Proof of Concept Trial of Gleevec (Imatinib) in Active Diffuse Scleroderma

Summary

The purpose of this study is to investigate the effectiveness and safety of the drug Gleevec (imatinib) as a new treatment for patients with active diffuse scleroderma. This drug has not been used previously to treat scleroderma, but it has been found to advance the treatment and life span of patients with a type of leukemia called chronic myeloid leukemia or CML. Gleevec acts on chemical signals in the cells that may decrease fibrosis (the hardening of the skin that occurs in scleroderma). It works by interfering in the process that activates many molecules that cause fibrosis, including TGFbeta (which may be a key part of disease activity in scleroderma). This study proposes to treat patients that have significant diffuse scleroderma with Gleevec for 6 months and investigate several measures of scleroderma disease activity before, during and at the end of treatment (0, 3 months and 6 months). This is a randomized, double blind, placebo-controlled trial: 20 patients will be divided into two groups in a 4:1 ratio, with 16 patients taking 400mg of Gleevec per day and 4 taking a placebo. The differences between the groups that will be measured include safety, Modified Rodnan skin score (mRSS), Health Assessment Questionnaire (HAQ), global assessments (100mm VAS) and changes in biomarkers in blood and skin biopsies.

Timeline

Start

2008-04

Primary completion

2008-12

Completion

2008-12

Outcome

Outcome not reported

Stopped: “Frequent adverse events occurred early in treatment with poor tolerability.”

Publications

• Background Nadashkevich O, Davis P, Fritzler MJ. A proposal of criteria for the classification of systemic sclerosis. Med Sci Monit. 2004 Nov;10(11):CR615-21. Epub 2004 Oct 26.
• Background LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N, Wollheim F. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb;15(2):202-5. No abstract available.
• Background Thompson AE, Pope JE. Increased prevalence of scleroderma in southwestern Ontario: a cluster analysis. J Rheumatol. 2002 Sep;29(9):1867-73.
• Background Haugeberg G, Brodin C, Johnsen V. [Systemic sclerosis. A rare connective tissue disease with manifestations in many organs]. Tidsskr Nor Laegeforen. 1995 Nov 30;115(29):3619-21. Norwegian.
• Background Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980 Feb;23(2):137-45. doi: 10.1002/art.1780230202.
• Background Lankat-Buttgereit B, Horsch D, Barth P, Arnold R, Blocker S, Goke R. Effects of the tyrosine kinase inhibitor imatinib on neuroendocrine tumor cell growth. Digestion. 2005;71(3):131-40. doi: 10.1159/000084647. Epub 2005 Mar 22.
• Background Newell DR. How to develop a successful cancer drug--molecules to medicines or targets to treatments? Eur J Cancer. 2005 Mar;41(5):676-82. doi: 10.1016/j.ejca.2004.12.024.
• Background Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 2004 Aug;15(4):255-73. doi: 10.1016/j.cytogfr.2004.03.006.
• Background Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med. 2005 Sep 29;353(13):1412-3. doi: 10.1056/NEJMc051946. No abstract available.
• Pope J, Walker KM, de Leon F, Vanderhoek L, Seney S, Summers KL. Correlations between changes in cytokines and clinical outcomes for early phase (proof of concept) trials in active diffuse systemic sclerosis using data from an imatinib study. Rheumatology (Oxford). 2014 Oct;53(10):1830-4. doi: 10.1093/rheumatology/keu216. Epub 2014 May 20.

Drugs

Indications