A Study to Evaluate Steroid-free Treatment for Standard-Risk aGVHD (BMT CTN 1501)

Study Overview
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Brief Summary
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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.

Detailed Description
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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. Patients with previously untreated, standard-risk acute GVHD, according to the refined Minnesota Criteria, who are in need of systemic therapy, will have a 5 mL blood sample collected prior to randomization to assess their biomarker Ann Arbor Risk status. Ann Arbor scoring results will be provided 48-72 hours after randomization. Patients will begin their study treatment assignments within 24 hours of randomization. Those with biomarker results of combined AA1/2 risk will continue on their randomized study treatment and will be included for primary endpoint analysis (Day 28 complete or partial response) and all planned study procedures and assessments. In contrast, patients with AA3 biomarker risk and those patients with missing biomarker results may continue on their randomized therapies or start another therapy at their physicians' discretion. In addition, AA3 risk patients and those with missing results will not be considered in primary endpoint analysis, but will be included in a subset analysis.

Official Title
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A Randomized, Phase II, Multicenter, Open Label, Study Evaluating Sirolimus and Prednisone in Patients With Refined Minnesota Standard Risk, Ann Arbor 1/2 Confirmed Acute Graft-Versus-Host Disease (BMT CTN 1501)

Conditions
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Acute GVHD

Intervention / Treatment
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* Drug: Sirolimus
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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: Single organ involvement (Stage 1-3 skin, Stage 1 upper GI, or Stage 1-2 lower GI) 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) Acute Minnesota Standard Risk GVHD requiring systemic immune suppressive therapy. 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. Patients NOT receiving systemic immune suppressive therapy for treatment of active GVHD (topical skin and GI corticosteroids are allowed). Ability to tolerate oral or enterically-administered medications. Patients of all ages. Absolute neutrophil count (ANC) greater than 500/µL. 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. Written informed consent and/or assent from patient, parent or guardian. 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: Patients receiving sirolimus (for any indication including GVHD prophylaxis) within 14 days of screening for enrollment. Relapsed, progressing or persistent malignancy requiring withdrawal of systemic immune suppression. Patients with acute GVHD developing after a donor lymphocyte infusion. Active or recent (within 7 days) episode of transplant associated microangiopathy. 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. Patients unlikely to be available for evaluation at the transplant center on Day 28 and 56 of therapy. A clinical presentation resembling de novo chronic GVHD or overlap syndrome developing before or present at the time of enrollment. 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. Patients who are pregnant or breastfeeding. 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. Patients on dialysis. Patients on mechanical ventilation. 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. Patients with a history of hypersensitivity to sirolimus or any component of the formulation.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus<br>Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established. | Drug: Sirolimus<br>* 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.<br>* Other names: Rapamune®;|
| Active Comparator: Prednisone<br>Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established. | Drug: Prednisone<br>* Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.<br>* Other names: Sterapred®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment | Scoring of CR/PR is in comparison to the participant's acute GVHD status at randomization. Complete response (CR) is defined as staging of 0 for in all target organs for GVHD - skin, GI tract, and liver. Partial response (PR) is defined as improvement in some target organ(s) without worsening in others. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are considered failures for this endpoint. Organ staging is defined below: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash on 25-50% of BSA Rash on >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level): 0: <2 mg/dL 2-3 mg/dL 3.01-6 mg/dL 6.01-15.0 mg/dL >15 mg/dL GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus | Days 28 and 56 Post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day | The proportion of patients with CR/PR and on a prednisone-equivalent steroid dose of 0.25 mg/kg/day or less is evaluated. CR/PR scoring is in comparison to acute GVHD status at randomization. CR is defined as staging of 0 in all target organs. PR is defined as improvement in some organ(s) without worsening in others. Death and initiation of steroid-free, systemic acute GVHD treatment beyond randomized therapy are considered failures for this endpoint. Organ staging is defined as: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash 25-50% of BSA Rash >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: <2 2-3 3.01-6 6.01-15.0 >15 mg/dL GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus | Day 28 Post-randomization | 
| Acute GVHD Response | Acute GVHD response is classified as CR, PR, mixed response (MR), no response (NR), and progression and scored by comparison to acute GVHD status at randomization. MR is defined as improvement in some organ(s) with worsening in another, progression as worsening in some organ(s) without improvement in others, and NR as absence of any improvement or worsening. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash 25-50% of BSA Rash >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: <2 2-3 3.01-6 6.01-15.0 >15 GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus | Days 28 and 56 Post-randomization | 
| Percentage of Participants With Treatment Failure | Treatment failure is defined as either no response (NR) or progression and scored by comparison to acute GVHD status at randomization. Progression is defined as worsening in some target organ(s) without improvement in others and NR is defined as absence of any improvement or worsening in target organs. Death and initiation of systemic acute GVHD treatment beyond randomized treatment are classified as NR. Organ staging is defined as: Skin stage: 0: No rash Rash <25% of body surface area (BSA) Rash 25-50% of BSA Rash >50% of BSA Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: <2 2-3 3.01-6 6.01-15.0 >15 GI stage: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus | Days 28 and 56 Post-randomization | 
| Percentage of Participants With Overall Survival | Overall survival is defined as survival of death from any cause. | 6 and 12 Months Post-randomization | 
| Percentage of Participants With Disease-free Survival | Disease-free survival is defined as freedom from death and relapse of the underlying malignancy. | 6 and 12 Months Post-randomization | 
| Proportion of Participants With Event-free Survival | Event-free survival is defined as freedom from acute GVHD progression, chronic GVHD, malignancy relapse, and death. | 6 and 12 Months Post-randomization | 
| Percentage of Participants With Non-relapse Mortality | Non-relapse mortality is defined as death due to any cause other than relapse of the underlying malignancy. The cumulative incidence of non-relapse mortality is described, with malignancy relapse treated as a competing risk. | 6 and 12 Months Post-randomization | 
| Percentage of Participants With Malignancy Relapse | The cumulative incidence of relapse of the primary malignancy is described, with death treated as a competing risk. | 6 and 12 Months Post-randomization | 
| Percentage of Participants With Chronic GVHD | Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. The cumulative incidence of chronic GVHD is described, with death and malignancy relapse treated as competing risks. | 6 and 12 Months Post-randomization | 
| Percentage of Participants With GVHD-free Survival | GVHD-free survival is defined as freedom from acute GVHD, chronic GVHD, and death. The proportion of participants alive and free of both acute and chronic GVHD are described at 6 and 12 months post-randomization. | 6 and 12 Months Post-randomization | 
| Percentage of Participants With Serious Infections | The cumulative incidence of serious infections (Grade 2 or 3 per BMT CTN MOP) is described, with death treated as a competing risk. | 6 and 12 Months Post-randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute GVHD, Standard-Risk, Sirolimus, Refined Minnesota Risk Criteria, Ann Arbor, Biomarker, Steroid-Free