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

October 19, 2021 updated by: National Heart, Lung, and Blood Institute (NHLBI)

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)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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).

Study Type

Interventional

Enrollment (Actual)

180

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Duarte, California, United States, 91010
        • City of Hope National Medical Center
      • San Diego, California, United States, 92093
        • University of California
      • Stanford, California, United States, 94305
        • Stanford Hospital and Clinics
    • Florida
      • Gainesville, Florida, United States, 32610
        • University of Florida College of Medicine (Shands)
    • Maryland
      • Baltimore, Maryland, United States, 21231
        • Johns Hopkins/SKCCC
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • DFCI/Brigham & Women's Hospital
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan Medical Center
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University/Barnes Jewish Hospital
    • Nebraska
      • Omaha, Nebraska, United States, 68198
        • University of Nebraska Medical Center
    • New Jersey
      • Hackensack, New Jersey, United States, 07601
        • Hackensack University Medical Center
    • New York
      • New York, New York, United States, 10021
        • Memorial Sloan-Kettering Cancer Center
    • North Carolina
      • Durham, North Carolina, United States, 27705
        • Duke University Medical Center (Peds)
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • University Hospitals of Cleveland/Case Western
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health Sciences University
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania Cancer Center
    • Texas
      • Houston, Texas, United States, 77030
        • University of Texas/MD Anderson CRC
      • San Antonio, Texas, United States, 78229
        • Texas Transplant Institute
    • Washington
      • Seattle, Washington, United States, 98109
        • Fred Hutchinson Cancer Research Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years and older (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Etanercept
Enroll within 48 hours of new onset acute GVHD and randomize to Etanercept
Drug: Etanercept
Etanercept [25 mg subcutaneously twice weekly for up to 4 weeks; discontinue if in complete response by 4 weeks].
Other Names:
  • ENBREL®
EXPERIMENTAL: Mycophenolate Mofetil
Enroll within 48 hours of new onset acute GVHD and randomize to Mycophenolate Mofetil
Drug: 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].
Other Names:
  • CellCept®
EXPERIMENTAL: Denileukin Diftitox
Enroll within 48 hours of new onset acute GVHD and randomize to Denileukin Diftitox
Drug: Denileukin Diftitox
Denileukin Diftitox (ONTAK®) [9 mcg/kg intravenously Days 1, 3, 5, 15, 17, 19].
Other Names:
  • ONTAK®
EXPERIMENTAL: Pentostatin
Enroll within 48 hours of new onset acute GVHD and randomize to Pentostatin
Drug: Pentostatin
Pentostatin [1.5 mg/m2 daily for 3 days; Days 1-3 and repeat Days 15-17
Other Names:
  • Nipent®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Complete Response (CR) at Day 28 of Therapy
Time Frame: Measured at Day 28
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Partial Response (PR), Mixed Response (MR), and Progression
Time Frame: Measured at Day 28
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
Proportion of Treatment Failure
Time Frame: Measured at Day 56
Measured at Day 56
Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90
Time Frame: Measured 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
Number of Patients Discontinuing Immune Suppression Without Flare
Time Frame: Measured at Days 90, 180, and 270 post-treatment
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
Number of Patients With Chronic Graft-versus-host Disease (GVHD)
Time Frame: Measured at 9 months
Number of patients with limited and extensive chronic GVHD at 9 months
Measured at 9 months
Number of Patients Surviving at 6 and 9 Months Post Randomization
Time Frame: Measured at 6 and 9 months
Measured at 6 and 9 months
Cumulative Incidence of Systemic Infections
Time Frame: Measured at Day 270
Measured at Day 270
Incidence of Epstein-Barr Virus (EBV)-Associated Lymphoma
Time Frame: Measured at 9 months
Measured at 9 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Collaborators

National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2005

Primary Completion (ACTUAL)

January 1, 2009

Study Completion (ACTUAL)

June 1, 2012

Study Registration Dates

First Submitted

September 21, 2005

First Submitted That Met QC Criteria

September 21, 2005

First Posted (ESTIMATE)

September 23, 2005

Study Record Updates

Last Update Posted (ACTUAL)

November 1, 2021

Last Update Submitted That Met QC Criteria

October 19, 2021

Last Verified

August 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BMTCTN0302
  • U01HL069294-05 (NIH)
  • BMT CTN 0302 (OTHER: Blood and Marrow Transplant Clinicial Trials Network)
  • 285 (National Heart, Lung, and Blood Institute)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).

IPD Sharing Time Frame

Within 6 months of official study closure at participating sites.

IPD Sharing Access Criteria

Available to the public

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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