This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Drevs, J. Articles by Unger, C. Search for Related Content PubMed PubMed Citation Articles by Drevs, J. Articles by Unger, C. Related Articles Related Editorial Social Bookmarking                            What's this?

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

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

From the Tumor Biology Center; MR Development and Application Center, Albert Ludwigs University; ProQinase GmbH; University Hospital, Freiburg, Germany; AstraZeneca, Macclesfield, Cheshire, United Kingdom; and AstraZeneca, Wilmington, DE

Address reprint requests to Joachim Drevs, MD, PhD, Clinic Sanafontis, An den Heilquellen 2, 79111 Freiburg, Germany; e-mail: drevs{at}sanafontis.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy.

Patients and Methods In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed.

Results Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (C_max) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t_1/2z) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC₆₀) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related.

Conclusion 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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Recognition of the importance of angiogenesis in solid tumor growth has led to the search for, and evaluation of, agents with antiangiogenic activity.¹ Vascular endothelial growth factor (VEGF) is a key proangiogenic factor that plays a critical role in blood vessel formation,^2-8 primarily through activation of VEGF receptor 2 (VEGFR-2; kinase insert domain receptor) located on vascular endothelial cells.^9,10

Inhibition of VEGF/VEGFR signaling represents a significant antitumor strategy. Combining bevacizumab, an anti–VEGF-A monoclonal antibody, with certain chemotherapy regimens has demonstrated clinically relevant improvements in survival in colorectal cancer¹¹ and non–small-cell lung cancer^12,13; antitumor activity has also been observed in renal cell carcinoma using multikinase inhibitors that possess VEGFR signaling inhibitory effects (sorafenib and sunitinib).^14,15 AZD2171 is an oral potent and selective inhibitor of VEGF signaling that inhibits VEGFR-2 tyrosine kinase activity at subnanomolar concentrations (inhibitory concentration of 50% [IC₅₀] < 1 nmol/L) in vitro.¹⁶ AZD2171 also potently inhibits VEGFR-1 (IC₅₀ = 5 nmol/L) and VEGFR-3 (IC₅₀ 3 nmol/L) tyrosine kinase activity.¹⁶ The antitumor activity of AZD2171 has been demonstrated in a range of histologically diverse xenograft models, and this activity is consistent with potent inhibition of VEGF signaling and angiogenesis.¹⁶

This study (2171IL/0001) was, to our knowledge, the first clinical evaluation of AZD2171, with the primary objective to assess the safety and tolerability of increasing doses of AZD2171 in patients with advanced solid tumors. Secondary objectives included determination of the pharmacokinetic profile of AZD2171 after single and multiple oral doses, investigation of the effect of AZD2171 on markers of biologic activity (dynamic contrast-enhanced magnetic resonance imaging [DCE-MRI] measures and VEGF/VEGFR levels), and preliminary evaluation of efficacy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patients
Adult patients with histologic or cytologic evidence of metastatic or advanced solid tumors refractory to standard treatments, or for whom no standard treatment existed, were recruited at a single center in Germany. Patients with liver metastases and tumors were required to have a liver lesion assessable using DCE-MRI. Patients were required to have a life expectancy of at least 12 weeks and a WHO performance status of 0 to 2. The main exclusion criteria were significant hematopoietic, hepatic, or renal dysfunction; a history of CNS tumors or metastases; a history of ischemic heart disease, myocardial infarction or unstable cardiac disease; left ventricular ejection fraction of 45% or less; poorly controlled hypertension; and other anticancer agents or surgery within the previous 4 weeks. All patients provided written informed consent, and the trial was conducted in accordance with the Declaration of Helsinki.

Study Design
This phase I, single-center, open-label study was conducted in two parts (A and B). The overall study design is summarized in Figure A1 (online only). Part A was a dose-escalation study in which successive cohorts of three to eight patients received a single oral dose of AZD2171 (0.5, 1, 2.5, 5, 10, 20, 30, 45, or 60 mg) followed by a 2- to 7-day observation period with safety and pharmacokinetic assessments and subsequent once-daily treatment at the same dose level. The primary objective of part A was to evaluate the safety and tolerability of single and multiple oral doses and to select three potentially active and well-tolerated doses for further assessment of biologic activity and safety in part B. In the open-label, randomized, parallel group, cohort-expansion phase (part B), patients were randomly assigned to once-daily oral AZD2171 (20 [n = 10], 30 [n = 14], or 45 mg [n = 12]). In both parts, patients received AZD2171 until tumor progression or uncontrollable toxicity was observed. All patients in part A had metastatic liver disease. In part B, a minimum of 30 patients with liver lesions were required for the DCE-MRI analysis, but additional patients without liver lesions were also considered eligible to assess the safety of AZD2171 in a broader patient population: Patients with liver lesions were randomly assigned to receive AZD2171 and patients without liver metastases (up to four per dose group) were randomly assigned separately.

In both parts, treatment continued until evidence of tumor progression or dose-limiting toxicity (DLT). If a DLT was observed in at least 50% of patients within a dose cohort, that dose was considered above the maximum-tolerated dose (MTD), and dose escalation was stopped. A DLT was defined as any adverse event (AE) of at least Common Terminology Criteria version 2.0 (CTC 2.0) grade 3 that was considered by the investigator to be related to AZD2171, or an increase from baseline in QT or QTc interval of at least 60 ms and/or a QT or QTc interval of more than 490 ms on two consecutive ECGs recorded at least 24 hours apart that occurred within the first 28 days of daily dosing with AZD2171. A modified CTC 2.0 definition of grade 3 hypertension was used (ie, that which required more intensive therapy than before and did not respond to treatment within 48 hours). Safety review meetings were held for each cohort.

Safety and Tolerability
Since this was the first clinical study of AZD2171, extensive safety and tolerability assessments were performed. After full physical examination at enrollment, AEs were recorded throughout the study and graded according to CTC 2.0. Because this was the first study in humans, routine 12-lead ECGs were performed and vital signs measured at screening and throughout the study. Assessments of blood pressure and ECGs were based on internationally standardized methods as described in the Appendix (online only).

Pharmacokinetic Assessments
Blood samples were collected after single and multiple doses at various time points during the study. Pharmacokinetic assessments are described in the Appendix.

Pharmacodynamic Assessments
Tumor blood flow and vascular permeability were assessed using DCE-MRI evaluation of liver lesions.¹⁷ Changes in DCE-MRI parameters iAUC₆₀ (mmol/L · sec) and area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC₆₀) and transport constant (K^trans; min^–1) were measured as indicators of tumor blood flow and permeability. ¹⁸ A review of the DCE-MRI data from the initial cohorts in part A found that iAUC₆₀ was less variable than K^trans, and subsequently, iAUC₆₀ was selected as the primary DCE-MRI measure for this trial.

Soluble markers of angiogenesis (VEGF, basic fibroblast growth factor [b-FGF], VEGFR-1, VEGFR-2, placental growth factor [PlGF], TIE-2, E-selectin, and interleukin 8 [IL-8] levels) were measured in serum and plasma samples. Details of the methods used to analyze the soluble markers of angiogenesis are described in the Appendix.

Tumor Response Evaluation
Baseline imaging was performed 4 weeks or less before the start of study treatment. Tumor size was evaluated every 4 weeks for the first 12 weeks after the start of daily dosing with AZD2171. Objective tumor response was evaluated by classifying a single lesion, measured predominately in the liver, as a target lesion, with other lesions representative of all involved organs classified and followed as nontarget lesions. Tumor size was assessed using the longest diameter for the target lesion. Response was then classified in an identical manner to Response Evaluation Criteria in Solid Tumors (RECIST)¹⁹ with an additional non-RECIST category of minor response, defined as a decrease from baseline of at least 10% and less than 30% on two consecutive visits with no other evidence of progressive disease. An unconfirmed partial response was defined as an isolated partial response without confirmatory follow-up data. Where patients are described as alive and progression free at week 12, a week-12 scan must have been performed to confirm their progression-free status.

Statistical Analyses
Statistical analyses are detailed in the Appendix. Briefly, analysis of covariance models were used to assess the dose response of AZD2171 on tumor size, blood pressure, and the DCE-MRI parameter of iAUC₆₀ for data from the randomly assigned part B. A power model was used to perform a preliminary assessment of dose proportionality for the multiple-dose pharmacokinetic parameters of maximum steady-state drug concentration in plasma during dosing interval (C_ss,max) and area under plasma concentration-time curve during any dosing interval at steady state (AUC_ss). Linear models were used to explore the relationship between percentage change from baseline in iAUC₆₀ and the following parameters: AUC_ss, C_ss,max, minimum steady-state drug concentration in plasma during dosing interval (C_ss,min), and dose first received.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patient Characteristics
A total of 83 patients were recruited into the study (Tables 1 and 2). Reasons for discontinuation with the study treatment included disease progression (n = 56) and AEs (n = 20).

In the randomized phase (part B), the mean change from baseline in systolic blood pressure after 28 days dosing was 5.5 (95% CI, –1.7 to 12.8), 7.9 (95% CI, 0.6 to 15.1) and 21.6 (95% CI, 12.9 to 30.3) mmHg for 20, 30, and 45 mg AZD2171, respectively. The relationship between systolic blood pressure and dose was shown to be statistically significant at the two-sided 5% level in the dose range 20 to 45 mg (overall P = .02; 45 mg v 30 mg, P = .02; 45 mg v 20 mg, P < .01; 30 mg v 20 mg, P = .64).

Pharmacokinetic Evaluation
After a single dose of AZD2171, maximal plasma concentrations were measured from 1 to 8 hours postdosing with an overall median value of 3.0 hours (Table 5; Fig A2A, online only). After attaining maximum serum concentration (C_max), the plasma concentration declined in an apparent biexponential manner with a terminal half-life ranging from 12.4 to 35.7 hours, with an overall arithmetic mean of approximately 22 hours (± 6.5 hours). The apparent oral clearance ranged from 2.52 to 61.0 L/h (overall arithmetic mean, 28.2 L/h; standard deviation [SD], 15.1 L/h).

DCE-MRI Analysis and Pharmacokinetic/ Pharmacodynamic Evaluation
A review of the DCE-MRI data from the initial cohorts in part A found that iAUC₆₀ was less variable than K^trans, and iAUC₆₀ was selected as the primary DCE-MRI measure for this trial (data not shown). The relationship between iAUC₆₀ and AUC_ss, C_ss,max, and C_ss,min obtained from multiple doses ranging from 0.5 to 60 mg from parts A and B is presented in Figure 1. The results of the statistical modeling showed that the pharmacokinetic parameters appear to be major determinants of the decrease in tumor vascular permeability as described by the DCE-MRI variable of iAUC₆₀ (R² range, 0.33 to 0.49) with all of the relationships being significant (two-sided P < .01). However, when the dose range was restricted to the doses explored in the randomly assigned part B (20, 30, and 45 mg), the pharmacokinetic parameters were not a major determinant (R² range, 0.12 to 0.35; data not shown). Furthermore, this can also be seen from statistical analysis of doses evaluated in randomly assigned part B (20, 30, and 45 mg). Similar pharmacokinetic/pharmacodynamic relationships were observed for K^trans as for iAUC₆₀ (data not shown). Other pharmacokinetic/pharmacodynamic models, including nonlinear models, were utilized to explore these relationships, but on the basis of model differentiation criteria and using the rule of parsimony, the linear regression model was optimal.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Plots showing the relationship between change in initial area under the curve, defined over 60 seconds postcontrast arrival in the tissue (iAUC60) obtained from day 28 and (A) area under plasma concentration-time curve during any dosing interval at steady state (AUCss), (B) maximum steady-state drug concentration in plasma during dosing interval (Css,max), and (C) minimum steady-state drug concentration in plasma during dosing interval (Css,min).

Statistical analyses revealed significant average reductions from baseline in iAUC₆₀ for all three doses in part B; however, there was no evidence of a dose effect within this range (Fig 2A). The average reduction in iAUC₆₀ from baseline was similar for each dose, and the magnitude of the reduction on day 2 was less compared with the reductions on days 28 and 56. Example DCE-MRI scans from a patient with a reduction in tumor iAUC₆₀ after single and multiple dosing with AZD2171 and corresponding MRI scans are shown in Figure 3. Findings from the statistical analysis of K^trans were consistent with those for iAUC₆₀ (data not shown).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Estimated percentage change (95% CI) from baseline in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) after 1, 28, and 56 days of dosing in study part B. Changes at doses 10 mg were not significant. No significant differences were detected between the doses. (B) Mean percentage change in soluble vascular endothelial growth factor receptor 2 (VEGFR-2) levels when AZD2171 is administered as once-daily doses from day 1. Baseline determined from screening and predose in single-dose phase. (C) Smallest postdose measurement of target lesion size from baseline in parts A and B. Scan data were not available for 18 patients. Of these, 16 withdrew before the first follow-up scan for the following reasons: adverse events (n = 11); progression that was not radiologically confirmed (n = 3); progression resulting from new lesion (n = 1); or unwillingness to continue study (n = 1). No target lesion data were available for two patients. Each bar in panel C represents one patient; dotted lines represent the boundaries for progressive disease (20%) and partial response (–30%).

View larger version (57K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) assessment of tumor blood flow and permeability. Example DCE-MRI parametric image of tumor initial area under the curve, defined over 60 seconds postcontrast arrival in the tissue (iAUC60) and transport constant (Ktrans) in a patient after single (24 hours [day 2]) and multiple (28 and 56 days) daily dosing with AZD2171 and corresponding T1 weighted pre- and postcontrast MRI scans. This patient with prostate cancer experienced a best overall response of partial response and had average tumor reductions in iAUC60 (68% reduction at 24 hours; 73% at 28 days and 84% at 56 days) and Ktrans (67% reduction at 24 hours; 83% at 28 days and 95% at 56 days).

Tumor Response Evaluation
The objective tumor responses from parts A and B combined are summarized in Figure A3 (online only). There were two confirmed partial responses; one in a patient with prostate cancer in the 45-mg cohort and one in a patient with renal cancer in the 60-mg cohort. In addition, 22 patients had stable disease comprising colorectal (n = 7), lung (n = 3), liver (n = 2), breast (n = 2), skin/soft tissue (n = 2), and stomach, head and neck, ovarian, biliary duct, thyroid, and pancreatic (n = 1 each) tumor types; these included two patients with an unconfirmed partial response and seven patients with a confirmed minor response (10% to 30% reduction). Minor responses were observed in patients with the following tumor types: breast (n = 2) and colorectal, lung, head and neck, liver and skin/soft tissue (n = 1 each). There was encouraging evidence of dose-related control of tumor growth. Dose-related increases in the percentage of patients with stable disease and dose-related reductions in the percentage of patients with progressive disease were observed (Fig A3). Furthermore, dose-related increases in the proportion of patients alive and progression free after 12 weeks of treatment were seen: AZD2171 10 mg or less, one (6%) of six; 20 mg, two (11%) of 19; 30 mg, two (10%) of 21; 45 mg, four (21%) of 19; and 60 mg, three (38%) of eight.

Figure 2C shows the smallest postdose measurement of the liver target lesion size for each patient obtained from scans conducted throughout the study. Analysis of the size of the single metastatic liver lesion for patients randomly assigned to doses in part B did not show a statistically significant dose effect within this range, but demonstrated a trend for a dose-related effect on change in tumor size (Fig A4, online only).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
In this phase I study of patients with advanced solid tumors with liver lesions, AZD2171 was generally well tolerated at doses of 45 mg or less. The most common dose-related AEs reported were hypertension, diarrhea, and dysphonia. Hypertension did not occur below 20 mg, and dose-related changes in blood pressure were observed at AZD2171 doses of 20 mg and higher. The increased incidence of dose-related hypertension seen in this study is most likely a result of the potent inhibitory effect of AZD2171 on VEGF signaling, and an increased incidence of hypertension has been reported in clinical investigations with other small-molecule VEGF tyrosine kinase inhibitors,^20-22 as well as with the anti–VEGF-A monoclonal antibody bevacizumab.^11,12 VEGF has vasodilatory activity, and agents that inhibit VEGF/VEGFR signaling may indirectly cause vasoconstriction by removing a single factor contributing to overall vasodilatory tone. In this study, hypertension was manageable by standard hypertension therapy (the most commonly prescribed antihypertensive agents were calcium channel antagonists). A hypertension management protocol, based on international guidelines,²³ has been developed for use in all future studies. It incorporates a standard, stepwise approach to the addition of antihypertension agents and clear guidelines for a temporary dose interruption or reduction. A randomized, double-blind phase II study to further investigate the management of hypertension at AZD2171 30 and 45 mg is currently ongoing in patients with advanced solid tumors.²⁴

After multiple oral doses of AZD2171 20 mg, the unbound C_ss,min was 4.86 times higher than the human umbilical vein endothelial cell proliferation IC₅₀, consistent with inhibition of target enzyme throughout the 24-hour dosing interval.¹⁶ This supports a once-daily oral dosing schedule for AZD2171. The interpatient variability in C_ss,max and AUC_ss is comparable with phase I data for other oral agents evaluated for the treatment of solid tumors.^25-28 Dose proportional increases in C_ss,max and AUC_ss were observed for multiple doses ranging from 0.5 to 60 mg. However, when data from part B were examined, this showed weak evidence to support dose proportionality with two-fold changes in dose resulting in less than two-fold changes in the pharmacokinetic parameters. It is likely that this analysis has been confounded by a disproportionate number of dose reductions in the higher doses; patients at the 30- and 45-mg dose who experience a higher than average exposure may have been more likely to undergo dose reduction, underestimating the true level of exposure at these doses and hence leading to less than proportional increases in exposure being obtained from the statistical analysis. Additional evaluation will be required to make a definitive statement about pharmacokinetic linearity.

Evaluation of novel targeted agents, such as VEGF signaling inhibitors, may be supported by the identification of suitable markers of biologic activity. These include measures of vascular density and permeability, as assessed using DCE-MRI.^29-31 The reduction in iAUC₆₀ on day 2 observed in this study suggests a reduction in vascular permeability, whereas the sustained effects on days 28 and 56 are likely to reflect changes in blood flow. Overall, the findings from the DCE-MRI investigation demonstrated that AZD2171 modulates tumor vascular physiology and reduces tumor blood flow and vascular permeability. Evaluation of an additional biologic marker, soluble VEGFR-2, showed dose- and time-dependent decreases at doses of 20 mg and lower. Although there was no evidence of a dose-response relationship for soluble VEGFR-2 levels at doses greater than 20 mg, the decrease was time dependent. The decreased levels of VEGFR-2 and increased levels of VEGF and PlGF in this clinical investigation of AZD2171 may be related to its highly potent antiangiogenic activity previously demonstrated in preclinical studies.¹⁶ In summary, the pharmacodynamic changes observed in the present study are consistent with inhibition of VEGF/VEGFR-dependent signaling with a dose/pharmacokinetic relationship, and similar findings have been reported for other agents.^15,30-32

There is encouraging evidence of dose-related control of tumor growth in this population of patients with advanced, treatment-refractory tumors. Dose-related increases in the percentage of patients with stable disease were observed, and there was evidence of dose-related reductions in the percentage of patients with progressive disease. These preliminary response data, in combination with the observed dose-related decreases in tumor size and the proportion of patients alive and progression free at week 12, suggest that AZD2171 monotherapy has activity in a range of tumor types, including those refractory to previous treatment. The preliminary evaluation of biologic activity of AZD2171 in this study using a combination of suitable markers and disease stabilization data demonstrate that it is biologically active at doses of 20 mg and higher, with a suggested MTD of 45 mg. As with all investigational compounds of this class, monitoring for signs of hypertension is advisable. AZD2171 (20, 30, and 45 mg) is currently being investigated in a range of tumor types, and recruitment to a series of randomized, double-blind phase II and phase II/III trials is ongoing.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Jane Robertson, AstraZeneca; Juliane M. Jürgensmeier, AstraZeneca; Thomas A. Puchalski, AstraZeneca; Helen Young, AstraZeneca; Owain Saunders, AstraZeneca Leadership: N/A Consultant: N/A Stock: Jane Robertson, AstraZeneca; Juliane M. Jürgensmeier, AstraZeneca; Thomas A. Puchalski, AstraZeneca; Owain Saunders, AstraZeneca Honoraria: N/A Research Funds: Klaus Mross, Funds, AstraZeneca Germany Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Joachim Drevs, Jane Robertson, Juliane M. Jürgensmeier, Thomas A. Puchalski, Helen Young, Owain Saunders

Administrative support: Klaus Mross

Provision of study materials or patients: Klaus Mross, Jane Robertson

Collection and assembly of data: Joachim Drevs, Patrizia Siegert, Michael Medinger, Klaus Mross, Ralph Strecker, Ute Zirrgiebel, Jan Harder, Hubert Blum, Clemens Unger

Data analysis and interpretation: Joachim Drevs, Patrizia Siegert, Michael Medinger, Klaus Mross, Ralph Strecker, Ute Zirrgiebel, Jan Harder, Hubert Blum, Jane Robertson, Juliane M. Jürgensmeier, Thomas A. Puchalski, Helen Young, Owain Saunders, Clemens Unger

Manuscript writing: Joachim Drevs, Patrizia Siegert, Ralph Strecker, Ute Zirrgiebel, Jan Harder, Hubert Blum, Jane Robertson, Thomas A. Puchalski, Helen Young, Clemens Unger

Final approval of manuscript: Joachim Drevs, Jane Robertson, Juliane M. Jürgensmeier, Thomas A. Puchalski, Helen Young, Owain Saunders, Clemens Unger

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Blood Pressure Measurements
Measurements were made after the patient has been resting supine for at least 5 minutes. Two or more readings were taken at 2-minute intervals and averaged. If the first two diastolic readings differed by more than 5 mmHg, an additional reading was obtained and averaged.

ECG Assessments
Twelve-lead ECGs were obtained after the patient has been lying down for 5 minutes. Two copies of ECG traces were recorded using the same ECG machine set at 25 and 50 mm/sec. Each study day, a physician reviewed the paper copies of each ECG. Heart rate; P and QRS duration; R-R, PQ, QT, and QTc intervals (ms); and height of the ST-segment and T-wave (mV) and T-wave morphology were determined by an external cardiologist.

Pharmacokinetic Assessments
The plasma pharmacokinetics of AZD2171 were characterized following both single dose (part A) and multiple doses (parts A and B). To estimate the single-dose pharmacokinetic profile of AZD2171 blood samples were obtained: 0 (pre), 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours postdose. For four patients in the 60-mg cohort, blood samples were obtained only up to 48 hours postdosing. To estimate the multiple-dose pharmacokinetic profile of AZD2171, blood samples were obtained before dosing on days 8, 15, 22, and 28 and at 1, 2, 3, 4, 6, 8, 12, and 24 hours after dosing on day 28. To be eligible for steady-state pharmacokinetic assessments, patients must have received once-daily oral administration for 7 consecutive days at the same dose before pharmacokinetic sampling on day 28.

Specimen Quantitation
Plasma concentrations of AZD2171 were determined by solid-phase extraction followed by reverse-phase liquid chromatography and detection by tandem mass spectrometry. The method was validated to cover the concentration range of 0.1 to 500 ng/mL, with 0.1 ng/mL adopted as the lower limit of quantification.

Pharmacokinetic Data Analysis
Single- and multiple-dose pharmacokinetic parameters of AZD2171 were determined by noncompartmental methods using the WINNonlin Professional Version software package (Scientific Consulting, Apex, NC). C_max, C_ss,max, C_ss,min, and time to reach peak or maximum concentration or maximum response after drug administration (t_max) were determined by visual inspection of the individual plasma concentration-time profiles. The half-life associated with terminal slope of a semilogarithmic concentration-time curve (t_1/2z) was determined by log-linear regression of those plasma time-concentrations considered to be in the terminal phase of drug disposition. The area under the plasma concentration-time curve from 0 to 24 hours after a single dose (AUC_0-24) and the area under the plasma concentration time curve from time zero to infinity (AUC) were estimated by the linear trapezoidal algorithm with extrapolation to time infinity for AUC using the slope of the terminal log concentration versus time data (-z). The apparent oral clearance (CL/F) was calculated as Dose/AUC. The AUC_ss was estimated by linear trapezoidal algorithm to the last data point of the 24-hour dosing interval. The TCP was calculated as the ratio of day-28 AUC_ss to AUC, and the R_ac was calculated as the ratio of AUC_ss to AUC_0-24.

Because some patients underwent dose reduction and/or took breaks in continuous dosing, it was necessary to present concentration and pharmacokinetic parameter data according to dose actually received to better understand the underlying pharmacokinetic properties of AZD2171. The dose received during the 7 days before pharmacokinetic sampling on day 28 of multiple dosing was the dose allocated for summarizing pharmacokinetic data. Pharmacokinetic sampling was not obtained before those scheduled on day 28 in patients who had their dose reduced during the first 28 days of repeated multiple doses.

Evaluation of Soluble Markers of Angiogenesis
Soluble markers of angiogenesis (VEGF, b-FGF, VEGFR-1, VEGFR-2, PlGF, TIE-2, E-selectin, and IL-8 levels) were measured in serum and plasma samples. VEGF and bFGF were measured in EDTA-plasma samples, with the remaining markers measured in serum. In part A, assessments were performed at screening and up to 36 hours after the first dose of AZD2171. Additional assessments were performed after 15 and 28 days of multiple dosing and every 28 days thereafter. In part B, assessments were performed at screening, 8 hours post–first dose, after 8 and 28 days of multiple dosing, and every 28 days thereafter.

Parameters were determined using the sandwich enzyme-linked immunosorbent assay (ELISA) technique with a specific capture antibody covering the bottom of the microtiter plate and a specific detection antibody recognizing the bound antigen. The resulting optical density values were translated into concentration by calibration against a standard curve obtained with the respective recombinant protein. With the exception of IL-8 (Bender MedSystems, Burlingame, CA), all ELISA sets were obtained from R&D Systems (Minneapolis, MN).

The parameter ELISA set included the following: VEGF, Quantikine Human VEGF immunoassay; bFGF, Quantikine HS Human FGF basic immunoassay; VEGFR-1, Quantikine Human Soluble VEGF R1/FLT-1 immunoassay; sVEGFR-2, Quantikine Human Soluble VEGFR-2 immunoassay; sTIE-2, Quantikine Human Tie-2 immunoassay; IL-8, Bender MedSystems human IL-8 immunoassay; and sE-Selectin, Parameter Human sE-Selectin immunoassay.

Statistical Analyses
Analysis of covariance (ANCOVA) models were used to assess the dose response of AZD2171 on tumor size, blood pressure, and the DCE-MRI parameter of iAUC₆₀ for data from the randomly assigned part B. Models contained a factor for dose (20, 30, or 45 mg) and a continuous baseline covariate. Tumor size was log transformed before analysis because it was found that this end point was multiplicative in nature. A statistically significant dose effect was declared if the corresponding test was significant at the two-sided 5% level. If this test was significant, P values associated with the pair-wise comparisons are presented. From the fitted models, adjusted means and associated 95% CIs were calculated for change from baseline at each dose level (20, 30, and 45 mg).

A preliminary assessment of dose proportionality was performed for the multiple-dose parameters of C_ss,max and AUC_ss. Dose proportionality was assessed using a power model [parameter = x dose^ß] where is the intercept and ß is the slope, measuring the extent of dose proportionality. Dose proportionality implies that a two-fold change in dose would result in a two-fold change in the pharmacokinetic parameter of interest (ie, ß = 1). Because of variability in the estimation of ß, dose proportionality was concluded if the range of the 90% CI for a two-fold change in dose contained 2 (ie, the range of the 90% CI for ß contained 1).

Linear models were used to explore the relationship between percentage change from baseline in iAUC₆₀ and the multiple-dose pharmacokinetic parameters of AUC_ss, C_ss,max, and C_ss,min. Models had baseline iAUC₆₀ fitted as a continuous covariate in the model. Statistical significance was concluded if the P value of the regression coefficient associated with the multiple-dose pharmacokinetic parameter was significant at the two-sided 5% level. In an attempt to better examine the pharmacokinetic/pharmacodynamic relationships, nonlinear models with various weighting schemes were also utilized, with the results compared to the linear model using penalized sums of squares. Furthermore, to assess whether the effect on iAUC₆₀ was best associated with the multiple-dose pharmacokinetic parameters or dose, percentage change from baseline in iAUC₆₀ was regressed against dose (0.5 to 60 mg). The dose used in this analysis was that first received, irrespective of dose reductions or delays.S

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Summary of study design. Part A (n = 36), increasing doses to define maximum-tolerated dose. Part B (n = 47), randomly assigned cohort expansion at potentially active doses: 20, 30, and 45 mg. Dotted line with arrow indicates sample obtained in part B only. DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; DLT, dose-limiting toxicity; PD, progressive disease; PK, pharmacokinetics; RECIST, Response Evaluation Criteria in Solid Tumors.

View larger version (29K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Geometric mean plasma concentration of (A) single and (B) multiple-dose AZD2171 (ng/mL).

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A3. Best overall response to treatment with AZD2171. Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). Twenty patients were nonassessable according to RECIST for the following reasons: withdrew before the first follow-up scan because of adverse events (n = 11); stable disease at day 28, but withdrew because of an adverse event before the stable disease cut-off at 6 weeks (n = 2); withdrew because of progression that was not radiologically confirmed (n = 4); stable disease at day 28, but took another study drug before the stable disease cut-off at 6 weeks (n = 1); unwilling to continue study (n = 1); or no nontarget lesion data available (n = 1).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A4. Estimated percentage change (95% CI) in size of target liver lesion after 56 days’ dosing in the randomly assigned study part B. Where data were not available from day 56, data from day 28 were used in the statistical plot.

	ACKNOWLEDGMENTS

	NOTES

 
Presented in part at the Gastrointestinal Cancers Symposium, San Francisco, CA, January 26-28, 2006; at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; and at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Ferrara N: VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2:795-803, 2002[CrossRef][Medline]

2. Asahara T, Murohara T, Sullivan A, et al: Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964-967, 1997[Abstract/Free Full Text]

3. Bates DO, Heald RI, Curry FE, et al: Vascular endothelial growth factor increases Rana vascular permeability and compliance by different signalling pathways. J Physiol 533:263-272, 2001[Abstract/Free Full Text]

4. Gerber HP, McMurtrey A, Kowalski J, et al: Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway: Requirement for Flk-1/KDR activation. J Biol Chem 273:30336-30343, 1998[Abstract/Free Full Text]

5. Jain RK: Molecular regulation of vessel maturation. Nat Med 9:685-693, 2003[CrossRef][Medline]

6. Keck PJ, Hauser SD, Krivi G, et al: Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309-1312, 1989[Abstract/Free Full Text]

7. Lamoreaux WJ, Fitzgerald ME, Reiner A, et al: Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc Res 55:29-42, 1998[CrossRef][Medline]

8. Senger DR, Galli SJ, Dvorak AM, et al: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983-985, 1983[Abstract/Free Full Text]

9. Gille H, Kowalski J, Li B, et al: Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2): A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 276:3222-3230, 2001[Abstract/Free Full Text]

10. Meyer M, Clauss M, Lepple-Wienhues A, et al: A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J 18:363-374, 1999[CrossRef][Medline]

11. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004[Abstract/Free Full Text]

12. Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004[Abstract/Free Full Text]

13. Sandler AB, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599. J Clin Oncol 23:2s, 2005 (suppl; abstr LBA4)

14. Escudier B, Szczylik C, Eisen T, et al: Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). J Clin Oncol 23:380s, 2005 (suppl; abstr LBA4510)

15. Motzer RJ, Michaelson MD, Redman BG, et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16-24, 2006[Abstract/Free Full Text]

16. Wedge SR, Kendrew J, Hennequin LF, et al: AZD2171: A highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389-4400, 2005[Abstract/Free Full Text]

17. Strecker R, Scheffler K, Buchert M, et al: DCE-MRI in clinical trials: Data acquisition techniques and analysis methods. Int J Clin Pharmacol Ther 41:603-605, 2003[Medline]

18. Leach MO, Brindle KM, Evelhoch JL, et al: The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: Issues and recommendations. Br J Cancer 92:1599-1610, 2005[CrossRef][Medline]

19. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

20. Drevs J, Muller-Driver R, Wittig C, et al: PTK787/ZK 222584, a specific vascular endothelial growth factor-receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging. Cancer Res 62:4015-4022, 2002[Abstract/Free Full Text]

21. Raymond E, Faivre S, Vera K, et al: Final results of a phase I and pharmacokinetic study of SU11248, a novel multi-target tyrosine kinase inhibitor, in patients with advanced cancers. Proc Am Soc Clin Oncol 21:192, 2003 (abstr 769)

22. Veronese ML, Flaherty KT, Townsend R, et al: Pharmacodynamic study of the raf kinase inhibitor BAY 43-9006: Mechanisms of hypertension. J Clin Oncol 22:135s, 2004 (suppl; abstr 2035)

23. Chobanian AV, Bakris GL, Black HR, et al: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 289:2560-2572, 2003[Abstract/Free Full Text]

24. Study to investigate the management of hypertension and efficacy of AZD2171 in patients with advanced solid tumours. http://www.clinicaltrials.gov/ct/show/NCT00264004?order=1

25. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001[Abstract/Free Full Text]

26. Judson I, Ma P, Peng B, et al: Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: A retrospective population pharmacokinetic study over time—EORTC Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 55:379-386, 2005[CrossRef][Medline]

27. Mross K, Drevs J, Muller M, et al: Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer 41:1291-1299, 2005[CrossRef][Medline]

28. Ranson M, Hammond LA, Ferry D, et al: ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 20:2240-2250, 2002[Abstract/Free Full Text]

29. Checkley D, Tessier JJ, Kendrew J, et al: Use of dynamic contrast-enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 prostate tumours. Br J Cancer 89:1889-1895, 2003[CrossRef][Medline]

30. Liu G, Rugo HS, Wilding G, et al: 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. J Clin Oncol 23:5464-5473, 2005[Abstract/Free Full Text]

31. Morgan B, Thomas AL, Drevs J, et al: Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies. J Clin Oncol 21:3955-3964, 2003[Abstract/Free Full Text]

32. Thomas AL, Morgan B, Horsfield MA, et al: Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol 23:4162-4171, 2005[Abstract/Free Full Text]

Submitted May 16, 2006; accepted March 7, 2007.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

• Hypertension, Proteinuria, and Antagonism of Vascular Endothelial Growth Factor Signaling: Clinical Toxicity, Therapeutic Target, or Novel Biomarker?
  Willem J. van Heeckeren, Jose Ortiz, Matthew M. Cooney, and Scot C. Remick
  JCO 2007 25: 2993-2995 [Full Text]

This article has been cited by other articles:

				P. Bhargava VEGF kinase inhibitors: how do they cause hypertension? Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2009; 297(1): R1 - R5. [Abstract] [Full Text] [PDF]

				J. Iwasaki and S.-i. Nihira Anti-angiogenic Therapy Against Gastrointestinal Tract Cancers Jpn. J. Clin. Oncol., June 16, 2009; (2009) hyp062v1. [Abstract] [Full Text] [PDF]

				H. Izzedine, S. Ederhy, F. Goldwasser, J. C. Soria, G. Milano, A. Cohen, D. Khayat, and J. P. Spano Management of hypertension in angiogenesis inhibitor-treated patients Ann. Onc., May 1, 2009; 20(5): 807 - 815. [Abstract] [Full Text] [PDF]

				L. Horn and A. B. Sandler Angiogenesis in the Treatment of Non-Small Cell Lung Cancer Proceedings of the ATS, April 15, 2009; 6(2): 206 - 217. [Abstract] [Full Text] [PDF]

				E. Chen, D. Jonker, I. Gauthier, M. MacLean, J. Wells, J. Powers, and L. Seymour Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer Clin. Cancer Res., February 15, 2009; 15(4): 1481 - 1486. [Abstract] [Full Text] [PDF]

				S. J. Crabb, D. Patsios, E. Sauerbrei, P. M. Ellis, A. Arnold, G. Goss, N. B. Leighl, F. A. Shepherd, J. Powers, L. Seymour, et al. Tumor Cavitation: Impact on Objective Response Evaluation in Trials of Angiogenesis Inhibitors in Non-Small-Cell Lung Cancer J. Clin. Oncol., January 20, 2009; 27(3): 404 - 410. [Abstract] [Full Text] [PDF]

				A. Idbaih, F. Ducray, M. Sierra Del Rio, K. Hoang-Xuan, and J.-Y. Delattre Therapeutic Application of Noncytotoxic Molecular Targeted Therapy in Gliomas: Growth Factor Receptors and Angiogenesis Inhibitors Oncologist, September 1, 2008; 13(9): 978 - 992. [Abstract] [Full Text] [PDF]

				C. A. Heckman, T. Holopainen, M. Wirzenius, S. Keskitalo, M. Jeltsch, S. Yla-Herttuala, S. R. Wedge, J. M. Jurgensmeier, and K. Alitalo The Tyrosine Kinase Inhibitor Cediranib Blocks Ligand-Induced Vascular Endothelial Growth Factor Receptor-3 Activity and Lymphangiogenesis Cancer Res., June 15, 2008; 68(12): 4754 - 4762. [Abstract] [Full Text] [PDF]

				J. O. Curwen, H. L. Musgrove, J. Kendrew, G. H.P. Richmond, D. J. Ogilvie, and S. R. Wedge Inhibition of Vascular Endothelial Growth Factor-A Signaling Induces Hypertension: Examining the Effect of Cediranib (Recentin; AZD2171) Treatment on Blood Pressure in Rat and the Use of Concomitant Antihypertensive Therapy Clin. Cancer Res., May 15, 2008; 14(10): 3124 - 3131. [Abstract] [Full Text] [PDF]

				S. A. Laurie, I. Gauthier, A. Arnold, F. A. Shepherd, P. M. Ellis, E. Chen, G. Goss, J. Powers, W. Walsh, D. Tu, et al. Phase I and Pharmacokinetic Study of Daily Oral AZD2171, an Inhibitor of Vascular Endothelial Growth Factor Tyrosine Kinases, in Combination With Carboplatin and Paclitaxel in Patients With Advanced Non-Small-Cell Lung Cancer: The National Cancer Institute of Canada Clinical Trials Group J. Clin. Oncol., April 10, 2008; 26(11): 1871 - 1878. [Abstract] [Full Text] [PDF]

				W. J. van Heeckeren, J. Ortiz, M. M. Cooney, and S. C. Remick Hypertension, Proteinuria, and Antagonism of Vascular Endothelial Growth Factor Signaling: Clinical Toxicity, Therapeutic Target, or Novel Biomarker? J. Clin. Oncol., July 20, 2007; 25(21): 2993 - 2995. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Drevs, J. Articles by Unger, C. Search for Related Content PubMed PubMed Citation Articles by Drevs, J. Articles by Unger, C. Related Articles Related Editorial Social Bookmarking                            What's this?