Clinical Trial: Sirolimus/Tacrolimus Combination After HLA Matched Related Peripheral Blood Stem Cell Transplants

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Multicenter Trials to Evaluate the Efficacy and Toxicity of Sirolimus/Tacrolimus Combination as a GVHD Prophylaxis After HLA Matched Related PBSCT

Brief Summary:

Study Design: To evaluate the efficacy of the combination of sirolimus and tacrolimus as a graft-versus-host disease prophylaxis, the investigators are going to perform a phase II, multicenter clinical trial after human leukocyte antigen (HLA)-matched, related peripheral blood stem cell transplants (PBSCT) in patients with hematologic malignancies. Total 116 patients will be accrued.

Objective: The primary objective is to evaluate the rates of 100 day Grade II-IV acute GVHD. Secondary objectives include the time to neutrophil and platelet engraftment, the incidence of grade III-IV acute GVHD, non-relapse mortality during 100 days after transplant, mucositis severity, all infectious complications including cytomegalovirus (CMV) reactivation, vascular complications (venoocclusive disease of liver; VOD, thrombotic microangiopathy; TMA), disease-free survival, and overall survival at 1 year after transplant.

Eligibility Criteria: Eligible patients are between 20 and 60 years of age, have acute leukemia, myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and adequate organ function. For available sibling donor, a serologic (or higher resolution) 6/6 Class I HLA-A and B and molecular Class II DRB1 must be matched.

Treatment Description: Conditioning regimens will vary by center and donor will donate peripheral blood stem cells according to local institutional practices. Peripheral blood stem cells will not be manipulated or T-depleted prior to infusion. Tacrolimus will be administered at 0.05 mg/kg/day intravenously by continuous infusion beginning on day -1 with a target serum concentration of 5 to 10 ng/mL. Sirolimus will be administered as a 6 mg oral loading dose on day -1, followed by a 3 mg/day single dose, with a target serum concentration of 3 to 12 ng/mL

Detailed Summary:

Rationale: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic HSCT. The combination of a calcineurin inhibitor and methotrexate has been the standard GVHD prophylactic regimen for the past 20 years. However, the incidence of acute GVHD remains high, with reported cumulative incidence of grade II-IV up to 60%. Serious acute GVHD or chronic GVHD has detrimental consequences in patients including death, disability, infections, or prolonged hospitalization.

Sirolimus is the first available inhibitor of the mammalian target of rapamycin (mTOR). And sirolimus binds uniquely to FK-binding protein (FKBP12) and forms a complex with mTOR. This complex inhibits several biochemical pathways, resulting in a reduction in DNA transcription, DNA translation, protein synthesis, and cell cycling, ultimately leading to T-cell immunosuppression. Sirolimus has been used alone and in combination with calcineurin inhibitors for prevention of allograft rejection after solid organ transplantation. In the field of hematopoietic stem cell transplantation, the combination of sirolimus and tacrolimus has also resulted in a low incidence of acute GVHD and reduced transplant-related toxicity.

In addition, the investigators demonstrated previously that the combination of tacrolimus and sirolimus is effective as a GVHD prophylaxis and well tolerated in cases of high risk transplantation using mismatched related or unrelated donor.

As discussed above, sirolimus has emerged as one of the most promising immunosuppressive agents in allogeneic hematopoietic stem cell transplantation. However, the benefit of GVHD prophylaxis regimens including sirolimus has not been confirmed consistently and there is controversy that the incorporation of sirolimus into GVHD prophy
Sponsor: The Korean Society of Blood and Marrow Transplantation

Current Primary Outcome: The rate of grade II-IV acute graft-versus host disease [ Time Frame: 100 days after allogeneic HSCT ]

Patients will be followed for 100 days post transplantation for evaluation of the primary endpoint (the incidence and severity of acute GVHD) and clinical data will be collected at 100 day after HSCT using case report form. Acute GVHD will be graded according to the consensus grading scale.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • The time to neutrophil and platelet engraftment [ Time Frame: within 6 weeks after transplant ]
    The time of engraftment is defined as the first of three consecutive days on which the absolute neutrophil counts exceed 0.5 X 10(9)/L and platelet count to 20 X 10(9)/L, respectively.
  • The incidence of grade III-IV acute GVHD [ Time Frame: During 100 days after transplant ]
    Acute GVHD will be graded according to the consensus grading scale.
  • Non-relapse mortality [ Time Frame: During 100 days after transplant ]
    All deaths without relapse or progression of underlying disease
  • Mucositis severity [ Time Frame: 100 days after transplant ]
    It will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE v3.0).
  • All infectious complications including CMV reactivation [ Time Frame: 100 days after transplant ]
    The incidence and type of infectious complications
  • Vascular complications [ Time Frame: 100 days after transplant ]
    The incidence of venoocclusive disease of liver and syndrome of thrombotic microangiopathy.
  • Clinical outcome at 1 year after transplant [ Time Frame: 1 year after transplant ]
    Disease-free survival and overall survival at 1 year after transplant


Original Secondary Outcome: Same as current

Information By: The Korean Society of Blood and Marrow Transplantation

Dates:
Date Received: November 20, 2011
Date Started: January 2012
Date Completion:
Last Updated: March 31, 2015
Last Verified: March 2015