	Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90	Flares were defined as any increase in symptoms of or therapy for acute GVHD after an initial response (i.e., progression from an earlier CR or PR).	Measured at Day 90
Secondary	Number of Patients Discontinuing Immune Suppression Without Flare	Immunosuppression discontinuation was defined as the discontinuation of corticosteroids and all additional immunosuppressives, except cyclosporine or tacrolimus, for treatment of acute GVHD without subsequent flare by Day 90 post-initiation of therapy and later by discontinuation of all immunosuppressive medications, including cyclosporine or tacrolimus.	Measured at Days 90, 180, and 270 post-treatment
Secondary	Number of Patients With Chronic Graft-versus-host Disease (GVHD)	Number of patients with limited and extensive chronic GVHD at 9 months	Measured at 9 months
Secondary	Number of Patients Surviving at 6 and 9 Months Post Randomization		Measured at 6 and 9 months
Secondary	Cumulative Incidence of Systemic Infections		Measured at Day 270
Secondary	Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma		Measured at 9 months

External Links

•   Blood and Marrow Clinical Trials Network Website