Phase I clinical evaluation of AZD2171, a highly potent VEGF receptor tyrosine kinase inhibitor, in patients with advanced tumors

Drevs, Joachim; Medinger, Michael; Mross, Klaus; Zirrgiebel, Ute; Strecker, Ralph; Unger, Clemens; Puchalski, T. A.; Fernandes, N.; Roberston, J F R; Siegert, Patrizia

doi:10.1200/jco.2005.23.16_suppl.3002

Cited by 48 publications

(22 citation statements)

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“…In apparent contrast to some preclinical findings [56], other groups have reported similar observations in cancer patients treated with various anti-VEGF receptor TKIs (e.g. vatalanib and sunitinib), and have also found a decrease in soluble VEGF receptor 2 levels in the plasma [57][58][59]. Recently, significant elevations in plasma VEGF and PlGF have been confirmed, together with a decrease in soluble VEGF receptor 2 in glioblastoma patients treated with the anti-VEGF receptor TKI cediranib [51].…”

Section: Biomarkers Of Anti-vegf Therapymentioning

confidence: 89%

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

Duda

Batchelor

Willett

et al. 2007

Trends in Molecular Medicine

125

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Despite setbacks, the clinical development of antiangiogenic agents has accelerated remarkably over the past 3-4 years. Consequently, there are currently three direct inhibitors of the VEGF pathway approved for use in cancer therapy. Other agents that block the VEGF pathway are in advanced stages of clinical development and have shown promising results. With these exciting developments come crucial questions regarding the use of these new molecular-targeted agents, alone or in combination with standard cytotoxic or targeted agents. Importantly, the mechanisms of action of anti-VEGF therapy remain unknown. Here, we discuss several potential mechanisms of action such as tumor vascular normalization, bone marrow-derived cell recruitment blockade and cytostatic effects of anti-VEGF therapy. We review the current progress, the major stumbling blocks and the future directions for anti-cancer therapy using anti-VEGF agents, emphasizing clarification of the underlying molecular mechanisms of action and biomarker identification and validation.

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Section: Biomarkers Of Anti-vegf Therapymentioning

confidence: 89%

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

Duda

Batchelor

Willett

et al. 2007

Trends in Molecular Medicine

125

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“…The pattern and magnitude of changes of sVEGFR-2 were similar between patients with CB and PD, suggesting that sVEGFR-2 may be useful as a pharmacodynamic marker of drug exposure but not CB in patients with GIST. Preliminary results from a phase I study of the pan-VEGFR inhibitor AZD2171 (40), and recently published results using SU11248 in a phase I study (41) and phase II study in patients with RCC (42), suggest that sVEGFR-2 may be a useful pharmacodynamic marker for other drugs targeting VEGFRs, and furthermore, have utility as a biomarker across other types of malignancies as well. Next, we investigated cellular markers in the peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor

Norden-Zfoni

Desai

Manola

et al. 2007

Clinical Cancer Research

193

126

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Purpose: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors. Experimental Design: Patients (n = 73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of >6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC). Results: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus −−0.01 CEC/μL/d, P = 0.03) and smaller decreases in monocyte levels (47% versus 60%, P = 0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment. Conclusions: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.

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“…However changes in K trans did not predict response rate (RR) (Wedam et al, 2006). Several tyrosine kinase inhibitors, notably AG-013736 (Liu et al, 2005), BIBF1120 (Mross et al, 2005b) and AZD2171 (Drevs et al, 2005) have all shown dose-dependent reductions in K trans and IAUC without demonstrating clinical response. Few trials have demonstrated a relationship between DCE-MRI biomarker and clinical outcome measure.…”

Section: Biomarker Evidence Of Drug Effect -What Does It Mean?mentioning

confidence: 99%

“…Reduction, in K i of X40% has predicted which patients progressed with glioblastoma multiforme in a trial of PTK787/ZK222584 (PTK/ZK) (Conrad et al, 2004). Changes in K trans following trials of AZD2171 (Drevs et al, 2005) and BMS-582664 (Rosen et al, 2006) have helped define the effective dose to take into phase II studies.…”

Section: Biomarker Evidence Of Drug Effect -What Does It Mean?mentioning

confidence: 99%

DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents

et al. 2007

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Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is now frequently used in early clinical trial assessment of antiangiogenic and vascular disrupting compounds. Evidence of drug efficacy and dose-dependent response has been demonstrated with some angiogenesis inhibitors. This review highlights the critical issues that influence T 1 -weighted DCE-MRI data acquisition and analysis, identifies important areas for future development and reviews the clinical trial findings to date.

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Phase I clinical evaluation of AZD2171, a highly potent VEGF receptor tyrosine kinase inhibitor, in patients with advanced tumors

Cited by 48 publications

References 0 publications

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor

DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents

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