Sirolimus/Tacrolimus Versus Tacrolimus/Methotrexate for Preventing Graft-Versus-Host Disease (GVHD) (BMT CTN 0402)

Phase 3

Completed

Conditions: Leukemia, Lymphocytic, Acute
Myelodysplastic Syndromes
Leukemia, Myelocytic, Acute
Leukemia, Myeloid, Chronic

Interventions: Drug: Tacrolimus
Drug: Methotrexate
Drug: Sirolimus

Registration Number: NCT00406393

Lead Sponsor: Medical College of Wisconsin

Brief Summary: The study is designed as a phase III, randomized, open label, multicenter, prospective, comparative trial of sirolimus and tacrolimus versus tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis after human leukocyte antigen (HLA)-matched, related, peripheral blood stem cell transplantation in individuals with hematologic cancer. Participants will be stratified by transplant center and will be randomly assigned to the sirolimus/tacrolimus or tacrolimus/methotrexate arms at a 1:1 ratio.

Detailed Description: BACKGROUND:

Stem cell transplantation is a standard therapy for acute and chronic leukemias and myelodysplastic disorders. A common problem that may occur after a stem cell transplant is a condition known as GVHD. The purpose of this study is to compare two combinations of medications to see which is better at preventing GVHD. The combinations of medications in this study are:

* Sirolimus and tacrolimus

* Methotrexate and tacrolimus

Doctors want to know if one combination is better than the other or if they both have the same result.

DESIGN NARRATIVE:

Participants will receive one of the two conditioning regimens described in the protocol, at the discretion of the transplant physician. The transplant physician must choose among these regimens prior to the participant's assignment to the GVHD prophylaxis treatment. Conditioning regimens will vary by center, but will be the same for all participants at each center. Stem cell donors will donate peripheral blood stem cells according to local institutional practices. Peripheral blood stem cells will not be manipulated or T-depleted prior to administration. Standard post-transplant care will be administered. Participants will be randomly assigned to one of two GVHD prophylaxis regimens and will be followed for the endpoints of interest.

Participants will be followed for 114 days post-randomization for evaluation of the primary endpoint, with additional follow-up for 2 years after transplantation for evaluation of secondary endpoints.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 304

Inclusion Criteria

6/6 HLA-matched sibling, defined by Class I (HLA-A and B) serologic typing (or higher resolution) and Class II (HLA-DRBI) molecular typing, who is willing to donate peripheral blood stem cells, and meets institutional criteria for stem cell donation. The donor must be medically eligible to donate stem cells, according to individual transplant center criteria. Pediatric patients for whom a pediatric sibling donor is not anticipated to be a suitable leukapheresis candidate are not eligible.
Karnofsky performance status of at least 70% or Lansky performance status of at least 70% for participants less than 16 years old
For participants less than 18 years old, willing and able to take oral medications, per the treating physician's recommendations

Exclusion Criteria

Prior allogeneic or autologous transplant using any hematopoietic stem cell source
Seropositive for the human immunodeficiency virus (HIV)
Uncontrolled bacterial, viral, or fungal infection (currently taking medication and progression of clinical symptoms)
Pregnant (positive serum human chorionic gonadotropin [β-HCG] test) or breastfeeding within 4 weeks of study entry
Kidney function: serum creatinine outside the normal range for age, or measured creatinine clearance less than 50 mL/min/1.72m^2 within 4 weeks of study entry
Liver function: most recent direct bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) greater than two times the upper limit of normal within 4 weeks of study entry
Lung disease: in adults, forced vital capacity (FVC) or forced expiratory volume in one second (FEV1) less than 60% of predicted value (corrected for hemoglobin); in children, overt hypoxemia, as measured by an oxygen saturation of less than 92% within 4 weeks of study entry
Cardiac ejection fraction of less than 45% in adults and children, or less than 26% shortening fraction in children within 4 weeks of study entry
Cholesterol level greater than 500 mg/dL or triglyceride level greater than 500 mg/dL while being treated, or not on appropriate lipid-lowering therapy within 4 weeks of study entry
Prior history of allergy to sirolimus
Requires voriconazole at time of study entry
Currently receiving another investigational drug unless cleared by the protocol officer or protocol chair
Participants with a history of cancer, other than resected basal cell carcinoma or treated carcinoma in-situ. Cancer treated with curative intent for more than 5 years previously will be allowed. Cancer treated with curative intent for less than 5 years previously will not be allowed unless approved by the protocol officer or protocol chair.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tacrolimus/Methotrexate	Tacrolimus	Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Tacrolimus/Methotrexate	Methotrexate	Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.
Tacrolimus/Sirolimus	Tacrolimus	Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.
Tacrolimus/Sirolimus	Sirolimus	Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.

Primary Outcome Measures

Name	Time	Method
Rate of Grades II-IV Acute GVHD-free Survival	Day 114	The primary objective is to compare rates of 114-day Grades II-IV acute GVHD-free survival post randomization for HLA-matched, related donor allogeneic peripheral blood stem cell transplantation using two different GVHD prophylaxis regimens. Participants are graded on a scale of 1 to 4 according to their symptoms and organs involved, where 4 represents a worse grade.

Secondary Outcome Measures

Name	Time	Method
Incidence of Acute GVHD	Measured at Day 100	Cumulative incidence of acute GVHD (grade II-IV) occurring 100 days from transplantation.
Time to Neutrophil and Platelet Engraftment	Measured through Day 100	Neutrophil engraftment is defined as achieving an Absolute Neutrophil Count (ANC) \> 500/mcL for three consecutive measurements on different days. Platelet engraftment is defined as a platelet count \> 20,000/mcL for three consecutive measurements over three or more days.
Mucositis Severity	Measured at Day 21	Mucositis severity will be scored per the modified Oral Mucositis Assessment Scale (OMAS) scoring system on a scale of 0 - 4, where 0 equals normal mucosa and 4 represents severe mucosa.
Rate of Veno-occlusive Disease (VOD)	Measured through Day 100	VOD will be defined as the occurrence of VOD (based on the Baltimore Criteria for the diagnosis of VOD) in conjunction with other end-organ dysfunction.
Thrombotic Microangiopathy (TMA) Infection	Measured through Day 100	The occurrence of TMA within the first 100 days after stem cell transplantation will be recorded. The first day of onset will be used for reporting purposes.
Reactivation of Cytomegalovirus (CMV) Infection	Measured at Year 2
Treatment-related Mortality	Measured at Day 100 and Year 2
Malignant Disease Relapse	Measured at Year 2	Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, MDS or CMML consistent with pre-transplant features.
Overall Survival	Measured at Year 2
Infections	Measured at Year 2
Time to Discharge After Transplant	Measured at Year 2

Trial Locations

Locations (24): Stanford Hospital and Clinics
🇺🇸
Stanford, California, United States
Washington University/Barnes Jewish Hospital
🇺🇸
Saint Louis, Missouri, United States
City of Hope National Medical Center
🇺🇸
Duarte, California, United States
Hopital Saint-Louis
🇫🇷
Paris, France
UCSD Medical Center
🇺🇸
La Jolla, California, United States
University of Iowa Hospitals and Clinics
🇺🇸
Iowa City, Iowa, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Emory University
🇺🇸
Atlanta, Georgia, United States
DFCI/Brigham & Women's Hospital
🇺🇸
Boston, Massachusetts, United States
Ohio State, Arthur G. James Cancer Hospital
🇺🇸
Columbus, Ohio, United States
University of Pennsylvania Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
University Hospitals of Cleveland/Case Western
🇺🇸
Cleveland, Ohio, United States
University of Pittsburgh Cancer Institute
🇺🇸
Pittsburgh, Pennsylvania, United States
University of Florida College of Medicine (Shands)
🇺🇸
Gainesville, Florida, United States
Indiana University Medical Center
🇺🇸
Indianapolis, Indiana, United States
University of Michigan Medical Center
🇺🇸
Ann Arbor, Michigan, United States
University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
University of Oklahoma Medical Center
🇺🇸
Oklahoma City, Oklahoma, United States
Oregon Health & Science University
🇺🇸
Portland, Oregon, United States
Texas Transplant Institute
🇺🇸
San Antonio, Texas, United States
Virginia Commonwealth University/MCV Hospital
🇺🇸
Richmond, Virginia, United States
University of Wisconsin Hospital & Clinics
🇺🇸
Madison, Wisconsin, United States