Clinical trial NCT00357084: Methotrexate and Glucocorticoids in Treating Patients With Newly Diagnosed Acute Graft-Versus-Host Disease After Donor Stem Cell Transplant
Official title: A Phase II Study to Evaluate Efficacy and Tolerability of Methotrexate in Combination With Glucocorticoids for the Treatment of Newly Diagnosed Acute Graft-Versus-Host Disease After Nonmyeloablative Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cancer
Keywords: graft versus host disease
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
accelerated phase chronic myelogenous leukemia
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
atypical chronic myeloid leukemia
blastic phase chronic myelogenous leukemia
childhood acute lymphoblastic leukemia in remission
childhood acute myeloid leukemia in remission
childhood chronic myelogenous leukemia
chronic eosinophilic leukemia
chronic idiopathic myelofibrosis
chronic myelomonocytic leukemia
chronic neutrophilic leukemia
chronic phase chronic myelogenous leukemia
de novo myelodysplastic syndromes
disseminated neuroblastoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
juvenile myelomonocytic leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
nodal marginal zone B-cell lymphoma
noncontiguous stage II 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
poor prognosis metastatic gestational trophoblastic tumor
previously treated childhood rhabdomyosarcoma
previously treated myelodysplastic syndromes
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
recurrent adult Burkitt lymphoma
recurrent adult Hodgkin lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent/refractory childhood Hodgkin lymphoma
recurrent childhood acute lymphoblastic leukemia
recurrent childhood acute myeloid leukemia
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood rhabdomyosarcoma
recurrent childhood small noncleaved cell lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent mycosis fungoides/Sezary syndrome
recurrent small lymphocytic lymphoma
recurrent Wilms tumor and other childhood kidney tumors
refractory chronic lymphocytic leukemia
refractory hairy cell leukemia
refractory multiple myeloma
relapsing chronic myelogenous leukemia
secondary acute myeloid leukemia
secondary myelodysplastic syndromes
splenic marginal zone lymphoma
stage I multiple myeloma
stage II multiple myeloma
stage II ovarian epithelial cancer
stage III adult Burkitt lymphoma
stage III adult Hodgkin lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III chronic lymphocytic leukemia
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III multiple myeloma
stage III small lymphocytic lymphoma
stage III malignant testicular germ cell tumor
stage IV adult Burkitt lymphoma
stage IV adult Hodgkin lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV chronic lymphocytic leukemia
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
Waldenstrom macroglobulinemia
childhood myelodysplastic syndromes
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-07-27
Enrollment: 53
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: SUPPORTIVE_CARE

Brief summary: RATIONALE: Methotrexate and glucocorticoid therapy, such as prednisone or methylprednisolone, may be an effective treatment for acute graft-versus-host disease caused by a donor stem cell transplant.

PURPOSE: This phase II trial is studying how well giving methotrexate together with glucocorticoids works in treating patients with newly diagnosed acute graft-versus-host disease after donor stem cell transplant.

Detailed description: OBJECTIVES:

* Determine, within the limits of a phase II study, whether low-dose methotrexate can accelerate withdrawal of glucocorticoids and decrease nonrelapsing mortality in patients with newly diagnosed acute graft-versus-host disease (GVHD) who have undergone nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT).
* Determine the tolerability of low-dose methotrexate and glucocorticoids in treating newly diagnosed acute GVHD in these patients.

OUTLINE: This is a cohort study. Patients receive concurrent low-dose methotrexate and a glucocorticoid for treatment of acute graft-versus-host disease (GVHD).

Patients receive the first dose of methotrexate IV ≥ 12 hours before initiation of glucocorticoid treatment (if glucocorticoid treatment has not been initiated) and the second dose 72 hours after dose 1. Patients then receive subsequent doses of methotrexate IV or orally once weekly for up to 1 year\* until resolution of GVHD in the absence of recurrent malignancy, refractory or chronic GVHD, administration of secondary treatment for GVHD, or unacceptable toxicity.

NOTE: \*Treatment with low-dose MTX may continue beyond 1 year at the discretion of the managing physician.

Patients receive glucocorticoid therapy comprising prednisone or methylprednisolone IV twice daily until objective evidence of improvement in GVHD manifestation. Patients with resolved or significantly improved GVHD receive treatment for 10 days followed by an accelerated taper for a total of 72 days of treatment in case of no flare up of GVHD during the glucocorticoid taper. Patients with exacerbation or recurrence of GVHD during the accelerated taper are treated for ≥ 1 week before resuming a less rapid taper. Patients who develop GVHD progression or primary refractory GVHD may receive secondary systemic therapy at the discretion of the managing physician.

After completion of study treatment, patients are followed at 1 year and then annually thereafter.

PROJECTED ACCRUAL: A total of 53 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Newly diagnosed acute graft-versus-host disease (GVHD)
* Has undergone nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-matched related or unrelated donor ≥ 14 days ago
* Treatment of GVHD with glucocorticoids indicated by 1 of the following criteria:

  * Initial treatment with prednisone or methylprednisolone at 2 mg/kg indicated (in the judgement of attending physician) by any of the following:

    * Severity of GVHD requires hospitalization
    * GVHD manifestations include symptoms other than anorexia, nausea, and vomiting
    * GVHD begins within 2-3 weeks after HSCT
    * GVHD manifestations progress rapidly from 1 day to the next before treatment
  * Initial treatment with prednisone or methylprednisolone at 1 mg/kg did not produce adequate clinical improvement within the first 4 days (in the judgement of attending physician)
* No pleural effusion or ascites (i.e., free-flowing fluid by lateral decubitus views)

  * Mere blunting of costo-phrenic angles on a posterior anterior chest x-ray is not sufficient
* No GVHD after donor lymphocyte infusion
* No hallmarks of chronic GVHD
* No bronchiolitis obliterans

PATIENT CHARACTERISTICS:

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 12 months after completion of study treatment
* No severe mucositis (grade 3 or 4) indicated by erythema, edema, or ulcerations requiring hydration, parenteral nutritional support, or intubation or resulting in aspiration pneumonia
* Absolute neutrophil count ≥ 1,500/mm\^3
* Bilirubin ≤ 2 times upper limit of normal (ULN) (unless abnormality attributable to GVHD)
* AST and ALT ≤ 2 times ULN (unless abnormality attributable to GVHD)
* Creatinine clearance ≥ 50 mL/min

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No prior prednisone or methylprednisolone at 2 mg/kg for \> 72 hours or at 1 mg/kg for \> 96 hours
* Concurrent topical therapy, including psoralen and ultraviolet A irradiation (PUVA), glucocorticoid creams, oral beclomethasone dipropionate, topical azathioprine, or ophthalmic glucocorticoids allowed
* No other concurrent treatment for GVHD

Primary outcomes:
measure: Proportion of patients treated with a methylprednisolone-equivalent glucocorticoid dose ≤ 0.75 mg/kg on day 28 after initiation of systemic glucocorticoid therapy for acute graft-versus-host disease (GVHD)
Secondary outcomes:
measure: Proportion of patients in whom methotrexate (MTX) had to be discontinued because of toxicity
measure: Incidence of severe acute GVHD (grades III or IV)
measure: Incidence of extensive chronic GVHD
measure: Incidence of secondary systemic immunosuppressive therapy
measure: Cumulative corticosteroid use over 1 year
measure: Nonrelapsing mortality at 1 year
measure: Incidence of invasive mold infections
measure: Incidence of recurrent/progressive malignancy
measure: Cumulative dose of methylprednisolone-equivalent treatment during the first 8 weeks after enrollment in patients who survive to day 56
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Center
name: Marco B. Mielcarek, MD
role: STUDY_CHAIR
References: