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

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.

- 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.