Clinical Trial: Imatinib and Rituximab in Treating Cutaneous Sclerosis in Patients With Chronic Graft-Versus-Host Disease

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Randomized Phase II Study of Imatinib and Rituximab for Cutaneous Sclerosis After Allogeneic Hematopoietic Cell Transplantation

Brief Summary: This randomized phase II trial is evaluating how well imatinib mesylate works compared to rituximab in treating cutaneous sclerosis in patients with chronic graft- versus-host disease (GVHD). Both imatinib and rituximab have been reported to decrease skin thickening and improve skin and joint flexibility in people with cutaneous sclerosis due to chronic GVHD.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To determine the best clinical response rate of cutaneous sclerosis (skin and/or fascial thickening) after 6 months of initial therapy with either imatinib (imatinib mesylate) or rituximab.

SECONDARY OBJECTIVES:

I. To determine the best response at either the 3 or 6 month assessment.

II. To determine the response rate at the 3 month assessment.

III. To determine the proportion of subjects who are able to taper corticosteroid after 6 months of imatinib or rituximab therapy.

IV. To determine the incidence of treatment failure to initial treatment with either imatinib or rituximab.

V. To evaluate if the Scleroderma Health Assessment Questionnaire (SHAQ) findings correlate with severity of cutaneous sclerosis clinical findings and response to study treatment.

VI. To correlate the detection of antibody against platelet derived growth factor receptor alpha (PDGFR A) with clinical response.

VII. To correlate change in B cell relevant parameters from baseline to 6 months or early crossover (antibody levels, skin collagen expression, B cell subsets) with therapeutic agent and best clinical response while on initial treatment.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive imatinib mesylate by mouth (PO) once daily (QD) for 6 months in the absence of progression of sclerosis or unacceptable toxicity. Subjects with a significant clini
Sponsor: Lee, Stephanie

Current Primary Outcome: Significant Clinical Response [ Time Frame: 6 months ]

Assessed by decline in an affected area's skin score as measured with the Vienna Skin Scale (from 4 [worst] to 2, 3 to 1, or 2 to 0 [best]) without a concurrent increase of two or more points in another area OR by an increase in the range of motion of the shoulders, elbows or wrists by two points (in a 1-7 scale where 1 is worst and 7 is best) or of the ankles by one point (in a 1 to 4 scale where 1 is worst and 4 is best) without a concurrent worsening in another area.


Original Primary Outcome: Significant clinical response in sclerosis [ Time Frame: At 6 months after enrollment and treatment with one of the two agents ]

  1. decline in the skin score from baseline, measured by the Vienna Skin Scale, from 4 to 2, 3 to 1 OR 2 to 0, in any affected area, without an increase by two or more points in other areas compared to baseline.

    OR

  2. increase in the range of motion by two points in a 1-7 (1 = poor and 7= full mobility) scale for the shoulders, elbows or wrists or by one point in a 1 to 4 scale (ankles) from baseline without worsening in any area (2 points for shoulders, elbows or wrists; 1 point for ankles) (photos diagram detailed in the protocol).


Current Secondary Outcome:

  • Patients Who Were Able to Taper Corticosteroids [ Time Frame: 6 months ]
    Patients who achieved a greater than or equal to 50% reduction in the daily corticosteroid dose at 6mo compared to baseline
  • Cumulative Incidence of Treatment Failure [ Time Frame: 6 months ]
    Defined as discontinuation of randomized treatment due to chronic GVHD progression or treatment intolerance or no significant clinical response in sclerosis.
  • Number of Patients Achieving Improvement in Cutaneous Sclerosis [ Time Frame: 6 months ]
    Assessed by decrease of >= 0.2 units (where 0 is best and 3.0 is worst ) in the Scleroderma Health Assessment Questionnaire (SHAQ).
  • Baseline Histopathologic Score in the Two Treatment Arms [ Time Frame: Enrollment ]

    Instrument: Nash dermal fibrosis grade. Measures extent of sclerosis in skin biopsies by histologic examination. Scale ranges from grade 0-5. Nash grade 5 is most severe fibrosis (0 is better outcome, 5 is worse outcome). No subscales are used in Nash grade. Please see table 1 in the reference for grading of dermal fibrosis.

    Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood 2007;110:1388-96.

  • Patients With Any Percentage Decline in Any Grade of Sclerosis Without Increase in Percentage of Higher Grades of Sclerosis in Other Areas on the Vienna Skin Scale [ Time Frame: 6 months ]
    Maximum of 10 body areas. Each area can be graded 0 (best) to 4 (worst). Each of those grades requires a percentage of involvement. Improvement is measured by reduction of involvement in any grade and any body area.
  • Percentage of CD27+ B Cells in Responders (SCR) and Non-responders [ Time Frame: 6 months ]
    %CD27+ B cells


Original Secondary Outcome:

  • Decrease in the daily corticosteroid dose [ Time Frame: After 6 months ]
    Corticosteroid dose <= 50% from the baseline dose
  • Cumulative Incidence of Treatment Failure [ Time Frame: 6 months ]
    1. Discontinuation of randomized treatment due to chronic GVHD progression or treatment intolerance within 6 months after enrollment, OR
    2. less than a significant clinical response in sclerosis (as defined above) at 6 months compared to baseline
  • Improvement in scleroderma by patient-self assessment [ Time Frame: 6 months ]
    Decrease in the SHAQ score by >= 0.2 units
  • Changes in biomarker profiles between the two arms of the study, and between responders and non-responders [ Time Frame: 6 months ]
    PDGF antibodies and B cell markers (blood and skin) and collagen expression and phospho-protein immunohistochemistry and gene profiling for PDGFR in the skin will be evaluated.


Information By: Fred Hutchinson Cancer Research Center

Dates:
Date Received: March 1, 2011
Date Started: March 2011
Date Completion:
Last Updated: May 10, 2016
Last Verified: May 2016