Nilotinib in the Treatment of Systemic Sclerosis

Institutional Review Board, Hospital for Special Surgery

November 22, 2011

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Principal Investigator

Robert F. Spiera, MD

Co-Investigators

Mary K. Crow, MD
Jessica K. Gordon, MD
Stephen Lyman, PhD
Horatio Wildman, MD
Morgana L. Davids, BA
Kamini Doobay, BA
Danielle Citrolo, Pharm.D

Summary

We will enroll 10 patients with diffuse scleroderma for this open label, 32 week study.  All patients will be treated with nilotinib, which is an oral medication administered twice daily.  Patients will be seen each month for physician assessment with physical exam and laboratory monitoring.  Additional monitoring with modified Rodnan Skin Score, EKGs, echocardiograms, and Pulmonary Function Testing will be performed.  Two 3 mm punch biopsies of skin affected by scleroderma will be obtained at baseline and at 6 months.  If participants enroll in the extension phase, two additional 3 mm punch biopsies of skin affected by scleroderma will be obtained at 12 months. Other data collected at each study visit will include the scleroderma health assessment questionnaire (sHAQ), SF-36 (quality of life assessment), Raynaud’s Condition Score, physician global assessment of disease activity, and patient global assessment of disease activity (data collection form appended).  Adverse events will be recorded at all study visits.

Inclusion/Exclusion Criteria

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 of atleast 16.
3. Disease duration of less than or equal to 3 years as defined by the date of onset of the first non-Raynaud’s symptom.
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 3 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. Limited scleroderma.
5. Systemic sclerosis-like illness associated with environmental or ingested agents such as toxic rapeseed oil, vinyl chloride, or bleomycin.
6. Ongoing treatment with immunosuppressive therapies including cyclophosphamide, azathioprine, mycophenolic acid, methotrexate, or cyclosporine, or use of those medications within 1 month of trial entry.
7. The use of other anti-fibrotic agents including colchicine, D-penicillamine, minocycline, or Type 1 oral Collagen in the month prior to enrollment.
8. 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 during the course of the study.
9. 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, hepatic impairment, serum creatinine of greater than 2.0, active infection, severe diabetes, unstable atherosclerotic cardiovascular disease, malignancy, HIV, or severe peripheral vascular disease.
10. History of pancreatitis.
11. Prolonged QTc interval defined as a QTc > 450 msec
12. Patients requiring the ongoing use of medications that are antiarrhythmics (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) or that prolong the QTc interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil and pimozide) will be excluded. 
13. Patients requiring the ongoing use of medications that are potent inhibitors or inducers of CYP3A4.
14. A positive pregnancy test 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. 
15. Breastfeeding.  Breastfeeding is contraindicated with the use of nilotinib.
16. Participation in another clinical research study involving the evaluation of another investigational drug within ninety days of entry into this study.
17. The presence of severe lung disease as defined by a diffusion capacity of less than 30% of predicted.
18. Severe lactose intolerance.  (Including galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products or of glucose-galactose malabsorption.)  Nilotinib tablets contain lactose.  
19. Prior use of a tyrosine kinase inhibitor for treatment of scleroderma.

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 of atleast 16.
3. Disease duration of less than or equal to 3 years as defined by the date of onset of the first non-Raynaud’s symptom.
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 3 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. Limited scleroderma.
5. Systemic sclerosis-like illness associated with environmental or ingested agents such as toxic rapeseed oil, vinyl chloride, or bleomycin.
6. Ongoing treatment with immunosuppressive therapies including cyclophosphamide, azathioprine, mycophenolic acid, methotrexate, or cyclosporine, or use of those medications within 1 month of trial entry.
7. The use of other anti-fibrotic agents including colchicine, D-penicillamine, minocycline, or Type 1 oral Collagen in the month prior to enrollment.
8. 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 during the course of the study.
9. 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, hepatic impairment, serum creatinine of greater than 2.0, active infection, severe diabetes, unstable atherosclerotic cardiovascular disease, malignancy, HIV, or severe peripheral vascular disease.
10. History of pancreatitis.
11. Prolonged QTc interval defined as a QTc > 450 msec
12. Patients requiring the ongoing use of medications that are antiarrhythmics (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) or that prolong the QTc interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil and pimozide) will be excluded. 
13. Patients requiring the ongoing use of medications that are potent inhibitors or inducers of CYP3A4.
14. A positive pregnancy test 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. 
15. Breastfeeding.  Breastfeeding is contraindicated with the use of nilotinib.
16. Participation in another clinical research study involving the evaluation of another investigational drug within ninety days of entry into this study.
17. The presence of severe lung disease as defined by a diffusion capacity of less than 30% of predicted.
18. Severe lactose intolerance.  (Including galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products or of glucose-galactose malabsorption.)  Nilotinib tablets contain lactose.  
19. Prior use of a tyrosine kinase inhibitor for treatment of scleroderma.

Contact Information

Morgana Davids
davidsm@hss.edu
212.774.2123