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

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ClinicalTrials.gov Identifier: NCT02806947
Recruitment Status : Active, not recruiting
First Posted : June 21, 2016
Last Update Posted : March 21, 2018
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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 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
Estimated Primary Completion Date : February 2019
Estimated Study Completion Date : February 2020


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. Complete Response (CR) or Partial Response (PR) [ Time Frame: Day 28 ]
    Scoring of CR/PR is in comparison to the participant's acute GVHD status (score) on the day of randomization. CR is defined as a score of 0 for the GVHD grading in all evaluable organs. Partial response (PR) is defined as improvement in one or more organs involved with GVHD symptoms without progression in others.


Secondary Outcome Measures :
  1. CR/PR and Steroid Dose less than 0.25 mg/kg per day [ Time Frame: Day 28 ]
    The proportion of patients with an acute GVHD response on Day 28 (CR or PR) and on a prednisone (or prednisone dose-equivalent corticosteroid) dose of 0.25 mg/kg per day or less.

  2. Proportion of Response [ Time Frame: Days 14, 28 and 56 ]
    Proportions of CR, PR, Mixed Response (MR), No Response (NR) and progression among surviving patients. MR is defined as improvement in one or more organs with deterioration in another organ manifesting symptoms of GVHD or development of symptoms of GVHD in a new organ. No response is defined as absence of any improvement or progression.

  3. Treatment Failure [ Time Frame: Days 14, 28, and 56 ]
    Treatment failure is defined as either death, no response, progression, or administration of additional therapy beyond primary therapy for GVHD.

  4. Incidence of Chronic GVHD [ Time Frame: 6 and 12 Months ]
    Chronic GVHD is defined per NIH Consensus Criteria. The incidence of chronic GVHD will be computed for each treatment arm, including organ involvement and severity, and overall global composite score (mild/moderate/severe).

  5. Incidence of Systemic Infections [ Time Frame: 6 Months ]
    All microbiologically documented infections or significant infections requiring antibiotic/antifungal therapy occurring after initiation of therapy will be reported by site of disease, date of onset, and severity.

  6. Disease-Free Survival (DFS) [ Time Frame: 6 and 12 Months ]
    The events for DFS are death and relapse of the underlying malignancy.

  7. Non-Relapse Mortality [ Time Frame: 6 and 12 Months ]
    The events for non-relapse mortality are death due to any cause other than relapse of the underlying malignancy. Cumulative incidence of non-relapse mortality will be estimated (treating relapse as a competing risk) and curves will be compared using Gray's test.

  8. GVHD-free Survival [ Time Frame: 6 and 12 Months ]
    Both acute and chronic GVHD will be considered in this estimate.

  9. Event Free Survival [ Time Frame: 6 and 12 Months ]
    Event-free survival is defined as freedom from acute GVHD progression, chronic GVHD, malignancy relapse and mortality.

  10. Overall Survival (OS) [ Time Frame: 6 and 12 Months ]
    OS is defined as alive at study endpoint



Information from the National Library of Medicine

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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


  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
Study Director: Mary Horowitz, MD, MS Center for International Blood and Marrow Transplant Research

Additional Information:
Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT02806947     History of Changes
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
Last Update Posted: March 21, 2018
Last Verified: March 2018
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:
Prednisone
Sirolimus
Everolimus
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