Imatinib Mesylate (Gleevec) in the Treatment of Systemic Sclerosis

Phase IIA Study of the Safety and Tolerability of the Use of Imatinib Mesylate (Gleevec) in the Treatment of Systemic Sclerosis

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 function.

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.

Inclusion Criteria:

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

Exclusion Criteria:

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.