Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study

Liu, Glenn; Rugo, Hope S.; Wilding, George; McShane, Teresa M.; Evelhoch, Jeffrey L.; Ng, Chaan S.; Jackson, Edward F.; Kelcz, Frederick; Yeh, Benjamin M.; Lee, Fred T.; Charnsangavej, Chusilp; Park, John W.; Ashton, Edward A.; Steinfeldt, Heidi; Pithavala, Yazdi K.; Reich, Steven D.; Herbst, Roy S.

doi:10.1200/jco.2005.04.143

Cited by 254 publications

(145 citation statements)

References 31 publications

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“…We believe the efficacious dose range was probably covered by the doses evaluated in the phase 1 study; each of these doses was safe. In future studies in phase 2 patient populations that are more homogeneous for disease, stage, and prior treatment history, we will assess biomarkers such as CEPs (Bertolini et al, 2003), and dce-MRI (Galbraith et al, 2003;Liu et al, 2005) to refine dose selection. Preclinical studies of ATN-161, for example, suggest that at least one of these biomarkers also exhibits a U-shape in the response to ATN-161.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2), a beta integrin antagonist, in patients with solid tumours

Kimmel²,

et al. 2006

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To evaluate the toxicity, pharmacological and biological properties of ATN-161, a five -amino-acid peptide derived from the synergy region of fibronectin, adult patients with advanced solid tumours were enrolled in eight sequential dose cohorts (0.1 -16 mg kg À1 ), receiving ATN-161 administered as a 10-min infusion thrice weekly. Pharmacokinetic sampling of blood and urine over 7 h was performed on Day 1. Twenty-six patients received from 1 to 14 4-week cycles of treatment. The total number of cycles administered to all patients was 86, without dose-limiting toxicities. At dose levels above 0.5 mg kg À1 , mean total clearance and volume of distribution showed dose-independent pharmacokinetics (PKs). At 8.0 and 16.0 mg kg À1 , clearance of ATN-161 was reduced, suggesting saturable PKs. Dose escalation was halted at 16 mg kg À1 when drug exposure (area under the curve) exceeded that associated with efficacy in animal models. There were no objective responses. Six patients received more than four cycles of treatment (4112 days). Three patients received 10 or more cycles (X280 days). ATN-161 was well tolerated at all dose levels. Approximately, 1/3 of the patients in the study manifested prolonged stable disease. These findings suggest that ATN-161 should be investigated further as an antiangiogenic and antimetastatic cancer agent alone or with chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2), a beta integrin antagonist, in patients with solid tumours

Kimmel²,

et al. 2006

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“…In addition to this, tissue uptake curves generated with values of T c on the order of 1 s result in errors well above 500% for v p (data not shown). Error is further increased when the AIF is mis-sampled, and it is particularly striking that when data are sampled at temporal resolutions greater than 9 s, which is typical of the temporal resolution currently employed in some studies (32)(33)(34)(35), errors for both K trans and v p are greatly increased.…”

Section: Discussionmentioning

confidence: 99%

Comparison of errors associated with single‐ and multi‐bolus injection protocols in low‐temporal‐resolution dynamic contrast‐enhanced tracer kinetic analysis

Roberts

Buckley

Parker

2006

Magnetic Resonance in Med

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Accurate sampling of the arterial input function (AIF) in lowtemporal-resolution quantitative dynamic contrast-enhanced MRI (DCE-MRI) studies is crucial for accurate and reproducible parameter estimation. However, when conventional AIFs are sampled at low temporal resolution, they introduce an unpredictable degree of error. An alternative double contrast agent (CA) bolus injection protocol designed to compensate for temporal mis-sampling of the AIF and tissue uptake curve was simulated in addition to a commonly used single CA bolus injection protocol. A range of tissue uptake curves for each AIF form were generated using a distributed parameter model, and Monte Carlo simulation studies were performed over a range of offset times (to mimic temporal mis-sampling), temporal resolutions and SNR in order to compare the performance of both AIF forms in compartmental modeling. Insufficient data sampling of the single bolus AIF at temporal resolutions in excess of 9 s leads to large errors, which can be reduced by employing an additional, appropriately administered, second CA bolus injection. Magn Reson Med 56:611-619, 2006.

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“…Such studies require careful quality control and are increasingly managed by contract research organisations specialising in advanced imaging applications. Multicentre DCE-MRI trial feasibility has been demonstrated by studies of the tyrosine kinase inhibitors AG-013736 (Liu et al, 2005) and BIBF 1120 . At present, two baseline scans are recommended for all studies (to define parameter reproducibility) , but guidelines on the timing of MRI scanning and the choice of imaging parameters are less clear.…”

Section: Imaging Protocolmentioning

confidence: 99%

“…A single averageenhancement curve can be extracted and used to generate values of parameters of interest (such as IAUC or K trans ), and the same parameters can then be compared following therapy (Dowlati et al, 2002;Morgan et al, 2003;Liu et al, 2005;Mross et al, 2005a;Thomas et al, 2005). This method ignores heterogeneity within the tumour.…”

Section: Region Of Interest and Statistical Analysismentioning

confidence: 99%

“…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%

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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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Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study

Cited by 254 publications

References 31 publications

Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2), a beta integrin antagonist, in patients with solid tumours

Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2), a beta integrin antagonist, in patients with solid tumours

Comparison of errors associated with single‐ and multi‐bolus injection protocols in low‐temporal‐resolution dynamic contrast‐enhanced tracer kinetic analysis

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

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