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”

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.

Study Type: Interventional

Study Design: Treatment, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Study Primary Completion Date: October 2010

Intervention(s) in this Clinical Trial

• 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.
• 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.
• 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.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • sirolimus, tacrolimus and short course methotrexate

Primary Measures

• Safety/Efficacy of a novel regimen of sirolimus, tacrolimus and methotrexate
  • Time Frame: Upon completion of study
    Safety Issue?: Yes

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 16 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Yale University

Overall Clinical Trial Officials and Contacts

Stuart Seropian, M.D. Principal Investigator Yale University  

Overall Contact: Jeannie Kluytenaar, RN 203-785-4903 jeannie.kluytenaar@yale.edu

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00612274

Study ID Number: 0703002455

ClinicalTrials.gov Identifier: NCT00612274

Health Authority: United States: Institutional Review Board