Sirolimus, Tacrolimus, and Methotrexate in Preventing Acute Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplantation

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Completed

Phase 2

Phase 1

Conditions

Graft Versus Host Disease

Multiple Myeloma and Plasma Cell Neoplasm

Chronic Myeloproliferative Disorders

Lymphoma

Leukemia

Myelodysplastic/Myeloproliferative Diseases

Myelodysplastic Syndromes

Treatments

Drug: sirolimus

Drug: methotrexate

Drug: tacrolimus

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00089037

1811.00

CDR0000378004 (Registry Identifier)

FHCRC-1811.00

Details and patient eligibility

About

RATIONALE: Sirolimus, tacrolimus, and methotrexate may be effective in preventing acute graft-versus-host disease in patients who are undergoing donor stem cell transplantation.

PURPOSE: This phase I/II trial is studying the side effects of sirolimus when given together with tacrolimus and methotrexate and to see how well they work in preventing acute graft-versus-host disease in patients who are undergoing donor stem cell transplantation for hematologic cancer.

Full description

OBJECTIVES:

Primary

Determine the safety and efficacy of sirolimus when administered with tacrolimus and methotrexate for the prevention of acute graft-versus-host disease (GVHD) in patients with hematological malignancies undergoing hematopoietic stem cell transplantation from unrelated donors.

Secondary

Determine the absorption and pharmacokinetics of sirolimus in patients treated with this regimen.
Correlate sirolimus blood concentration with prevention of GVHD or toxicity in patients treated with this regimen.
Determine the severity of post-transplantation mucositis in patients treated with this regimen.

OUTLINE: This is a nonrandomized, open-label, pilot study.

Patients receive oral sirolimus once daily on days -3 to 175 and tacrolimus IV continuously beginning on day -3 and continuing until the patient is able to tolerate food and then orally twice daily until day 175. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Treatment continues in the absence of acute graft-vs-host disease or unacceptable toxicity.

Patients are followed for 5 years.

PROJECTED ACCRUAL: A total of 15-30 patients will be accrued for this study within 3 years.

Sex

All

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Diagnosis of hematological malignancy
- No chronic phase chronic myelogenous leukemia, de novo acute leukemia in first remission, or myelodysplastic syndromes with refractory anemia
Scheduled for hematopoietic stem cell transplantation from unrelated donors
Currently receiving conditioning regimen comprising cyclosporine and total body radiotherapy (1,200 to 1,350 cGy) or busulfan and cyclosporine
Donor must be typed to the highest level of resolution
- One single non-serologic disparity for A, B, or C alleles allowed provided the disparity is within the third or fourth digit of the allele
- No mismatch at DRB1 or DQB1

PATIENT CHARACTERISTICS:

Age

Per primary treatment protocol

Performance status

Not specified

Life expectancy

Not specified

Hematopoietic

Not specified

Hepatic

SGOT and SGPT ≤ 2.0 times upper limit of normal
Bilirubin normal
Hepatitis B and C virus negative

Renal

Creatinine clearance ≥ 70 mL/min

Cardiovascular

No cardiac insufficiency requiring treatment
No coronary artery disease

Pulmonary

No acute pulmonary infection by chest x-ray
No severe hypoxemia with pO_2 < 70 mm Hg AND DLCO < 70% of predicted
No mild hypoxemia with pO_2 < 80 mm Hg AND DLCO < 60% of predicted

Other

Not pregnant or nursing
Negative pregnancy test
HIV negative
No active systemic infection
No known hypersensitivity to macrolide antibiotics (e.g., erythromycin, azithromycin, or clarithromycin)
No prior intolerance or unresponsiveness to sirolimus

PRIOR CONCURRENT THERAPY:

Biologic therapy