Phase I Clinical Study of AZD2171, an Oral Vascular Endothelial Growth Factor Signaling Inhibitor, in Patients With Advanced Solid Tumors

Drevs, Joachim; Siegert, Patrizia; Medinger, Michael; Mross, Klaus; Strecker, Ralph; Zirrgiebel, Ute; Harder, Jan; Blum, Hubert E.; Robertson, Jane; Jürgensmeier, Juliane M.; Puchalski, Thomas A.; Young, Helen; Saunders, O.; Unger, Clemens

doi:10.1200/jco.2006.07.2066

Cited by 289 publications

(244 citation statements)

References 30 publications

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“…VEGF, being one of the main pro-angiogenic growth factors in many cancers, was the first to be targeted and anti-VEGF treatments are now in wide clinical use (15). Recently, the VEGF receptors have also shown promise as targets for anticancer drugs (28,29). So far, little has been known about the expression of VEGF and its receptors in GCTs.…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are highly expressed in ovarian granulosa cell tumors

Färkkilä¹,

Anttonen²,

Pociuviene³

et al. 2011

European Journal of Endocrinology

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Objective: Ovarian granulosa cell tumors (GCTs) are hormonally active sex cord stromal tumors accounting for 3-5% of all ovarian cancers. These tumors are generally diagnosed at an early stage but there is a high risk of recurrence, associated with high mortality. Treatment of recurrent GCTs is difficult, and biologically targeted treatment modalities are lacking. GCTs are highly vascularized, and angiogenic factors most probably play a role in their pathology. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis, but in GCTs, the role of VEGF and its receptors VEGFR-1 (FLT1) and VEGFR-2 (KDR) remains largely unknown. Our objective is to study the expression of VEGF and its receptors in human GCTs. Methods: We analyzed GCTs from 106 patients for the expressions of VEGF and its receptors utilizing tumor tissue microarray, tumor mRNA, and patient serum samples. Results: We found that VEGF and its main biologically active receptor VEGFR-2 were highly expressed in primary and recurrent GCTs, when compared with normal granulosa-lutein cells. The expression of VEGF correlated positively to tumor microvessel density and to VEGFR-2 expression at the protein (P!0.05) and mRNA (P!0.05) levels. In contrast to VEGFR-2, the expression of VEGFR-1 was weak. Tumor VEGF protein expression was not prognostic for recurrence, however, we found high levels of circulating VEGF in the serum of patients with primary GCT. Conclusions:The results suggest an important role of VEGF and VEGFR-2 in GCT pathology and support the possibility of applying novel VEGF-or VEGFR-2-targeted treatments to patients with GCT.

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Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are highly expressed in ovarian granulosa cell tumors

Färkkilä¹,

Anttonen²,

Pociuviene³

et al. 2011

European Journal of Endocrinology

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“…Tyrosine kinase inhibitors therefore represent attractive anti-tumour or anti-vascular targets in the clinic [7,9]. Several multi-target tyrosine kinase inhibitors that include targeting VEGF receptors have reached clinical practice or are in clinical trial [10,11]. Under some dosing strategies, treatment with VEGFR-2 receptor antibodies or small molecule inhibitors can result in tumour vascular 'normalisation', whereby vascular morphology is altered and blood flow is improved over a limited time-frame [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Microflow of fluorescently labelled red blood cells in tumours expressing single isoforms of VEGF and their response to vascular targeting agents

Akerman

Reyes-Aldasoro

Fisher

et al. 2011

Medical Engineering & Physics

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“…1; refs. [8][9][10]. In preclinical studies, BIBF 1120 has been shown to inhibit the growth of and to reduce vessel density in s.c. implanted human tumor xenografts in nude mice (8,11).…”

Section: Introductionmentioning

confidence: 99%

“…[8][9][10]. In preclinical studies, BIBF 1120 has been shown to inhibit the growth of and to reduce vessel density in s.c. implanted human tumor xenografts in nude mice (8,11). A previous phase I BIBF 1120 monotherapy study in patients with advanced and heavily pretreated malignancies showed encouraging antitumor activity and a tolerable safety profile.…”

Section: Introductionmentioning

confidence: 99%

Phase I Safety, Pharmacokinetic, and Biomarker Study of BIBF 1120, an Oral Triple Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors

Okamoto

Kaneda

Satoh

et al. 2010

Molecular Cancer Therapeutics

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BIBF 1120 is an oral multitargeted tyrosine kinase inhibitor that blocks the activity of vascular endothelial growth factor (VEGF) and other growth factor receptors. We have done a phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamic biomarkers of BIBF 1120. Patients with advanced refractory solid tumors were treated with BIBF 1120 at oral doses of 150 to 250 mg twice daily. Drug safety and pharmacokinetics were evaluated, as were baseline and post-treatment levels of circulating CD117-positive bone marrow-derived progenitor cells and plasma soluble VEGF receptor 2 as potential biomarkers for BIBF 1120. Twenty-one patients were treated at BIBF 1120 doses of 150 (n = 3), 200 (n = 12), or 250 mg twice daily (n = 6). Dose-limiting toxicities of reversible grade 3 or 4 elevations of liver enzymes occurred in 3 of 12 patients at 200 mg twice daily and 3 of 6 patients at 250 mg twice daily. Stable disease was achieved in 16 (76.2%) patients, and median progression-free survival was 113 days (95% confidence interval, 77-119 d). Pharmacokinetic analysis indicated that the maximum plasma concentration and area under the curve for BIBF 1120 increased with the dose within the dose range tested. Levels of CD117-positive bone marrow-derived progenitors and soluble VEGF receptor 2 decreased significantly during treatment over all BIBF 1120 dose cohorts. In conclusion, the maximum tolerated dose of BIBF 1120 in the current study was determined to be 200 mg twice daily, and our biomarker analysis indicated that this angiokinase inhibitor is biologically active. Mol Cancer Ther; 9(10); 2825-33. ©2010 AACR.

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Phase I Clinical Study of AZD2171, an Oral Vascular Endothelial Growth Factor Signaling Inhibitor, in Patients With Advanced Solid Tumors

Abstract: Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.

Cited by 289 publications

References 30 publications

Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are highly expressed in ovarian granulosa cell tumors

Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are highly expressed in ovarian granulosa cell tumors

Microflow of fluorescently labelled red blood cells in tumours expressing single isoforms of VEGF and their response to vascular targeting agents

Phase I Safety, Pharmacokinetic, and Biomarker Study of BIBF 1120, an Oral Triple Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors

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