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Pharmacodynamic and Pharmacokinetic Markers For Anti-angiogenic Cancer Therapy: Implications for Dosing and Selection of Patients

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Abstract

Angiogenesis is integral to tumour growth and invasion, and is a key target for cancer therapeutics. However, for many of the licensed indications, only a modest clinical benefit has been observed for both monoclonal antibody and small-molecule tyrosine kinase inhibitor anti-angiogenic therapy. Pre-clinical and clinical studies have attempted to evaluate circulating, imaging, genomic, pharmacokinetic, and pharmacodynamic markers that may aid both the selection of patients for treatment and define dosing. Correct dosing is likely to be critical in the context of vascular normalization to allow better delivery of concomitant anti-cancer therapy and novel imaging techniques hold much promise in the early evaluation of pharmacodynamic response to improve efficacy.

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References

  1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  CAS  PubMed  Google Scholar 

  2. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6. doi:10.1056/NEJM197111182852108.

    Article  CAS  PubMed  Google Scholar 

  3. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47. doi:10.1038/nrc704.

    Article  CAS  PubMed  Google Scholar 

  4. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3(6):401–10. doi:10.1038/nrc1093.

    Article  CAS  PubMed  Google Scholar 

  5. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet. 2016;388(10043):518–29. doi:10.1016/S0140-6736(15)01088-0.

    Article  CAS  PubMed  Google Scholar 

  6. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8(8):592–603. doi:10.1038/nrc2442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. McIntyre A, Harris AL. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality. EMBO Mol Med. 2015;7(4):368–79. doi:10.15252/emmm.201404271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 2016;15(6):385–403. doi:10.1038/nrd.2015.17.

    Article  CAS  PubMed  Google Scholar 

  9. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438(7070):967–74. doi:10.1038/nature04483.

    Article  CAS  PubMed  Google Scholar 

  10. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76. doi:10.1038/nm0603-669.

    Article  CAS  PubMed  Google Scholar 

  11. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23(5):1011–27. doi:10.1200/JCO.2005.06.081.

    Article  CAS  PubMed  Google Scholar 

  12. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9(6):685–93. doi:10.1038/nm0603-685.

    Article  CAS  PubMed  Google Scholar 

  13. Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis. 2010;13(1):1–14. doi:10.1007/s10456-009-9160-6.

    Article  CAS  PubMed  Google Scholar 

  14. Kano MR, Morishita Y, Iwata C, Iwasaka S, Watabe T, Ouchi Y, et al. VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling. J Cell Sci. 2005;118(Pt 16):3759–68. doi:10.1242/jcs.02483.

    Article  CAS  PubMed  Google Scholar 

  15. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400. doi:10.1038/nrd1381.

    Article  CAS  PubMed  Google Scholar 

  16. Sanz-Garcia E, Sauri T, Tabernero J, Macarulla T. Pharmacokinetic and pharmacodynamic evaluation of aflibercept for the treatment of colorectal cancer. Expert Opin Drug Metab Toxicol. 2015;11(6):995–1004. doi:10.1517/17425255.2015.1041920.

    Article  CAS  PubMed  Google Scholar 

  17. Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99(17):11393–8. doi:10.1073/pnas.172398299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mould DR, Sweeney KR. The pharmacokinetics and pharmacodynamics of monoclonal antibodies—mechanistic modeling applied to drug development. Curr Opin Drug Discov Dev. 2007;10(1):84–96.

    CAS  Google Scholar 

  19. Flessner MF, Dedrick RL. Monoclonal antibody delivery to intraperitoneal tumors in rats: effects of route of administration and intraperitoneal solution osmolality. Cancer Res. 1994;54(16):4376–84.

    CAS  PubMed  Google Scholar 

  20. Tabrizi MA, Tseng CM, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11(1–2):81–8. doi:10.1016/S1359-6446(05)03638-X.

    Article  CAS  PubMed  Google Scholar 

  21. Ordas I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91(4):635–46. doi:10.1038/clpt.2011.328.

    Article  CAS  PubMed  Google Scholar 

  22. Ghetie V, Ward ES. Transcytosis and catabolism of antibody. Immunol Res. 2002;25(2):97–113. doi:10.1385/IR:25:2:097.

    Article  CAS  PubMed  Google Scholar 

  23. Ghetie V, Hubbard JG, Kim JK, Tsen MF, Lee Y, Ward ES. Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice. Eur J Immunol. 1996;26(3):690–6. doi:10.1002/eji.1830260327.

    Article  CAS  PubMed  Google Scholar 

  24. Cohen-Solal JF, Cassard L, Fridman WH, Sautes-Fridman C. Fc gamma receptors. Immunol Lett. 2004;92(3):199–205. doi:10.1016/j.imlet.2004.01.012.

    Article  CAS  PubMed  Google Scholar 

  25. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002;99(3):754–8.

    Article  CAS  PubMed  Google Scholar 

  26. Caulet M, Lecomte T, Bouche O, Rollin J, Gouilleux-Gruart V, Azzopardi N, et al. Bevacizumab pharmacokinetics influence overall and progression-free survival in metastatic colorectal cancer patients. Clin Pharmacokinet. 2016;55(11):1381–94. doi:10.1007/s40262-016-0406-3.

    Article  CAS  PubMed  Google Scholar 

  27. Falk AT, Barriere J, Francois E, Follana P. Bevacizumab: a dose review. Crit Rev Oncol Hematol. 2015;94(3):311–22. doi:10.1016/j.critrevonc.2015.01.012.

    Article  PubMed  Google Scholar 

  28. Zhi J, Chen E, Major P, Burns I, Robinson B, McKendrick J, et al. A multicenter, randomized, open-label study to assess the steady-state pharmacokinetics of bevacizumab given with either XELOX or FOLFOX-4 in patients with metastatic colorectal cancer. Cancer Chemother Pharmacol. 2011;68(5):1199–206. doi:10.1007/s00280-011-1606-z.

    Article  CAS  PubMed  Google Scholar 

  29. Horita Y, Yamada Y, Hirashima Y, Kato K, Nakajima T, Hamaguchi T, et al. Effects of bevacizumab on plasma concentration of irinotecan and its metabolites in advanced colorectal cancer patients receiving FOLFIRI with bevacizumab as second-line chemotherapy. Cancer Chemother Pharmacol. 2010;65(3):467–71. doi:10.1007/s00280-009-1051-4.

    Article  CAS  PubMed  Google Scholar 

  30. Farkouh A, Scheithauer W, Buchner P, Georgopoulos A, Schueller J, Gruenberger B, et al. Clinical pharmacokinetics of capecitabine and its metabolites in combination with the monoclonal antibody bevacizumab. Anticancer Res. 2014;34(7):3669–73.

    CAS  PubMed  Google Scholar 

  31. Morotti M, Valenzano Menada M, Venturini PL, Ferrero S. Bevacizumab in endometrial cancer treatment. Expert Opin Biol Ther. 2012;12(5):649–58. doi:10.1517/14712598.2012.672558.

    Article  CAS  PubMed  Google Scholar 

  32. Ueda S, Satoh T, Gotoh M, Gao L, Doi T. A phase ib study of safety and pharmacokinetics of ramucirumab in combination with paclitaxel in patients with advanced gastric adenocarcinomas. Oncologist. 2015;20(5):493–4. doi:10.1634/theoncologist.2014-0440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224–35. doi:10.1016/S1470-2045(14)70420-6.

    Article  CAS  PubMed  Google Scholar 

  34. Verdaguer H, Tabernero J, Macarulla T. Ramucirumab in metastatic colorectal cancer: evidence to date and place in therapy. Ther Adv Med Oncol. 2016;8(3):230–42. doi:10.1177/1758834016635888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. EMA. EU summary of product characteristics. Zaltrap (aflibercept). 2013.

  36. FDA. US Prescribing information. Zaltrap® (aflibercept). 2012.

  37. Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(10):633–59. doi:10.2165/11535960-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  38. Keizer RJ, Huitema AD, Schellens JH, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(8):493–507. doi:10.2165/11531280-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  39. Mayer BJ. Perspective: dynamics of receptor tyrosine kinase signaling complexes. FEBS Lett. 2012;586(17):2575–9. doi:10.1016/j.febslet.2012.05.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9(1):28–39. doi:10.1038/nrc2559.

    Article  PubMed  CAS  Google Scholar 

  41. Zhang J, Zhang L, Wang Y, Zhao G. Development of anti-angiogenic tyrosine kinases inhibitors: molecular structures and binding modes. Cancer Chemother Pharmacol. 2016;77(5):905–26. doi:10.1007/s00280-016-2961-6.

    Article  CAS  PubMed  Google Scholar 

  42. Morotti M, Becker CM, Menada MV, Ferrero S. Targeting tyrosine-kinases in ovarian cancer. Expert Opin Investig Drugs. 2013;22(10):1265–79. doi:10.1517/13543784.2013.816282.

    Article  CAS  PubMed  Google Scholar 

  43. Di Gion P, Kanefendt F, Lindauer A, Scheffler M, Doroshyenko O, Fuhr U, et al. Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles. Clin Pharmacokinet. 2011;50(9):551–603. doi:10.2165/11593320-000000000-00000.

    Article  PubMed  Google Scholar 

  44. Scheffler M, Di Gion P, Doroshyenko O, Wolf J, Fuhr U. Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on 4-anilinoquinazolines. Clin Pharmacokinet. 2011;50(6):371–403. doi:10.2165/11587020-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  45. Wulkersdorfer B, Zeitlinger M, Schmid M. Pharmacokinetic aspects of vascular endothelial growth factor tyrosine kinase inhibitors. Clin Pharmacokinet. 2016;55(1):47–77. doi:10.1007/s40262-015-0302-2.

    Article  CAS  PubMed  Google Scholar 

  46. van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009;35(8):692–706. doi:10.1016/j.ctrv.2009.08.004.

    Article  PubMed  CAS  Google Scholar 

  47. Klumpen HJ, Samer CF, Mathijssen RH, Schellens JH, Gurney H. Moving towards dose individualization of tyrosine kinase inhibitors. Cancer Treat Rev. 2011;37(4):251–60. doi:10.1016/j.ctrv.2010.08.006.

    Article  PubMed  CAS  Google Scholar 

  48. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25(7):884–96. doi:10.1200/JCO.2006.06.3602.

    Article  CAS  PubMed  Google Scholar 

  49. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol. 2010;66(2):357–71. doi:10.1007/s00280-009-1170-y.

    Article  CAS  PubMed  Google Scholar 

  50. Najjar YG, Mittal K, Elson P, Wood L, Garcia JA, Dreicer R, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer. 2014;50(6):1084–9. doi:10.1016/j.ejca.2014.01.025.

    Article  CAS  PubMed  Google Scholar 

  51. Kalra S, Rini BI, Jonasch E. Alternate sunitinib schedules in patients with metastatic renal cell carcinoma. Ann Oncol. 2015;26(7):1300–4. doi:10.1093/annonc/mdv030.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Rini BI, Melichar B, Ueda T, Grunwald V, Fishman MN, Arranz JA, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol. 2013;14(12):1233–42. doi:10.1016/S1470-2045(13)70464-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rini BI, Tomita Y, Melichar B, Ueda T, Grunwald V, Fishman MN, et al. Overall survival analysis from a randomized phase II study of axitinib with or without dose titration in first-line metastatic renal cell carcinoma. Clin Genitourin Cancer. 2016;14(6):499–503. doi:10.1016/j.clgc.2016.04.005.

    Article  PubMed  Google Scholar 

  54. Prasad V, Massey PR, Fojo T. Oral anticancer drugs: how limited dosing options and dose reductions may affect outcomes in comparative trials and efficacy in patients. J Clin Oncol. 2014;32(15):1620–9. doi:10.1200/JCO.2013.53.0204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ou SH, Janne PA, Bartlett CH, Tang Y, Kim DW, Otterson GA, et al. Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol. 2014;25(2):415–22. doi:10.1093/annonc/mdt572.

    Article  PubMed  Google Scholar 

  56. Park I, Ryu MH, Sym SJ, Lee SS, Jang G, Kim TW, et al. Dose escalation of imatinib after failure of standard dose in Korean patients with metastatic or unresectable gastrointestinal stromal tumor. Jpn J Clin Oncol. 2009;39(2):105–10. doi:10.1093/jjco/hyn134.

    Article  PubMed  Google Scholar 

  57. Ornstein MC, Wood L, Elson P, Allman K, Beach J, Martin A, et al. Clinical effect of dose escalation after disease progression in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2017;15(2):e275–80. doi:10.1016/j.clgc.2016.08.014.

    Article  PubMed  Google Scholar 

  58. Rini BI, Melichar B, Fishman MN, Oya M, Pithavala YK, Chen Y, et al. Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma. Ann Oncol. 2015;26(7):1372–7. doi:10.1093/annonc/mdv103.

    Article  CAS  PubMed  Google Scholar 

  59. Suttle AB, Ball HA, Molimard M, Hutson TE, Carpenter C, Rajagopalan D, et al. Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma. Br J Cancer. 2014;111(10):1909–16. doi:10.1038/bjc.2014.503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Eechoute K, Fransson MN, Reyners AK, de Jong FA, Sparreboom A, van der Graaf WT, et al. A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients. Clin Cancer Res. 2012;18(20):5780–7. doi:10.1158/1078-0432.CCR-12-0490.

    Article  CAS  PubMed  Google Scholar 

  61. Verheijen RB, Bins S, Mathijssen RH, Lolkema MP, van Doorn L, Schellens JH, et al. Individualized pazopanib dosing: a prospective feasibility study in cancer patients. Clin Cancer Res. 2016;22(23):5738–46. doi:10.1158/1078-0432.CCR-16-1255.

    Article  CAS  PubMed  Google Scholar 

  62. de Wit D, van Erp NP, den Hartigh J, Wolterbeek R, den Hollander-van Deursen M, Labots M, et al. Therapeutic drug monitoring to individualize the dosing of pazopanib: a pharmacokinetic feasibility study. Ther Drug Monit. 2015;37(3):331–8. doi:10.1097/FTD.0000000000000141.

    Article  PubMed  CAS  Google Scholar 

  63. Chrisoulidou A, Mandanas S, Margaritidou E, Mathiopoulou L, Boudina M, Georgopoulos K, et al. Treatment compliance and severe adverse events limit the use of tyrosine kinase inhibitors in refractory thyroid cancer. Onco Targets Ther. 2015;8:2435–42. doi:10.2147/OTT.S86322.

    PubMed  PubMed Central  Google Scholar 

  64. Antoun S, Baracos VE, Birdsell L, Escudier B, Sawyer MB. Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma. Ann Oncol. 2010;21(8):1594–8. doi:10.1093/annonc/mdp605.

    Article  CAS  PubMed  Google Scholar 

  65. Huillard O, Mir O, Peyromaure M, Tlemsani C, Giroux J, Boudou-Rouquette P, et al. Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients. Br J Cancer. 2013;108(5):1034–41. doi:10.1038/bjc.2013.58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mir O, Coriat R, Blanchet B, Durand JP, Boudou-Rouquette P, Michels J, et al. Sarcopenia predicts early dose-limiting toxicities and pharmacokinetics of sorafenib in patients with hepatocellular carcinoma. PLoS One. 2012;7(5):e37563. doi:10.1371/journal.pone.0037563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ornstein MC, Rini BI. Pharmacokinetically guided dosing of oral drugs: true precision oncology? Clin Cancer Res. 2016;22(23):5626–8. doi:10.1158/1078-0432.CCR-16-1833.

    Article  CAS  PubMed  Google Scholar 

  68. Mpekris F, Baish JW, Stylianopoulos T, Jain RK. Role of vascular normalization in benefit from metronomic chemotherapy. Proc Natl Acad Sci USA. 2017;114(8):1994–9. doi:10.1073/pnas.1700340114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7(9):987–9. doi:10.1038/nm0901-987.

    Article  CAS  PubMed  Google Scholar 

  70. Zhou F, Hu J, Shao JH, Zou SB, Shen SL, Luo ZQ. Metronomic chemotherapy in combination with antiangiogenic treatment induces mosaic vascular reduction and tumor growth inhibition in hepatocellular carcinoma xenografts. J Cancer Res Clin Oncol. 2012;138(11):1879–90. doi:10.1007/s00432-012-1270-7.

    Article  CAS  PubMed  Google Scholar 

  71. Liu Y, Suzuki M, Masunaga S, Chen YW, Kashino G, Tanaka H, et al. Effect of bevacizumab treatment on p-boronophenylalanine distribution in murine tumor. J Radiat Res. 2013;54(2):260–7. doi:10.1093/jrr/rrs102.

    Article  CAS  PubMed  Google Scholar 

  72. Yanagisawa M, Yorozu K, Kurasawa M, Nakano K, Furugaki K, Yamashita Y, et al. Bevacizumab improves the delivery and efficacy of paclitaxel. Anticancer Drugs. 2010;21(7):687–94. doi:10.1097/CAD.0b013e32833b7598.

    CAS  PubMed  Google Scholar 

  73. Dobosz M, Ntziachristos V, Scheuer W, Strobel S. Multispectral fluorescence ultramicroscopy: three-dimensional visualization and automatic quantification of tumor morphology, drug penetration, and antiangiogenic treatment response. Neoplasia. 2014;16(1):1–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Pastuskovas CV, Mundo EE, Williams SP, Nayak TK, Ho J, Ulufatu S, et al. Effects of anti-VEGF on pharmacokinetics, biodistribution, and tumor penetration of trastuzumab in a preclinical breast cancer model. Mol Cancer Ther. 2012;11(3):752–62. doi:10.1158/1535-7163.MCT-11-0742-T.

    Article  CAS  PubMed  Google Scholar 

  75. Heskamp S, Boerman OC, Molkenboer-Kuenen JD, Oyen WJ, van der Graaf WT, van Laarhoven HW. Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti-insulin-like growth factor 1 receptor antibodies. Int J Cancer. 2013;133(2):307–14. doi:10.1002/ijc.28046.

    Article  CAS  PubMed  Google Scholar 

  76. Arjaans M, Oosting SF, Schroder CP, de Vries EG. Bevacizumab-induced vessel normalization hampers tumor uptake of antibodies–response. Cancer Res. 2013;73(23):7147–8. doi:10.1158/0008-5472.CAN-13-2532.

    Article  CAS  PubMed  Google Scholar 

  77. Arjaans M, Oude Munnink TH, Oosting SF, Terwisscha van Scheltinga AG, Gietema JA, Garbacik ET, et al. Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake. Cancer Res. 2013;73(11):3347–55. doi:10.1158/0008-5472.CAN-12-3518.

    Article  CAS  PubMed  Google Scholar 

  78. Daldrup-Link HE, Okuhata Y, Wolfe A, Srivastav S, Oie S, Ferrara N, et al. Decrease in tumor apparent permeability-surface area product to a MRI macromolecular contrast medium following angiogenesis inhibition with correlations to cytotoxic drug accumulation. Microcirculation. 2004;11(5):387–96. doi:10.1080/10739680490457665.

    Article  CAS  PubMed  Google Scholar 

  79. Goel S, Wong AH, Jain RK. Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. Cold Spring Harb Perspect Med. 2012;2(3):a006486. doi:10.1101/cshperspect.a006486.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Chauhan VP, Stylianopoulos T, Martin JD, Popovic Z, Chen O, Kamoun WS, et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol. 2012;7(6):383–8. doi:10.1038/nnano.2012.45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Van der Veldt AA, Lubberink M, Bahce I, Walraven M, de Boer MP, Greuter HN, et al. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell. 2012;21(1):82–91. doi:10.1016/j.ccr.2011.11.023.

    Article  PubMed  CAS  Google Scholar 

  82. Mehta S, Hughes NP, Li S, Jubb A, Adams R, Lord S, et al. Radiogenomics monitoring in breast cancer identifies metabolism and immune checkpoints as early actionable mechanisms of resistance to anti-angiogenic treatment. EBioMedicine. 2016;10:109–16. doi:10.1016/j.ebiom.2016.07.017.

    Article  PubMed  PubMed Central  Google Scholar 

  83. O’Connor JP, Jackson A, Parker GJ, Roberts C, Jayson GC. Dynamic contrast-enhanced MRI in clinical trials of antivascular therapies. Nat Rev Clin Oncol. 2012;9(3):167–77. doi:10.1038/nrclinonc.2012.2.

    Article  PubMed  CAS  Google Scholar 

  84. Salem A, O’Connor JP. Assessment of tumor angiogenesis: dynamic contrast-enhanced MR imaging and beyond. Magn Reson Imaging Clin N Am. 2016;24(1):45–56. doi:10.1016/j.mric.2015.08.010.

    Article  PubMed  Google Scholar 

  85. Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, 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(21):3045–54. doi:10.1200/JCO.2006.07.2066.

    Article  CAS  PubMed  Google Scholar 

  86. Hahn OM, Yang C, Medved M, Karczmar G, Kistner E, Karrison T, et al. Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. J Clin Oncol. 2008;26(28):4572–8. doi:10.1200/JCO.2007.15.5655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Morgan B, Thomas AL, Drevs J, Hennig J, Buchert M, Jivan A, et al. 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. 2003;21(21):3955–64. doi:10.1200/JCO.2003.08.092.

    Article  CAS  PubMed  Google Scholar 

  88. Yau T, Chen PJ, Chan P, Curtis CM, Murphy PS, Suttle AB, et al. Phase I dose-finding study of pazopanib in hepatocellular carcinoma: evaluation of early efficacy, pharmacokinetics, and pharmacodynamics. Clin Cancer Res. 2011;17(21):6914–23. doi:10.1158/1078-0432.CCR-11-0793.

    Article  CAS  PubMed  Google Scholar 

  89. Lockhart AC, Rothenberg ML, Dupont J, Cooper W, Chevalier P, Sternas L, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol. 2010;28(2):207–14. doi:10.1200/JCO.2009.22.9237.

    Article  CAS  PubMed  Google Scholar 

  90. Thomas AL, Morgan B, Horsfield MA, Higginson A, Kay A, Lee L, et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J Clin Oncol. 2005;23(18):4162–71. doi:10.1200/JCO.2005.09.034.

    Article  CAS  PubMed  Google Scholar 

  91. Liu G, Rugo HS, Wilding G, McShane TM, Evelhoch JL, Ng C, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol. 2005;23(24):5464–73. doi:10.1200/JCO.2005.04.143.

    Article  CAS  PubMed  Google Scholar 

  92. Kim YE, Joo B, Park MS, Shin SJ, Ahn JB, Kim MJ. Dynamic contrast-enhanced magnetic resonance imaging as a surrogate biomarker for bevacizumab in colorectal cancer liver metastasis: a single-arm, exploratory trial. Cancer Res Treat. 2016;48(4):1210–21. doi:10.4143/crt.2015.374.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Guo J, Glass JO, McCarville MB, Shulkin BL, Daryani VM, Stewart CF, et al. Assessing vascular effects of adding bevacizumab to neoadjuvant chemotherapy in osteosarcoma using DCE-MRI. Br J Cancer. 2015;113(9):1282–8. doi:10.1038/bjc.2015.351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Flaherty KT, Hamilton BK, Rosen MA, Amaravadi RK, Schuchter LM, Gallagher M, et al. Phase I/II trial of imatinib and bevacizumab in patients with advanced melanoma and other advanced cancers. Oncologist. 2015;20(8):952–9. doi:10.1634/theoncologist.2015-0108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Choi SH, Jung SC, Kim KW, Lee JY, Choi Y, Park SH, et al. Perfusion MRI as the predictive/prognostic and pharmacodynamic biomarkers in recurrent malignant glioma treated with bevacizumab: a systematic review and a time-to-event meta-analysis. J Neurooncol. 2016;128(2):185–94. doi:10.1007/s11060-016-2102-4.

    Article  CAS  PubMed  Google Scholar 

  96. Sweis RF, Medved M, Towey S, Karczmar GS, Oto A, Szmulewitz RZ, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic biomarker for pazopanib in metastatic renal carcinoma. Clin Genitourin Cancer. 2016;. doi:10.1016/j.clgc.2016.08.011.

    PubMed  Google Scholar 

  97. Baar J, Silverman P, Lyons J, Fu P, Abdul-Karim F, Ziats N, et al. A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: impact on angiogenic biomarkers. Clin Cancer Res. 2009;15(10):3583–90. doi:10.1158/1078-0432.CCR-08-2917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wedam SB, Low JA, Yang SX, Chow CK, Choyke P, Danforth D, et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol. 2006;24(5):769–77. doi:10.1200/JCO.2005.03.4645.

    Article  CAS  PubMed  Google Scholar 

  99. Nagengast WB, Hooge MN, van Straten EM, Kruijff S, Brouwers AH, den Dunnen WF, et al. VEGF-SPECT with (1)(1)(1)In-bevacizumab in stage III/IV melanoma patients. Eur J Cancer. 2011;47(10):1595–602. doi:10.1016/j.ejca.2011.02.009.

    Article  CAS  PubMed  Google Scholar 

  100. Lamberts LE, Koch M, de Jong JS, Adams AL, Glatz J, Kranendonk ME, et al. Tumor-specific uptake of fluorescent bevacizumab-IRDye800CW microdosing in patients with primary breast cancer: a phase I feasibility study. Clin Cancer Res. 2016;. doi:10.1158/1078-0432.CCR-16-0437.

    Google Scholar 

  101. Gaykema SB, Brouwers AH, Lub-de Hooge MN, Pleijhuis RG, Timmer-Bosscha H, Pot L, et al. 89Zr-bevacizumab PET imaging in primary breast cancer. J Nucl Med. 2013;54(7):1014–8. doi:10.2967/jnumed.112.117218.

    Article  CAS  PubMed  Google Scholar 

  102. Shi J, Jin Z, Liu X, Fan D, Sun Y, Zhao H, et al. PET imaging of neovascularization with (68)Ga-3PRGD2 for assessing tumor early response to Endostar antiangiogenic therapy. Mol Pharm. 2014;11(11):3915–22. doi:10.1021/mp5003202.

    Article  CAS  PubMed  Google Scholar 

  103. Azam F, Mehta S, Harris AL. Mechanisms of resistance to antiangiogenesis therapy. Eur J Cancer. 2010;46(8):1323–32. doi:10.1016/j.ejca.2010.02.020.

    Article  CAS  PubMed  Google Scholar 

  104. Fleming IN, Manavaki R, Blower PJ, West C, Williams KJ, Harris AL, et al. Imaging tumour hypoxia with positron emission tomography. Br J Cancer. 2015;112(2):238–50. doi:10.1038/bjc.2014.610.

    Article  CAS  PubMed  Google Scholar 

  105. Hegde PS, Jubb AM, Chen D, Li NF, Meng YG, Bernaards C, et al. Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab. Clin Cancer Res. 2013;19(4):929–37. doi:10.1158/1078-0432.CCR-12-2535.

    Article  CAS  PubMed  Google Scholar 

  106. Lambrechts D, Claes B, Delmar P, Reumers J, Mazzone M, Yesilyurt BT, et al. VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials. Lancet Oncol. 2012;13(7):724–33. doi:10.1016/S1470-2045(12)70231-0.

    Article  CAS  PubMed  Google Scholar 

  107. Beuselinck B, Karadimou A, Lambrechts D, Claes B, Wolter P, Couchy G, et al. VEGFR1 single nucleotide polymorphisms associated with outcome in patients with metastatic renal cell carcinoma treated with sunitinib—a multicentric retrospective analysis. Acta Oncol. 2014;53(1):103–12. doi:10.3109/0284186X.2013.770600.

    Article  PubMed  Google Scholar 

  108. Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2008;26(11):1810–6. doi:10.1200/JCO.2007.14.5375.

    Article  CAS  PubMed  Google Scholar 

  109. Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010;28(3):453–9. doi:10.1200/JCO.2009.24.8252.

    Article  CAS  PubMed  Google Scholar 

  110. Goede V, Coutelle O, Neuneier J, Reinacher-Schick A, Schnell R, Koslowsky TC, et al. Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br J Cancer. 2010;103(9):1407–14. doi:10.1038/sj.bjc.6605925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ronzoni M, Manzoni M, Mariucci S, Loupakis F, Brugnatelli S, Bencardino K, et al. Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients. Ann Oncol. 2010;21(12):2382–9. doi:10.1093/annonc/mdq261.

    Article  CAS  PubMed  Google Scholar 

  112. Brown-Glaberman U, Marron M, Chalasani P, Livingston R, Iannone M, Specht J, et al. Circulating carbonic anhydrase IX and antiangiogenic therapy in breast cancer. Dis Markers. 2016;2016:9810383. doi:10.1155/2016/9810383.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Favaro E, Ramachandran A, McCormick R, Gee H, Blancher C, Crosby M, et al. MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PLoS One. 2010;5(4):e10345. doi:10.1371/journal.pone.0010345.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Agency EM. Avastin (bevacizumab) 25 mg/mL concentrate for solution for infusion: EU summary of product characteristics. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf. Accessed 9 Oct 2017.

  115. BV ELN. Cyramza 10 mg/ml concentrate for solution for infusion: EU summary of product characteristics. 2015.

  116. Company ELa. Cyramza (ramucirumab) injection, for intravenous use: US prescribing information. 2015.

  117. Lu JF, Bruno R, Eppler S, Novotny W, Lum B, Gaudreault J. Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol. 2008;62(5):779–86. doi:10.1007/s00280-007-0664-8.

    Article  CAS  PubMed  Google Scholar 

  118. Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19(3):843–50.

    Article  CAS  PubMed  Google Scholar 

  119. Chiorean EG, Hurwitz HI, Cohen RB, Schwartz JD, Dalal RP, Fox FE, et al. Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors. Ann Oncol. 2015;26(6):1230–7. doi:10.1093/annonc/mdv144.

    Article  CAS  PubMed  Google Scholar 

  120. Van Cutsem E, Khayat D, Verslype C, Billemont B, Tejpar S, Meric JB, et al. Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours. Eur J Cancer. 2013;49(1):17–24. doi:10.1016/j.ejca.2012.07.007.

    Article  PubMed  CAS  Google Scholar 

  121. Yoshino T, Yamazaki K, Yamaguchi K, Doi T, Boku N, Machida N, et al. A phase I study of intravenous aflibercept with FOLFIRI in Japanese patients with previously treated metastatic colorectal cancer. Invest New Drugs. 2013;31(4):910–7. doi:10.1007/s10637-012-9895-6.

    Article  CAS  PubMed  Google Scholar 

  122. EMA. Summary of product characteristics: Cabozantinib (Cometriq).

  123. FDA. Highlights of prescribing information: Cabozantinib (Cometriq). 2012.

  124. Ltd EE. Lenvima 4 mg hard capsules: summary of product characteristics. 2016.

  125. Inc E. Lenvima (lenvatinib) capsules, for oral use: US prescribing information. 2015.

  126. EMA. 2015. Summary of product characteristics: Pazopanib (Votrient).

  127. FDA. Highlights of prescribing information: pazopanib (Votrient). 2014.

  128. EMA. Stivarga: summary of product characteristics. 2015.

  129. FDA. Stivarga (regorafenib): prescribing information. 2015.

  130. EMA. Summary of product characteristics: sorafenib (Nexavar). 2015.

  131. FDA. Highlights of prescribing information: sorafenib (Nexavar). 2013.

  132. EMA. Summary of product characteristics: sunitinib (Sutent). 2014.

  133. FDA. Highlights of prescribing information: sunitinib (Sutent). 2014.

  134. EMA. Summary of product characteristics: vandetanib (Caprelsa).. 2014.

  135. FDA. Highlights of prescribing information: vandetanib (Caprelsa®. 2014.

  136. EMA. Summary of product characteristics: axitinib (Inlyta®). 2014.

  137. FDA. Highlights of prescribing information: axitinib (Inlyta®). 2014. 2015.

  138. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, 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(24):5474–83. doi:10.1200/JCO.2005.04.192.

    Article  CAS  PubMed  Google Scholar 

  139. Pithavala YK, Tortorici M, Toh M, Garrett M, Hee B, Kuruganti U, et al. Effect of rifampin on the pharmacokinetics of Axitinib (AG-013736) in Japanese and Caucasian healthy volunteers. Cancer Chemother Pharmacol. 2010;65(3):563–70. doi:10.1007/s00280-009-1065-y.

    Article  CAS  PubMed  Google Scholar 

  140. Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29(19):2660–6. doi:10.1200/JCO.2010.32.4145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Strumberg D, Scheulen ME, Schultheis B, Richly H, Frost A, Buchert M, et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer. 2012;106(11):1722–7. doi:10.1038/bjc.2012.153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Boss DS, Glen H, Beijnen JH, Keesen M, Morrison R, Tait B, et al. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer. 2012;106(10):1598–604. doi:10.1038/bjc.2012.154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Yamada K, Yamamoto N, Yamada Y, Nokihara H, Fujiwara Y, Hirata T, et al. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res. 2011;17(8):2528–37. doi:10.1158/1078-0432.CCR-10-2638.

    Article  CAS  PubMed  Google Scholar 

  144. Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, 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(7):2012–21. doi:10.1158/1535-7163.MCT-07-0193.

    Article  CAS  PubMed  Google Scholar 

  145. Boudou-Rouquette P, Tlemsani C, Blanchet B, Huillard O, Jouinot A, Arrondeau J, et al. Clinical pharmacology, drug-drug interactions and safety of pazopanib: a review. Expert Opin Drug Metab Toxicol. 2016;12(12):1433–44.

    Article  CAS  PubMed  Google Scholar 

  146. Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005;23(5):965–72. doi:10.1200/JCO.2005.06.124.

    Article  CAS  PubMed  Google Scholar 

  147. Kane RC, Farrell AT, Saber H, Tang S, Williams G, Jee JM, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006;12(24):7271–8. doi:10.1158/1078-0432.CCR-06-1249.

    Article  CAS  PubMed  Google Scholar 

  148. Jain L, Woo S, Gardner ER, Dahut WL, Kohn EC, Kummar S, et al. Population pharmacokinetic analysis of sorafenib in patients with solid tumours. Br J Clin Pharmacol. 2011;72(2):294–305. doi:10.1111/j.1365-2125.2011.03963.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Mross K, Frost A, Steinbild S, Hedbom S, Buchert M, Fasol U, et al. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012;18(9):2658–67. doi:10.1158/1078-0432.CCR-11-1900.

    Article  CAS  PubMed  Google Scholar 

  150. Cleton ASI, Jirakova Z, Trnkova J, Grevel J, Fiala-Buskies S, Lettieri J. Pharmacokinetics of regorafenib in the phase 3 CONCUR and CORRECT trials in patients with metastatic colorectal cancer (mCRC). Ann Oncol. 2015;26(Suppl 4):1–100.

    Article  Google Scholar 

  151. Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13(5):1367–73. doi:10.1158/1078-0432.CCR-06-2328.

    Article  CAS  PubMed  Google Scholar 

  152. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24(1):25–35. doi:10.1200/JCO.2005.02.2194.

    Article  CAS  PubMed  Google Scholar 

  153. Broniscer A, Baker JN, Tagen M, Onar-Thomas A, Gilbertson RJ, Davidoff AM, et al. Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. J Clin Oncol. 2010;28(31):4762–8. doi:10.1200/JCO.2010.30.3545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Broniscer A, Baker SD, Wetmore C, Pai Panandiker AS, Huang J, Davidoff AM, et al. Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. Clin Cancer Res. 2013;19(11):3050–8. doi:10.1158/1078-0432.CCR-13-0306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Cabebe EC, Fisher GA, Sikic BI. A phase I trial of vandetanib combined with capecitabine, oxaliplatin and bevacizumab for the first-line treatment of metastatic colorectal cancer. Invest New Drugs. 2012;30(3):1082–7. doi:10.1007/s10637-011-9656-y.

    Article  CAS  PubMed  Google Scholar 

  156. Drappatz J, Norden AD, Wong ET, Doherty LM, Lafrankie DC, Ciampa A, et al. Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys. 2010;78(1):85–90. doi:10.1016/j.ijrobp.2009.07.1741.

    Article  CAS  PubMed  Google Scholar 

  157. Halmos B, Jia Y, Bokar JA, Fu P, Adelstein DJ, Juergens R, et al. A phase I study of the combination of oxaliplatin/docetaxel and vandetanib for the treatment of advanced gastroesophageal cancer. Invest New Drugs. 2013;31(5):1244–50. doi:10.1007/s10637-013-9945-8.

    Article  CAS  PubMed  Google Scholar 

  158. Herbst RS, Heymach JV, O’Reilly MS, Onn A, Ryan AJ. Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opin Investig Drugs. 2007;16(2):239–49. doi:10.1517/13543784.16.2.239.

    Article  CAS  PubMed  Google Scholar 

  159. Kessler ER, Eckhardt SG, Pitts TM, Bradshaw-Pierce EL, O’Byrant CL, Messersmith WA, et al. Phase I trial of vandetanib in combination with gemcitabine and capecitabine in patients with advanced solid tumors with an expanded cohort in pancreatic and biliary cancers. Invest New Drugs. 2016;34(2):176–83. doi:10.1007/s10637-015-0316-5.

    Article  CAS  PubMed  Google Scholar 

  160. Kreisl TN, McNeill KA, Sul J, Iwamoto FM, Shih J, Fine HA. A phase I/II trial of vandetanib for patients with recurrent malignant glioma. Neuro Oncol. 2012;14(12):1519–26. doi:10.1093/neuonc/nos265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Martin P, Oliver S, Kennedy SJ, Partridge E, Hutchison M, Clarke D, et al. Pharmacokinetics of vandetanib: three phase I studies in healthy subjects. Clin Ther. 2012;34(1):221–37. doi:10.1016/j.clinthera.2011.11.011.

    Article  CAS  PubMed  Google Scholar 

  162. Tamura T, Minami H, Yamada Y, Yamamoto N, Shimoyama T, Murakami H, et al. A phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors. J Thorac Oncol. 2006;1(9):1002–9.

    Article  PubMed  Google Scholar 

  163. Zhang L, Li S, Zhang Y, Zhan J, Zou BY, Smith R, et al. Pharmacokinetics and tolerability of vandetanib in Chinese patients with solid, malignant tumors: an open-label, phase I, rising multiple-dose study. Clin Ther. 2011;33(3):315–27. doi:10.1016/j.clinthera.2011.04.005.

    Article  CAS  PubMed  Google Scholar 

  164. Holden SN, Eckhardt SG, Basser R, de Boer R, Rischin D, Green M, 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(8):1391–7. doi:10.1093/annonc/mdi247.

    Article  CAS  PubMed  Google Scholar 

  165. Pithavala YK, Tong W, Mount J, Rahavendran SV, Garrett M, Hee B, et al. Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers. Invest New Drugs. 2012;30(1):273–81. doi:10.1007/s10637-010-9511-6.

    Article  CAS  PubMed  Google Scholar 

  166. Pithavala YK, Chen Y, Toh M, Selaru P, LaBadie RR, Garrett M, et al. Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers. Cancer Chemother Pharmacol. 2012;70(1):103–12. doi:10.1007/s00280-012-1888-9.

    Article  CAS  PubMed  Google Scholar 

  167. Sharma S, Abhyankar V, Burgess RE, Infante J, Trowbridge RC, Tarazi J, et al. A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors. Ann Oncol. 2010;21(2):297–304. doi:10.1093/annonc/mdp489.

    Article  CAS  PubMed  Google Scholar 

  168. Shumaker R, Aluri J, Fan J, Martinez G, Ren M, Chen K. Evaluation of the effects of formulation and food on the pharmacokinetics of lenvatinib (E7080) in healthy volunteers. Int J Clin Pharmacol Ther. 2014;52(4):284–91. doi:10.5414/CP201937.

    Article  CAS  PubMed  Google Scholar 

  169. Tsuruoka A, Matsui J, Suzuki T, Koyama N, Watanabe T, Funahashi Y. Preclinical and clinical researches of lenvatinib mesylate (Lenvima capsule), a novel antitumor agent approved for thyroid cancer treatment. Nihon Yakurigaku Zasshi. 2015;146(5):283–90. doi:10.1254/fpj.146.283.

    Article  CAS  PubMed  Google Scholar 

  170. Shumaker R, Aluri J, Fan J, Martinez G, Thompson GA, Ren M. Effects of ketoconazole on the pharmacokinetics of lenvatinib (E7080) in healthy participants. Clin Pharmacol Drug Dev. 2015;4(2):155–60. doi:10.1002/cpdd.140.

    Article  CAS  PubMed  Google Scholar 

  171. Shumaker RC, Aluri J, Fan J, Martinez G, Thompson GA, Ren M. Effect of rifampicin on the pharmacokinetics of lenvatinib in healthy adults. Clin Drug Investig. 2014;34(9):651–9. doi:10.1007/s40261-014-0217-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Heath EI, Chiorean EG, Sweeney CJ, Hodge JP, Lager JJ, Forman K, et al. A phase I study of the pharmacokinetic and safety profiles of oral pazopanib with a high-fat or low-fat meal in patients with advanced solid tumors. Clin Pharmacol Ther. 2010;88(6):818–23. doi:10.1038/clpt.2010.199.

    Article  CAS  PubMed  Google Scholar 

  173. Heath EI, Forman K, Malburg L, Gainer S, Suttle AB, Adams L, et al. A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing administered as crushed tablet or oral suspension in patients with advanced solid tumors. Invest New Drugs. 2012;30(4):1566–74. doi:10.1007/s10637-011-9725-2.

    Article  CAS  PubMed  Google Scholar 

  174. Tan AR, Gibbon DG, Stein MN, Lindquist D, Edenfield JW, Martin JC, et al. Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol. 2013;71(6):1635–43. doi:10.1007/s00280-013-2164-3.

    Article  CAS  PubMed  Google Scholar 

  175. Tan AR, Dowlati A, Stein MN, Jones SF, Infante JR, Bendell J, et al. Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies. Br J Cancer. 2014;110(11):2647–54. doi:10.1038/bjc.2014.233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Awada A, Hendlisz A, Gil T, Bartholomeus S, Mano M, de Valeriola D, et al. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer. 2005;92(10):1855–61. doi:10.1038/sj.bjc.6602584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res. 2005;11(15):5472–80. doi:10.1158/1078-0432.CCR-04-2658.

    Article  CAS  PubMed  Google Scholar 

  178. Kupsch P, Henning BF, Passarge K, Richly H, Wiesemann K, Hilger RA, et al. Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin Colorectal Cancer. 2005;5(3):188–96.

    Article  PubMed  Google Scholar 

  179. Moore M, Hirte HW, Siu L, Oza A, Hotte SJ, Petrenciuc O, et al. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol. 2005;16(10):1688–94. doi:10.1093/annonc/mdi310.

    Article  CAS  PubMed  Google Scholar 

  180. Mross K, Steinbild S, Baas F, Reil M, Buss P, Mersmann S, et al. Drug-drug interaction pharmacokinetic study with the Raf kinase inhibitor (RKI) BAY 43-9006 administered in combination with irinotecan (CPT-11) in patients with solid tumors. Int J Clin Pharmacol Ther. 2003;41(12):618–9.

    Article  CAS  PubMed  Google Scholar 

  181. Richly H, Kupsch P, Passage K, Grubert M, Hilger RA, Kredtke S, et al. A phase I clinical and pharmacokinetic study of the Raf kinase inhibitor (RKI) BAY 43-9006 administered in combination with doxorubicin in patients with solid tumors. Int J Clin Pharmacol Ther. 2003;41(12):620–1.

    Article  CAS  PubMed  Google Scholar 

  182. Richly H, Kupsch P, Passage K, Grubert M, Hilger RA, Voigtmann R, et al. Results of a phase I trial of BAY 43-9006 in combination with doxorubicin in patients with primary hepatic cancer. Int J Clin Pharmacol Ther. 2004;42(11):650–1.

    Article  CAS  PubMed  Google Scholar 

  183. Strumberg D, Voliotis D, Moeller JG, Hilger RA, Richly H, Kredtke S, et al. Results of phase I pharmacokinetic and pharmacodynamic studies of the Raf kinase inhibitor BAY 43-9006 in patients with solid tumors. Int J Clin Pharmacol Ther. 2002;40(12):580–1.

    Article  CAS  PubMed  Google Scholar 

  184. Wilhelm S, Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des. 2002;8(25):2255–7.

    Article  CAS  PubMed  Google Scholar 

  185. Keating GM, Santoro A. Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs. 2009;69(2):223–40. doi:10.2165/00003495-200969020-00006.

    Article  CAS  PubMed  Google Scholar 

  186. Ghassabian S, Rawling T, Zhou F, Doddareddy MR, Tattam BN, Hibbs DE, et al. Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized metabolites. Biochem Pharmacol. 2012;84(2):215–23. doi:10.1016/j.bcp.2012.04.001.

    Article  CAS  PubMed  Google Scholar 

  187. Bello CL, Sherman L, Zhou J, Verkh L, Smeraglia J, Mount J, et al. Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs. 2006;17(3):353–8.

    Article  CAS  PubMed  Google Scholar 

  188. Maayah ZH, El Gendy MA, El-Kadi AO, Korashy HM. Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation. Arch Toxicol. 2013;87(5):847–56. doi:10.1007/s00204-012-0996-y.

    Article  CAS  PubMed  Google Scholar 

  189. Sugiyama M, Fujita K, Murayama N, Akiyama Y, Yamazaki H, Sasaki Y. Sorafenib and sunitinib, two anticancer drugs, inhibit CYP3A4-mediated and activate CY3A5-mediated midazolam 1′-hydroxylation. Drug Metab Dispos. 2011;39(5):757–62. doi:10.1124/dmd.110.037853.

    Article  CAS  PubMed  Google Scholar 

  190. van Erp NP, Baker SD, Zandvliet AS, Ploeger BA, den Hollander M, Chen Z, et al. Marginal increase of sunitinib exposure by grapefruit juice. Cancer Chemother Pharmacol. 2011;67(3):695–703. doi:10.1007/s00280-010-1367-0.

    Article  PubMed  Google Scholar 

  191. Martin P, Oliver S, Robertson J, Kennedy SJ, Read J, Duvauchelle T. Pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or itraconazole. Drugs R D. 2011;11(1):37–51. doi:10.2165/11586980-000000000-00000.

    Article  PubMed  Google Scholar 

  192. Johansson S, Read J, Oliver S, Steinberg M, Li Y, Lisbon E, et al. Pharmacokinetic evaluations of the co-administrations of vandetanib and metformin, digoxin, midazolam, omeprazole or ranitidine. Clin Pharmacokinet. 2014;53(9):837–47. doi:10.1007/s40262-014-0161-2.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Hypoxia and Angiogenesis Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK

    Matteo Morotti, Adrian L. Harris & Simon Lord

  2. Department of Gynaecology Oncology, University of Oxford, Oxford, UK

    Matteo Morotti

  3. Department of Oncology, Churchill Hospital, University of Oxford, Oxford, OX3 9DU, UK

    Matteo Morotti, Prashanth Hari Dass, Adrian L. Harris & Simon Lord

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  1. Matteo Morotti
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  2. Prashanth Hari Dass
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  3. Adrian L. Harris
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  4. Simon Lord
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Correspondence to Matteo Morotti.

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Conflict of interest

Matteo Morotti, Prashanth Hari Dass, Adrian L. Harris, and Simon Lord have no conflicts of interest.

Funding

ALH is funded by the Cancer Research UK, Breast Cancer Research Foundation; MM is supported by Fondazione Umberto Veronesi Fellowship.

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Morotti, M., Dass, P.H., Harris, A.L. et al. Pharmacodynamic and Pharmacokinetic Markers For Anti-angiogenic Cancer Therapy: Implications for Dosing and Selection of Patients. Eur J Drug Metab Pharmacokinet 43, 137–153 (2018). https://doi.org/10.1007/s13318-017-0442-x

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