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

NCT02806947 | Completed Phase 2 Results DMC

• 3 other identifiers: BMT CTN 15012U10HL069294-115U24CA076518
• Study Type: interventional
• Target: 127
• Locations: 1 country
• Sites: 21

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.

Conditions

Acute GVHD

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 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

  Days 28 and 56 Post-randomization

Secondary Outcomes (11)

• 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

• Acute GVHD Response

  Days 28 and 56 Post-randomization

• Percentage of Participants With Treatment Failure

  Days 28 and 56 Post-randomization

• Percentage of Participants With Overall Survival

  6 and 12 Months Post-randomization

• Percentage of Participants With Disease-free Survival

  6 and 12 Months Post-randomization

Study Arms (2)

Sirolimus

EXPERIMENTAL

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

Drug: Sirolimus

Prednisone

ACTIVE COMPARATOR

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

Drug: Prednisone

Interventions

Sirolimus 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.

Also known as: Rapamycin, Rapamune®

Sirolimus

Prednisone DRUG

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

Also known as: Deltasone®, Orasone®, Cortan®, Sterapred®

Prednisone

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Medical College of Wisconsin: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• National Cancer Institute (NCI): collaborator
• Blood and Marrow Transplant Clinical Trials Network: collaborator
• National Marrow Donor Program: collaborator

Study Sites (21)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

University of Florida College of Medicine (Shands)

Gainesville, Florida, 32610, United States

Location

H. Lee Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Blood & Marrow Transplant Program at Northside Hospital

Atlanta, Georgia, 30342, United States

Location

University of Kansas Hospital

Kansas City, Kansas, 66160, United States

Location

University of Michigan Medical Center

Ann Arbor, Michigan, 48105, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

Location

Washington University/Barnes Jewish Hospital

St Louis, Missouri, 63110, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Ohio State/Arthur G. James Cancer Hospital

Columbus, Ohio, 43210, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

University of Texas/MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Virginia Commonwealth University MCV Hospitals

Richmond, Virginia, 23298, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (3)

• 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.

  PMID: 16338616 BACKGROUND

• 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.

  PMID: 33297779 DERIVED

• 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.

  PMID: 31738834 DERIVED

MeSH Terms

Interventions

Sirolimus; Prednisone

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Adam Mendizabal, PhD
• Organization: The Emmes Corporation

amendizabal@emmes.com

301-251-1161

Study Officials

• Mary Horowitz, MD, MS

  Center for International Blood and Marrow Transplant Research

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 8, 2016
• First Posted: June 21, 2016
• Study Start: October 1, 2016
• Primary Completion: August 17, 2018
• Study Completion: February 19, 2019
• Last Updated: November 1, 2021
• Results First Posted: December 17, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Within 6 months of official study closure at participating sites.
• Access Criteria: Available to the public

Locations

US (21)