Clinical trial NCT00089037: Sirolimus, Tacrolimus, and Methotrexate in Preventing Acute Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplantation
Official title: A Phase I/II Study of Sirolimus in Addition to Tacrolimus and Methotrexate for the Prevention of Acute-Graft-Versus-Host Disease in Patients Undergoing Hematopoietic Stem Cell Transplantation From Unrelated Donors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Chronic Myeloproliferative Disorders
Graft Versus Host Disease
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Keywords: graft versus host disease
accelerated phase chronic myelogenous leukemia
atypical chronic myeloid leukemia
blastic phase chronic myelogenous leukemia
chronic eosinophilic leukemia
chronic idiopathic myelofibrosis
chronic myelomonocytic leukemia
chronic neutrophilic leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
previously treated myelodysplastic syndromes
recurrent adult acute lymphoblastic leukemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
de novo myelodysplastic syndromes
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
childhood acute lymphoblastic leukemia in remission
childhood acute myeloid leukemia in remission
recurrent adult acute myeloid leukemia
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult Hodgkin lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent mycosis fungoides/Sezary syndrome
recurrent small lymphocytic lymphoma
refractory chronic lymphocytic leukemia
refractory hairy cell leukemia
refractory multiple myeloma
relapsing chronic myelogenous leukemia
secondary acute myeloid leukemia
secondary myelodysplastic syndromes
noncontiguous stage II adult Burkitt lymphoma
stage III adult Burkitt lymphoma
stage IV adult Burkitt lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II grade 1 follicular lymphoma
noncontiguous stage II grade 2 follicular lymphoma
noncontiguous stage II grade 3 follicular lymphoma
noncontiguous stage II mantle cell lymphoma
noncontiguous stage II marginal zone lymphoma
noncontiguous stage II small lymphocytic lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
stage III small lymphocytic lymphoma
stage IV small lymphocytic lymphoma
stage III marginal zone lymphoma
stage IV marginal zone lymphoma
childhood chronic myelogenous leukemia
recurrent childhood acute lymphoblastic leukemia
recurrent childhood acute myeloid leukemia
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
untreated childhood acute lymphoblastic leukemia
untreated childhood acute myeloid leukemia and other myeloid malignancies
recurrent/refractory childhood Hodgkin lymphoma
juvenile myelomonocytic leukemia
splenic marginal zone lymphoma
untreated adult acute lymphoblastic leukemia
untreated adult acute myeloid leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
refractory cytopenia with multilineage dysplasia
recurrent cutaneous T-cell non-Hodgkin lymphoma
recurrent marginal zone lymphoma
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-08-05
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

Detailed 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.

Eligibility 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

* See Disease Characteristics
* No concurrent T-cell depleted transplantations

Chemotherapy

* See Disease Characteristics

Endocrine therapy

* Not specified

Radiotherapy

* See Disease Characteristics

Surgery

* Not specified

Other

* No concurrent grapefruit juice
* No concurrent voriconazole

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Center
name: Hans-Peter Kiem, MD
role: PRINCIPAL_INVESTIGATOR
References: