A Study to Evaluate Steroid-free Treatment for Standard-Risk aGVHD (BMT CTN 1501)
Condition: Acute GVHD
Intervention: Sirolimus; Prednisone
Intervention description: Sirolimus will be administered with a starting dose of 6 mg for patients older than 12 years, or 5 mg/m^2 for patients ≤ 12 years. Trough levels will be routinely measured and sirolimus will be kept at maintenance dosing for target therapeutic levels for minimum duration through Day 56 post-randomization.; Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Intervention MeSH terms: Sirolimus; Prednisone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 127.0
Sex: All
Healthy volunteers: No
Keywords: Acute GVHD; Standard-Risk; Sirolimus; Refined Minnesota Risk Criteria; Ann Arbor; Biomarker; Steroid-Free

Summary:

      The study is a Phase II randomized, open label, multicenter trial designed to identify
      whether sirolimus is a potential alternative to prednisone as an up-front treatment for
      patients with standard-risk acute GVHD defined according to clinical and biomarker-based risk
      stratification. This trial incorporates both a novel up front GVHD therapy (sirolimus) as
      well as a novel BMT CTN developed acute GVHD biomarker test.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients with standard-risk acute GVHD, according to refined Minnesota Criteria.
             Refined Minnesota Criteria are available at
             https://redcap.ahc.umn.edu/surveys/?s=bNmFhseJIf.

             Standard-risk acute GVHD according to the refined Minnesota Risk Criteria requires
             meeting one of the criteria below:

               1. Single organ involvement (Stage 1-3 skin, Stage 1 upper GI, or Stage 1-2 lower
                  GI)

               2. Multiple organ involvement (Stage 1-3 skin plus stage 1 upper GI, Stage 1-3 skin
                  plus stage 1 lower GI, Stage 1-3 skin plus stage 1 lower GI plus stage 1 upper
                  GI, Stage 1-3 skin plus stage 1-4 liver, or Stage 1 lower GI plus stage 1 upper
                  GI)

          2. Acute Minnesota Standard Risk GVHD requiring systemic immune suppressive therapy.

          3. Acute GVHD developing after allogeneic hematopoietic cell transplantation using either
             bone marrow, peripheral blood, or umbilical cord blood. Recipients of
             non-myeloablative, reduced intensity conditioning and myeloablative transplants are
             eligible. All allogeneic donor sources are permitted, including siblings, unrelated
             donors, human leukocyte antigen (HLA)-haploidentical related donors and umbilical cord
             blood.

          4. Patients NOT receiving systemic immune suppressive therapy for treatment of active
             GVHD (topical skin and GI corticosteroids are allowed).

          5. Ability to tolerate oral or enterically-administered medications.

          6. Patients of all ages.

          7. Absolute neutrophil count (ANC) greater than 500/µL.

          8. Biopsy confirmation of GVHD is not required. Enrollment should not be delayed for
             biopsy or pathology results unless local institutional practice mandates biopsy
             confirmation to make a GVHD treatment decision.

          9. Written informed consent and/or assent from patient, parent or guardian.

         10. Collection of a 5 ml blood sample (red top for serum) from the patient for Ann Arbor
             Scoring and ready to be shipped immediately after randomization.

        Exclusion Criteria:

          1. Patients receiving sirolimus (for any indication including GVHD prophylaxis) within 14
             days of screening for enrollment.

          2. Relapsed, progressing or persistent malignancy requiring withdrawal of systemic immune
             suppression.

          3. Patients with acute GVHD developing after a donor lymphocyte infusion.

          4. Active or recent (within 7 days) episode of transplant associated microangiopathy.

          5. Patients with uncontrolled infections will be excluded. Infections are considered
             controlled if appropriate therapy has been instituted and, at the time of enrollment,
             no signs of progression are present. Progression of infection is defined as
             hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs
             or radiographic findings attributable to infection. Persisting fever without other
             signs or symptoms will not be interpreted as progressing infection.

          6. Patients unlikely to be available for evaluation at the transplant center on Day 28
             and 56 of therapy.

          7. A clinical presentation resembling de novo chronic GVHD or overlap syndrome developing
             before or present at the time of enrollment.

          8. Patients receiving corticosteroids for any indication within 7 days before the onset
             of acute GVHD, except the following: Stable replacement doses of corticosteroids for
             adrenal insufficiency are permitted (e.g. hydrocortisone total dose of 10-12
             mg/m^2/day or prednisone 5-7.5mg daily or equivalent). Corticosteroids administered as
             premedication before transfusion of blood products or before intravenous medications
             to prevent infusion reactions are allowed.

          9. Patients who are pregnant or breastfeeding.

         10. Females of childbearing potential (FCBP) or a man who has sexual contact with a FCBP
             and is unwilling to use effective birth control for the duration of the study.

         11. Patients on dialysis.

         12. Patients on mechanical ventilation.

         13. Patients with severe hepatic sinusoidal obstruction syndrome who in the judgment of
             the treating physician are not expected to have normalized bilirubin by Day 56 after
             enrollment.

         14. Patients with a history of hypersensitivity to sirolimus or any component of the
             formulation.