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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

Scott A. Laurie, Isabelle Gauthier, Andrew Arnold, Frances A. Shepherd, Peter M. Ellis, Eric Chen, Glenwood Goss, Jean Powers, Wendy Walsh, Dongsheng Tu, Jane Robertson, Thomas A. Puchalski, Lesley Seymour

From the From the Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa; Juravinski Cancer Centre, McMaster University, Hamilton; Princess Margaret Hospital, University of Toronto, Toronto; National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada; and AstraZeneca, Macclesfield, United Kingdom

Corresponding author: Scott A. Laurie, MD, FRCPC, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa ON K1H 8L6, Canada; e-mail: slaurie{at}ottawahospital.on.ca

	ABSTRACT

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

 
Purpose AZD2171 is a potent inhibitor of vascular endothelial growth factor receptors that showed broad antitumor activity in preclinical models. Doses of up to 45 mg/d of AZD2171 are tolerable when administered alone. This study evaluated escalating doses of AZD2171 in combination with standard chemotherapy in patients with advanced non–small-cell lung cancer.

Patients and Methods Eligible patients received carboplatin targeted to an area under the concentration time curve of 6 mg · min/mL and paclitaxel 200 mg/m², both on day 1 of a 3-week cycle; daily oral AZD2171 at either 30 mg or 45 mg commenced day 2 of cycle 1. Pharmacokinetics of all drugs were performed, and tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST).

Results Twenty patients were enrolled. No dose-limiting toxicities were observed during cycle 1 at either dose. Fatigue, diarrhea, anorexia, and granulocytopenia were common; hypertension was manageable with a treatment algorithm designed for this protocol. No clinically significant drug-related bleeding was observed. At 45 mg/d, fatigue and diarrhea were increased, and headache and hoarseness were observed. Paclitaxel clearance decreased during cycle 2, but no other significant pharmacokinetic interactions were observed. After radiology review, confirmed responses were observed in nine patients (response rate, 45%; 95% CI, 23% to 68%); all but one enrolled patient showed evidence of tumor shrinkage, some with cavitation.

Conclusion AZD2171 can be combined with standard doses of carboplatin/paclitaxel with encouraging antitumor activity. Toxicity is increased, but predictable and manageable.

	INTRODUCTION

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More than 130,000 patients were estimated to die in the United States in 2006 as a result of non–small-cell lung cancer (NSCLC).¹ For advanced disease, the expected median survival with standard platinum-based regimens is less than 12 months.^2,3 Docetaxel⁴ and erlotinib⁵ lead to modest improvements in survival in the second-line setting. New treatment approaches are clearly needed.

Tumors require the ingrowth of new blood vessels (angiogenesis), and vascular endothelial growth factor (VEGF) is a key angiogenic factor.⁶ It also has a permeabilizing effect that may contribute to tumor progression by facilitating both nutrient exchange and tumor cell intravasation during the metastatic process. Two high-affinity receptors, vascular endothelial growth factor receptor (VEGFR)-1 and VEGFR-2 are found on vascular endothelial cells, while a third, VEGFR-3, is expressed on lymphatic endothelium. Markers of angiogenesis, such as serum VEGF levels and high tumor microvessel density, may be negatively prognostic in lung cancers.⁷

Two studies have shown that the addition of bevacizumab, a humanized monoclonal antibody against VEGF-A (a ligand for VEGFR-1 and -2), to standard platinum-based doublet chemotherapy improves outcomes over chemotherapy alone in advanced NSCLC,^8,9 although the three-drug combination is associated with greater toxicity, and, in one subgroup analysis, the survival benefit was limited to men. These studies excluded patients with brain metastases and tumors of squamous histology, those with a history of hemoptysis or prior thromboembolic events and patients requiring therapeutic anticoagulation, because of episodes of fatal hemoptysis observed in the pilot randomized phase II trial.¹⁰

AZD2171 (cediranib, AstraZeneca, Macclesfield, UK) is a small-molecule inhibitor of the tyrosine kinase domain of all three VEGFRs, with a median inhibition concentration (IC₅₀) value of less than 1 nmol/L for VEGFR-2, and less than 5 nmol/L for the other VEGFRs.¹¹ Preclinical studies have shown broad antitumor activity, including in NSCLC. For AZD2171 as a single agent, continuous daily oral dosing up to 45 mg seems tolerable, with the most frequently reported adverse events (AEs) being fatigue, nausea, diarrhea, and hypertension¹²; there was some suggestion of a dose-related antitumor effect. In combination with cytotoxic chemotherapy, the maximum-tolerated dose has varied between 20 and 45 mg.^13-15 We report here a phase I study of AZD2171 in combination with standard carboplatin/paclitaxel for advanced NSCLC.

	PATIENTS AND METHODS

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Patients
Eligible patients had advanced, incurable NSCLC (stage IV, or IIIB with effusion or unsuitable for chemoradiotherapy), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, adequate hematology (CBC) and organ function, and no more than one prior single-agent (nontaxane) chemotherapy (prior adjuvant or neoadjuvant chemotherapy was permitted if completed > 6 months before enrollment). Prior epidermal growth factor receptor (EGFR) therapy was permissible. At least 28 days must have elapsed from prior therapies, with recovery from all toxicities.

Patients were excluded if they had received prior angiogenesis inhibitor therapy, or if they had uncontrolled hypertension, serious medical or cardiac conditions, QTc prolongation, significant proteinuria, hemoptysis or cavitation of central pulmonary lesions, untreated brain metastases that were symptomatic or required steroids, were pregnant (or refused contraception if of childbearing potential), or had had prior malignancy within 5 years of entry. Therapeutic anticoagulation was not a contraindication, but for patients receiving warfarin, increased monitoring of the international normalized ratio was recommended, as was a switch to low molecular weight heparin (LMWH), if medically appropriate.

This study was approved by the research ethics boards of each center. All patients provided written informed consent, and the study was conducted in accordance with good clinical practice guidelines. The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) sponsored the trial and performed all data management and analyses. The primary objective was to determine the recommended phase II dose (RP2D) of daily oral AZD2171 in combination with standard carboplatin/paclitaxel in these patients. Secondary objectives were to determine the toxicity and pharmacokinetics (PK) profile, and antitumor activity.

Patient Evaluation
Pretreatment evaluation included a physical examination, CBC and differential, biochemistry, thyroid function, coagulation parameters, ECG, chest x-ray, and other imaging to document disease. On treatment, CBCs were performed weekly (cycles 1 and 2) and a physical examination, CBC, and biochemistry every 3 weeks. Disease status was assessed every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST).¹⁶ Toxicity was graded using the Common Toxicity Criteria for AEs version 3.0 (National Cancer Institute, Bethesda, MD).

Therapy
Paclitaxel (200 mg/m² over 3 hours with standard premedication) and carboplatin (area under the concentration-time curve (AUC) of 6 mg · min/mL) were administered every 3 weeks for up to eight cycles.

AZD2171 was administered orally daily starting on day 2 of the first cycle. Planned dose levels were 30 mg and 45 mg. Three patients were enrolled to each cohort, and three additional patients were enrolled if a dose-limiting toxicity (DLT) was observed. Escalation to 45 mg was planned if fewer than two patients experienced DLT. De-escalation to 20 mg was planned if required. The highest administered dose was the dose at which two or more patients experienced DLT, and the next lower dose level would be the RP2D of AZD2171 in combination.

DLT was defined as the following AZD2171-related toxicities in cycle 1: grade 3 or worse renal toxicity, fatigue or hand-foot syndrome; delay of cycle 2 chemotherapy by 14 days or longer; grade 4 hypertension or uncontrollable grade 3 hypertension; and an increase in severity or frequency of the expected toxicity of chemotherapy.

Dose Modifications for Toxicity
Paclitaxel and carboplatin were adjusted for toxicities according to manufacturers' guidelines. Patients who discontinued chemotherapy could continue AZD2171 in the absence of disease progression or unacceptable toxicity. Therapy with AZD2171 was discontinued for grade 4 toxicity, and held for grade 2 to 3 toxicity. AZD2171 could be restarted after resolution to grade 1 at either the same dose (for grade 2 toxicity) or at one dose level lower (for grade 3 toxicity). For renal toxicity of grade 2 or 3, weekly 24-hour urine collections for creatinine clearance and protein were obtained. Patients requiring a delay of more than 2 weeks for any toxicity, and those who required more than two dose reductions, were removed from protocol therapy.

The standardized algorithm for the management of AZD2171-induced hypertension developed for this protocol is shown in Fig A1 (online only) and was designed to facilitate continued administration of AZD2171 without dose reduction or interruption when possible. The guidelines suggested a dihydropyridine calcium-channel blocker as the initial agent and recommended drugs with minimal CYP3A4 interactions.

PK
Blood samples were drawn for carboplatin and paclitaxel on day 1 of cycles 1 and 2, and for AZD2171 on day 1 of cycle 2, were centrifuged immediately, and were stored at –20°C until analysis. Both plasma carboplatin and paclitaxel were analyzed using validated high-performance liquid chromatograph with UV detection methods,^17,18 whereas AZD2171 plasma concentrations were measured as previously described.¹² PK parameters were calculated using noncompartmental methods (WINNonlin [Scientific Consultant, Apex, NC] 4.1, Pharsight Corp, Cary, NC). Effects of AZD2171 on PK parameters were analyzed using repeated two-way analysis of variance (SAS Inc, Cary, NC), whereas associations between day 1 and day 22 carboplatin and paclitaxel PK parameters (AUC, clearance and maximum serum concentration[C_max]) and myelosuppression and selected GI toxicities were analyzed using Kendall's correlation.¹⁹

	RESULTS

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Patients
Characteristics of the 20 enrolled patients are summarized in Tables 1 and 2. No patient had previously received chemotherapy; two had received a prior EGFR tyrosine kinase inhibitor. All patients were assessable for both toxicity and response.

One patient with DLT was observed in the first three enrolled to 45 mg (grade 3 febrile neutropenia, anorexia, diarrhea, and dehydration). Three additional patients were accrued without DLT, and the cohort was expanded as planned without further cycle-1 DLT.

Four patients (30 mg) were hospitalized for GI toxicity (cycles 2, 5, and 6); one patient died with a complex presentation attributed to possible sepsis. At 45 mg, four patients were hospitalized for febrile neutropenia (cycles 1 to 4), three patients had pulmonary emboli (cycle 4), and one patient had grade 3 hemoptysis (cycle 6, associated with disease progression and considered unrelated). Two 45-mg patients discontinued protocol therapy because of grade 3 arthralgias and grade 2 neuralgia (cycle 6), and grade 3 fatigue and grade 4 thrombosis (cycle 3), respectively, and one 30-mg patient discontinued therapy for acute cholecystitis in cycle 1.

Toxicity
Table 3 summarizes AZD2171 related AEs occurring with a frequency more than 15% or were grade 3 or worse for both cycle 1 and all cycles; the most common were fatigue, hypertension, diarrhea, mucositis, and anorexia. The 45-mg cohort experienced more severe fatigue and diarrhea and more common hoarseness, headache, and thrombotic events. All toxicities were more frequent in later cycles. Hematologic toxicity (Table 4) seemed similar at both doses. No clinically relevant biochemical toxicities were noted. Elevations in thyroid-stimulating hormone were observed in six patients, but there were no significant abnormalities observed in T3 or T4 levels, and no association with fatigue was noted. Proteinuria was never worse than grade 1 in severity.

Hypertension occurred in eight patients in each cohort, occurring in 11 of 15 patients with no prior history and in all five patients with preexisting hypertension. Initially, before the development of the algorithm, brief interruptions of AZD2171 were required. Grade 3 hypotension, thought to be related to diarrhea and subsequent dehydration, was observed in one patient.

Drug Delivery
The median actual dose intensity (ADI) of paclitaxel and carboplatin was similar in both dose levels, and dose delays and/or reductions of these drugs were commonly a result of myelosuppression (Table 6). Median ADI of AZD2171 dropped at each dose level after cycle 1. Ten percent of all doses of AZD2171 at 30 mg and 15% at 45 mg were missed, the majority because of nonhematologic toxicities.

Antitumor Activity
After central radiology review, there were nine confirmed partial responses (response rate, 45%; 95% CI, 23% to 68%), with a median duration of 8.1 months (range, 3.0 to 15 months). Eleven patients had stable disease, for a median duration of 6.4 months (range, 3.4 to 16 months). Cavitation of lung lesions was observed in four patients (one with squamous, three with other histologies). There was no relation between cavitation and hemoptysis. Responses for all 20 patients are detailed in Figure 1. Median time to progression was 7.6 months (range, 0.99 to 16.4 months).

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Response assessment. Asterisks indicate those patients with confirmed partial responses; one patient had a response that was not confirmed due to death during cycle 6 of therapy. AZD, AZD2171.

	DISCUSSION

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Although 45 mg was found to be the RP2D of daily single-agent AZD2171,¹² this dose was not tolerable in patients with advanced hepatocellular carcinoma²⁷ or in the majority of those with renal cell carcinoma.²⁸ In men with hormone-refractory prostate cancer, 20 mg/d was the maximum-tolerated dose.²⁹ The requirement for dose modification of the single-agent RP2D for use in combination with other anticancer agents is well described. In combination with 250 mg/d of gefitinib, 30 mg/d of AZD2171 was the maximum-tolerated dose.³⁰ In heavily-pretreated patients, when AZD2171 was administered in combination with standard cytotoxic agents such as pemetrexed, irinotecan, capecitabine and the combination of fluorouracil/leucovorin/oxaliplatin (mFOLFOX), 30 mg seemed more commonly tolerated.³¹ Interestingly, in another NCIC-CTG study, 45 mg was tolerable in less-heavily pretreated and carefully selected and managed patients in combination with mFOLFOX.¹⁵

We demonstrated that AZD2171 can be added to carboplatin and paclitaxel in patients with advanced NSCLC with incremental but manageable fatigue, GI toxicity, and possibly myelosuppression. Although the classical RP2D, based on cycle 1 DLT, was 45 mg for AZD2171, this dose seemed less well tolerated than 30 mg for prolonged usage with carboplatin/paclitaxel, and 30 mg/d was chosen as the RP2D for future studies in this patient population. In a second NCIC-CTG study in advanced NSCLC, there were no DLTs observed at 45 mg in combination with cisplatin and gemcitabine, but again, 30 mg was felt to be more tolerable for longer-term administration.¹⁴

The coadministration of carboplatin and paclitaxel with AZD2171 did not have an apparent effect on carboplatin or AZD2171 PK, but we noted a significant reduction in paclitaxel clearance on day 22 compared with day 1. Although an apparent increase in paclitaxel exposure in cycle 2 and later cycles has been demonstrated by other authors even when it is administered alone,³² AZD2171 is a weak inhibitor of CYP3A4 (AZD2171 investigator brochure), and could impair the biliary excretion of paclitaxel. In this study, there was a correlation between paclitaxel clearance and increased thrombocytopenia observed.

The decision to recommend a dose in this combination that is lower than the single-agent RP2D was carefully considered in view of concerns of a dose response. In combination with carboplatin/paclitaxel, a phase II study suggested improved efficacy with a higher dose of bevacizumab¹⁰; though in the phase III trial of cisplatin and gemcitabine with two doses of bevacizumab, there was no dose effect for progression-free survival—the primary outcome.⁹ The first phase I trial of AZD2171, which enrolled patients with all solid tumors, suggested a dose-response relationship.¹² In the current trial, antitumor activity was seen at both dose levels, with no suggestion of a dose effect. This was also observed in the second NCIC-CTG trial of cisplatin/gemcitabine in combination with AZD2171 in advanced NSCLC.¹⁴

As angiogenesis inhibitors enter into routine clinical use, medical oncologists will need to learn to manage their unique toxicities. The mechanism of hypertension associated with these agents is not fully understood. In patients treated with sorafenib, elevations in blood pressure did not seem to be related to alterations in renal function or perfusion, or to changes in humoral factors, such as catecholamine levels.³³ Measures of vascular stiffness, however, increased over the period of observation. VEGF is involved in nitrous oxide generation, and its inhibition may increase peripheral vascular resistance and vasoconstriction. Preclinical data suggest that vasodilators are effective at controlling the hypertension associated with these agents.³⁴ The algorithm developed for this clinical trial greatly facilitated clinical management of this mechanistic effect. Diarrhea was manageable with prompt institution of antidiarrheal agents and patient education. Fatigue, commonly reported with angiogenesis inhibitors, and occasionally associated in this trial with mild generalized weakness, is of uncertain etiology, and may be difficult to manage. Abnormalities of thyroid function are often observed with these agents, but it is not clear that exogenous thyroid hormone replacement improves fatigue in the absence of depressed levels of T3 or T4.³⁵ Clinically significant clearly drug-related bleeding episodes, renal dysfunction, or proteinuria were not observed in our study. Three episodes of venous thromboembolism were seen at 45 mg, but given the known risk of these events in patients with NSCLC receiving chemotherapy alone (8% in all patients enrolled on BR.18³⁶), the relative contribution of AZD2171 is unclear. Venous thromboembolic events were not increased when bevacizumab was added to standard chemotherapy for NSCLC.^8,9

In conclusion, in combination with a standard regimen of carboplatin-paclitaxel, AZD2171 administered daily at 30 mg is tolerable in patients with advanced NSCLC. Encouraging antitumor activity was observed with all but one patient showing some degree of tumor shrinkage. This combination is currently being studied in a randomized phase II/III trial, NCIC-CTG BR.24, in which patients with advanced NSCLC of any histology receive carboplatin/paclitaxel and either AZD2171 at 30 mg/d or placebo.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: Jane Robertson, AstraZeneca (C); Thomas A. Puchalski, AstraZeneca (C) Consultant or Advisory Role: Glenwood Goss, AstraZeneca (C) Stock Ownership: Jane Robertson, AstraZeneca; Thomas A. Puchalski, AstraZeneca Honoraria: Scott A. Laurie, AstraZeneca; Andrew Arnold, AstraZeneca; Frances A. Shepherd, AstraZeneca; Peter M. Ellis, AstraZeneca; Eric Chen, AstraZeneca; Glenwood Goss, AstraZeneca Research Funding: Scott A. Laurie, AstraZeneca Canada; Andrew Arnold, AstraZeneca; Glenwood Goss, AstraZeneca; Lesley Seymour, AstraZeneca Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Scott A. Laurie, Isabelle Gauthier, Frances A. Shepherd, Lesley Seymour

Administrative support: Jean Powers

Provision of study materials or patients: Scott A. Laurie, Andrew Arnold, Frances A. Shepherd, Peter M. Ellis, Glenwood Goss

Collection and assembly of data: Scott A. Laurie, Eric Chen, Jean Powers, Lesley Seymour

Data analysis and interpretation: Scott A. Laurie, Frances A. Shepherd, Eric Chen, Wendy Walsh, Dongsheng Tu, Lesley Seymour

Manuscript writing: Scott A. Laurie, Isabelle Gauthier, Andrew Arnold, Frances A. Shepherd, Peter M. Ellis, Eric Chen, Glenwood Goss, Jean Powers, Wendy Walsh, Dongsheng Tu, Jane Robertson, Lesley Seymour

Final approval of manuscript: Scott A. Laurie, Thomas A. Puchalski, Lesley Seymour

	Appendix

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View larger version (32K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Management of AI-induced hypertension. AI, angiogenesis inhibitor; DHP CCB, dihydropyridine calcium-channel blocker; BP, blood pressure.

View this table: [in this window] [in a new window]   Table A5. and β Blocker

	Glossary Terms

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Angiogenesis:

The process involved in the generation of new blood vessels. While this is a normal process that naturally occurs and is controlled by "on" and "of" switches, blocking tumor angiogenesis (antiangiogenesis) disrupts the blood supply to tumors, thereby preventing tumor growth.

VEGF (vascular endothelial growth factor):

VEGF is a cytokine that mediates numerous functions of endothelial cells including proliferation, migration, invasion, survival, and permeability. VEGF is also known as vascular permeability factor. VEGF naturally occurs as a glycoprotein and is critical for angiogenesis. Many tumors overexpress VEGF, which correlates to poor prognosis. VEGF-A, -B, -C, -D, and -E are members of the larger family of VEGF-related proteins.

VEGFR (vascular endothelial growth factor receptor):

VEGFRs are transmembrane tyrosine kinase receptors to which the VEGF ligand binds. VEGFR-1 (also called Flt-1) and VEGFR-2 (also called KDR/Flk-1[murine homologue]) are expressed on endothelial cells, while VEGFR-3 (also called Flt-4) is expressed on cells of the lymphatic and vascular endothelium. VEGFR-2 is thought to be principally responsible for angiogenesis and for the proliferation of endothelial cells. Typically, most VEGFRs have seven extracellular immunoglobulin-like domains, responsible for VEGF binding, and an intracellular tyrosine kinase domain.

Tyrosine kinase:

Generic name for enzymes that transfers a terminal phosphate group from ATP to specific protein tyrosine residues. Tyrosine kinases are a member of the family of protein kinases.

EGFR (epidermal growth factor receptor):

Also known as HER-1, EGFR belongs to a family of receptors (HER-2, HER-3, HER-4 are other members of the family) and binds to the EGF, TGF-, and other related proteins, leading to the generation of proliferative and survival signals within the cell. It also belongs to the larger family of tyrosine kinase receptors and is generally overexpressed in several solid tumors of epithelial origin.

Pharmacokinetics:

A branch of pharmacology that studies the relationship between drug exposure level, time course of exposure, and the overall response of an organism. Although it is largely applied to drugs, it is also applicable to other compounds such as nutrients, toxins, hormones, etc. Pharmacokinetics is subdivided into absorption and disposition (distribution, metabolism, and excretion) and is generally referred to as ADME (absorption, distribution, metabolism, excretion). With respect to drugs administered, all processes occur in tandem once a drug dose is administered. In clinical trials, phase I studies will typically study pharmacokinetics and safety of the drug.

CYP3A4:

Gene encoding cytochrome P450, subfamily IIIA (niphedipine oxidase), polypeptide 4. Notably present in the liver, the mixed-function oxidase is the most important enzyme involved in the metabolism of xenobiotics and oxidizes a wide range of substrates, including taxanes.

	NOTES

 
Supported by a grant from the Canadian Cancer Society. AstraZeneca Canada provided AZD2171 for this trial as well as partial funding.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA; the 8th International Symposium on Angiogenesis, February 3-5, 2006, San Diego, CA; and the 17th European Organisation for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research Symposium on Molecular Targets and Cancer Therapeutics, November 14-17, 2005, Philadelphia, PA.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

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

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Submitted September 19, 2007; accepted January 17, 2008.

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