Nilotinib (Tasigna™) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial

Abstract

IntroductionTyrosine kinase inhibitors (TKI) are medications of interest in the treatment of Systemic Sclerosis (SSc) because of their ability to inhibit pathways involved in fibrosis. In this open-label pilot trial, our objectives were to assess the safety, efficacy, and molecular change associated with treatment of patients with diffuse cutaneous (dc)SSc with the TKI nilotinib (Tasigna™).MethodsTen adult patients with early dcSSc were treated with nilotinib. Primary endpoints were safety and change in modified Rodnan Skin Score (MRSS) after 6 months. Lesional skin biopsies at baseline, 6 and 12 months of treatment were assessed by histopathology, immunohistochemistry, and DNA microarray.ResultsPatients had early and active dcSSc with median disease duration of 0.7 years (range 0.5, 1.7) and increasing MRSS in the month prior to baseline (mean +2.9, p=0.02). Seven out of ten patients completed 6 and 12 months of treatment. Seventy-one adverse events (AEs) including 2 serious AEs were observed, and 92 % of AEs were grade 1-2. Two patients discontinued the medication due to mild QTc prolongation. MRSS improved by a mean of 4.2 points (16 %) at 6 months and by 6.3 points (23 %) at 12 months in the 7 completers, p=0.02 and 0.01, respectively. Patients with a decrease in MRSS >20 % from baseline at 12 months (classified as improvers) had significantly higher expression of transforming growth factor beta receptor (TGFBR) and platelet-derived growth factor receptor beta (PDGFRB) signaling genes at baseline than non-improvers, and the expression of these genes significantly decreased in improvers post-treatment.ConclusionNilotinib was well tolerated by the majority of patients in this study, with tolerability limited primarily by mild QTc-prolongation. Significant MRSS improvement was observed in these early, active patients, but is not conclusive of treatment effect given the open-label study-design and small number of patients in this pilot study. Improvers had higher levels of expression of genes associated with TGFBR and PDGFRB signaling at baseline, and a significant decrease in the expression of these genes occurred only in patients with higher MRSS improvement. The findings of this pilot study warrant more conclusive evaluation.Trial registrationClinicaltrials.gov NCT01166139, July 1, 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0721-3) contains supplementary material, which is available to authorized users.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…The weighted proportion of QTc prolongation of any grade with nilotinib was 2.7% with QTc of >500 ms, seen in 0.3% of cases. Caution and periodic ECG monitoring are advised when using nilotinib 71, 73, 74, 76, 77, 79, 80. QTc prolongation was common (37%) in patients with hepatic impairment treated with bosutinib,10 but this was not seen in other smaller studies 11, 12.…”

Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity

“…We identified 4 clinical microarray gene expression datasets from the NCBI's Gene Expression Omnibus (GEO) database comprising 282 samples obtained from skin ( Figure 1 and Supplemental Table 1; supplemental material available online with this article; doi:10.1172/jci.insight.89073DS1) (7,(10)(11)(12), which were derived from healthy control subjects, patients with diffuse cutaneous SSc or limited cutaneous SSc, and with various disease duration. Two of these datasets profiled longitudinally collected samples from study participants during treatment with rituximab (10) and nilotinib (7). Furthermore, we generated whole-genome transcriptional profiles for 3 additional cohorts, referred to as the Northwestern cohort, the UCSF2 cohort, and the Stanford cohort.…”

“…A growing body of evidence supports the use of skin, lung, and peripheral blood transcriptomes as SSc biomarkers to quantify interpatient heterogeneity, to identify dysregulated molecular pathways underlying disease, and to identify appropriate patients for specific SSc therapies (6)(7)(8)(9). These studies have identified remarkable homogeneity in skin biopsies obtained from the same patient such that transcriptomic profiles of clinically unaffected back and clinically affected forearm biopsies are nearly identical (10)(11)(12).…”

A functional genomic meta-analysis of clinical trials in systemic sclerosis: towards precision medicine and combination therapy

“…First, since SSc is a rare disease, clinical trials tend to have small sample sizes. Thus, few differentially expressed genes (DEGs) can be detected after multiple hypothesis testing correction (Chakravarty et al, 2015;Gordon et al, 2015).…”

“…To gain mechanistic insight into the action of experimental therapies, clinical trials in SSc have collected genome-wide gene expression data from skin biopsies pre-and post-treatment (Chakravarty et al, 2015;Gordon et al, 2015;Rice et al, 2015a;Hinchcliff et al, 2013;Chung et al, 2009) (Martyanov et al Submitted). However, these studies in clinical trials face limitations.…”