Novel VEGF signalling inhibitors: How helpful are biomarkers in their early development?

Expert Opinion on Investigational Drugs

Volumn 18, Issue 11, 2009, Pages 1701-1714

  Wood, Joanna ^a   Scott, Edwina ^a   Thomas, Anne L ^a  

^a UNIVERSITY OF LEICESTER   (United Kingdom)

Author keywords

Angiogenesis inhibitor; Biomarkers; Tyrosine kinase inhibitor; VEGF

Indexed keywords

ALPHA2 INTERFERON; AXITINIB; BIOLOGICAL MARKER; BRIVANIB; BRIVANIB ALANINATE; CALCITONIN; CEDIRANIB; COLONY STIMULATING FACTOR 1; CUTANEOUS T CELL ATTRACTING CHEMOKINE; DOVITINIB; GAMMA INTERFERON INDUCIBLE PROTEIN 10; INTERLEUKIN 1 RECEPTOR ACCESSORY PROTEIN; INTERLEUKIN 12; INTERLEUKIN 16; INTERLEUKIN 2 RECEPTOR; INTERLEUKIN 4; MITOGEN ACTIVATED PROTEIN KINASE; MONOCYTE CHEMOTACTIC PROTEIN 3; MOTESANIB; PAZOPANIB; PLACEBO; PROTEIN TYROSINE KINASE INHIBITOR; RANTES; STROMAL CELL DERIVED FACTOR 1ALPHA; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND; UNINDEXED DRUG; VANDETANIB; VASCULOTROPIN INHIBITOR; VASCULOTROPIN RECEPTOR; XL 647; XL 880;

ANGIOGENESIS; ANOREXIA; ATAXIA; CLINICAL TRIAL; COMPARATIVE STUDY; DATA BASE; DIARRHEA; DIZZINESS; DRUG DEVELOPMENT; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG TARGETING; FATIGUE; GASTROINTESTINAL STROMAL TUMOR; HAND FOOT SYNDROME; HEADACHE; HUMAN; HYPERTENSION; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; LIVER METASTASIS; LUNG NON SMALL CELL CANCER; MEDLINE; MELANOMA; MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; NAUSEA; OVARY CANCER; PERITONEUM CANCER; PROSTATE CANCER; PROTEINURIA; QT PROLONGATION; REVIEW; SEIZURE; SOFT TISSUE SARCOMA; SOLID TUMOR; STOMACH CANCER; SYSTEMATIC REVIEW; THROMBOEMBOLISM; THYROID CANCER; UTERINE TUBE CARCINOMA; VALIDATION PROCESS; VOMITING;

ANGIOGENESIS INHIBITORS; ANTINEOPLASTIC AGENTS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; NEOPLASMS; PROTEIN KINASE INHIBITORS; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR; SIGNAL TRANSDUCTION; TUMOR MARKERS, BIOLOGICAL; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

EID: 73849088366     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728220903336466     Document Type: Review

References (111)

1. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:2505-2512 (Pubitemid 46630627)
2. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007;25:884-896
3. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 2008;14:7272-7283
4. Fruehauf JP, Lutzky J, McDermott DF, et al. Axitinib (AG-013736) in patients with metastatic melanoma: a phase II study [abstract 9006]. Proc ASCO 2008;26(Suppl 15):484S
5. Cohen EE, Rosen LS, Vokes EE, et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 2008;26:4708-4713
6. Jonker DJ, Rosen LS, Sawyer M, et al. A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in patients (pts) with advanced/metastatic solid tumors: safety, pharmacokinetic (PK), and pharmacodynamic (PD) findings [abstract 3559]. Proc ASCO 2007;25:152S
7. Zeng ZS, Cohen AM, Guillem JG. Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis. Carcinogenesis 1999;20:749-755
8. Wang X, Saro J, Wei Z, et al. Modelling TKI258 exposure and biomarker response in support of phase I dosing schedule finding [abstract 14691]. Proc ASCO 2008;26(Suppl 15):642S
9. Eder JP, Appleman L, Heath E, et al. A phase I study of a novel spectrum selective kinase inhibitor (SSKI), XL880, administered orally in patients (pts) with advanced solid tumors (STs) [abstract 3041]. Proc ASCO 2006;24(Suppl 18):131S
10. Lorusso PM, Eder JP. Therapeutic potential of novel selective-spectrum kinase inhibitors in oncology. Expert Opin Investig Drugs 2008;17:1013-1028
11. Maulik G, Shrikhande A, Kijima T, et al. Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev 2002;13:41-59
12. Ross RW, Stein M, Sarantopoulos J, et al. A phase II study of the c-Met RTK inhibitor XL880 in patients (pts) with papillary renal-cell carcinoma (PRC) [abstract 15601]. Proc ASCO 2007;25(Suppl 18):658S
13. Srinivasan R, Choueiri TK, Vaishampayan U, et al. A phase II study of the dual MET/VEGFR2 inhibitor XL880 in patients (pts) with papillary renal carcinoma (PRC) [abstract 5103]. Proc ASCO 2008;26(Suppl 15):275S
14. Bhatt RS, Norden-Zfoni A, O'Neill A, et al. Circulating endothelial cells are a potential biomarker for patients with renal cell carcinoma (RCC) with and without von Hippel Lindau (VHL) syndrome [abstract 5098]. Proc ASCO 2008;26(Suppl 15):274S
15. Batchelor T, Sorensen AG, Ancukiewicz M, et al. A phase II trial of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma [abstract 2001]. Proc ASCO 2007;25:75S
16. Ramalingam SS, Mack PC, Vokes EE, et al. Cediranib (AZD2171) for the treatment of recurrent small cell lung cancer (SCLC): a California Consortium phase II study (NCI # 7097) [abstract 8078]. Proc ASCO 2008;26(Suppl 15):443S
17. Rosen LS, Kurzrock R, Mulay M, et al. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 2007;25:2369-2376
18. Altorki N, Guarino M, Lee P, et al. Preoperative treatment with pazopanib (GW786034), a multikinase angiogenesis inhibitor in early-stage non-small cell lung cancer (NSCLC): a proof-of-concept phase II study [abstract 7557]. Proc ASCO 2008;26(Suppl 15):411S
19. Nikolinakos P, Altorki N, Guarino M, et al. Analyses of plasma cytokine/angiogenic factors (C/AFs) profile during preoperative treatment with pazopanib (GW786034) in early-stage non-small cell lung cancer [abstract 7568]. Proc ASCO 2008;26(15S):414S
20. Hanrahan EO, Lin HY, Du DZ, et al. Correlative analyses of plasma cytokine/angiogenic factor (C/AF) profile, gender and outcome in a randomized, three-arm, phase II trial of first-line vandetanib (VAN) and/or carboplatin plus paclitaxel (CP) for advanced non-small cell lung cancer (NSCLC) [abstract 7593]. Proc ASCO 2007;25(Suppl 18):407S
21. Heymach JV, Hanrahan EO, Mann H, et al. Baseline VEGF as a potential predictive biomarker of vandetanib clinical benefit in patients with advanced NSCLC [abstract 8009]. Proc ASCO 2008;26(Suppl 15):426S
22. Natale RB, Bodkin D, Govindan R, et al. Vandetanib versus gefitinib in patients with advanced non-small-cell lung cancer: results from a two-part, double-blind, randomized phase II study. J Clin Oncol 2009;27:2523-2529
23. Heymach JV, Johnson BE, Prager D, et al. Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. J Clin Oncol 2007;25:4270-4277
24. Heymach JV, Paz-Ares L, De Braud F, et al. Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 2008;26:5407-5415
25. Ball DW. Medullary thyroid cancer: therapeutic targets and molecular markers. Curr Opin Oncol 2007:19:18-23
26. Wells SA, Gosnell JE, Gagel RF, et al. Vandetanib in metastatic hereditary medullary thyroid cancer: Follow-up results of an open-label phase II trial [abstract 6018]. Proc ASCO 2007;25(Suppl 18):303S
27. Sherman SI, Wirth LJ, Droz JP, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med 2008;359:31-42
28. Platero S, Mokliatchouk O, Jayson GC, et al. Correlation of FGF2 tumor expression with tumor response, PFS, and changes in plasma pharmacodynamic (PD) markers following treatment with brivanib alaninate, an oral dual inhibitor of VEGFR and FGFR tyrosine kinases [abstract 3506]. Proc ASCO 2008;26(Suppl 15):154S
29. Rizvi NA, Kris MG, Miller VA, et al. Activity of XL647 in clinically selected NSCLC patients (pts) enriched for the presence of EGFR mutations: results from phase 2 [abstract 8053]. Proc ASCO 2008;26(15 Suppl):437S
30. Wakelee HA, Adjei AA, Halsey J, et al. A phase I dose-escalation and pharmacokinetic (PK) study of a novel spectrum selective kinase inhibitor, XL647, in patients with advanced solid malignancies (ASM) [abstract 3044]. Proc ASCO 2006;24:131S
31. Jhawer MP, Kindler HL, Wainberg ZA, et al. Preliminary activity of XL880, a dual MET/VEGFR2 inhibitor, in MET amplified poorly differentiated gastric cancer (PDGC): interim results of a multicenter phase II study [abstract 4572]. Proc ASCO 2008;26(Suppl 15):231S
32. Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 2005;23:5474-5483
33. Drevs J, Siegert P, Medinger M, et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 2007;25:3045-3054
34. Karakunnel JJ, Gulley JL, Arlen P, et al. Cediranib (AZD2171) in docetaxel-resistant, castrate-resistant prostate cancer (CRPC) [abstract 5141]. Proc ASCO 2009;27(Suppl 15):269S
35. Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83-95
36. Meijerink MR, van Cruijsen H, Hoekman K, et al. The use of perfusion CT for the evaluation of therapy combining AZD2171 with gefitinib in cancer patients. Eur Radiol 2007;17:1700-1713
37. Kim KB, Saro J, Moschos SS, et al. A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanoma [abstract 9026]. Proc ASCO 2008;26(Suppl 15):489S
38. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115:2761-2788
39. Rini BI, Schiller JH, Fruehauf JP, et al. Association of diastolic blood pressure (dBP) > 90 mmHg with overall survival (OS) in patients treated with axitinib (AG- 013736) [abstract 3543]. Proc ASCO 2008;26(Suppl 15):163S
40. Eskens FA, Verweij J. 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 2006;42:3127-3139
41. Arnold AM, Seymour L, Smylie M, et al. Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20. J Clin Oncol 2007;25:4278-4284
42. Alberts SR, Morlan BW, Kim GP, et al. NCCTG phase II trial (N044J) of AZD2171 for patients with hepatocellular carcinoma (HCC) - Interim review of toxicity [abstract 186]. ASCO Gastrointestinal Cancer Symp 2007;178
43. AstraZeneca Provides Update On RECENTIN™ Clinical Development Programme, 2008. Available from: www.astrazeneca.com/media/latest-press- releases/2008/5377?itemId=3892274. [Last accessed 12 March 2009]
44. Amgen, Takeda and Millennium Provide Update on Phase 3 Trial of Motesanib in Patients with Non-Small Cell Lung Cancer, 2008. Available from: www.amgen.com/media/media-pr-detail.jsp?year=2008&releaseID=1228588. [Last accessed 12 March 2009]
45. Van Heecheren WJ, Ortiz J, Cooney MM, Remick SC. Hypertension, proteinuria and antagonism of vascular endothelial growth factor signalling: clinical toxicity, therapeutic target or novel biomarker. J Clin Oncol 2007;25:2993-2995
46. Slamon D, Gomez HL, Kabbinavar FF, et al. Randomized study of pazopanib + lapatinib vs. lapatinib alone in patients with HER2- positive advanced or metastatic breast cancer [abstract 1016]. Proc ASCO 2008;26(Suppl 15):45S
47. Herbst R, Sun Y, Korfee S, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non- small cell lung cancer (NSCLC): a randomised, double blind phase III trial (ZODIAC). [abstract CRA8003]. Proc ASCO 2009;27(Suppl 18):807S
48. De Boer R, Arrieta O, Gottfried M, et al. Vandetanib plus pemetrexed versus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer (NSCLC): a randomized, double-blind phase III trial (ZEAL) [abstract 8010]. Proc ASCO 2009;27(Suppl 15):409S
49. Natale R, Thongprasert S, Greco F, et al. Vandetanib versus erlotinib in patients with advanced non-small cell lung cancer (NSCLC) after failure of at least one prior cytotoxic chemotherapy: A randomized, double-blind phase III trial (ZEST) [abstract 8009]. Proc ASCO 2009;27(Suppl 15):409S
50. National Cancer Institute Clinical Trials (US National Institutes of Health). Available from: www.cancer.gov/clinicaltrials. [Last accessed 16th August 2009]
51. Bergh J. Quo vadis with targeted therapies in the 21st century. J Clin Oncol 2008;27:2-5
52. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004:3:711-716
53. DiMasi JA, Hansen RW, Grabowski H. The price of innovation: new estimates of drug treatment costs. J Health Econ 2003:22:151-185
54. Walker I, Newell H. Do molecularly targeted agents in oncology have reduced attrition rates. Nat Drug Discov 2009;8:15-16
55. Sassa C, Guibal A, Del Conte G, Rüegg C. Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations. Nat Clin Pract 2008:5:378-391
56. O'Connor JPB, Jackson A, Parker GJM, Jayson GC. DCE-MRI biomarkers in the clinical evaluation of antoangiogenic and vascular disrupting agents. Br J Cancer 2007:96:189-195
57. Iagaru A, Chen X, Gambhir S. Molecular imaging can accelerate anti-angiogenic drug development and testing. Nat Clin Pract 2007;4:556-557
58. Booth CM, Calvert AH, Giaccone G, et al. Endpoints and other considerations in phase I studies of targeted anticancer therapy: recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT). Eur J Cancer 2008;44:19-24 (Pubitemid 350256933)
59. Booth CM, Calvert AH, Giaccone G, et al. Design and conduct of phase II studies of targeted anticancer therapy: recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT). Eur J Cancer 2008:44:25-29 (Pubitemid 350256934)
60. Hecht JR, Trarbach T, Jaeger E, et al. A randomised, double-blind, placebo-controlled, phase III study in patients with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin.5-fluorouracil/leucovorin and PTK787/ZK222584 or placebo [abstract 3]. Proc ASCO 2005;16S:2S
61. Thomas AL, Morgan B, Horsfield MA, et al. Phase I study of the safety, tolerability, pharmacokinetics and pharmacodynamics of PTK787/ZK222584 administered twice daily in patients with advanced cancer. J Clin Oncol 2005;23:4162-4171
62. Kohne C, Bajetta E, LinFinal E, et al. Final results of CONFIRM 2: a multinational, randomized, double-blind, phase III study in 2nd line patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo [abstract 4033]. Proc ASCO 2007;25(Suppl 18):171S
63. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 2008;14:7272:83
64. Rini BI, Wilding GT, Hudes G, et al. Axitinib (AG-013736; AG) in patients (pts) with metastatic renal cell cancer (RCC) refractory to sorafenib [abstract 5032]. Proc ASCO 2007;25(Suppl 18):242S
65. Garrett CR, Siu LL, El-Khoueiry AB, et al. A phase I study of brivanib alaninate (BMS-582664), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full dose cetuximab (BC) in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy [abstract 4111]. Proc ASCO 2008;26(Suppl 15):205S
66. Huynh H, Ngo VC, Fargnoli J, et al. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res 2008;14:6146-6153
67. Ayers M, Awad M, Malone D, et al. Correlation between K-ras status and efficacy results from a phase I/II study of brivanib alaninate in combination with cetuximab in patients (pts) with advanced or metastatic colorectal cancer (CRC) [abstract 379]. Proc ASCO 2009;27
68. Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002;62:4645-4655
69. Shi MM, Motwani M, Wang J, et al. The pharmacodynamic effect of TKI258 on plasma biomarkers of angiogenesis in patients with AML and advanced melanoma [abstract 14680]. Proc ASCO 2008;26(Suppl 15):641S
70. Lopes de Menezes DE, Peng J, Garrett EN, et al. CHIR-258: a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia. Clin Cancer Res 2005;11:5281-5291
71. Sarker D, Molife R, Evans TR, et al. A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res 2008;14:2075-2081
72. Polverino A, Coxon A, Starnes C, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res 2006;66:8715-8721
73. Kumar R, Knick VB, Rudolph SK, et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 2007;6:2012-2021
74. 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 2005;65:4389-4400
75. Kiura K, Nakagawa K, Shinkai T, et al. A randomized, double-blind, phase IIa dose-finding study of Vandetanib (ZD6474) in Japanese patients with non-small cell lung cancer. J Thorac Oncol 2008;3:386-393
76. Gendreau SB, Ventura R, Keast P, et al. Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647. Clin Cancer Res 200715;13:3713-3723
77. Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 2007;8:975-984
78. Dutcher JP, Wilding G, Hudes GR, et al. Sequential axitinib (AG-013736) therapy of patients (pts) with metastatic clear cell renal cell cancer (RCC) refractory to sunitinib and sorafenib, cytokines and sorafenib, or sorafenib alone [abstract 5127]. Proc ASCO 2008;26(Suppl 15):281S
79. Schiller JH, Larson T, Ou SI, et al. Efficacy and safety of axitinib (AG-013736; AG) in patients (pts) with advanced non-small cell lung cancer (NSCLC): a phase II trial [abstract 7507]. Proc ASCO 2007;25(Suppl 18):386S
80. Finn RS, Kang Y, Park J, et al. Phase II, open label study of brivanib alaninate in patients (pts) with hepatocellular carcinoma (HCC) who failed prior antiangiogenic therapy [abstract 4577]. Proc ASCO 2009;27:221S
81. Ryan CJ, Stadler WM, Roth B, et al. Phase I dose escalation and pharmacokinetic study of AZD2171, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinase, in patients with hormone refractory prostate cancer (HRPC). Invest New Drugs 2007;25:445-451
82. Hirte HW, Vidal L, Fleming GF, et al. A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: final results of a PMH, Chicago and California consortia trial [abstract 5521]. Proc ASCO 2008;26(Suppl 15):298S
83. Matulonis UA, Berlin ST, Krasner CN, et al. Cediranib (AZD2171) is an active agent in recurrent epithelial ovarian cancer [abstract 5501]. Proc ASCO 2008;26(Suppl 15):293S
84. Sridhar SS, Mackenzie MJ, Hotte SJ, et al. Activity of cediranib (AZD2171) in patients (pts) with previously untreated metastatic renal cell cancer (RCC). A phase II trial of the PMH Consortium [abstract 5047]. Proc ASCO 2008;26(Suppl 15):261S
85. Yamada Y, Sawaki A, Nishida T, et al. Phase II study of motesanib diphosphate (AMG 706) in Japanese patients (pts) with advanced gastrointestinal stromal tumors (GISTs) who developed progressive disease or relapsed while on imatinib mesylate [abstract 107]. Proc ASCO GI Cancer Symp 2008;121
86. Friedlander M, Hancock KC, Benigno B, et al. Pazopanib (GW786034) is active in women with advanced epithelial ovarian, fallopian tube and peritoneal cancers: initial results of a phase II study [abstract 5561]. Proc ASCO 2007;25:289S
87. Hutson TE, Davis ID, Machiels JH, et al. Biomarker analysis and final efficacy and safety results of a phase II renal cell carcinoma trial with pazopanib (GW786034), a multi-kinase angiogenesis inhibitor [abstract 5046]. Proc ASCO 2008;26(Suppl 15):261S
88. Prince HM, Honemann D, Spencer A, et al. Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of pazopanib (GW786034). Blood 2009;113:4819-4820
89. Chen E, Jonker D, Gauthier I, et al. Phase I study of cediranib in combination with oxaliplatin and infusional 5-Fluorouracil in patients with advanced colorectal cancer. Clin Cancer Res 2009;15:1481-1486
90. Sleijfer S, Papai Z, Le Cesne A, et al. Phase II study of pazopanib (GW786034) in patients (pts) with relapsed or refractory soft tissue sarcoma (STS): EORTC 62043 [abstract 10031]. Proc ASCO 2007;25:552S
91. Holden SN, Eckhardt SG, Basser R, et al. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol 2005;16:1391-1397
92. Tamura T, Minami H, Yamada Y, et al. A phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors. J Thorac Oncol 2006;1:1002-1009 (Pubitemid 47181370)
93. Mross K, Frost A, Benkelmann R, et al. A randomized open-label phase I study to assess the effect of vandetanib on vascular permeability in patients with advanced colorectal cancer and liver metastases [abstract 4113]. Proc ASCO 2008;26(Suppl 15):206S
94. Haddad RI, Krebs AD, Vasselli J, et al. A phase II open-label study of vandetanib in patients with locally advanced or metastatic hereditary medullary thyroid cancer [abstract 6024]. Proc ASCO 2008;26(Suppl 15):322S
95. Wakelee HA, Fehling JM, Molina JR, et al. A phase I study of XL647, an EGFR, HER2, VEGFR2 inhibitor, administered orally daily to patients (pts) with advanced solid malignancies (ASM) [abstract 3528]. Proc ASCO 2008;26(Suppl 15):160S
96. Miller VA, Wakelee HA, Lara PN, et al. Activity and tolerance of XL647 in NSCLC patients with acquired resistance to EGFR-TKIs: preliminary results of a phase II trial [abstract 8028]. Proc ASCO 2008;26(Suppl 15):430S
97. Eder JP, Heath E, Appleman L, et al. Phase I experience with c-MET inhibitor XL880 administered orally to patients (pts) with solid tumors [abstract 3526]. Proc ASCO 2007;25(Suppl 18):144S
98. Abhyankar VV, Sharma S, Trowbridge RC, et al. Axitinib (AG-013736) in combination with FOLFOX and bevacizumab (Bev) in patients (pts) with metastatic solid tumors: a phase I study [abstract 4112]. Proc ASCO 2008;26(Suppl 15):206S
99. Sharma S, Trowbridge RC, Robles RL, et al. A phase I study of axitinib (AG-013736) in combination with bevacizumab and chemotherapy in patients with metastatic colorectal cancer (mCRC) [abstract 365]. ASCO Gastrointestinal Cancer Symp 2008;251
100. Rugo HS, Stopeck A, Joy A, et al. A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC) [abstract 1003]. Proc ASCO 2007;25(Suppl 18):32S
101. Spano J, Chodkiewicz C, Maurel J, et al. A randomized phase II study of axitinib (AG-013736) and gemcitabine versus gemcitabine in advanced pancreatic cancer, preceded by a phase I component [abstract 4551]. Proc ASCO 2007;25(Suppl 18):210S
102. Goss G, Shepherd FA, Laurie S, et al. A phase I and pharmacokinetic study of daily oral cediranib, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group. Eur J Cancer 2008;45:782-788
103. Laurie SA, Gauthier I, Arnold A, 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 2008;26:1871-1878
104. Cunningham D, Wong RP, D'haens G, et al. A phase II, double-blind, randomized multicenter study of cediranib with FOLFOX versus bevacizumab with FOLFOX in patients with previously treated metastatic colorectal cancer (mCRC): final PFS results [abstract 4028]. Proc ASCO 2008;26(Suppl 15):185S
105. Price TJ, Lipton L, McGreivy J, et al. Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours. Br J Cancer 2008;99:1387-1394
106. Kotasek D, Tebbutt NC, Welch S, et al. Safety and pharmacokinetics (PK) of motesanib diphosphate in combination with gemcitabine (G) and erlotinib (E) for the treatment of patients (pts) with solid tumors [abstract 3560]. Proc ASCO 2008;26(Suppl 15):168S
107. Dejonge M, Savage S, Verweij J, et al. A phase I, open-label study of the safety and pharmacokinetics (PK) of pazopanib (P) and lapatinib (L) administered concurrently [abstract 3088]. Proc ASCO 2006;24:142S
108. Suttle B, Jones S, Dowlati A, et al. Phase I study of the safety and pharmacokinetics (PK) of paclitaxel or paclitaxel with carboplatin administered in combination with pazopanib (GW786034) [abstract 14118]. Proc ASCO 2007;25:621S
109. Michael M, Tebbutt N, Gibbs P, et al. Vandetanib with mFOLFOX6 in advanced colorectal adenocarcinoma: an open-label, multicenter phase I study [abstract 4095]. Proc ASCO 2007;25(Suppl 18):187S
110. Saunders M, Van Cutsem E, Wilson R, et al. Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: an open-label, multicenter Phase I study [abstract 4085]. Proc ASCO 2007;25(Suppl 18):184S
111. De Boer R, Vansteenkiste J, Humblet Y, et al. Vandetanib with pemetrexed in patients with previously treated non-small cell lung cancer (NSCLC): an open-label, multicenter phase I study [abstract 7654]. Proc ASCO 2007;25(Suppl 18):422S