Phase I Dose Escalation Study of Telatinib, a Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor 2 and 3, Platelet-Derived Growth Factor Receptor β, and c-Kit, in Patients With Advanced or Metastatic Solid Tumors

  1. Hans Gelderblom
  1. From the Department of Medical Oncology, Erasmus University Medical Center, Rotterdam; Departments of Clinical Oncology and Radiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Clinical Pharmacology, Bayer Pharmaceuticals Corporation, Montville, NJ; and the Department of Clinical Pharmacology, Bayer Schering Pharma, Wuppertal, Germany.
  1. Corresponding author: Ferry A.L.M. Eskens, Department of Medical Oncology, Room HE-120, Erasmus University Medical Center, PO Box 2040, Rotterdam, 3000 CA, the Netherlands; e-mail: f.eskens{at}erasmusmc.nl.

  1. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006: and at the 2006 Annual Meeting of the American Association for Cancer Research, National Cancer Institute, European Organisation for the Research and Treatment of Cancer, November 7-10, Prague, Czech Republic.

  1. F.A.L.M.E. and N.S. contributed equally to this article.

 
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Abstract

Purpose Telatinib (BAY 57-9352) is an orally available tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor-β, and c-Kit. This phase I dose escalation study was conducted to evaluate the safety and tolerability of telatinib, with additional pharmacokinetic, pharmacodynamic, and efficacy assessments.

Patients and Methods Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Doses of continuously administered telatinib were escalated from 20 mg once daily to 1,500 mg twice daily.

Results Fifty-three patients were enrolled. Most frequently observed drug-related adverse events were nausea (26.4%; grade ≥ 3, 0%) and hypertension (20.8%; grade 3, 11.3%; grade 4, 0%). Two dose-limiting toxicities were observed: one poorly controlled hypertension (600 mg twice daily), and one grade 2 weight loss, anorexia, and fatigue (1,500 mg twice daily). A formal maximum-tolerated dose was not reached. Telatinib was rapidly absorbed, with median time to peak concentration (tmax) lower than 3 hours after dose. A nearly dose-proportional increase in exposure was observed with substantial variability. Telatinib half-life averaged 5.5 hours. Biomarker analyses showed dose-dependent increase in VEGF levels and decrease in plasma soluble VEGFR-2 levels, with a plateau at 900 mg twice daily. A decrease in tumor blood flow (Ktrans and IAUC60) was observed with dynamic contrast-enhanced magnetic resonance imaging. Best tumor response was stable disease, observed in 50.9% of patients.

Conclusion Telatinib was safe and well tolerated up to 1,500 mg twice daily. Based on pharmacodynamic and pharmacokinetic end points, telatinib 900 mg twice daily is the recommended dose for subsequent phase II studies.

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INTRODUCTION

The vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play a pivotal role in tumor-related angiogenesis, and the VEGF/VEGFR pathway is an important target for antiangiogenic drug development and tumor therapy.1–8

Telatinib (BAY 57-9352) is an orally available, potent inhibitor of VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR-β), and c-Kit tyrosine kinases. Telatinib inhibits VEGFR-2 autophosphorylation in a whole-cell assay of receptor autophosphorylation with an inhibitory concentration (IC50) of 19 nmol/L. Telatinib also inhibits VEGF-dependent proliferation of human umbilical vein endothelial cells with an IC50 of 26 nmol/L and PDGF-stimulated growth of human aortic smooth muscle cells with an IC50 of 249 nmol/L. Telatinib demonstrates antitumor activity in various cancer models. Formation of the N-glucuronides of telatinib is identified as the major biotransformation pathway in man. Telatinib is metabolized by various cytochrome-P450 isoforms and UGT1A4.9,10

We performed a phase I, pharmacologic, and biomarker study of telatinib. Objectives were to determine maximum-tolerated dose (MTD) and define dose-limiting toxicities (DLT); characterize safety; pharmacokinetics; and biomarkers of biologic activity, including serum markers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) results, and evaluate antitumor activity.

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PATIENTS AND METHODS

Eligibility Criteria

Patients with histologically or cytologically confirmed advanced or metastatic solid tumors for whom no standard therapy was available, with an Eastern Cooperative Oncology Group performance status ≤ 2, were eligible. Other inclusion criteria were assessable or measurable disease by Response Evaluation Criteria in Solid Tumors; age ≥ 18 years; life expectancy ≥ 12 weeks; adequate bone marrow, liver, and renal function (hemoglobin ≥ 9.0 g/dL; absolute neutrophil count ≥ 1,500/mm3; platelet count ≥ 100,000/mm3; total bilirubin ≤ 1.5× the upper limit of normal (ULN); ALT and AST ≤ 2.5× ULN, (liver metastases AST/ALT < 5× ULN); alkaline phosphatase ≤ 4× ULN; prothrombin international normalized ratio and prothrombin time less than 1.5× ULN; serum creatinine ≤ 1.5× ULN). Exclusion criteria were: history of cardiac disease; HIV, hepatitis B or C infection; active infection; serious nonhealing wound, ulcer, or bone fracture; symptomatic metastatic brain or meningeal tumors unless more than 6 months after definitive therapy without evidence of tumor growth, and clinically stable; seizure disorder requiring anticonvulsant medication; history of organ allograft; pregnancy or breast feeding; history of any condition that could endanger the safety of the patient; anticancer treatment fewer than 4 weeks before the first dose; previous antiangiogenic therapies/VEGFR-2 inhibitors.

Written informed consent from all patients and approval from the institutional review boards was obtained.

Drug Administration and Dose Escalation Procedure

Telatinib was administered orally, once daily or twice daily, on a continuous basis. Based on toxicologic data, pharmacokinetic data, and a parallel phase I study with telatinib administered in a 14 days on/7 days off schedule, the starting dose was 20 mg once daily. The formulations used in this study were: solution formulation (20 mg once daily cohort), 25 mg telatinib mesylate tablet formulation (75 mg once daily cohort), and 150 mg telatinib mesylate tablet formulation (twice daily dosing cohorts). For the purpose of analysis, one cycle was defined as 21 days of administration.

Doses were doubled for subsequent cohorts if no drug-related toxicity in cycle 1 was observed. When DLT had been observed or following toxicity ≥ grade 2 in ≥ 2 patients, subsequent dose increments were 33% to 66%.

DLT was defined as grade 4 neutropenia ≥ 7 days, febrile neutropenia, grade 4 thrombocytopenia, grade 3 thrombocytopenic bleeding, and any drug-related grade 3 or 4 nonhematologic toxicity excluding alopecia, nausea, and vomiting not refractory to antiemetics, and hypertension not refractory to antihypertensive medication during the first cycle.

If DLT was observed in one patient, three additional patients were recruited at that dose level, with dose escalation proceeding if fewer than two of six patients exhibited DLT. Because pharmacokinetic results of the initial two cohorts showed significant interpatient variability, all subsequent cohorts were expanded to a minimum of six patients. If DLT was observed in ≥ two of three or ≥ two of six patients, the MTD had been exceeded, and additional patients were recruited at the next lower dose level. The MTD was defined as the highest dose level that could be given to six patients with fewer than one patient experiencing DLT. If a patient experienced a drug-related DLT, telatinib was withheld for up to 3 weeks. If toxicity resolved to ≤ grade 1, the dose of telatinib was reduced to the next lower dose level. Otherwise, the patient was withdrawn from the study. Administration of telatinib was continued until disease progression or unacceptable toxicity.

One additional cohort of four patients was enrolled (as part of a larger group in a companion study) to evaluate the bioavailability of a new 300-mg mesylate tablet formulation in comparison to the 150-mg mesylate tablet formulation. Patients received a single dose of 900 mg using the 300-mg tablet and continued with 150-mg tablets.

Pretreatment Evaluation and Safety Assessment

Pretreatment evaluation consisted of a complete medical history, physical examination, Eastern Cooperative Oncology Group performance status assessment, vital signs, baseline 12 lead ECG, blood sample for CBC, coagulation analysis, biochemistry analysis, sample for urinalysis, serum pregnancy test, plasma and urine sampling for biomarkers, baseline tumor measurements, and DCE-MRI.

On days 1 and 14 of each cycle, evaluation consisted of a brief history and physical examination, vital signs, blood samples for CBC, biochemistry, and coagulation analysis, urinalysis, 12-lead ECG. Response evaluation was performed every two cycles and was assessed according to Response Evaluation Criteria in Solid Tumors.11 Patients were evaluated weekly in the first cycle and every 1 or 2 weeks in additional cycles for adverse events and toxicity according to the National Cancer Institute Common Toxicity Criteria, version 3.0.

Pharmacokinetic Evaluation

Pharmacokinetic (PK) evaluation was performed by collecting blood samples on days 1 and 14 of cycle 1, and day 14 of cycles 2 and 4 via an indwelling intravenous catheter. In cycle 1, a 5-mL sample was collected predose and at 0.5, 1, 2, 3, 4, 6, 8, 12 hours postdose. An additional sample was collected at 24 hours postdose for once daily regimen. In cycles 2 and 4, an abbreviated sampling schedule was used. PK parameters peak plasma concentration (Cmax), time to peak plasma concentration (tmax), area under the plasma concentration curve (AUC) to infinity (AUC0-tn), AUC0-24 (for once daily regimen), AUC0-12 (for twice daily regimen), and half-life for telatinib and its metabolite (BAY 60-8246) were calculated by noncompartmental analysis using WINNonlin (Scientific Consultant, Apex, NC; version 4.1.a).

Pharmacodynamic Analysis

Urine samples and 20 mL blood samples for pharmacodynamic (PD) analysis were collected at baseline, predose, and 8 hours postdose on days 1 and 14 of cycles 1 and 2 and on day 1 of cycle 3, and predose on day 1 of each subsequent cycle. The following parameters were measured: plasma soluble VEGFR-2 (sVEGFR-2), plasma VEGF, plasma basic fibroblast growth factor, plasma interleukin-8, urinary VEGF. Samples were analyzed using the relevant quantitative enzyme linked immunosorbent assay (R&D Systems Europe, Oxford, United Kingdom) according to the manufacturer's instructions.

DCE-MRI scans were performed at baseline, on day 2 of cycle 1, and on day 14 of cycles 2 and 3. We used a 1.5-T magnetic resonance (MR) imaging system (Philips Medical Systems, Best, the Netherlands) using a body coil in retroperitoneal and abdominal lesions. The tumors were localized using standard T1- and T2-fat saturated fast spin echo sequences. Subsequently, dynamic MR imaging was performed using T1-weighted turbo field-echo sequence with repitition time 5.4 seconds/echo time 1.4 seconds, flip angle of 20°, nonselective inversion preparatory pulse, with delay time of 165 milliseconds, and section thickness of 5 to 8 mm, with a temporal resolution, of 3 seconds during at least the first 84 seconds. Total acquisition time lasted 5 minutes. A power injector (Spectris; Medrad, Indianola, PA) with injection flow rate of 2 mL/sec was used to start intravenous administration of gadopentetate dimeglumine (Magnevist, Bayer-Schering, Berlin, Germany), which was followed by a 20-mL saline flush. Bolus injection was initiated 5 seconds after the start of data acquisition.12

Assessed parameter was Ktrans, describing the volume transfer coefficient of contrast between blood plasma and the tumor. Empirical quantitative methods were used to quantify the signal-intensity time curve using the initial area under the contrast-agent concentration-time curve after 60 seconds (iAUC60) and time to peak enhancement (TTPE; time period between arterial enhancement and the enhancement of the index lesions).13,14 The second precontrast dynamic images were automatically subtracted from all dynamic contrast-enhanced MR images using software of the MR system.

Statistical Analysis

Continuous variables are presented as mean values with or without standard deviation and categoric variables as frequencies (percentages), unless otherwise stated. Comparison between variables at baseline and postdose was performed with paired samples t-test or Wilcoxon signed rank test as appropriate. Correlations with drug exposure were assessed by Spearman's rank correlation coefficient. All analyses were performed using SPSS version 12.01 (SPSS, Chicago, IL) and were two sided, with a level of significance of α = .05.

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RESULTS

Between July 2004 and October 2006, 53 patients were enrolled. Patient characteristics are summarized in Table 1.

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Table 1.

Baseline Demographics and Patient Characteristics

Safety and Tolerability

All treatment-related adverse events are summarized in Table 2. Most frequently reported treatment-related adverse events were nausea (26.4%) and hypertension (20.8%). Six episodes of grade 3 drug-related hypertension were observed. There was no apparent dose relationship. Grade 4 drug-related hypertension was not observed. Hypertension was easily manageable with antihypertensive medication in most cases.

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Table 2.

Patients With Treatment-Related Adverse Events

Two DLTs were observed. At 600 mg twice daily, one episode of poorly controlled hypertension in a patient with metastatic renal cell carcinoma, prior nephrectomy, and pre-existing hypertension was observed. Despite addition of a third antihypertensive agent and two dose reductions, grade 3 hypertension persisted and telatinib was permanently discontinued. At 1,500 mg twice daily, one episode of the combination of persistent grade 2 weight loss, grade 2 anorexia, and grade 2 fatigue was felt to be intolerable by the patient and therefore was considered DLT. Despite two dose reductions, this patient did not tolerate telatinib. Four additional patients experienced possible drug-related adverse events requiring dose reduction, interruption, or discontinuation. One patient at 300 mg twice daily reported grade 2 diarrhea requiring permanent discontinuation of telatinib. One patient at 600 mg twice daily experienced grade 3 AST and ALT elevation, normalizing after dose reduction. One patient at 900 mg twice daily with well-controlled pre-existing hypertension reported grade 3 headache requiring two dose reductions of telatinib. One patient at 1,500 mg twice daily discontinued telatinib after an episode of otherwise uncomplicated grade 3 esophageal varices bleeding. Due to the low incidence of treatment-related DLT, a formal MTD could not be defined.

PK

Telatinib PK parameters are summarized in Table 3. Telatinib was rapidly absorbed, with tmax values observed fewer than 3 hours postdose.

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Table 3.

Best Tumor Response Related to Telatinib Dose Administered

Although an overall dose proportional increase in exposure was observed in the 150- to 1,500-mg twice daily dose range, high interpatient variability was observed, similar to that observed with other VEGFR or epidermal growth factor receptor tyrosine kinase inhibitors.15–20 In the intermediate dose levels (eg, 300 mg twice daily and 600 mg twice daily) deviation from dose proportionality was observed likely due to PK variability. Plasma half-life of telatinib averaged 5.5 hours and was consistent with the observation that steady-state is achieved within the first 14 days of telatinib administration. A limited number of patients provided cycle 4 PK samples, yielding comparable results at cycle 2 day 14 and cycle 4 day 14.

There was no correlation between telatinib exposure and toxicity or time to progression. This is partly due to the low incidence of some of the toxicities and the relatively small number of patients per cohort.

Comparison of geometric mean AUC of telatinib and its metabolite BAY 60-8246 indicate that exposure to the metabolite is lower than 20% of exposure to parent compound.

In a cohort of four patients for whom bioavailability of the 300-mg mesylate tablet was compared to that of the 150-mg mesylate tablet, high interpatient variability in the PK parameters precluded a definitive conclusion.

PD: sVEGFR-2 and VEGF Plasma Levels

Changes in plasma levels of VEGF and sVEGFR-2 in relation to telatinib dose are summarized in Figures 1A and 1B. Over the dose range studied, increasing exposure to telatinib resulted in lower plasma sVEGFR-2 levels (both predose and postdose) after 14 continuous days of dosing (Figs 1C and 1D; Table 4) There was no statistical correlation between dose of telatinib and plasma levels of VEGF and sVEGFR-2. Changes in plasma levels of VEGF and sVEGFR-2 plateaued at 900 mg twice daily, suggesting a saturable effect. There were no consistent changes in plasma levels of basic fibroblast growth factor, and interleukin-8 and urinary levels of VEGF.

Fig 1.
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Fig 1.

Biomarker results: (A) plasma vascular endothelial growth factor (VEGF) and (B) soluble VEGF receptor 2 (sVEGFR-2) levels; individual patient ratios over baseline value for cycle 1 days 1 through cycle 2 day 14, predose and postdose. Plasma sVEGFR-2 ratio over baseline value versus (C) telatinib area under the plasma concentration curve for 24 hours (AUC0-24) on cycle 1 day 14 and versus (D) telatinib peak plasma concentration on cycle 1 day 14.

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Table 4.

Pharmacokinetics of Telatinib

DCE-MRI

Reproducible DCE-MRI results for screening and at least for one postscreening assessment were available from 16 subjects for evaluation of Ktrans and iAUC60, and from 32 patients for evaluation of TTPE. DCE-MRI data for evaluation of Ktrans and iAUC60 were missing from 37 patients for several reasons: no DCE-MRI performed (n = 17), analysis unreliable due to poor quality (ie, low signal-to-noise ratio), interference artifacts (n = 14), only one scan performed (n = 4), no contrast agent given (n = 1), or unknown (n = 1). DCE-MRI data for evaluation of TTPE were missing from 21 patients for the following reasons: no DCE-MRI performed (n = 17), only one scan performed (n = 1), no contrast agent given (n = 1), or unknown (n = 2).

DCE-MRI results are summarized in Table 5. For TTPE, a clear dose-response relationship was seen. TTPE changes from baseline were positively correlated to telatinib AUC.

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Table 5.

DCE-MRI Results

Antitumor Activity

A disease control rate of 50.9% was observed with 27 of 53 patients having stable disease as best tumor response (Table 5). Disease control for 6 to 12 months was seen in three patients, 12 to 18 months in two patients, and longer than 18 months in four patients. There were no complete or partial responses, however, some degree of tumor shrinkage was observed in 16 patients (30.2%).

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DISCUSSION

In this phase I dose escalation study, we explored tolerability, safety, and biologic activity of the selective VEGFR tyrosine kinase inhibitor telatinib (BAY 57-9352).

With regard to safety, the most frequently reported treatment-related adverse events were nausea (26.4%) and hypertension (20.8%). Nausea occurred throughout all dose levels and was mild. Hypertension was easily managed with a maximum of two antihypertensive agents in all but one patient. Based on previous experience and considering the potential underlying mechanisms of the observed hypertension, angiotensine converting enzyme inhibitors, and calcium antagonists were most frequently prescribed. It is conceivable that hypertension should be considered an indication of biologic activity of VEGF inhibitors rather than as an adverse effect.1,3,15,21–25

As only one of six patients at 1500 mg twice daily experienced DLT (combination of grade 2 weight loss, anorexia, and fatigue), we formally could not define the MTD of telatinib based on clinical toxicity. Even though grade 2 toxicity formally did not define DLT in this study, on ongoing (combination of) grade 2 toxicity induced by continuous drug administration must be considered to be cumbersome and therefore can define as intolerable.

In our study, PK of telatinib were dose proportional in the overall dose range studied, albeit with substantial interpatient variability and deviation from dose proportionality in the intermediate dose levels. This observation may be attributed to inherent variability in absorption and/or metabolism of telatinib, as well as various patient and tumor characteristics. In a parallel study with telatinib, a markedly less than dose proportional increase in exposure was observed at dose levels exceeding 900 mg twice daily.26

Telatinib induced changes in plasma levels of VEGF and sVEGFR-2 that are consistent with findings in trials with telatinib and other VEGFR inhibitors.15,16,19,26,27 These changes plateaued at 900 mg twice daily suggesting a saturable effect.

Based on the combined analysis of PK and PD results observed in the two dose escalation studies with telatinib, and based on practical issues such as number of tablets to be taken, we defined 900 mg twice daily as the dose recommended for phase II studies. Based on the mechanism of action of VEGFR-2 tyrosine kinase inhibitors, a continuous dosing schedule may prove to have optimal activity, and therefore studies exploring continuous administration of telatinib in combination with various anticancer therapies have been initiated.28

DCE-MRI analysis revealed changes in TTPE that are correlated to telatinib exposure. Similar studies with other angiogenesis inhibitors support our results.29–31 A trend to a dose-effect relationship was seen, but no significant correlation could be assessed. We could not determine a statistical correlation between DCE-MRI results and clinical outcome such as disease control rate (data not shown separately). Even though DCE-MRI analyses should be considered a nonvalidated technique, results obtained in our study indicate an antiangiogenic effect of telatinib and seem to support the results of additional analyses of changes in flow-mediated dilation, nitroglycerin-mediated dilation, and capillary density that were done in this study and are reported separately.32

Determining antitumor activity of telatinib was a secondary end point of this study. Complete or partial responses were not observed in this study, but some minor tumor regressions and prolonged periods of disease stabilization are indicative of antitumor activity and merit confirmation in a phase II study program. Among cases of prolonged disease stabilization was a young patient with an epitheloid hemangioendothelioma of the scalp who was on medication for longer than 3 years.

Two VEGF tyrosine kinase inhibitors (sunitinib and sorafenib) have gained regulatory approval. Telatinib may have some theoretical advantages over sunitinib and sorafenib. Theoretically, adverse effects like thyroid dysfunction, cardiac function impairment, and reversible posterior leukoencephalopathy syndrome observed with sunitinib or sorafenib may be caused by blocking pathways not described in the preclinical or clinical studies or by the redirection of signals through other pathways.33–38 These adverse effects can therefore by agent specific and to date, albeit in a relatively small number of patients, telatinib has not induced any of these adverse effects.

Compared to telatinib, vatalanib (PTK787/ZK222584) seems to have some similarities. In our opinion, telatinib has potential benefit over vatalanib. The IC50 of vatalanib for VEGFR-3, c-kit, and PDGFRβ are 18, 20, and 16 times higher, respectively, than the IC50 for VEGFR-2. For telatinib these IC50s are 0.66, 0.17, and 2.5 times higher, respectively. Activation of VEGFR-3 in lymphatic endothelial cells can facilitate lymphangiogenesis and lymphatic spread of tumor cells.39 Therefore, theoretically, the superior potency of telatinib compared to vatalanib with regard to VEGFR-3 inhibition will hopefully translate into increased clinical efficacy. Future studies will have to prove this optimism.

In conclusion, telatinib (BAY 57-9352) administered as continuous treatment is safe and well tolerated. Based on the combined analysis of clinical, PD, and PK end points, 900 mg twice daily is the dose recommended for future phase II studies.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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: Olaf Christensen, Bayer Pharmaceuticals (C); Joern Kraetzschmar, Bayer Healthcare AG (C); Prabhu Rajagopalan, Bayer Pharmaceuticals (C) Consultant or Advisory Role: None Stock Ownership: Joern Kraetzschmar, Bayer AG Honoraria: Jaap Verweij, Bayer Research Funding: Jaap Verweij, Bayer Expert Testimony: None Other Remuneration: None

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AUTHOR CONTRIBUTIONS

Conception and design: Ferry A.L.M. Eskens, Neeltje Steeghs, Jaap Verweij, Olaf Christensen, Hans Gelderblom

Administrative support: Leni van Doorn, Jan Ouwerkerk, Maja J.A. de Jonge

Provision of study materials or patients: Ferry A.L.M. Eskens, Neeltje Steeghs, Jaap Verweij, Johan L. Bloem, Leni van Doorn, Jan Ouwerkerk, Maja J.A. de Jonge, Hans Gelderblom

Collection and assembly of data: Ferry A.L.M. Eskens, Neeltje Steeghs, Jaap Verweij, Johan L. Bloem, Leni van Doorn, Jan Ouwerkerk, Maja J.A. de Jonge, Joern Kraetzschmar, Hans Gelderblom

Data analysis and interpretation: Ferry A.L.M. Eskens, Neeltje Steeghs, Jaap Verweij, Johan L. Bloem, Olaf Christensen, Maja J.A. de Jonge, Joern Kraetzschmar, Prabhu Rajagopalan, Hans Gelderblom

Manuscript writing: Ferry A.L.M. Eskens, Neeltje Steeghs, Jaap Verweij, Maja J.A. de Jonge, Joern Kraetzschmar, Prabhu Rajagopalan, Hans Gelderblom

Final approval of manuscript: Ferry A.L.M. Eskens, Neeltje Steeghs, Jaap Verweij, Johan L. Bloem, Olaf Christensen, Maja J.A. de Jonge, Johan W.R. Nortier, Prabhu Rajagopalan, Hans Gelderblom

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Footnotes

  • Supported by Bayer, Brussels, Belgium, and Bayer AG Leverkusen, Germany.

  • 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.

  • Glossary Terms

    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.
    Angiogenic factors:
    A group of small proteins and cytokines that are involved in the growth of new bloodvessels.
    Antiangiogenic:
    A process involved blocking the generation of new blood vessels in a tumor, which disrupts the blood supply thereby preventing tumor growth.
    DCE-MRI (dynamic contrast-enhanced magnetic resonance imaging):
    A magnetic resonance imaging acquisition strategy involving multiple scans over a set volume during injection of a MR contrast agent.
    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.
  • Received June 25, 2008.
  • Accepted February 20, 2009.
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REFERENCES

  1. ↵
    1. Hurwitz H,
    2. Fehrenbacher L,
    3. Novotny W,
    4. et al.
    (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342.
    CrossRefMedline
    1. Giantonio BJ,
    2. Levy DE,
    3. O'Dwyer PJ,
    4. et al.
    (2006) A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group study E2200. Ann Oncol 17:1399–1403.
    Abstract/FREE Full Text
  3. ↵
    1. Motzer RJ,
    2. Hutson TE,
    3. Tomczak P,
    4. et al.
    (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124.
    CrossRefMedline
    1. Escudier B,
    2. Eisen T,
    3. Stadler WM,
    4. et al.
    (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134.
    CrossRefMedline
    1. Sandler A,
    2. Gray R,
    3. Perry MC,
    4. et al.
    (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550.
    CrossRefMedline
    1. Escudier B,
    2. Pluzanska A,
    3. Koralewski P,
    4. et al.
    (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet 370:2103–2111.
    CrossRefMedline
    1. Miller K,
    2. Wang M,
    3. Gralow J,
    4. et al.
    (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676.
    CrossRefMedline
  8. ↵
    1. Llovet J,
    2. Ricci S,
    3. Mazzaferro V,
    4. et al.
    (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390.
    CrossRefMedline
  9. ↵
    1. Chang YS,
    2. Cortes C,
    3. Polony B,
    4. et al.
    (2005) AACR Meeting Abstracts Preclinical chemotherapy with the VEGFR-2 and PDGFR inhibitor, BAY 57-9352, in combination with capecitabine and paclitaxel, 2005, pp 475b–447b, abstr 475.
    Search Google Scholar
  10. ↵
    1. Dixon JA,
    2. Boyer SJ,
    3. Brini W,
    4. et al.
    (2005) AACR Meeting Abstracts Identification of novel VEGFR-2 inhibitors, 2005, pp 913c–991c, abstr 913.
    Search Google Scholar
  11. ↵
    1. Therasse P,
    2. Arbuck SG,
    3. Eisenhauer EA,
    4. et al.
    (2000) New guidelines to evaluate the response to treatment in solid tumors: European Organisation 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.
    Abstract/FREE Full Text
  12. ↵
    1. Strecker R,
    2. Scheffler K,
    3. Buchert M,
    4. et al.
    (2003) DCE-MRI in clinical trials: Data acquisition techniques and analysis methods. Int J Clin Pharmacol Ther 41:603–605.
    Medline
  13. ↵
    1. Leach MO,
    2. Brindle KM,
    3. Evelhoch JL,
    4. et al.
    (2005) 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.
    CrossRefMedline
  14. ↵
    1. van Rijswijk CS,
    2. Geirnaerdt MJ,
    3. Hogendoorn PC,
    4. et al.
    (2004) Soft-tissue tumors: Value of static and dynamic gadopentetate dimeglumine-enhanced MR imaging in prediction of malignancy. Radiology 233:493–502.
    Abstract/FREE Full Text
  15. ↵
    1. Eskens FA,
    2. Planting A,
    3. van Doorn L,
    4. et al.
    (2006) An open-label phase I dose escalation study of KRN951, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 1 in a 4 week on, 2 week off schedule in patients with advanced solid tumors. J Clin Oncol 24(suppl):87s, abstr 2034.
    Search Google Scholar
  16. ↵
    1. Drevs J,
    2. Siegert P,
    3. Medinger M,
    4. et al.
    (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25:3045–3054.
    Abstract/FREE Full Text
    1. Hidalgo M,
    2. Siu LL,
    3. Nemunaitis J,
    4. et al.
    (2001) 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.
    Abstract/FREE Full Text
    1. Judson I,
    2. Ma P,
    3. Peng B,
    4. et al.
    (2005) 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.
    CrossRefMedline
  19. ↵
    1. Mross K,
    2. Drevs J,
    3. Muller M,
    4. et al.
    (2005) 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.
    CrossRefMedline
  20. ↵
    1. Eskens FA,
    2. Mom CH,
    3. Planting AS,
    4. et al.
    (2008) A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer 98:80–85.
    CrossRefMedline
  21. ↵
    1. Verheul HM,
    2. Pinedo HM
    (2005) Inhibition of angiogenesis in cancer patients. Expert Opin Emerg Drugs 10:403–412.
    CrossRefMedline
    1. Sane DC,
    2. Anton L,
    3. Brosnihan KB
    (2004) Angiogenic growth factors and hypertension. Angiogenesis 7:193–201.
    CrossRefMedline
    1. Veronese ML,
    2. Mosenkis A,
    3. Flaherty KT,
    4. et al.
    (2006) Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol 24:1363–1369.
    Abstract/FREE Full Text
    1. Hurwitz HI,
    2. Fehrenbacher L,
    3. Hainsworth JD,
    4. et al.
    (2005) Bevacizumab in combination with fluorouracil and leucovorin: An active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502–3508.
    Abstract/FREE Full Text
  25. ↵
    1. Eskens FALM,
    2. Verweij J
    (2006) The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors: A review. Eur J Cancer 42:3127–3139.
    CrossRefMedline
  26. ↵
    1. Strumberg D,
    2. Mross K,
    3. Scheulen M,
    4. et al.
    (2006) Phase I study of BAY 57-9352, a VEGFR-2 inhibitor, in cycles of 14 days on/7 days off in patients with advanced solid tumors. J Clin Oncol 24(suppl):143s, abstr 3089.
    Search Google Scholar
  27. ↵
    1. Norden-Zfoni A,
    2. Desai J,
    3. Manola J,
    4. et al.
    (2007) Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer Res 13:2643–2650.
    Abstract/FREE Full Text
  28. ↵
    1. Witteveen P,
    2. Langenberg M,
    3. Verheul H,
    4. et al.
    (2008) Phase I evaluation of telatinib, a VEGF receptor tyrosine kinase inhibitor, in combination with irinotecan and capecitabine in patients with advanced solid tumors. J Clin Oncol 26(suppl):119s, abstr 2530.
    Search Google Scholar
  29. ↵
    1. Wedam SB,
    2. Low JA,
    3. Yang SX,
    4. et al.
    (2006) Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol 24:769–777.
    Abstract/FREE Full Text
    1. Liu G,
    2. Rugo HS,
    3. Wilding G,
    4. et al.
    (2005) 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.
    Abstract/FREE Full Text
  31. ↵
    1. Morgan B,
    2. Thomas AL,
    3. Drevs J,
    4. et al.
    (2003) Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, 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.
    Abstract/FREE Full Text
  32. ↵
    1. Steeghs N,
    2. Gelderblom H,
    3. op 't Roodt J,
    4. et al.
    (2008) Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res 14:3470–3476.
    Abstract/FREE Full Text
  33. ↵
    1. Tamaskar I,
    2. Bukowski R,
    3. Elson P,
    4. et al.
    (2008) Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol 19:265–268.
    Abstract/FREE Full Text
    1. Rini BI,
    2. Tamaskar I,
    3. Shaheen P,
    4. et al.
    (2007) Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 99:81–83.
    Abstract/FREE Full Text
    1. Desai J,
    2. Yassa L,
    3. Marqusee E,
    4. et al.
    (2006) Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 145:660–664.
    Abstract/FREE Full Text
    1. Kapiteijn E,
    2. Brand A,
    3. Kroep J,
    4. et al.
    (2007) Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome. Ann Oncol 18:1745–1747.
    FREE Full Text
    1. Martin G,
    2. Bellido L,
    3. Cruz JJ
    (2007) Reversible posterior leukoencephalopathy syndrome induced by sunitinib. J Clin Oncol 25:3559.
    FREE Full Text
  38. ↵
    1. Chu TF,
    2. Rupnick MA,
    3. Kerkela R,
    4. et al.
    (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370:2011–2019.
    CrossRefMedline
  39. ↵
    1. Su JL,
    2. Yen CJ,
    3. Chen PS,
    4. et al.
    (2007) The role of the VEGF-C/VEGFR-3 axis in cancer progression. Br J Cancer 96:541–545.
    CrossRefMedline
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  1. Published online before print July 27, 2009, doi: 10.1200/JCO.2008.18.8193 JCO vol. 27 no. 25 4169-4176
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