Surrogate markers in antiangiogenesis clinical trials

Davis, Darren W.; McConkey, David J.; Abbruzzese, James L.; Herbst, Roy S.

doi:10.1038/sj.bjc.6601035

Cited by 75 publications

(50 citation statements)

References 33 publications

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“…This is consistent with earlier studies in sarcoma and other diseases in which elevated VEGF correlated with higher stage and/or poor outcome (20,51), although in one study of synovial sarcoma a correlation was not observed (53). It remains to be seen whether urinary VEGF levels will useful for predicting or monitoring responses to therapy (22).…”

Section: Discussionsupporting

confidence: 80%

“…Laser scanning cytometry was performed using a laser scanning cytometry instrument (CompuCyte, Corporation, Cambridge, MA) consisting of a base unit containing an Olympus BX50 fluorescent microscope and an optics unit coupled to an Argon and HeNe laser. The laser scanning cytometry analysis and identification of endothelial cells was performed as described previously (22,24). Briefly, endothelial cells were stained using a monoclonal antihuman CD31 (clone JC/70A, Dako Corporation, Carpinteria, CA) followed by Cy5-conjugated goat antimouse secondary (Jackson ImmunoResearch Laboratories, West Grove, PA).…”

Section: Methodsmentioning

confidence: 99%

“…For this reason, we have conducted a Phase II study of SU5416 in patients with advanced or metastatic soft tissue sarcoma. We have also explored potential markers of antiangiogenic activity including urine VEGF and basic fibroblast growth factor (bFGF) levels and tumor endothelial cell VEGFR phosphorylation assessed by laser scanning cytometry (22).…”

Section: Introductionmentioning

confidence: 99%

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Phase II Study of the Antiangiogenic Agent SU5416 in Patients with Advanced Soft Tissue Sarcomas

Heymach¹,

Desai²,

Manola

et al. 2004

Clinical Cancer Research

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Purpose: SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase II study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas.Experimental Design: Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m 2 twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment.Results: The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P ‫؍‬ 0.04). No grade 4 toxicities were observed.The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after 1 month of treatment (P ‫؍‬ 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting >36 months.Conclusions: SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor or KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.

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Section: Discussionsupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phase II Study of the Antiangiogenic Agent SU5416 in Patients with Advanced Soft Tissue Sarcomas

Heymach¹,

Desai²,

Manola

et al. 2004

Clinical Cancer Research

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“…Despite this activity, it has been difficult to assess the biological effects of these agents as they seem to be primarily cytostatic when used as monotherapy. To optimize the clinical testing of these agents, there is an unmet need for validated biomarkers to measure their biological effects, determine their optimal dose level, identify patients most likely to benefit from a given agent, and monitor responses to treatment (4,5).…”

mentioning

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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“…This has led to the interest of in developing surrogate pharmacokinetic, pharmacodynamic, correlative science or radiological parameters of antiangiogenesis activity (Davis et al, 2003). Plasma VEGF levels are one potential surrogate marker.…”

Section: Predictors Of Response To Bevacizumabmentioning

confidence: 99%