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

NCT ID: NCT00612274

Last Updated: 2016-11-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-10-31
• Study Completion Date: 2014-10-31

Brief Summary

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.

Conditions

Stem Cell Transplantation

Keywords

allogeneic

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

sirolimus, tacrolimus and short course methotrexate

Group Type: EXPERIMENTAL

tacrolimus

Intervention Type: DRUG

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.

Sirolimus

Intervention Type: DRUG

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.

Methotrexate

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

FK506; Prograf(TM); Rapamune

Eligibility Criteria

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.

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Yale University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stuart Seropian, M.D.

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

Yale University School of Medicine

New Haven, Connecticut, United States

Countries

United States

Other Identifiers

0703002455

Identifier Type: -

Identifier Source: org_study_id