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

Graft Versus Host Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01309997
• Other study ID #: 2343.00
• Secondary ID: NCI-2011-00098RD
• Status: Active, not recruiting
• Phase: Phase 2
• First received: March 1, 2011
• Last updated: August 10, 2015
• Start date: March 2011

Study information

• Verified date: August 2015
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 74
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Graft Versus Host Disease
• Graft vs Host Disease
• Scleroderma, Diffuse
• Scleroderma, Systemic
• Systemic Scleroderma

Intervention

Drug:
• imatinib mesylate
Given PO

Biological:
• rituximab
Given IV

Other:
• laboratory biomarker analysis
Correlative studies
• questionnaire administration
Ancillary studies

Locations

Country	Name	City	State
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center	Cleveland	Ohio
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington
United States	Stanford University Hospitals and Clinics	Stanford	California
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Lee, Stephanie	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Significant clinical response	Assessed by decline in an affected area's skin score as measured with the Vienna Skin Scale (from 4 to 2, 3 to 1, or 2 to 0) 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) or of the ankles by one point (in a 1 to 4 scale) without a concurrent worsening in another area.	3 and 6 months	No
Secondary	Proportion of patients achieving a greater than or equal to 50% reduction in the daily corticosteroid dose		6 months	No
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.	6 months	No
Secondary	Number of patients achieving improvement in cutaneous sclerosis	Assessed by decrease of >= 0.2 units in the Scleroderma Health Assessment Questionnaire (SHAQ).	6 months	No
Secondary	Correlation of blood and skin biomarker profile with each therapeutic agent and clinical response		6 months	No
Secondary	Proportion of subjects 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	No