Clinical trial NCT01309997: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Graft Versus Host Disease
Systemic Scleroderma
Keywords: Imatinib
Rituximab
Chronic Graft-vs-Host Disease
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2011-03-07
Enrollment: 72
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Significant Clinical Response
timeFrame: 6 months
Secondary outcomes:
measure: Patients Who Were Able to Taper Corticosteroids
timeFrame: 6 months
measure: Cumulative Incidence of Treatment Failure
timeFrame: 6 months
measure: Number of Patients Achieving Improvement in Cutaneous Sclerosis
timeFrame: 6 months
measure: Baseline Histopathologic Score in the Two Treatment Arms
timeFrame: Enrollment
measure: 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
timeFrame: 6 months
measure: Percentage of CD27+ B Cells in Responders (SCR) and Non-responders
timeFrame: 6 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Stanford
country: United States
facility: Stanford University Hospitals and Clinics
state: California
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
city: Milwaukee
country: United States
facility: Froedtert and the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
name: Stephanie Lee
role: PRINCIPAL_INVESTIGATOR
References:
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.