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Sirolimus, Tacrolimus and Short Course Methotrexate for Prevention of Acute GVHD in Recipients of Mismatched Unrelated Donor Allogeneic Stem Cell Transplantation

This study has been completed.
Information provided by (Responsible Party):
Yale University Identifier:
First received: January 29, 2008
Last updated: November 29, 2016
Last verified: November 2016
The primary objective of this trial is to study the safety and efficacy of a novel regimen of sirolimus, tacrolimus and methotrexate as prophylaxis against acute graft versus host disease (GVHD) in recipients of mismatched unrelated donor stem cell grafts. Methotrexate is administered in a low dose format of 5mg/m2 on days +1,3 and 6 only.

Condition Intervention Phase
Stem Cell Transplantation
Drug: tacrolimus
Drug: Sirolimus
Drug: Methotrexate
Early Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot Study of Sirolimus, Tacrolimus and Short Course Methotrexate for Prevention of Acute Graft Versus Host Disease in Recipients of Mismatched Unrelated Donor Allogeneic Stem Cell Transplantation

Resource links provided by NLM:

Further study details as provided by Yale University:

Primary Outcome Measures:
  • Safety/Efficacy of a novel regimen of sirolimus, tacrolimus and methotrexate [ Time Frame: Upon completion of study ]

Enrollment: 26
Study Start Date: October 2007
Study Completion Date: October 2014
Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
sirolimus, tacrolimus and short course methotrexate
Drug: tacrolimus
Tacrolimus will be administered at a dose of .02mg/kg/d IVCI beginning day -3 until able to take oral medicines reliably. Blood levels will be maintained at 5-10 ng/ml. The oral dose will be 4 times the IV dose. Tacrolimus will be converted to oral dosing prior to hospital discharge. Tacrolimus will be continued until 4 months post transplant (day +120) unless toxicity, refractory GVHD or the development of disease recurrence mandate discontinuation of the drug.
Other Names:
  • FK506
  • Prograf(TM)
Drug: Sirolimus
Sirolimus will be administered as a 12 mg oral loading dose on day -3 followed by 4mg daily. Sirolimus levels will be obtained on day +0 and then at least twice weekly to maintain a trough serum level of 3-12 ng/ml. Sirolimus will be continued until 5 months post transplant (day +150) unless toxicity, refractory GVHD or the development of disease recurrence mandate discontinuation of the drug.
Other Name: Rapamune
Drug: Methotrexate
Methotrexate, dose #1 will be administered on day +1 post transplantation, as an IV bolus, provided at least 24 hours have elapsed following infusion of donor stem cells at a dose of 10mg/m2. Dose #2 of Methotrexate will be administered 48 hours later, as IV bolus on day +3 at a dose of 5mg/m2.


Ages Eligible for Study:   16 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must have an identified 8/10 or 9/10 matched unrelated donor identified following a formal search with confirmatory typing through the national marrow donor program as the best available donor. No matched sibling or fully matched unrelated donor has been identified. HLA typing of donor and recipient will be performed by high resolution molecular typing at HLA A, B, C and DRB1/DQ loci. Patients whose best available donor is matched at 8/10 loci must have at least one of the mismatches at the DQ locus. (no more than one mismatch at HLA A,B,C,DR allowed).
  • Candidates for this trial will meet the following criteria:

    1. Adequate organ function for conditioning type:

      For patients receiving ablative conditioning

      • Left Ventricular ejection fraction >45%
      • DLCO >50%
      • Creatinine <1.5
      • Hepatic enzymes <3x upper limit of normal.
      • KPS >70%

      For patients receiving non-ablative conditioning:

      • KPS >70%
    2. Patients with the following diseases will be considered eligible:

      • AML in first remission with high risk features (poor risk cytogenetic abnormalities9, persistent elevated blast count on day +15 or recovery marrow after induction therapy).
      • AML beyond first remission
      • ALL in first remission with high risk features (ph+, t4:11)
      • ALL beyond first remission
      • High risk Myelodysplasia (RAEB-II, RAEB-I with poor-risk cytogenetics)
      • Recurrent Aggressive Non-Hodgkins or Hodgkins lymphoma (indolent histologies excluded) who have failed autologous transplant or have had inadequate response to salvage therapy.
      • CML with transformation
      • CLL with transformation or Fludarabine failure.
      • Severe aplastic anemia with recurrence or failure after immunosuppressive therapy.

Exclusion Criteria:

  • Prior allogeneic transplantation
  • Active CNS leukemia.
  • Female patients who are pregnant or breast feeding
  • Karnofsky performance status <70%.
  • Active viral, bacterial or fungal infection.
  • Patients seropositive for HIV -1,2; HTLV -1,2 (due to the additional immunodeficiency induced by transplantation and immunosuppressive therapy) Requirement for antifungal prophylaxis with Voriconazole for the first 30 days is prohibited.
  • Patients not providing informed consent.
  Contacts and Locations
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Please refer to this study by its identifier: NCT00612274

United States, Connecticut
Yale University School of Medicine
New Haven, Connecticut, United States, 06520
Sponsors and Collaborators
Yale University
Principal Investigator: Stuart Seropian, M.D. Yale University
  More Information

Responsible Party: Yale University Identifier: NCT00612274     History of Changes
Other Study ID Numbers: 0703002455
Study First Received: January 29, 2008
Last Updated: November 29, 2016

Keywords provided by Yale University:

Additional relevant MeSH terms:
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antineoplastic Agents
Dermatologic Agents
Folic Acid Antagonists
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents processed this record on May 25, 2017