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

• Number of Partial Response (PR), Mixed Response (MR), and Progression [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]
  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.
• Proportion of Treatment Failure [ Time Frame: Measured at Day 14 ] [ Designated as safety issue: No ]
• Number of Patients With Acute Graft-versus-host Disease (GVHD) Flares at Day 90 [ Time Frame: Measured at Day 90 ] [ Designated as safety issue: No ]
  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).
• Number of Patients Discontinuing Immune Suppression Without Flare [ Time Frame: Measured at Days 90, 180, and 270 post-treatment ] [ Designated as safety issue: No ]
  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.
• Number of Patients With Chronic Graft-versus-host Disease(GVHD) at 9 Months [ Time Frame: Measured at 9 months ] [ Designated as safety issue: No ]
  Number of patients with limited and extensive chronic GVHD.
• Number of Patients Surviving at 6 and 9 Months Post Randomization [ 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 ]

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.

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).

• Graft vs Host Disease
• Immune System Disorders

• Drug: Etanercept
  Etanercept [25 mg subcutaneously twice weekly for up to 4 weeks; discontinue if in complete response by 4 weeks].
• 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].
• Drug: Denileukin Diftitox
  Denileukin Diftitox (ONTAK®) [9 mcg/kg intravenously Days 1, 3, 5, 15, 17, 19].
• Drug: Pentostatin
  Pentostatin [1.5 mg/m2 daily for 3 days; Days 1-3 and repeat Days 15-17

• Experimental: 1
  Etanercept
  Intervention: Drug: Etanercept
• Experimental: 2
  Mycophenolate Mofetil
  Intervention: Drug: Mycophenolate Mofetil
• Experimental: 3
  Denileukin Diftitox
  Intervention: Drug: Denileukin Diftitox
• Experimental: 4
  Pentostatin
  Intervention: Drug: Pentostatin

• Levine JE, Logan BR, Wu J, Alousi AM, Bolaños-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. Epub 2012 Mar 1.
• 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 Clinical Trials Network. Biol Blood Marrow Transplant. 2010 Mar;16(3):421-9.
• 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.

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

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