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Motzer R.J.,Sloan Kettering Cancer Center | Porta C.,University of Pavia | Vogelzang N.J.,Comprehensive Cancer Centers of Nevada | Sternberg C.N.,San Camillo and Forlanini Hospitals | And 17 more authors.
The Lancet Oncology | Year: 2014

Background: An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. Methods: In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. Findings: 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). Interpretation: Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. Funding: Novartis Pharmaceuticals Corporation. © 2014 Elsevier Ltd.


PubMed | Novartis, Hannover Medical School, Maria Curie Sklodowska University, Hospital Universitario Central Of Asturias and 13 more.
Type: Clinical Trial, Phase III | Journal: The Lancet. Oncology | Year: 2014

An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma.In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027.284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 113 months (IQR 79-146). Median PFS was 37 months (95% CI 35-39) in the dovitinib group and 36 months (35-37) in the sorafenib group (hazard ratio 086, 95% CI 072-104; one-sided p=0063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively).Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting.Novartis Pharmaceuticals Corporation.


Chudzicka A.,Military Institute of Health Services in Warsaw
Polski Merkuriusz Lekarski | Year: 2010

Idiopathic pulmonary fibrosis (IPF) is the most common of interstitial lung diseases and is characterised by a significant mortality rate. That is way both clinicists and patients are interested to identify factors that may influence outcome of disease. This factors are named biological markers or biomarkers. Their usefulness in diagnostic, monitoring and prognosis of interstitial pneumonia, and idiopathic pulmonary fibrosis was estimated in many researches. The most of them was concerned to serum biomarkers, such as surfactant proteins, mucin-connected proteins, Clara cells proteins, cytoceratines and cytokines.


Smoter M.,Military Institute of Health Services in Warsaw | Bodnar L.,Military Institute of Health Services in Warsaw | Grala B.,Military Institute of Health Services in Warsaw | Stec R.,Military Institute of Health Services in Warsaw | And 3 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2013

Background: The aim of the study was to evaluate predictive and prognostic significance of microtubule-associated protein Tau in epithelial ovarian cancer (EOC) patients treated with paclitaxel and platinum-based chemotherapy. Methods. 74 patients with EOC (stage I-IV) who underwent cytoreductive surgery followed by standard paclitaxel/platinum chemotherapy were included in the retrospective analysis. Their formalin-fixed, paraffin-embedded tissue specimens were immunohistochemically stained for Tau protein, using semi-quantitative DAKO test. Tau expression was acknowledged as negative (0 and 1+) or positive (2+ and 3+). The correlation between Tau expression, progression free survival (PFS) and overall survival (OS) was evaluated. Statistical analysis included Kaplan-Meyer estimator, long rank test, Mann Whitney test and Cox proportional hazards model. Results: 25.7% (19/74) and 74.3% (55/74) of the patients were classified as Tau-negative and Tau-positive, respectively. Median PFS was 28.7 months for Tau-negative group and 15.9 months for Tau-positive group (p = 0.0355). In the univariate analysis 3-year OS in Tau-negative and Tau-positive groups was 80.2% and 52.4%, respectively (p = 0.0198). Low expression of protein Tau was associated with better OS, whereas an advanced stage at diagnosis, suboptimal surgery, serous histological type and resistance to first line chemotherapy were each correlated with worse OS (p <0,05). In multivariate analysis only resistance to first line chemotherapy remained significant (HR 22.59; 95% CI, 8.71-58.55; p <0.0001). Conclusions: Negative tau protein seems to be both good prognostic factor and a predictor of response to paclitaxel/platinum-based chemotherapy in EOC patients. © 2013 Smoter et al.; licensee BioMed Central Ltd.


Stec R.,Military Institute of Health Services in Warsaw | Bodnar L.,Military Institute of Health Services in Warsaw | Szczylik C.,Military Institute of Health Services in Warsaw
Journal of Cancer Research and Clinical Oncology | Year: 2010

Purpose A retrospective analysis was conducted to compare the tolerability and efficacy of single-agent capecitabine and 5-fluorouracil/leucovorin/ irinotecan (FOLFIRI) in the first-line treatment of patients aged ≥65 years with metastatic colorectal cancer (mCRC). Methods Consecutive patients with mCRC treated at the Military Medical Institute, Warsaw, between January 2003 and June 2008 were eligible. A total of 123 patients were identified (FOLFIRI, n = 67; capecitabine, n = 56). Results The overall response rate with FOLFIRI was 28.1 versus 16.4% with capecitabine (P = 0.1398). Median time to disease progression with FOLFIRI was 8.8 versus 7.5 months with capecitabine (P = 0.20), and median overall survival was 19.0 versus 15.4 months (P = 0.93). In the FOLFIRI group, neutropenia and anaemia were significantly more frequent than in the capecitabine group. The main non-haematological toxicity was hand-foot syndrome found only in the capecitabine group. Conclusion Single-agent capecitabine and FOLFIRI are effective first-line regimens in patients aged ≥65 years with mCRC. © Springer-Verlag 2009.

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