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Home > Studies > Blood and Marrow Clinical Trials Network (BMT CTN) A Phase III Randomized, Multicenter Trial Comparing Sirolimus/Tacrolimus With Tacrolimus/Methotrexate as Graft-versus-Host Disease Prophylaxis After HLA-Matched, Related Peripheral Blood Stem Cell Transplantation (0402)

Blood and Marrow Clinical Trials Network (BMT CTN) A Phase III Randomized, Multicenter Trial Comparing Sirolimus/Tacrolimus With Tacrolimus/Methotrexate as Graft-versus-Host Disease Prophylaxis After HLA-Matched, Related Peripheral Blood Stem Cell Transplantation (0402)

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Accession Number
HLB01411620a

Study Type
Clinical Trial

Collection Type
Open BioLINCC Study See bottom of this webpage for request information

Study Period
November 2006 - October 2015

NHLBI Division
DBDR

Dataset(s) Last Updated
December 17, 2020

Study Website
https://web.emmes.com/study/bmt2/protocol/0402_protocol/0402_protocol.html

Clinical Trial URLs
https://clinicaltrials.gov/ct2/show/NCT00406393

Primary Publication URLs
https://www.ncbi.nlm.nih.gov/pubmed/24982504

Consent

Commercial Use Data Restrictions No

Data Restrictions Based On Area Of Research No

Commercial Use Specimen Restrictions No

Non-Genetic Use Specimen Restrictions Based On Area Of Use No

Genetic Use Of Specimens Allowed? Yes

Genetic Use Area Of Research Restrictions No

Specific Consent Restrictions
None.

Objectives

The primary objective was to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute graft-versus-host disease and early mortality after allogeneic related donor hematopoietic cell transplantation.

Background

Stem cell transplantation is a standard therapy for leukemia and myelodysplastic disorders. Recipients of human leukocyte antigen (HLA)-matched, related donor (MRD) stem cell transplants are at risk for a number of infections and complications. One of these complications is a condition known as acute graft-versus-host disease (GVHD). Recipients of HLA-MRD stem cell transplants for the treatment of myelodysplastic disorders and leukemia experience a 35% incidence of GVHD. Furthermore, GVHD contributes significantly to 1-year early treatment-related mortality (TRM) estimates of approximately 20%.

The standard prophylaxis regimen for GVHD is a calcineurin inhibitor combined with methotrexate. Calcineurin inhibitors block calcineurin, a protein phosphatase that catalyzes some of the intracellular processes associated with T-lymphocyte activation. Inhibition is achieved by binding to immunophilins. The result is reduced production of interleukin-2 and reduced proliferation of T-cells. Methotrexate, an antineoplastic antimetabolite, has immunosuppressant properties that prevents the synthesis of tetrahydrofolate. Tetrahydrofolate is necessary for synthesis of thymidylate, an essential component of DNA. Of particular clinical concern is the theory that the injury caused by methotrexate to tissues could play a contributory role in initiation of the cytokine cascade associated with GVHD.

The standard prophylaxis regimen for GVHD was established in the mid-1980s. Minor alterations to the standard regimen have shown limited effect on TRM outcomes in spite of the improvements that have been made to allogeneic hematopoietic cell transplantation (HCT) outcomes. Sirolimus, a rapamycin inhibitor, has been suggested as an alternative for methotrexate. Previous studies have suggested that sirolimus use results in decreased incidence of acute GVHD and treatment-related toxicity after HLA-MRD and unrelated donor transplantation, at the expense of higher rates of endothelial injury syndromes. Sirolimus has additional immunomodulatory properties that include effects on antigen-presenting cells, the thymus, and preservation of regulatory T-cell subsets after transplantation. The purpose of this study was to determine if sirolimus, in place of methotrexate, would produce improved outcomes in GVHD and TRM.

Subjects

Eligible participants were 2 to 60 years of age, of either gender, and were undergoing transplantation for one of the following conditions: acute leukemia in remission, myelodysplastic disorder, or chronic myeloid leukemia in chronic or accelerated phase. All participants were required to have a 6/6 Class I HLA-A and B and molecular Class II DRB1 matched sibling donor medically able and willing to donate peripheral blood stem cells that also met institutional criteria for stem cell donation.

Participants were excluded from participating in the trial for the following: prior allogenic or autologous transplant, HIV or another uncontrolled active infection, pregnant or breast-feeding, known allergy to sirolimus, requiring voriconazole at time of study entry, currently receiving another investigational drug (unless cleared by protocol officer or chair), or participants with a history of cancer.

Participants were excluded from continuation for the following laboratory criteria if measured within 4 weeks of study entry: measured creatinine clearance <50mL/min/1.72m2 ; direct bilirubin, ALT, or AST greater than two times the upper limit of normal; cholesterol or triglycerides level >500mg/dL; forced vital capacity (FVC) or forced expiratory volume (FEV1) <60% predicted value, corrected for Hemoglobin (adults only); overt hypoxemia in children measured by <92% SaO2; cardiac ejection fraction >45% in adults or <26% children.

A total of 304 participants were enrolled in the study. 151 participants were randomized to the tacrolimus/sirolimus (Tac/Sir) treatment, which 149 completed and 2 did not undergo transplantation. 153 participants were randomized to the tacrolimus/methotrexate (Tac/Mtx) treatment, which 152 completed and 1 did not undergo transplantation.

Design

BMT 0402 was an interventional study with the purpose of determining the best combination of medications for the prevention of GVHD after HLA-MRD peripheral blood stem cell transplantation. Two GVHD prophylaxis conditioning regimens were tested: tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/Mtx). The study was Phase III, and designed to be multicenter, randomized, open label, and with parallel assignment treatment arms. Randomization occurred within 7 days of initiation of pretransplantation conditioning therapy, and was performed in a 1:1 ratio with the use of random block sites, stratified by transplantation center. The transplant physician selection of treatment occurred prior to participant’s assignment to the study. All parties involved in the trial knew the treatment arm assigned to each participant.

Participants received pretransplantation myeloablative conditioning with total body irradiation in combination with either cyclophosphamide or etoposide. Initially, a conditioning regimen comprised of myeloablative doses of busulfan with CY was permitted, however this was removed due to excess toxicity and veno-occulusive disease of the liver. The participants that received busulfan-based conditioning were not included in the primary outcome analyses. PBSC donors received filgrastim and underwent large volume apheresis with a goal of collecting 2 to 10 × 106/kg CD34+ stem cells. No graft manipulation was allowed prior to the infusion of the stem-cell product.

For GVHD prophylaxis, tacrolimus was begun on day −3 for all participants at a dose of 0.02 mg/kg/day by continuous IV infusion, adjusted to maintain a serum concentration of 5 to 10 ng/mL. For participants in the Tac/Sir group, sirolimus was started on day −3 with a 12 mg oral loading dose, followed by daily oral doses of 4 mg, adjusted to maintain a serum trough concentration of 3 to 12 ng/mL. For participants in the Tac/Mtx group, methotrexate was IV administered on day +1 (15 mg/m2), +3, +6, and +11 (10 mg/m2 each day).

The primary endpoint of grades II-IV acute GVHD-free survival was assessed 114 days from the time of randomization based on intention-to-treat. The study had 80% power to detect a 15% difference between the 2 prophylaxis strategies based on the standardized difference in Kaplan-Meier estimates with a 2-sided α of 5%. A committee of investigators blinded to GVHD prophylaxis assignment reviewed all case records, focusing on the incidence of acute and chronic GVHD, relapse, toxicity, and causes of death. Participants were followed for two years after transplantation for evaluation of secondary endpoints, which included cumulative incidence of acute GVHD, time to neutrophil and platelet engraftment, mucositis severity, rate of veno-occlusive disease, thrombotic microangiopathy infection, cytomegalovirus reactivation, treatment-related mortality, malignant disease relapse, all infections, overall survival, and time to discharge after transplant.

Conclusions

Participants who received Tac/Sir engrafted significantly earlier and had significantly less severe oropharyngeal mucositis after transplantation; however, no difference was observed in the primary end point of GVHD-free survival at 114 days post randomization between participants treated with Tac/Sir and Tac/Mtx.

Blood. 2014 Aug 21; 124(8): 1372–1377.

Additional Details

Study Population

Subjects:

Total of 304 subjects:
151 in the Sirolimus/Tacrolimus arm
153 in the Tacrolimus/Methotrexate arm

Age:
  Sirolimus/Tacrolimus Tacrolimus/Methotrexate All
N % N % N %
10 - <15 0 0 1 0.65 1 0.33
15 - <20 4 2.65 3 1.96 7 2.30
20 - <25 4 2.65 6 3.92 10 3.29
25 - <30 12 7.95 19 12.42 31 10.20
30 - <35 13 8.61 12 7.84 25 8.22
35 - <40 15 9.93 19 12.42 34 11.18
40 - <45 28 18.54 25 16.34 53 17.43
45 - <50 40 26.49 29 18.95 69 22.70
50 - <55 25 16.56 24 15.69 49 16.12
55 - <60 10 6.62 15 9.80 25 8.22

 
Sex:
  Sirolimus/Tacrolimus Tacrolimus/Methotrexate All
N % N % N %
Male 77 50.99 85 55.56 162 53.29
Female 74 49.01 68 44.44 142 46.71

 
Race:
  Sirolimus/Tacrolimus Tacrolimus/Methotrexate All
N % N % N %
White 133 88.08 130 84.97 263 86.51
Black 7 4.64 6 3.92 13 4.28
Asian 5 3.31 5 3.27 10 3.29
Other or Unknown 3 1.99 9 5.88 12 3.95
Not Answered 3 1.99 3 1.96 6 1.97

Available Biospecimens

Please note that biospecimen availability is subject to review by the NHLBI, BioLINCC, and the NHLBI Biorepository. Certain biospecimens may not be made available for your request. Section 3 of the BioLINCC handbook describes the components of the review process

Material Types:

Plasma, Serum, White blood cells

Visits (Vials):

10/26/2018

  Serum Plasma White Blood Cells Total
Day 0 2,132 744 0 2,876
Day 28 1,978 501 0 2,479
Day 100 1,750 435 0 2,185
Day 180 1,558 843 0 2,401
Day 270 87 54 0 141
Day 365 1,234 646 0 1,880
Day 730 868 593 0 1,461
Donor 282 938 919 2,139

 
Visits (Subjects):
10/26/2018
 
  Serum
Total number of subjects Average volume (ml) per subject
Day 0 243 4.63
Day 28 233 4.77
Day 100 213 4.78
Day 180 184 4.77
Day 270 9 4.71
Day 365 151 4.49
Day 730 99 4.66
Donor 30 4.44
 
  Plasma
Total number of subjects Average volume (ml) per subject
Day 0 230 1.98
Day 28 206 1.50
Day 100 185 1.54
Day 180 183 2.71
Day 270 9 3.35
Day 365 150 2.64
Day 730 99 3.55
Donor 175 2.76
 
  White Blood Cells
Total number of subjects Average vials per subject
Donor 145 6.34

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Resources Available

Specimens and Study Datasets

Study Catalog

Study Publications (0)

Materials Available

  • Plasma
  • Serum
  • WBC Pellets
  • More Details

Study Documents

  • PDF Data Dictionary (PDF - 659.3 KB)
  • PDF Case Report Forms (PDF - 886.3 KB)
  • PDF Documentation for Outcomes Dataset (PDF - 723.4 KB)
  • PDF Lab Sample Information (PDF - 296.8 KB)
  • PDF Protocol (PDF - 1.3 MB)

Persons using assistive technology may not be able to fully access information in the study documents. For assistance, Contact BioLINCC and include the web address and/or publication title in your message. If you need help accessing information in different file formats such as PDF, XLS, DOC, see Instructions for Downloading Viewers and Players.

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