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

NCT ID: NCT02806947

Last Updated: 2021-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 127 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-10-31
• Study Completion Date: 2019-02-19

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.

Conditions

Acute GVHD

Keywords

Acute GVHD; Standard-Risk; Sirolimus; Refined Minnesota Risk Criteria; Ann Arbor; Biomarker; Steroid-Free

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Sirolimus

Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established.

Group Type: EXPERIMENTAL

Sirolimus

Intervention Type: DRUG

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

Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established.

Group Type: ACTIVE_COMPARATOR

Prednisone

Intervention Type: DRUG

Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.

Interventions

Sirolimus

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.

Intervention Type: DRUG

Prednisone

Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.

Intervention Type: DRUG

Other Intervention Names

Rapamycin; Rapamune®; Deltasone®; Orasone®; Cortan®; Sterapred®

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.

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Blood and Marrow Transplant Clinical Trials Network

NETWORK

Sponsor Role: collaborator

National Marrow Donor Program

OTHER

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mary Horowitz, MD, MS

Role: STUDY_DIRECTOR

Center for International Blood and Marrow Transplant Research

Locations

City of Hope National Medical Center

Duarte, California, United States

Children's Hospital Los Angeles

Los Angeles, California, United States

University of Florida College of Medicine (Shands)

Gainesville, Florida, United States

H. Lee Moffitt Cancer Center

Tampa, Florida, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Emory University

Atlanta, Georgia, United States

Blood & Marrow Transplant Program at Northside Hospital

Atlanta, Georgia, United States

University of Kansas Hospital

Kansas City, Kansas, United States

University of Michigan Medical Center

Ann Arbor, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Washington University/Barnes Jewish Hospital

St Louis, Missouri, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Ohio State/Arthur G. James Cancer Hospital

Columbus, Ohio, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

University of Texas/MD Anderson Cancer Center

Houston, Texas, United States

Virginia Commonwealth University MCV Hospitals

Richmond, Virginia, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004.

Reference Type: BACKGROUND

PMID: 16338616 (View on PubMed)

Giaccone L, Faraci DG, Butera S, Lia G, Di Vito C, Gabrielli G, Cerrano M, Mariotti J, Dellacasa C, Felicetti F, Brignardello E, Mavilio D, Bruno B. Biomarkers for acute and chronic graft versus host disease: state of the art. Expert Rev Hematol. 2021 Jan;14(1):79-96. doi: 10.1080/17474086.2021.1860001. Epub 2020 Dec 24.

Reference Type: DERIVED

PMID: 33297779 (View on PubMed)

Pidala J, Hamadani M, Dawson P, Martens M, Alousi AM, Jagasia M, Efebera YA, Chhabra S, Pusic I, Holtan SG, Ferrara JLM, Levine JE, Mielcarek M, Anasetti C, Antin JH, Bolanos-Meade J, Howard A, Logan BR, Leifer ES, Pritchard TS, Horowitz MM, MacMillan ML. Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CTN 1501 trial. Blood. 2020 Jan 9;135(2):97-107. doi: 10.1182/blood.2019003125.

Reference Type: DERIVED

PMID: 31738834 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2U10HL069294-11

Identifier Type: NIH

Identifier Source: secondary_id

View Link

5U24CA076518

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMT CTN 1501

Identifier Type: -

Identifier Source: org_study_id