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

Phase 2

Completed

Conditions: Imatinib Mesylate
Sclerotic Graft Versus Host Disease

Interventions: Drug: Gleevec, STI571(Imatinib Mesylate)

Registration Number: NCT00702689

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Imatinib mesylate in patients with cGVHD	Gleevec, STI571(Imatinib Mesylate)	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)

Primary Outcome Measures

Name	Time	Method
Percent Change in Absolute Range of Motion (ROM) From Baseline to 6 Months	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.
Primary Range of Motion (ROM) Response	6 months	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.

Secondary Outcome Measures

Name	Time	Method
Lung Function Score at Baseline and 6 Months	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.
Number of Participants With Adverse Events	Date treatment consent signed to date off study, approximately, 41 months, 27 days	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.
Average Percentage Change in Range of Motion (ROM) Deficit	6 months	One or more joints were assessed for ROM deficit by a physiatrist with expertise in graft versus host disease and joint ROM.
Total Skin Score at Baseline and 6 Months	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.
Total Chronic Graft Versus Host Disease (cGVHD) Provider Global Rating Score at Baseline and 6 Months	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).
Change in Immunosuppression	6 months	Change in immunosuppression was defined by an increase or decrease in steroid use form baseline.