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

Tracking Information
First Submitted Date ICMJE	March 1, 2011
First Posted Date ICMJE	March 7, 2011
Results First Submitted Date	September 21, 2015
Results First Posted Date	June 15, 2016
Last Update Posted Date	June 15, 2016
Study Start Date ICMJE	March 2011
Actual Primary Completion Date	December 2014 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: May 10, 2016)	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 Measures ICMJE; (submitted: March 4, 2011)	Significant clinical response in sclerosis [ Time Frame: At 6 months after enrollment and treatment with one of the two agents ]; 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; 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).
Change History	Complete list of historical versions of study NCT01309997 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: May 10, 2016)	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 Measures ICMJE; (submitted: March 4, 2011)	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 ] Discontinuation of randomized treatment due to chronic GVHD progression or treatment intolerance within 6 months after enrollment, OR 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.
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Imatinib and Rituximab in Treating Cutaneous Sclerosis in Patients With Chronic Graft-Versus-Host Disease
Official Title ICMJE	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 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.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Graft Versus Host Disease; Systemic Scleroderma
Intervention ICMJE	Drug: imatinib mesylate Given PO Other Names: CGP 57148 Gleevec Glivec; Biological: rituximab Given IV Other Names: IDEC-C2B8 IDEC-C2B8 monoclonal antibody Mabthera MOAB IDEC-C2B8 Rituxan
Study Arms	Experimental: Arm I (enzyme inhibitor) Patients receive imatinib mesylate PO QD for 6 months in the absence of progression of sclerosis or unacceptable toxicity. Intervention: Drug: imatinib mesylate; Experimental: 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. Intervention: Biological: rituximab
Publications *	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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: May 10, 2016)	72
Original Estimated Enrollment ICMJE; (submitted: March 4, 2011)	90
Actual Study Completion Date	December 2015
Actual Primary Completion Date	December 2014 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	2 Years and older (Child, Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01309997
Other Study ID Numbers ICMJE	2343.00; NCI-2011-00098 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); RDCRN 6502 ( Other Identifier: Rare Diseases Clinical Research Network II ); 2343.00 ( Other Identifier: Fred Hutchinson Cancer Research Center ); U54CA163438 ( U.S. NIH Grant/Contract ); P30CA015704 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Plan to Share IPD: Yes Plan Description: De-identified patient data and samples may be available with the appropriate approvals. Contact the PI for information.
Responsible Party	Lee, Stephanie, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Study Sponsor ICMJE	Lee, Stephanie
Collaborators ICMJE	National Cancer Institute (NCI)
Investigators ICMJE	Principal Investigator: Stephanie Lee Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
PRS Account	Fred Hutchinson Cancer Research Center
Verification Date	May 2016
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP