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

Primary Purpose

Graft Versus Host Disease, Systemic Scleroderma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
imatinib mesylate
rituximab
Sponsored by
Lee, Stephanie
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft Versus Host Disease focused on measuring Imatinib, Rituximab, Chronic Graft-vs-Host Disease

Eligibility Criteria

2 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis within the past 18 months of cutaneous sclerosis after hematopoietic cell transplant (HCT) with sclerotic skin, morphea, myofascial involvement or joint contractures; must have a score of 2 or greater on the Vienna skin scale in any area, or a range-of-motion (ROM) score of 5 or less at the shoulder, elbow or wrist, or 3 or less at the ankle
  • No medication added for the treatment of graft versus host disease (GVHD) within the past 4 weeks
  • Receiving corticosteroids at a dose greater than required for treatment of adrenal insufficiency, unless the physician documents why steroids are contraindicated
  • Age 2-99 years
  • Karnofsky performance status >= 60% at enrollment
  • All females of childbearing potential must have a negative serum or urine pregnancy test =< 7 days prior to starting study therapy
  • All females of childbearing potential must agree to use a form of Food and Drug Administration (FDA) approved contraception from enrollment to one month after study treatment ends
  • Subject has the ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

  • Total bilirubin > 1.5x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN
  • Renal insufficiency (serum creatinine > 2.0 mg/dl)
  • Platelets < 30,000/ul or absolute neutrophil count < 1500/ul
  • Known hypersensitivity to rituximab or other anti-B cell antibodies
  • Known imatinib intolerance or allergy
  • Evidence of any active viral, bacterial, or fungal infection that is progressive despite appropriate treatment
  • Hepatitis B surface antigen positive
  • Hepatitis B core antibody positive, unless hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is undetectable
  • Hepatitis C antibody positive, unless hepatitis C virus (HCV) ribonucleic acid (RNA) is undetectable
  • Pregnant, lactating, or planning a pregnancy while in the study
  • Distal leg skin score 3 or higher as the only manifestation of sclerosis
  • Prior treatment of chronic GVHD with imatinib, rituximab, or any other monoclonal B-cell antibody (e.g. ofatumumab)
  • Receipt of imatinib within the previous 6 months for any indication
  • Receipt of any monoclonal B-cell antibody (e.g. rituximab, ofatumumab) within the previous 12 months for any indication
  • Treatment with anti-B-cell cellular therapy (e.g. chimeric antigen-receptor-engineered cells) at any time after transplant
  • Current treatment with extracorporeal photopheresis (ECP) at the time of enrollment
  • History of psychiatric disorder that would interfere with normal participation in this study
  • Inability or unwillingness of subject and/or parent guardian to provide informed consent or comply with study protocol
  • Use of non-FDA approved drugs within 4 weeks of participation
  • Patient with any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with the study requirements
  • Patients with uncontrolled substance abuse

Sites / Locations

  • Mayo Clinic in Arizona
  • Stanford University Hospitals and Clinics
  • H. Lee Moffitt Cancer Center and Research Institute
  • Washington University School of Medicine
  • Roswell Park Cancer Institute
  • Weill Cornell Medical College
  • University of North Carolina
  • Vanderbilt-Ingram Cancer Center
  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • Froedtert and the Medical College of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I (enzyme inhibitor)

Arm II (monoclonal antibody)

Arm Description

Patients receive imatinib mesylate PO QD for 6 months in the absence of progression of sclerosis or unacceptable toxicity.

Patients receive rituximab IV on days 1, 8, 15, and 22. A second treatment cycle is repeated at 3 months for a total of 8 doses of rituximab in the absence of progression of sclerosis or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Significant Clinical Response
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.

Secondary Outcome Measures

Patients Who Were Able to Taper Corticosteroids
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
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
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
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
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
%CD27+ B cells

Full Information

First Posted
March 1, 2011
Last Updated
May 10, 2016
Sponsor
Lee, Stephanie
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01309997
Brief Title
Imatinib and Rituximab in Treating Cutaneous Sclerosis in Patients With Chronic Graft-Versus-Host Disease
Official Title
A Randomized Phase II Study of Imatinib and Rituximab for Cutaneous Sclerosis After Allogeneic Hematopoietic Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
March 2011 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Lee, Stephanie
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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 Description
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 clinical response will continue to receive study drug for an additional 6 months. ARM II: Patients receive rituximab intravenously (IV) on days 1, 8, 15, and 22 (first cycle). A second cycle of treatment with rituximab is repeated at 3 months for a total of 8 doses of rituximab in the absence of progression of sclerosis or unacceptable toxicity. Patients with progression, treatment intolerance at any time up to 6 months, or no clinical response at 6 months will crossover to the other treatment arm.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Versus Host Disease, Systemic Scleroderma
Keywords
Imatinib, Rituximab, Chronic Graft-vs-Host Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
72 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (enzyme inhibitor)
Arm Type
Experimental
Arm Description
Patients receive imatinib mesylate PO QD for 6 months in the absence of progression of sclerosis or unacceptable toxicity.
Arm Title
Arm II (monoclonal antibody)
Arm Type
Experimental
Arm Description
Patients receive rituximab IV on days 1, 8, 15, and 22. A second treatment cycle is repeated at 3 months for a total of 8 doses of rituximab in the absence of progression of sclerosis or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
imatinib mesylate
Other Intervention Name(s)
CGP 57148, Gleevec, Glivec
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
rituximab
Other Intervention Name(s)
IDEC-C2B8, IDEC-C2B8 monoclonal antibody, Mabthera, MOAB IDEC-C2B8, Rituxan
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Significant Clinical Response
Description
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.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Patients Who Were Able to Taper Corticosteroids
Description
Patients who achieved a greater than or equal to 50% reduction in the daily corticosteroid dose at 6mo compared to baseline
Time Frame
6 months
Title
Cumulative Incidence of Treatment Failure
Description
Defined as discontinuation of randomized treatment due to chronic GVHD progression or treatment intolerance or no significant clinical response in sclerosis.
Time Frame
6 months
Title
Number of Patients Achieving Improvement in Cutaneous Sclerosis
Description
Assessed by decrease of >= 0.2 units (where 0 is best and 3.0 is worst ) in the Scleroderma Health Assessment Questionnaire (SHAQ).
Time Frame
6 months
Title
Baseline Histopathologic Score in the Two Treatment Arms
Description
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.
Time Frame
Enrollment
Title
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
Description
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.
Time Frame
6 months
Title
Percentage of CD27+ B Cells in Responders (SCR) and Non-responders
Description
%CD27+ B cells
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis within the past 18 months of cutaneous sclerosis after hematopoietic cell transplant (HCT) with sclerotic skin, morphea, myofascial involvement or joint contractures; must have a score of 2 or greater on the Vienna skin scale in any area, or a range-of-motion (ROM) score of 5 or less at the shoulder, elbow or wrist, or 3 or less at the ankle No medication added for the treatment of graft versus host disease (GVHD) within the past 4 weeks Receiving corticosteroids at a dose greater than required for treatment of adrenal insufficiency, unless the physician documents why steroids are contraindicated Age 2-99 years Karnofsky performance status >= 60% at enrollment All females of childbearing potential must have a negative serum or urine pregnancy test =< 7 days prior to starting study therapy All females of childbearing potential must agree to use a form of Food and Drug Administration (FDA) approved contraception from enrollment to one month after study treatment ends Subject has the ability to understand and willingness to sign a written informed consent document Exclusion Criteria: Total bilirubin > 1.5x upper limit of normal (ULN) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN Renal insufficiency (serum creatinine > 2.0 mg/dl) Platelets < 30,000/ul or absolute neutrophil count < 1500/ul Known hypersensitivity to rituximab or other anti-B cell antibodies Known imatinib intolerance or allergy Evidence of any active viral, bacterial, or fungal infection that is progressive despite appropriate treatment Hepatitis B surface antigen positive Hepatitis B core antibody positive, unless hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is undetectable Hepatitis C antibody positive, unless hepatitis C virus (HCV) ribonucleic acid (RNA) is undetectable Pregnant, lactating, or planning a pregnancy while in the study Distal leg skin score 3 or higher as the only manifestation of sclerosis Prior treatment of chronic GVHD with imatinib, rituximab, or any other monoclonal B-cell antibody (e.g. ofatumumab) Receipt of imatinib within the previous 6 months for any indication Receipt of any monoclonal B-cell antibody (e.g. rituximab, ofatumumab) within the previous 12 months for any indication Treatment with anti-B-cell cellular therapy (e.g. chimeric antigen-receptor-engineered cells) at any time after transplant Current treatment with extracorporeal photopheresis (ECP) at the time of enrollment History of psychiatric disorder that would interfere with normal participation in this study Inability or unwillingness of subject and/or parent guardian to provide informed consent or comply with study protocol Use of non-FDA approved drugs within 4 weeks of participation Patient with any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with the study requirements Patients with uncontrolled substance abuse
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephanie Lee
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
Stanford University Hospitals and Clinics
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
H. Lee Moffitt Cancer Center and Research Institute
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
Weill Cornell Medical College
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
University of North Carolina
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Vanderbilt-Ingram Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Froedtert and the Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
De-identified patient data and samples may be available with the appropriate approvals. Contact the PI for information.
Citations:
PubMed Identifier
26378033
Citation
Arai S, Pidala J, Pusic I, Chai X, Jaglowski S, Khera N, Palmer J, Chen GL, Jagasia MH, Mayer SA, Wood WA, Green M, Hyun TS, Inamoto Y, Storer BE, Miklos DB, Shulman HM, Martin PJ, Sarantopoulos S, Lee SJ, Flowers ME. A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation. Clin Cancer Res. 2016 Jan 15;22(2):319-27. doi: 10.1158/1078-0432.CCR-15-1443. Epub 2015 Sep 16.
Results Reference
result

Learn more about this trial

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

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