Imatinib Mesylate to Treat Skin Changes in Patients With Chronic Graft-Versus-Host Disease

Study Overview
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Brief Summary
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Background: Chronic graft-versus-host disease (GVHD) is a common complication of stem cell transplant, resulting from the donor's immune cells attacking the cells of the body of the recipient. One effect of GVHD is fibrosis (scarring) of the skin that can lead to impaired function, decreased quality of life and increased risk of death. This is known as sclerotic skin changes of GVHD, or sclerodermatous graft versus host disease (ScGVHD). Imatinib mesylate (Gleevec) is a drug that has been approved by the Food and Drug Administration to treat cancer in humans and fibrosing conditions in animals. Objectives: To see if imatinib mesylate can improve ScGVHD and evaluate its effect on other GVHD symptoms To assess the side effects of imatinib mesylate in patients with GVHD To evaluate blood, body fluids and tissue samples in patients to try to better understand the biology of ScGVHD Eligibility: Patients 4 years of age and older with ScGVHD Design: Initial treatment: Participants take imatinib mesylate tablets once a day for up to 6 months, as long as their GVHD does not get worse and they do not develop unacceptable side effects of the drug. Evaluations: Participants are evaluated at 1, 3 and 6 months at the National Institutes of Health (NIH) Clinical Center with procedures that may include the following: Medical history and physical examination Blood and urine tests Lung function test Skin biopsy Magnetic resonance imaging (MRI) scan Specialty consultations (e.g., physical or rehabilitative therapy, dentist, eye doctor, dermatologist) Electrocardiogram (EKG) Echocardiogram (ultrasound test of the heart) Muga scan (nuclear medicine test of the heart) Quality-of-life questionnaires Apheresis (procedure for collecting quantities of white blood cells) Office visits with local physician once a week for 1 month, then once every 2 weeks for 5 months Followup visits at National Institutes of Health (NIH) every 6 months for 1 year Continuing treatment: Patients who improve continue to receive imatinib mesylate for up to 6 months after their best response and are followed for up to 2 years. Patients who continue to respond or who become worse after stopping treatment may receive additional treatment for up to 2 years.

Detailed Description
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Background: Chronic graft versus host disease (cGVHD) is a major complication of allogeneic stem cell transplant (alloHSCT). The sclerotic skin manifestations of chronic cutaneous GVHD (ScGVHD) can lead to significant functional impairment and no satisfactory therapy exists to adequately treat this form of cGVHD. Imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor with potent activity against platelet derived growth factor receptor (PDGFR) signaling, a key cytokine pathway which has been implicated in fibrotic disease in general, and in extensive cGVHD in particular. We hypothesize that treatment with imatinib mesylate will reduce the sclerotic manifestations of cGVHD as assessed by quantitative range of motion assessment of an affected joint. Objectives: Primary Objective: To investigate whether imatinib mesylate results in clinical improvement in skin fibrosis in children and adults with ScGVHD using range of motion assessment of affected joints. To determine if imatinib mesylate 200 mg daily is tolerated by patients with cGVHD. Secondary Objectives: To assess toxicity associated with imatinib mesylate in patients with cGVHD. To establish outcome criteria for the evaluation of ScGVHD using multi-modality objective and subjective assessments, including magnetic resonance imaging, skin scoring, and patient self-reported measures. To evaluate biomarkers of disease activity and correlative response measures to treatment with imatinib mesylate. To assess quality of life and functional measures of disease activity and to evaluate changes through the course of therapy. To evaluate the response of other organ manifestations affected by cGVHD to treatment with imatinib mesylate. To evaluate steady-state pharmacokinetics of imatinib mesylate in the cGVHD patient population. Eligibility: Patients age 4 years of age or older with the diagnosis of ScGVHD. Design: This is an open-label, pilot study of imatinib mesylate. Treatment cycles are 28-day cycles with no rest period between cycles. A target of 10 evaluable patients will be enrolled on this trial.

Official Title
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A Phase II Study of Imatinib Mesylate in Children and Adults With Sclerotic Skin Changes of Chronic Graft-Versus-Host Disease

Conditions
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Sclerotic Graft Versus Host Disease, Imatinib Mesylate

Intervention / Treatment
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* Drug: Gleevec, STI571(Imatinib Mesylate)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Sclerodermatous graft versus host disease (ScGVHD) manifesting after at least 100 days following allogeneic hematopoietic stem cell transplantation is considered diagnostic for chronic graft versus host disease (cGVHD) according to National Institutes of Health (NIH) cGVHD Consensus Statement diagnostic criteria. This diagnosis can be made clinically or by histopathology. The diagnosis must be confirmed by the principal investigator (PI), or lead associate investigator (LAI). Skin biopsies will be reviewed by the National Cancer Institute (NCI) Laboratory of Pathology to confirm the diagnosis of ScGVHD. Patients must have measurable limitation in range of motion, defined as ScGVHD with or without fasciitis, restricting range of motion (ROM) of at least one joint with a minimum deficit of 25 percent. Prior therapy: Patients must have cGVHD refractory to at least one treatment regimen for cGVHD. One prior regimen must have included systemic corticosteroids at the equivalent prednisone dosing of 1mg/kg/day times 14 days. Patients in whom calcineurin inhibitors or corticosteroids are medically contraindicated may also be eligible for enrollment. Patients who have had stabilization of disease on calcineurin inhibitors or steroids, but in whom these medications cannot be tapered without disease flare are also eligible. Patient must be on stable or tapering immunosuppressive regimen for at least one month. Age: 4 years of age or older at the time of enrollment. Lower age limit set by lower established age limit norms of ROM scores for measurement criteria. Life expectancy of greater than 6 months. Karnofsky greater than or equal to 60 percent. Patients must be platelet transfusion and growth factor independent at the time of study entry. Patients must have adequate organ and marrow function as defined below. Patients with Gilbert syndrome are excluded from the requirement of a normal bilirubin. (Gilbert syndrome is found in 3-10 percent of the general population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis). absolute neutrophil count greater than or equal to 1,000/mcL platelets greater than or equal to 50,000/mcL total bilirubin less than 3 times upper limit of normal aspartate aminotransferase (AST)serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT)serum glutamic pyruvic transaminase (SGPT) less than 5 times upper limit of normal creatinine age-adjusted within normal limits OR creatinine clearance greater than 20mL/min/1.73 m^2 for adults and pediatric patients with body surface area (BSA) greater than 0.97 m^2 with creatinine levels above institutional normals and greater than or equal to 40 mL/min 1.73 m^2 for pediatric patients with BSA less than 0.97 m^2. Age less than 5 years old Maximum Serum Creatinine 0.8 mg/dL Age 5 or less than 10 years old Maximum Serum Creatinine 1.0 mg/dL Age 10 or less than 15 years old Maximum Serum Creatinine 1.2 mg/dL Age 15 years old or greater Maximum Serum Creatinine 1.5 mg/dL Normal cardiac function for age as determined by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) (normal left ventricular (LV) function as measured by ejection fraction or shortening fraction). The effects of imatinib mesylate on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for six months following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Ability to understand and the willingness to sign a written informed consent document. All patients or their legal guardian (for patients less than 18 years old) must sign an institutional review board (IRB) approved document of informed consent (chronic graft versus host disease (cGVHD) natural history or any National Cancer Institute (NCI) protocol allowing for screening procedures) prior to performing studies to determine patient eligibility. After confirmation of patient eligibility all patients or their legal guardian must sign the protocol-specific informed consent. Pediatric patients will be included in age appropriate discussions and age appropriate assent will be obtained in accordance with National Institutes of Health (NIH) guidelines. Durable Power of Attorney (DPA): All patients 18 years of age at the time of enrollment will be offered the opportunity to assign DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired. EXCLUSION CRITERIA: Patients who have had chemotherapy, radiotherapy, or immunotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients may not be receiving any other investigational agents, including extracorporeal photopheresis. Patients may not have received monoclonal antibody therapy within 6 weeks. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. History of allergic reactions attributed to compounds of similar chemical or biologic composition to imatinib mesylate. Patients receiving any of the following medications or substances that are inhibitors or inducers of P450 3A4 are ineligible. Use of the following medications must be discontinued at least two weeks prior to starting therapy: Alfuzosin Aprepitant Carbamazepine Clarithromycin Eletriptan Erythromycin Pimozide St John's Wort Warfarin A list of medications and substances known or with the potential to interact with the P450 3A4 isoenzyme is provided in Section 8. Imatinib mesylate is likely to increase the blood level of drugs that are substrates of CYP2C9, CYP2D6 and CYP3A4/5. Close monitoring is warranted when using agents metabolized by these enzymes. Grapefruit juice should not be consumed while on therapy. Prior treatment with imatinib mesylate or other tyrosine kinase inhibitor after the date of transplant. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary, hepatic, or other organ dysfunction, or psychiatric illness/social situations that would limit compliance with study requirements or compromise the patient's ability to tolerate protocol therapy. Pregnant women are excluded from this study because imatinib mesylate is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with imatinib mesylate, breastfeeding should be discontinued if the mother is treated with imatinib mesylate. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with imatinib mesylate and the possibility of associated severe immunosuppression. Patients with active hepatitis C or hepatitis B infection as defined by seropositivity for hepatitis C or hepatitis B (HepBSAg) and elevated transaminases, as GVHD manifestations involving the liver will be indistinguishable and drug-toxicity uninterpretable. Persistent malignancy, requiring ongoing therapy.

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imatinib mesylate in patients with cGVHD<br>Cohort 1 - Pts 1-8:Adults: 400mg imatinib mesylate daily; Children: 260mg/m^2 daily (400mg maximum), followed by dose de-escalation for adverse events. Cohort 2 - Pts 9-20:Adults - 100 mg oral dose daily (increase to 200 mg daily after 28 days if well tolerated). Children - 65 mg/m^2 oral dose daily (increase to 130 mg/m^2 daily after 28 days if well tolerated) | Drug: Gleevec, STI571(Imatinib Mesylate)<br>* Cohort 1 - Pts 1-8:Adults: 400mg imatinib mesylate daily; Children: 260mg/m^2 daily (400mg maximum), followed by dose de-escalation for adverse events. Cohort 2 - Pts 9-20:Adults - 100 mg oral dose daily (increase to 200 mg daily after 28 days if well tolerated). Children - 65 mg/m^2 oral dose daily (increase to 130 mg/m^2 daily after 28 days if well tolerated)<br>* Other names: ST1571;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Absolute Range of Motion (ROM) From Baseline to 6 Months | A change in ROM is 25% or greater from baseline. A partial response required improvement in 25% or more in ROM. Progression required 25% or greater loss of ROM.Patients with negative values in the Table are those who lost ROM. Percent improvement in ROM for 1-3 target joints. For patients with >1 target joint, the average ROM improvement was calculated. The average percentage change in ROM deficit from baseline to 6 months was obtained based on the number of degrees of ROM change (6 months)/total ROM deficit (baseline) at each joint. | 6 months | 
| Primary Range of Motion (ROM) Response | Progressive disease is defined as joint ROM: decrease of >25% in composite ROM score on 2 consecutive evaluations at least 2 weeks apart, but not greater than 4 weeks apart or steroid pulse: >1 steroid pulse per 3 month period if administered for sclerotic-type chronic graft versus host disease (ScGVHD). Response is joint ROM: increase of >25% in composite ROM score. Maximal response is a response with no further improvement over 2 sequential 3-month evaluations. Stable disease does not meet the criteria for progression, response, or maximal response. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately, 41 months, 27 days | 
| Average Percentage Change in Range of Motion (ROM) Deficit | One or more joints were assessed for ROM deficit by a physiatrist with expertise in graft versus host disease and joint ROM. | 6 months | 
| Total Skin Score at Baseline and 6 Months | Total skin score was graded by the National Institutes of Health Consensus Criteria. Skin score was calculated by dividing the total score by seven domains (skin, eye, oral, joint, gastrointestinal, hepatic, pulmonary) in men and 8 domains in women (previous domains noted plus gynecologic). Total skin score is a percentage of body surface area (BSA) involvement (range 0-100%). It was calculated from the sum of moveable body surface BSA and non-moveable BSA. Higher numbers = greater body surface area affected. | Baseline and 6 Months | 
| Total Chronic Graft Versus Host Disease (cGVHD) Provider Global Rating Score at Baseline and 6 Months | The provider global rating is a physician impression of severity of cGVHD symptoms from a scale of zero (no symptoms) to 10 (most severe GVHD symptoms possible). | Baseline and 6 months | 
| Lung Function Score at Baseline and 6 Months | Lung function was graded by the National Institutes of Health Chronic Graft Versus Host Disease organ response criteria. The Lung function score = forced expiratory volume 1 (FEV1) score + carbon monoxide diffusing capacity (DLCO) score, with a possible range of 2 (better outcome)-12 (worst outcome). The percent predicted FEV1 and DLCO (adjusted for hematocrit but not alveolar volume) should be converted to a numeric score as follows: >80% =1; 70-79% = 2; 60-69% = 3; 50-59% = 4; 40-49% = 5; <40% = 6. | Baseline and 6 Months | 
| Change in Immunosuppression | Change in immunosuppression was defined by an increase or decrease in steroid use form baseline. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Skin Sclerosis, Graft Versus Host Disease