Graft Versus Host Disease, Systemic Scleroderma
Conditions
Keywords
Imatinib, Rituximab, Chronic Graft-vs-Host Disease
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.
Interventions
DRUGimatinib mesylate
Given PO
BIOLOGICALrituximab
Given IV
Sponsors
National Cancer Institute (NCI)
Lee, Stephanie
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Significant Clinical Response | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Treatment Failure | 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 | 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). |
| Patients Who Were Able to Taper Corticosteroids | 6 months | Patients who achieved a greater than or equal to 50% reduction in the daily corticosteroid dose at 6mo compared to baseline |
| 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 | 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 | 6 months | %CD27+ B cells |
| Baseline Histopathologic Score in the Two Treatment Arms | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Enzyme Inhibitor) Patients receive imatinib mesylate PO QD for 6 months in the absence of progression of sclerosis or unacceptable toxicity. During the 6mo study treatment period, if drug intolerance or disease progression is observed, they are crossed over to rituximab. | 35 |
| Arm II (Monoclonal Antibody) 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. TDuring the 6mo study treatment period, if drug intolerance or disease progression is observed, they are crossed over to imatinib. | 37 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 1 | 3 |
| Overall Study | Lack of Efficacy | 2 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Arm I (Enzyme Inhibitor) | Arm II (Monoclonal Antibody) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 7 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 31 Participants | 30 Participants | 61 Participants |
| Sex: Female, Male Female | 18 Participants | 22 Participants | 40 Participants |
| Sex: Female, Male Male | 17 Participants | 15 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 35 | 12 / 37 | 21 / 23 | 1 / 19 |
| serious Total, serious adverse events | 11 / 35 | 19 / 37 | 19 / 23 | 15 / 19 |
Outcome results
Primary
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.
Time frame: 6 months
Population: Patients were not eligible for evaluation if they discontinued participation or had missing 6 mo data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Enzyme Inhibitor) | Significant Clinical Response | 9 participants |
| Arm II (Monoclonal Antibody) | Significant Clinical Response | 10 participants |
Secondary
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.
Time frame: Enrollment
Population: Only patients with skin biopsies at enrollment are included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Enzyme Inhibitor) | Baseline Histopathologic Score in the Two Treatment Arms | 2 units on a scale |
| Arm II (Monoclonal Antibody) | Baseline Histopathologic Score in the Two Treatment Arms | 2 units on a scale |
Secondary
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.
Time frame: 6 months
Population: Only patients who were evaluable for SCR are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Enzyme Inhibitor) | Cumulative Incidence of Treatment Failure | 24 participants |
| Arm II (Monoclonal Antibody) | Cumulative Incidence of Treatment Failure | 26 participants |
Secondary
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).
Time frame: 6 months
Population: Only patients evaluable at 6 mo are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Enzyme Inhibitor) | Number of Patients Achieving Improvement in Cutaneous Sclerosis | 2 participants |
| Arm II (Monoclonal Antibody) | Number of Patients Achieving Improvement in Cutaneous Sclerosis | 9 participants |
Secondary
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
Time frame: 6 months
Population: Patients with no corticosteroid dose data missing from baseline or 6mo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Enzyme Inhibitor) | Patients Who Were Able to Taper Corticosteroids | 7 participants |
| Arm II (Monoclonal Antibody) | Patients Who Were Able to Taper Corticosteroids | 9 participants |
Secondary
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.
Time frame: 6 months
Population: Only patients who were evaluable at 6mo are included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Enzyme Inhibitor) | 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 | 14 participants |
| Arm II (Monoclonal Antibody) | 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 | 9 participants |
Secondary
Percentage of CD27+ B Cells in Responders (SCR) and Non-responders
%CD27+ B cells
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I (Enzyme Inhibitor) | Percentage of CD27+ B Cells in Responders (SCR) and Non-responders | 10 percentage of CD27+ B cells |
| Arm II (Monoclonal Antibody) | Percentage of CD27+ B Cells in Responders (SCR) and Non-responders | 4.3 percentage of CD27+ B cells |
| Imatinib Responders | Percentage of CD27+ B Cells in Responders (SCR) and Non-responders | 14.2 percentage of CD27+ B cells |
| Imatinib Nonresponders | Percentage of CD27+ B Cells in Responders (SCR) and Non-responders | 17.1 percentage of CD27+ B cells |
p-value: 0.01Wilcoxon (Mann-Whitney)
p-value: 0.64Wilcoxon (Mann-Whitney)