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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02806947
Recruitment Status : Completed
First Posted : June 21, 2016
Results First Posted : December 17, 2019
Last Update Posted : December 30, 2019
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Marrow Donor Program
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Acute GVHD Drug: Sirolimus Drug: Prednisone Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 127 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 2016
Actual Primary Completion Date : August 17, 2018
Actual Study Completion Date : February 19, 2019


Arm Intervention/treatment
Experimental: Sirolimus
Sirolimus, a steroid-free therapy, will be administered after a diagnosis of standard-risk aGVHD is clinically established.
Drug: 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.
Other Names:
  • Rapamycin
  • Rapamune®

Active Comparator: Prednisone
Prednisone, standard of care therapy for GVHD, will be administered after a diagnosis of standard-risk aGVHD is clinically established.
Drug: Prednisone
Prednisone will be administered at 2mg/kg/day x 3 days, and then tapered according to individual treating clinician judgment.
Other Names:
  • Deltasone®
  • Orasone®
  • Cortan®
  • Sterapred®




Primary Outcome Measures :
  1. Percentage of Participants With Complete or Partial Response (CR/PR) to Acute GVHD Treatment [ Time Frame: 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 :
  1. Percentage of Participants With Complete or Partial Response (CR/PR) and Steroid Dose Less Than 0.25 mg/kg Per Day [ Time Frame: 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

  2. Acute GVHD Response [ Time Frame: 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

  3. Percentage of Participants With Treatment Failure [ Time Frame: 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

  4. Percentage of Participants With Overall Survival [ Time Frame: 6 and 12 Months Post-randomization ]
    Overall survival is defined as survival of death from any cause.

  5. Percentage of Participants With Disease-free Survival [ Time Frame: 6 and 12 Months Post-randomization ]
    Disease-free survival is defined as freedom from death and relapse of the underlying malignancy.

  6. Proportion of Participants With Event-free Survival [ Time Frame: 6 and 12 Months Post-randomization ]
    Event-free survival is defined as freedom from acute GVHD progression, chronic GVHD, malignancy relapse, and death.

  7. Percentage of Participants With Non-relapse Mortality [ Time Frame: 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.

  8. Percentage of Participants With Malignancy Relapse [ Time Frame: 6 and 12 Months Post-randomization ]
    The cumulative incidence of relapse of the primary malignancy is described, with death treated as a competing risk.

  9. Percentage of Participants With Chronic GVHD [ Time Frame: 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.

  10. Percentage of Participants With GVHD-free Survival [ Time Frame: 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.

  11. Percentage of Participants With Serious Infections [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02806947


Locations
Show Show 21 study locations
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Marrow Donor Program
Investigators
Layout table for investigator information
Study Director: Mary Horowitz, MD, MS Center for International Blood and Marrow Transplant Research
  Study Documents (Full-Text)

Documents provided by Medical College of Wisconsin:
Study Protocol  [PDF] July 7, 2017
Statistical Analysis Plan  [PDF] June 7, 2018


Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT02806947    
Other Study ID Numbers: BMTCTN1501
2U10HL069294-11 ( U.S. NIH Grant/Contract )
5U24CA076518 ( U.S. NIH Grant/Contract )
First Posted: June 21, 2016    Key Record Dates
Results First Posted: December 17, 2019
Last Update Posted: December 30, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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).
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public
URL: https://biolincc.nhlbi.nih.gov/home/
Keywords provided by Medical College of Wisconsin:
Acute GVHD
Standard-Risk
Sirolimus
Refined Minnesota Risk Criteria
Ann Arbor
Biomarker
Steroid-Free
Additional relevant MeSH terms:
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Sirolimus
Prednisone
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors