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

NCT ID: NCT00406393

Last Updated: 2023-01-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 304 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-11-30
• Study Completion Date: 2015-10-31

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Tacrolimus/Methotrexate

Patients will be given Tacrolimus and Methotrexate for GVHD prophylaxis.

Group Type: ACTIVE_COMPARATOR

Tacrolimus

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Tacrolimus/Sirolimus

Patients will be given Tacrolimus and Sirolimus for GVHD prophylaxis.

Group Type: EXPERIMENTAL

Tacrolimus

Intervention Type: DRUG

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.

Sirolimus

Intervention Type: DRUG

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.

Interventions

Tacrolimus

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.

Intervention Type: DRUG

Methotrexate

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.

Intervention Type: DRUG

Sirolimus

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.

Intervention Type: DRUG

Other Intervention Names

Prograf®; FK506; MTX; Rapamycin; Rapamune

Eligibility Criteria

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.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Blood and Marrow Transplant Clinical Trials Network

NETWORK

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mary Horowitz, MD

Role: STUDY_DIRECTOR

Center for International Blood and Marrow Transplant Research

Locations

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

Mayo Clinic

Rochester, Minnesota, United States

Washington University/Barnes Jewish Hospital

St Louis, Missouri, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

University Hospitals of Cleveland/Case Western

Cleveland, Ohio, United States

Ohio State, Arthur G. James Cancer Hospital

Columbus, Ohio, United States

University of Oklahoma Medical Center

Oklahoma City, Oklahoma, United States

Oregon Health & Science University

Portland, Oregon, United States

University of Pennsylvania Cancer Center

Philadelphia, Pennsylvania, United States

University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, 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

Hopital Saint-Louis

Paris, , France

Countries

United States; France

References

Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D, Hogan WJ, Pasquini M, MacMillan ML, Hsu JW, Waller EK, Grupp S, McCarthy P, Wu J, Hu ZH, Carter SL, Horowitz MM, Antin JH. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014 Aug 21;124(8):1372-7. doi: 10.1182/blood-2014-04-567164. Epub 2014 Jun 30.

Reference Type: RESULT

PMID: 24982504 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

U01HL069294

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMT CTN 0402

Identifier Type: OTHER

Identifier Source: secondary_id

U01HL069294-05

Identifier Type: NIH

Identifier Source: secondary_id

View Link

BMTCTN0402

Identifier Type: -

Identifier Source: org_study_id