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

Phase 2

Completed

Conditions: Acute GVHD

Interventions: Drug: Prednisone
Drug: Sirolimus

Registration Number: NCT02806947

Lead Sponsor: Medical College of Wisconsin

Brief 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 127

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:
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)
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Prednisone	Prednisone	Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established.
Sirolimus	Sirolimus	Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment	Days 28 and 56 Post-randomization	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 1. Rash \<25% of body surface area (BSA) 2. Rash on 25-50% of BSA 3. Rash on \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level): 0: \<2 mg/dL 1. 2-3 mg/dL 2. 3.01-6 mg/dL 3. 6.01-15.0 mg/dL 4. \>15 mg/dL GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With GVHD-free Survival	6 and 12 Months Post-randomization	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.
Percentage of Participants With Overall Survival	6 and 12 Months Post-randomization	Overall survival is defined as survival of death from any cause.
Proportion of Participants With Event-free Survival	6 and 12 Months Post-randomization	Event-free survival is defined as freedom from acute GVHD progression, chronic GVHD, malignancy relapse, and death.
Percentage of Participants With Chronic GVHD	6 and 12 Months Post-randomization	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.
Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day	Day 28 Post-randomization	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 1. Rash \<25% of body surface area (BSA) 2. Rash 25-50% of BSA 3. Rash \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: \<2 1. 2-3 2. 3.01-6 3. 6.01-15.0 4. \>15 mg/dL GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus
Percentage of Participants With Non-relapse Mortality	6 and 12 Months Post-randomization	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.
Percentage of Participants With Malignancy Relapse	6 and 12 Months Post-randomization	The cumulative incidence of relapse of the primary malignancy is described, with death treated as a competing risk.
Acute GVHD Response	Days 28 and 56 Post-randomization	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 1. Rash \<25% of body surface area (BSA) 2. Rash 25-50% of BSA 3. Rash \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: \<2 1. 2-3 2. 3.01-6 3. 6.01-15.0 4. \>15 GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus
Percentage of Participants With Treatment Failure	Days 28 and 56 Post-randomization	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 1. Rash \<25% of body surface area (BSA) 2. Rash 25-50% of BSA 3. Rash \>50% of BSA 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level in mg/dL): 0: \<2 1. 2-3 2. 3.01-6 3. 6.01-15.0 4. \>15 GI stage: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus
Percentage of Participants With Disease-free Survival	6 and 12 Months Post-randomization	Disease-free survival is defined as freedom from death and relapse of the underlying malignancy.
Percentage of Participants With Serious Infections	6 and 12 Months Post-randomization	The cumulative incidence of serious infections (Grade 2 or 3 per BMT CTN MOP) is described, with death treated as a competing risk.

Trial Locations

Locations (21): Emory University
🇺🇸
Atlanta, Georgia, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Blood & Marrow Transplant Program at Northside Hospital
🇺🇸
Atlanta, Georgia, United States
University of Texas/MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Fred Hutchinson Cancer Research Center
🇺🇸
Seattle, Washington, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
University of Kansas Hospital
🇺🇸
Kansas City, Kansas, United States
University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
Children's Healthcare of Atlanta
🇺🇸
Atlanta, Georgia, United States
City of Hope National Medical Center
🇺🇸
Duarte, California, United States
H. Lee Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
Mayo Clinic Rochester
🇺🇸
Rochester, Minnesota, United States
Medical College of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
University of Florida College of Medicine (Shands)
🇺🇸
Gainesville, Florida, United States
University of Michigan Medical Center
🇺🇸
Ann Arbor, Michigan, United States
Icahn School of Medicine at Mount Sinai
🇺🇸
New York, New York, United States
Washington University/Barnes Jewish Hospital
🇺🇸
Saint Louis, Missouri, United States
Ohio State/Arthur G. James Cancer Hospital
🇺🇸
Columbus, Ohio, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Virginia Commonwealth University MCV Hospitals
🇺🇸
Richmond, Virginia, United States