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

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

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.

Study Overview

• Status: Completed
• Conditions: Systemic Scleroderma; Graft Versus Host Disease
• Intervention / Treatment: Biological: rituximab; Drug: imatinib mesylate

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: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • California
    • Stanford, California, United States, 94305
      • Stanford University Hospitals and Clinics
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center and Research Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and the Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (enzyme inhibitor); Patients receive imatinib mesylate PO QD for 6 months in the absence of progression of sclerosis or unacceptable toxicity.	Drug: imatinib mesylate; Given PO; Other Names: Gleevec; CGP 57148; Glivec
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.	Biological: rituximab; Given IV; Other Names: Rituxan; Mabthera; IDEC-C2B8; IDEC-C2B8 monoclonal antibody; MOAB IDEC-C2B8

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	6 months
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.	6 months
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).	6 months
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.	Enrollment
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.	6 months
Percentage of CD27+ B Cells in Responders (SCR) and Non-responders	%CD27+ B cells	6 months

Collaborators and Investigators

• Sponsor: Lee, Stephanie
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Stephanie Lee, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: March 1, 2011
• First Submitted That Met QC Criteria: March 4, 2011
• First Posted (Estimate): March 7, 2011

Study Record Updates

• Last Update Posted (Estimate): June 15, 2016
• Last Update Submitted That Met QC Criteria: May 10, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Rituximab; Imatinib; Chronic Graft-vs-Host Disease
• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Connective Tissue Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Rituximab; Imatinib Mesylate
• Other Study ID Numbers: 2343.00 (Other Identifier: Fred Hutchinson Cancer Research Center); P30CA015704 (U.S. NIH Grant/Contract); U54CA163438 (U.S. NIH Grant/Contract); NCI-2011-00098 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); RDCRN 6502 (Other Identifier: Rare Diseases Clinical Research Network II)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified patient data and samples may be available with the appropriate approvals. Contact the PI for information.