The purpose of this study is to assess the safety and tolerability of imatinib mesylate
(Gleevec) in patients with systemic sclerosis (scleroderma). Gleevec is a medication already
FDA approved for the treatment of chronic myelogenous leukemia (CML), gastrointestinal
stromal tumors (GIST), dermatofibrosarcoma protuberans tumors, Philadelphia
chromosome-positive acute lymphoblastic leukemia, hypereosinophilic syndrome, and aggressive
systemic mastocytosis. In-vitro studies have suggested that imatinib may inhibit collagen
production by scleroderma fibroblasts, and in mouse models of fibrosis imatinib has been
shown to decrease skin thickness.
This is a Phase IIa, single center, prospective open label clinical trial of Gleevec in
patients with systemic sclerosis. All patients will be treated with active drug for 12
months. The primary objective of this study will be to determine the safety and tolerability
of Gleevec in patients with systemic sclerosis, but important secondary outcomes of relevance
will be improvement in disease status as defined by skin scores and indices of pulmonary
Patients who complete the initial phase (described above) of the study will be eligible to
participate in an extension phase. The purpose of the extension phase of the study is to give
patients who participated in the phase IIa clinical trial of Gleevec at the Hospital for
Special Surgery the opportunity to continue Gleevec treatment if both the treating physicians
and the patient are in agreement that Gleevec had acceptable safety and tolerability, as well
as possible efficacy during the initial year of therapy.
Further description of extension phase:
Patients will first be evaluated for inclusion in the extension phase of the study at either
the follow-up visit following three month withdrawal from Gleevec treatment or at the visit
after the follow-up visit. Patients can undergo evaluation for inclusion in the extension
phase up to six months following their completion of the initial one year trial. All patients
evaluated for inclusion in the extension phase will sign a new informed consent form
detailing the purpose and procedures associated with the extension phase at the initial
visit. After the initial visit, patients who meet inclusion criteria will be required to
undergo evaluation every three months for the 27 months following initiation of treatment, or
more frequently if deemed clinically necessary. Treatment will consist of Gleevec, at doses
ranging from 100 to 400 mg daily (100 mg pills will be distributed for oral administration).
At each study visit, a history and physical exam will be performed and urine and blood tests
will be conducted for disease activity and organ function. Additional blood for research may
also be collected at study visits. The Modified Rodnan Skin Score will be measured to assess
the degree of skin involvement associated with the patient's disease. Patients will also
continue to complete questionnaires about their ability to function and quality of life.
Patients will be financially responsible for all professional and clinical services, as well
as all laboratory and diagnostic tests, associated with the extension phase of the study. All
co-pays, deductibles and co-insurances will be paid by the participants. Any additional costs
for parking and travel the patients incur as a result of participating in the extension phase
will not be reimbursed by the study. Novartis Pharmaceuticals will donate drug supply.
1. Age greater than or equal to eighteen years.
2. Clinical diagnosis of diffuse systemic sclerosis by ACR criteria, with a stable
modified Rodnan skin score in the one month preceding introduction of oral Gleevec
therapy. The modified Rodnan skin score must be greater than or equal to sixteen at
screening and initiation of therapy.
3. Disease duration of less than or equal to 10 years.
4. Estimated ejection fraction of greater than 50% by echocardiography
1. Inability to render informed consent in accordance with institutional guidelines.
2. Disease duration of greater than 10 years.
3. Patients with mixed connective tissue disease or "overlap" (i.e. those who satisfy
more than one set of ACR criteria for a rheumatic disease.)
4. Ongoing treatment with other immunosuppressive therapies including cyclophosphamide,
azathioprine, mycophenolic acid, methotrexate, or cyclosporine, or use of those
medications within 3 months of trial entry.
5. Concurrent serious medical condition which in the opinion of the investigator makes
the patient inappropriate for this study such as uncontrollable CHF, arrhythmia,
severe pulmonary or systemic hypertension, severe GI involvement, serum creatinine of
greater than 2.0, active infection, severe diabetes, unstable atherosclerotic
cardiovascular disease, malignancy, HIV, or severe peripheral vascular disease.
6. The use of other anti-fibrotic agents including colchicine, D-penicillamine,
minocycline, or Type 1 oral Collagen in the three months prior to enrollment.
7. Limited scleroderma.
8. Systemic sclerosis-like illness associated with environmental or ingested agents such
as toxic rapeseed oil, vinyl chloride, or bleomycin.
9. A positive pregnancy at entry into this study. Men and women with reproductive
potential will be required to use effective means of contraception through the course
of the study.
10. Use in the prior month of corticosteroids at doses exceeding the equivalent of
prednisone 10 mg daily. Use of corticosteroid at < 10 mg of prednisone can continue
but not be increased during the course of the study.
11. Participation in another clinical research study involving the evaluation of another
investigational drug within ninety days of entry into this study.
12. The presence of severe lung disease as defined by a diffusion capacity of less than
30% of predicted.