Chronic Graft-versus-Host Disease Treatment (BMT CTN 0801)

A Phase II/III Randomized, Multicenter Trial Comparing Sirolimus Plus Prednisone and Sirolimus/Calcineurin Inhibitor Plus Prednisone for the Treatment of Chronic Graft-versus-Host Disease (BMT CTN Protocol #0801)

This study is designed as a combined Phase II/III, randomized, open label, multicenter, prospective comparative study of sirolimus plus prednisone versus sirolimus/calcineurin-inhibitor plus prednisone for the treatment of chronic GVHD. Patients will be stratified by transplant center and will be randomized to an experimental arm of one of the two pre-specified experimental arms (sirolimus + prednisone or the comparator arm of sirolimus + calcineurin inhibitor + prednisone) in a 1:1 ratio.

Study Overview

• Status: Completed
• Conditions: Chronic GVHD
• Intervention / Treatment: Drug: Sirolimus + calcineurin inhibitor + prednisone; Drug: Sirolimus + prednisone

Detailed Description

Background: Chronic GVHD is a medical condition that can become very serious. Chronic GVHD is a common development after allogeneic transplant that occurs when the donor cells attack and damage tissues. The primary purpose of this study is to compare treatment regimens that contain sirolimus without a calcineurin inhibitor to a comparator regimen of sirolimus with a calcineurin inhibitor and evaluate how well chronic GVHD responds to treatment. The combinations of medications in this study are:

• Sirolimus + calcineurin inhibitor + prednisone
• Sirolimus + prednisone

The goal is to select a treatment regimen for further comparison in the Phase III trial.

Design Narrative: The intent is to enroll subjects at the start of initial therapy for chronic GVHD, or before their chronic GVHD is refractory to glucocorticoid therapy, or is chronically dependent upon glucocorticoid therapy and multiple secondary systemic immunosuppressive agents. Patients will be stratified by transplant center and will be randomized to one of two arms.

• Study Type: Interventional
• Enrollment (Actual): 151
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope National Medical Center
    • La Jolla, California, United States, 92093
      • University of California San Diego Medical Center
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
  • Florida
    • Gainesville, Florida, United States, 32610-0277
      • University of Florida College of Medicine (Shands)
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Atlanta, Georgia, United States, 30342
      • Blood & Marrow Transplant Program at Northside Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University Of Kansas Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48105-2967
      • University of Michigan Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University, Barnes Jewish Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198-7680
      • University of Nebraska Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10174
      • Memorial Sloan-Kettering Cancer Center
    • Rochester, New York, United States, 55905
      • Mayo Clinic
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7305
      • University of North Carolina Hospital at Chapel Hill
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • Jewish Hospital BMT Program
    • Cleveland, Ohio, United States, 44106-5061
      • University Hospitals of Cleveland/ Case Western
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health & Science University (A) and (P)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15224
      • Western Pennsylvania Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas/MD Anderson CRC
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/MCV Hospitals
  • Washington
    • Seattle, Washington, United States, 98109-1024
      • Fred Hutchinson Cancer Research Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-5156
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Suitable candidates are patients with classic chronic GVHD or overlap syndrome (classic chronic plus acute GVHD)that is: a)Previously untreated (newly diagnosed) as defined by having received < 14 days of prednisone (or equivalent) before enrollment/randomization to study therapy; b)Previously treated but inadequately responding after ≤ 16 weeks of initial therapy with prednisone and/or calcineurin inhibitor (CNI) ± additional non-sirolimus agent (started at the time of chronic GVHD diagnosis).
• Patient or guardian willing and able to provide informed consent.
• Stated willingness to use contraception in women of childbearing potential.
• Stated willingness of patient to comply with study procedures and reporting requirements.

Exclusion Criteria:

• Patients with late persistent acute GVHD or recurrent acute GVHD only.
• Inability to begin prednisone therapy at a dose of greater than 0.5 mg/kg/day.
• Receiving sirolimus for treatment of chronic GVHD (sirolimus for prophylaxis or treatment of acute GVHD is acceptable).
• Already receiving sirolimus (for prophylaxis or treatment of acute GVHD) with prednisone at ≥ 0.25 mg/kg/day (or equivalent) ± additional agents.
• Receiving therapy for chronic GVHD for more than 16 weeks.
• Invasive fungal or viral infection not responding to appropriate antifungal or antiviral therapies.
• Inadequate renal function defined as measured creatinine clearance less than 50 mL/min/1.73 m^2 based on the Cockcroft-Gault formula (adults) or Schwartz formula (age less than or equal to 12 years). Adults: estimated creatinine clearance rate (eCCr) (mL/min/) = (140 - age) x mass (kg) x (0.85 if female)/72 x serum creatinine (mg/dL; Creatinine clearance (mL/min/1.73m^2) = eCCr x 1.73/Body Surface Area (BSA) (m^2); Children: eCCr (mL/min/1.73 m^2) = k x height (cm) / serum creatinine (mg/dL) k = 0.33 (pre-term), 0.45 (full term to 1 year old), 0.55 (age 1-12 years).
• Inability to tolerate oral medications.
• Absolute neutrophil count less than 1500 per microliter.
• Requirement for platelet transfusions.
• Pregnancy (positive serum β-HCG) or breastfeeding.
• Receiving any treatment for persistent, progressive or recurrent malignancy.
• Progressive or recurrent malignancy defined other than by quantitative molecular assays.
• Known hypersensitivity to sirolimus.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: calcineurin inhibitor; Sirolimus + calcineurin inhibitor + prednisone	Drug: Sirolimus + calcineurin inhibitor + prednisone; The target serum level for sirolimus is 3-12 ng/mL. The target serum level for tacrolimus is 5-10 ng/mL. The target serum level for cyclosporine is 120-200 ng/mL. Prednisone is administered initially as a single early morning dose of 1 mg/kg/day (or equivalent). If prednisone at a dose of 1 mg/kg/day (or equivalent) is contraindicated, patients may begin prednisone between 0.5-1 mg/kg/day.; Other Names: Prograf; Rapamune; Gengraf; Neorall
Experimental: Sirolimus and prednisone; Sirolimus + prednisone	Drug: Sirolimus + prednisone; The target serum level for sirolimus is 3-12 ng/mL. Prednisone is administered initially as a single early morning dose of 1 mg/kg/day (or equivalent). If prednisone at a dose of 1 mg/kg/day (or equivalent) is contraindicated, patients may begin prednisone between 0.5-1 mg/kg/day.; Other Names: Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With Treatment Success	Treatment success was evaluated at 6 months in Phase II and is defined as a complete or partial response without secondary systemic immunosuppressive therapy and no recurrent malignancy or death. In Phase III, treatment success was evaluated at 24 months and is defined as a complete response without secondary systemic immunosuppressive therapy and no recurrent malignancy or death.	6 months and 24 months post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Overall Survival	Overall survival is defined as survival of death from any cause.	6 months and 24 months post-randomization
Percentage of Participants With Progression-free Survival	Progression-free Survival is defined as survival without malignancy relapse. Relapse and death are considered failures for this endpoint.	6 months and 24 months post-randomization
Percentage of Participants With Failure-free Survival	Failure-free Survival is defined as survival without malignancy progression or initiation of secondary therapy for chronic GVHD. Progression, initiation of secondary therapy for chronic GVHD, and death are considered failures for this endpoint.	6 months and 24 months post-randomization
Percentage of Participants With Relapse	Relapse is defined as recurrence of the primary malignancy. Death is considered a competing risk for this endpoint.	6 months and 24 months post-randomization
Percentage of Participants With Secondary Immunosuppressive Therapy Initiated	The percentage of participants initiating secondary immunosuppressive therapy for chronic GVHD is described. Death is considered a competing risk for this endpoint.	6 months and 24 months post-randomization
Percentage of Participants With Discontinuation of Systemic Immunosuppressive Therapy at Two Years	The percentage of participants discontinuing all systemic immunosuppressive therapy by two years post-randomization is described. Death is considered a competing risk for this endpoint.	2 years post-randomization
Prednisone Dose	Daily dose of prednisone is described by treatment arm at baseline, 6 months, and 1 year post-randomization.	Baseline, 6 months, and 1 year post-randomization
Change in Prednisone Dose From Baseline	Change in the daily dose of prednisone from baseline, the time of randomization, is described by treatment arm at 6 months and 1 year post-randomization.	6 months and 1 year post-randomization
Serum Creatinine Level	Creatinine level is described by treatment arm at baseline, 6 months, and 1 year post-randomization.	Baseline, 6 months, and 1 year post-randomization
Change in Serum Creatinine Level From Baseline	Change in creatinine level from baseline, the time of randomization, is described by treatment arm at 6 months and 1 year post-randomization.	6 months and 1 year post-randomization
Patient-reported Chronic GVHD Severity	Each patient's perception of the severity of the chronic GVHD was collected at baseline and at 6 months, 1 year, and 2 years post-randomization. Severity is categorized as none, mild, moderate, and severe.	Baseline, 6 months, 1 year, and 2 years post-randomization
Provider-reported Chronic GVHD Severity	Each patient's care provider's perception of the severity of the chronic GVHD was collected at baseline and at 6 months, 1 year, and 2 years post-randomization. Severity is categorized as none, mild, moderate, and severe.	Baseline, 6 months, 1 year, and 2 years post-randomization
NIH Consensus Criteria Chronic GVHD Severity	Chronic GVHD severity was determined at baseline and at 6 months, 1 year, and 2 years post-randomization per the 2005 NIH Consensus Criteria (Filipovich et al. 2005). Severity is categorized as none, mild, moderate, and severe.	Baseline, 6 months, 1 year, and 2 years post-randomization
SF-36 Physical Component Summary	The Medical Outcome Study SF-36 Physical Component Summary (PCS) is a subscale of the SF-36 intended to measure physical well-being. It is scored on a scale of 0-100, with higher scores indicating higher levels of well-being.	Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization
SF-36 Mental Component Summary	The Medical Outcome Study SF-36 Mental Component Summary (MCS) is a subscale of the SF-36 intended to measure mental well-being. It is scored on a scale of 0-100, with higher scores indicating higher levels of well-being.	Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization
FACT-BMT Score	The Functional Assessment of Cancer Therapy-Bone Marrow Transplant scale (FACT-BMT) is a quality of life instrument that assesses the effects of bone marrow transplantation (BMT) on a patient's physical, social/family, emotional, and functional well-being while taking into consideration BMT-specific concerns. The assessment has 37 questions, each scored on a Likert scale from 0-4. The overall score is computed by adding scores of the questions and falls in the range 0-148, with higher scores indicating higher levels of overall well-being.	Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization

Collaborators and Investigators

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

Publications and helpful links

General 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.
• Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolanos-Meade J, Sarantopoulos S, Alousi AM, Abhyankar S, Waller EK, Mendizabal A, Zhu J, O'Brien KA, Lazaryan A, Wu J, Nemecek ER, Pavletic SZ, Cutler CS, Horowitz MM, Arora M; BMT CTN.. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica. 2018 Nov;103(11):1915-1924. doi: 10.3324/haematol.2018.195123. Epub 2018 Jun 28.

Helpful Links

• National Marrow Donor Program
• BMT CTN Website

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2010
• Primary Completion (Actual): February 14, 2017
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: April 16, 2010
• First Submitted That Met QC Criteria: April 16, 2010
• First Posted (Estimate): April 20, 2010

Study Record Updates

• Last Update Posted (Actual): December 5, 2018
• Last Update Submitted That Met QC Criteria: November 13, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: Chronic Graft-versus-Host Disease (cGVHD)
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Prednisone; Sirolimus; Calcineurin Inhibitors
• Other Study ID Numbers: BMTCTN0801; U01HL069294 (U.S. NIH Grant/Contract); 5U24CA076518 (U.S. NIH Grant/Contract); U01HL06929406 (Other Grant/Funding Number: National Cancer Institute (NCI)); BMT CTN 0801 (Other Identifier: Blood and Marrow Transplant Clinical Trials Network)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Findings will be published in a manuscript
• IPD Sharing Time Frame: Within 6 months of official study closure at participating sites.
• IPD Sharing Access Criteria: Available to the public