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Acute GVHDPhase 2NCT02806947

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

A Phase 2 study testing Sirolimus and Prednisone in people with Acute GVHD, run by Medical College of Wisconsin at 21 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Any age
Conditions the study is for
Acute GVHD
What is being tested?
Sirolimus and Prednisone
Could I receive a placebo?
No, everyone receives an active treatment
How many people
127 participants
Where
21 sitesUnited States
Study dates
Oct 2016to 19 Feb 2019
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Any age
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

21 sites in 1 country.

21 sites in 1 country

United States21 sites

  • University of Michigan Medical Center

    Ann Arbor, Michigan, 48105

  • Children's Healthcare of Atlanta

    Atlanta, Georgia, 30322

  • Emory University

    Atlanta, Georgia, 30322

  • Blood & Marrow Transplant Program at Northside Hospital

    Atlanta, Georgia, 30342

  • Cleveland Clinic Foundation

    Cleveland, Ohio, 44195

  • Ohio State/Arthur G. James Cancer Hospital

    Columbus, Ohio, 43210

  • City of Hope National Medical Center

    Duarte, California, 91010

  • Duke University Medical Center

    Durham, North Carolina, 27705

  • University of Florida College of Medicine (Shands)

    Gainesville, Florida, 32610

  • University of Texas/MD Anderson Cancer Center

    Houston, Texas, 77030

  • University of Kansas Hospital

    Kansas City, Kansas, 66160

  • Children's Hospital Los Angeles

    Los Angeles, California, 90027

  • Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • University of Minnesota

    Minneapolis, Minnesota, 55455

  • Vanderbilt University Medical Center

    Nashville, Tennessee, 37232

  • Icahn School of Medicine at Mount Sinai

    New York, New York, 10029

  • Virginia Commonwealth University MCV Hospitals

    Richmond, Virginia, 23298

  • Mayo Clinic Rochester

    Rochester, Minnesota, 55905

  • Fred Hutchinson Cancer Research Center

    Seattle, Washington, 98109

  • Washington University/Barnes Jewish Hospital

    St Louis, Missouri, 63110

  • H. Lee Moffitt Cancer Center

    Tampa, Florida, 33612

Other trials in United States

About this study

Official title: 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)

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.

Read the 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
Being tested
Sirolimus, Prednisone
Keywords
Acute GVHD, Standard-Risk, Sirolimus, Refined Minnesota Risk Criteria, Ann Arbor, Biomarker, Steroid-Free

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SirolimusDrug

    Also called Rapamycin, Rapamune®

    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.

  • PrednisoneDrug

    Also called Deltasone®, Orasone®, Cortan®, Sterapred®

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

Study groups in NCT02806947
Study groupRoleWhat they receive
SirolimusExperimentalSirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established.
Receives: Drug: Sirolimus
PrednisoneActive comparatorPrednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established.
Receives: Drug: Prednisone

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: Days 28 and 56 Post-randomization

Secondary outcomes (11)

  1. 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

    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

    Measured: Day 28 Post-randomization

  2. 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

    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

    Measured: Days 28 and 56 Post-randomization

  3. 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

    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

    Measured: Days 28 and 56 Post-randomization

  4. Percentage of Participants With Overall Survival

    Overall survival is defined as survival of death from any cause.

    Measured: 6 and 12 Months Post-randomization

  5. Percentage of Participants With Disease-free Survival

    Disease-free survival is defined as freedom from death and relapse of the underlying malignancy.

    Measured: 6 and 12 Months Post-randomization

  6. Proportion of Participants With Event-free Survival

    Event-free survival is defined as freedom from acute GVHD progression, chronic GVHD, malignancy relapse, and death.

    Measured: 6 and 12 Months Post-randomization

  7. 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.

    Measured: 6 and 12 Months Post-randomization

  8. Percentage of Participants With Malignancy Relapse

    The cumulative incidence of relapse of the primary malignancy is described, with death treated as a competing risk.

    Measured: 6 and 12 Months Post-randomization

  9. 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.

    Measured: 6 and 12 Months Post-randomization

  10. 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.

    Measured: 6 and 12 Months Post-randomization

  11. 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.

    Measured: 6 and 12 Months Post-randomization

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jun 2016 (estimated)
  2. Study startOct 2016
  3. Primary completion17 Aug 2018
  4. Study completion19 Feb 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
127 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02806947
Sponsor's protocol ID
BMT CTN 1501
Other IDs
2U10HL069294-11, 5U24CA076518
Status last verified
Jun 2019
First submitted
8 Jun 2016
Last updated
1 Nov 2021
Data monitoring committee
Yes
Individual data sharing
Yes: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).

Publications

  • 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.

    PubMed 16338616

  • 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.

    PubMed 33297779

  • 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.

    PubMed 31738834

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Sirolimus and Prednisone in people with Acute GVHD, run by Medical College of Wisconsin at 21 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 21 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Dec 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment (time frame: Days 28 and 56 Post-randomization). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02806947, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Nov 2021.

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