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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
304
Adults and Children: Tacrolimus will be given at a dose of 0.02 mg/kg every 24 hours as a continuous intravenous infusion beginning on Day -3. An effort will be made to convert the tacrolimus to oral dosing at 2-3 times the total 24-hour intravenous dose, split into 2 doses given every 12 hours as soon as clinically feasible. The target serum level for tacrolimus is 5-10 ng/mL.
Methotrexate will be given at a dose of 15 mg/m2 on Day 1 after transplantation, and at a dose of 10 mg/m2 on Days 3, 6 and 11 after transplantation.
Adults: Sirolimus will be given in a loading dose of 12 mg on Day -3 followed by a daily oral dose of 4 mg per day. Doses may be repeated if the subject vomits within 15 minutes of an oral dose. Children: Children aged \< 12.0 years OR weighing \< 40.0 kg will be given an oral loading dose of sirolimus of 3 mg/m2 followed by a daily oral dose of 1 mg/m2, rounded to the nearest full milligram. The target serum level for sirolimus is 3-12 ng/mL.
City of Hope National Medical Center
Duarte, California, United States
UCSD Medical Center
La Jolla, California, United States
Stanford Hospital and Clinics
Stanford, California, United States
University of Florida College of Medicine (Shands)
Gainesville, Florida, United States
Emory University
Atlanta, Georgia, United States
Indiana University Medical Center
Indianapolis, Indiana, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States
DFCI/Brigham & Women's Hospital
Boston, Massachusetts, United States
University of Michigan Medical Center
Ann Arbor, Michigan, United States
University of Minnesota
Minneapolis, Minnesota, United States
...and 14 more locations
Rate of Grades II-IV Acute GVHD-free Survival
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.
Time frame: Day 114
Incidence of Acute GVHD
Cumulative incidence of acute GVHD (grade II-IV) occurring 100 days from transplantation.
Time frame: Measured at Day 100
Time to Neutrophil and Platelet Engraftment
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.
Time frame: Measured through Day 100
Mucositis Severity
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.
Time frame: Measured at Day 21
Rate of Veno-occlusive Disease (VOD)
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.
Time frame: Measured through Day 100
Thrombotic Microangiopathy (TMA) Infection
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.
Time frame: Measured through Day 100
Reactivation of Cytomegalovirus (CMV) Infection
Time frame: Measured at Year 2
Treatment-related Mortality
Time frame: Measured at Day 100 and Year 2
Malignant Disease Relapse
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.
Time frame: Measured at Year 2
Overall Survival
Time frame: Measured at Year 2
Infections
Time frame: Measured at Year 2
Time to Discharge After Transplant
Time frame: Measured at Year 2
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