Imatinib Mesylate to Treat Skin Changes in Patients With Chronic Graft-Versus-Host Disease
Condition: Sclerotic Graft Versus Host Disease; Imatinib Mesylate
MeSH terms: Bronchiolitis Obliterans Syndrome; Graft vs Host Disease; Sclerosis
Intervention: Gleevec, STI571(Imatinib Mesylate)
Intervention description: 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)
Intervention MeSH terms: Imatinib Mesylate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 4 Years
Healthy volunteers: No
Keywords: Skin Sclerosis; Graft Versus Host Disease

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.
    

Eligibility criteria:

        -  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.