A phase I/II study of dovitinib (TKI258), a FGFR and VEGFR inhibitor, in patients (pts) with advanced or metastatic renal cell cancer: Phase I results.

Angevin, Eric; Lin, Chieh‐Yu; Pande, A. U.; Lopez, James; Gschwend, Jürgen E.; Harzstark, Andrea L.; Shi, Michael; Anak, Özlem; Escudier, B.

doi:10.1200/jco.2010.28.15_suppl.3057

Cited by 16 publications

(9 citation statements)

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“…Next, we compared the antitumor activity of dovitinib with NVP-BGJ398 by assessing the inhibition of anchorage-independent growth using soft agar assays using a clinically achievable drug concentration for both dovitinib and NVP-BGJ398 (24,25). At a concentration of 1 mmol/L, dovitinib showed pronounced GI (!50% GI) in all FGFR2-mutated cell lines, but also in 8 of 11 (73%) endometrial cancer cell lines with wild-type FGFR2.…”

Section: Activity Of Dovitinib and Nvp-bgj398 On Anchorageindependentmentioning

confidence: 99%

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells

Konecny

Kolarova

O’Brien

et al. 2013

Molecular Cancer Therapeutics

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The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer has generated an opportunity for a novel target-based therapy. Here, we explore the therapeutic potential of 2 FGFR inhibitors, the multikinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of endometrial cancer. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle, and apoptosis using a panel of 20 molecularly characterized human endometrial cancer cell lines. Anchorage-independent growth was studied using soft agar assays. In vivo studies were conducted using endometrial cancer xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared with their FGFR2 wild-type counterparts (P ¼ 0.073 and P ¼ 0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell-cycle arrest, and significantly increased apoptosis in FGFR2-mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2-mutant endometrial cancer cells, but the activity of dovitinib was less restricted to FGFR2-mutant lines when compared with NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2-mutated endometrial cancer xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type endometrial cancer xenograft models including complete tumor regressions in a long-term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2-mutated endometrial cancer. Dovitinib may have antitumor activity in endometrial cancer beyond FGFR2-mutated cases and may permit greater flexibility in patient selection. Mol Cancer Ther; 12(5); 632-42. Ó2013 AACR.

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Section: Activity Of Dovitinib and Nvp-bgj398 On Anchorageindependentmentioning

confidence: 99%

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells

Konecny

Kolarova

O’Brien

et al. 2013

Molecular Cancer Therapeutics

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“…146 A phase I study showed that dovitinib was well tolerated and had encouraging antitumor activity in heavily pretreated patients. 147 Subjects had high baseline VEGF and FGF levels, which may have been a reflection of prior anti-VEGF therapy. 147 The toxicity profile of dovitinib was considered acceptable, with nausea, diarrhea, vomiting, and asthenia the most common adverse events.…”

Section: Promising Agents In Developmentmentioning

confidence: 99%

“…147 Subjects had high baseline VEGF and FGF levels, which may have been a reflection of prior anti-VEGF therapy. 147 The toxicity profile of dovitinib was considered acceptable, with nausea, diarrhea, vomiting, and asthenia the most common adverse events. The median PFS was 6.1 months in this small study of 20 patients who underwent prior VEGFR-TKI or mTOR inhibitor treatment.…”

Section: Promising Agents In Developmentmentioning

confidence: 99%

NCCN Task Force Report: Optimizing Treatment of Advanced Renal Cell Carcinoma With Molecular Targeted Therapy

Hudes¹,

Carducci²,

Choueiri³

et al. 2011

J Natl Compr Canc Netw

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The outcome of patients with metastatic renal cell carcinoma has been substantially improved with administration of the currently available molecularly targeted therapies. However, proper selection of therapy and management of toxicities remain challenging. NCCN convened a multidisciplinary task force panel to address the clinical issues associated with these therapies in attempt to help practicing oncologists optimize patient outcomes. This report summarizes the background data presented at the task force meeting and the ensuing discussion.

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“…Published phase I data from the phase I/II trial of dovitinib in 20 heavily pretreated patients indicated that the ORR was 10% and the preliminary median PFS duration was 5.5 months. The maximum-tolerated dose for further study in the phase II portion of the trial was 500 mg daily [24].…”

Section: Dovitinib (Tki258)mentioning

confidence: 99%

Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Clinical Evidence

2011

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Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin-2 and interferon (IFN)-␣, in recent years several targeted therapies have become available for first-and second-line use. These include sorafenib, sunitinib, bevacizumab (plus IFN-␣), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular-targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow-up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression-free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions. The Oncologist 2011;16(suppl 2):14 -22

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A phase I/II study of dovitinib (TKI258), a FGFR and VEGFR inhibitor, in patients (pts) with advanced or metastatic renal cell cancer: Phase I results.

Cited by 16 publications

References 0 publications

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells

NCCN Task Force Report: Optimizing Treatment of Advanced Renal Cell Carcinoma With Molecular Targeted Therapy

Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Clinical Evidence

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