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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase III Randomized, Multicenter Trial Comparing Sirolimus/Tacrolimus With Tacrolimus/Methotrexate as Graft-versus-Host Disease (GVHD) Prophylaxis After HLA-Matched, Related Peripheral Blood Stem Cell Transplantation (BMT CTN #0402)

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

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Methotrexate
* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tacrolimus/Methotrexate<br>Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis. | Drug: Tacrolimus<br>* 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.<br>* Other names: FK506;Drug: Methotrexate<br>* 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.<br>* Other names: MTX;|
| Experimental: Tacrolimus/Sirolimus<br>Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis. | Drug: Tacrolimus<br>* 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.<br>* Other names: FK506;Drug: Sirolimus<br>* 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.<br>* Other names: Rapamune;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 114 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Acute GVHD | Cumulative incidence of acute GVHD (grade II-IV) occurring 100 days from transplantation. | 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. | 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. | 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. | 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. | Measured through Day 100 | 
| Reactivation of Cytomegalovirus (CMV) Infection |  | Measured at Year 2 | 
| Treatment-related Mortality |  | 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. | Measured at Year 2 | 
| Overall Survival |  | Measured at Year 2 | 
| Infections |  | Measured at Year 2 | 
| Time to Discharge After Transplant |  | Measured at Year 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia