Methotrexate and Glucocorticoids in Treating Patients With Newly Diagnosed Acute Graft-Versus-Host Disease After Donor Stem Cell Transplant

Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00357084
• Other study ID #: 1978.00
• Secondary ID: FHCRC-1978.00CDR
• Status: Completed
• Phase: Phase 2
• First received: July 26, 2006
• Last updated: September 10, 2010
• Start date: May 2006

Study information

• Verified date: September 2010
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 53
• Est. primary completion date: August 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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

Study Design

Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Cancer
• Graft vs Host Disease

Intervention

Drug:
• methotrexate

• methylprednisolone

• prednisone

Locations

Country	Name	City	State
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)			No
Secondary	Proportion of patients in whom methotrexate (MTX) had to be discontinued because of toxicity			Yes
Secondary	Incidence of severe acute GVHD (grades III or IV)			Yes
Secondary	Incidence of extensive chronic GVHD			Yes
Secondary	Incidence of secondary systemic immunosuppressive therapy			Yes
Secondary	Cumulative corticosteroid use over 1 year			No
Secondary	Nonrelapsing mortality at 1 year			Yes
Secondary	Incidence of invasive mold infections			Yes
Secondary	Incidence of recurrent/progressive malignancy			Yes
Secondary	Cumulative dose of methylprednisolone-equivalent treatment during the first 8 weeks after enrollment in patients who survive to day 56			No