Summary
Background: SU5416 (semaxanib) is a synthetic small molecule inhibitor of the tyrosine kinase domain of vascular endothelial growth factor receptor 2 (VEGFR2). This Phase II study was conducted to determine the safety and efficacy of SU5416 in patients with recurrent or metastatic head and neck cancers.
Patients and methods: This was an open label, single arm, Phase 2 study for patients who had received no more than 2 cytotoxic regimens. Thirty-five patients received intravenous SU5416 (145 mg/m2) twice per week by intravenous catheter. Radiologic imaging for response assessment was planned at the conclusion of each 8 week cycle. Serum VEGF levels and power Doppler ultrasound tumor imaging were explored as potential surrogate markers for SU5416 activity.
Results: Thirty-two patients had received prior radiotherapy, including 18 patients who received prior concurrent chemoradiotherapy. Twelve patients had received prior chemotherapy in the recurrent disease setting. Thirty-one patients were evaluable for response. There was one partial response and one minor response. The median number of 8-week cycles received was 1 (range 1–4). Median overall survival was 6.25 months. The most common ≥ grade 3 toxicity was headache (31%). There was one fatal carotid artery hemorrhage. Fatigue, nausea, and vomiting were common grade 1–2 adverse events. Power Doppler ultrasound demonstrated decreased tumor vascularity in 5 of 7 patients.
Conclusions: Treatment with SU5416 in patients with head and neck cancers is feasible, but objective responses are rare. Studies evaluating more potent anti-angiogenic agents in this disease are of interest.
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Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK, Von Hoff DD (1992) Randomized comparison of cisplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group Study. J Clin Oncol 10:1245–1251
Gibson MK, Li Y, Murphy B, Hussain MHA, DeConti RC, Ensley JF, Forastiere AA (2005) Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and cancer (E1395): An intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol 23:3562–3567
Fanucchi M, Khuri FR (2004) Chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck. Semin Oncol 31:809–815
Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027
Kyzas PA, Cunha IW, Ionnidis JPA (2005) Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res 11:1434–1440
Fong TAT, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, Hirth KP, McMahon G (1999) SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 59:99–106
O'Donnell A, Padhani A, Hayes C, Kakkar AJ, Leach M, Trigo JM, Scurr M, Raynaud F, Phillips S, Aherne W, Hardcastle A, Workman P, Hannah A, Judson I (2005) A phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumors, incorporating dynamic contrast MR pharmacodynamic end points. Br J Cancer 93:876–883
Rosen L, Mulay M, Mayers A, Kabbinavar F, Rosen P, Cropp G, Hannah A (1999) Phase I dose-escalating trial of SU5416, a novel angiogenesis inhibitor in patients with advanced malignancies. Proc Am Soc Clin Oncol 18:618
Gee MS, Saunders HM, Lee JC, Sanzo JF, Jenkins WT, Evans SM, Trinchieri G, Sehgal CM, Feldman MD, Lee WMF (2001) Doppler ultrasound imaging detects changes in tumor perfusion during antivascular therapy associated with vascular anatomic alterations. Cancer Res 61:2974–2982
Miller AB, Hogestraeten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214
Jacobs C, Lyman G, Velez-Garcia E, Sridhar KS, Knight W, Hochster H, Goodnough LT, Mortimer JE, Einhorn LH, Schachter L, Cherng N, Dalton T, Burroughs J, Rozencweig M (1992) A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10:257–263
Tschammler A, Ott G, Schang T, Seelbach-Goebel B, Schwager K, Hahn D, (1998) Lymphadenopathy: Differentiation of benign from malignant disease—color doppler us assessment of intranodal architecture. Radiology 208:117–123
CH W, Shih JC, Chang YL, Lee SY, Hsieh FJ (1998) Two-dimensional and three-dimensional power doppler sonographic classification of vascular patterns in cervical lymphadenopathies. J Ultrasound Med 17:459–464
Stadler WM, Cao D, Vogelzang NJ, Ryan CW, Hoving K, Wright R, Karrison T, Vokes EE (2004) A randomized phase II trial of the anti-angiogenic agent SU5416 in hormone-refractory prostate cancer. Clin Cancer Res 10:3365–3370
Peterson AC, Swiger S, Stadler WM, Medved M, Karczmar G, Gajewski TF (2004) Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in advanced melanoma. Clin Cancer Res 10:4048–4054
Kuenen BC, Tabernero J, Baselga J, Cavalli F, Pfanner E, Conte PF, Seeber S, Madhusudan S, Deplanque G, Huisman H, Scigalla P, Hoekman K, Harris AL (2003) Efficacy and toxicity of the angiogenesis inhibitor SU5416 as a single agent in patients with advanced renal cell carcinoma, melanoma, and soft tissue sarcoma. Clin Cancer Res 9:1648–1655
Heymach JV, Desai J, Manola J, Davis DD, McConkey DJ, Harmon D, Ryan DP, Goss G, Quigley T, Van Den Abbeele AD, Silverman SG, Connors S, Folkman J, Fletcher CDM, Demetri GD (2004) Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas. Clin Cancer Res 10:5732– 5740
Motzer RJ, Rini BI, Michaelson MD, Redman BG, Hudes GR, Wilding G, Bukowski RM, George DJ, Kim ST, Baum CM (2005) Phase 2 trials of SU11248 show antitumor activity in second-line therapy in patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 23:4508
Dowlati A, Robertson K, Radivoyevitch T, Waas J, Ziats NP, Hartman P, Abdul-Karim FW, Wasman JK, Jesberger J, Lewin J, McCrae K, Ivy P, Remick SC (2005) Novel phase I dose-de-escalation design trial to determine the biological modulatory dose of the antiangiogenic agent SU5416. Clin Cancer Res 11:7938–7944
Sandler AB, Gray R, Brahmer J, Dowlati A, Schiller JH, Perry MC, Johnson DH (2005) Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial-E4599. Proc Am Soc Clin Oncol 23:4
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Eng J Med 350:2335–2342
Deprimo S, Bello C, Smeraglia J, Shalinsky DR, Freddo J, Baum CM, Rini BI, Michaelson D, Motzer RJ, Spinella DG (2005) Soluble protein biomarkers of pharmacodynamic acitivity of the multi-targeted kinase inhibitor SU11248 in patients with metastatic renal cell cancer. Proc Am Assoc Cancer Res 46:464
Krystal GW, Honsawek S, Kiewlich D, Liang C, Vasile S, Sun L, McMahon G, Lipson KE (2001) Indoline tyrosine kinase inhibitors block Kit activation and growth of small cell lung cancer cells. Cancer Res 61:3660–3669
Smolich BD, Yuen HA, West KA, Giles FJ, Albitar M, Cherrington JM (2001) The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood 97:1413–1421
Itokawa T, Nokihara H, Nishioka Y, Sone S, Iwamoto Y, Yamada Y, Cherrington JM, McMahon G, Shibuya M, Kuwano M, Ono M (2002) Antiangiogenic effect by SU5416 partly attributable to inhibtion of Flt-1 receptor signaling. Mol Cancer Ther 1:295–302
Yee KWH, O'Farrell AM, Smolich BD, Cherrington JM, McMahon G, Wait CL, McGreevey LS, Griffith DJ, Heinrich MC (2002) SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood 100:2941– 2949
Wang SY, Chen B, Zhan YQ, Wu WX, Li CY, Yang RF, Zheng H, Yue PB, Larsen SH, Sun HB, Yang X (2004) SU5416 is a potent inhibitor of hepatocyte growth factor receptor (c-Met) and blocks HGF-induced invasiveness of human HepG2 hepatoma cells. J Hepatol 41:267–273
Vokes EE, Cohen EE, Mauer AM, Karrison TG, Wong SJ, Skoog-Sluman LJ, Kozloff MF, Dancey J, Dekker A (2005) A phase I/II study of erlotinib and bevacizumab for recurrent or metastatic squamous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol 23:5504
Cooney MM, Tserng K-Y, Makar V, McPeak RJ, Ingalls ST, Dowlati A, Overmoyer B, McCrae K, Ksenich P, Lavertu P, Ivy P, Hoppel CL, Remick S (2005) A phase IB clinical and pharmacokinetic study of the angiogenesis inhibitor SU5416 and paclitaxel in recurrent or metastatic carcinoma of the head and neck. Cancer Chemother Pharmacol 55:295–300
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We wish to thank Simone Lake for administrative support during the study.
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Supported in Part by CTEP (NCI 79) U01-CA69913.
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Fury, M.G., Zahalsky, A., Wong, R. et al. A Phase II study of SU5416 in patients with advanced or recurrent head and neck cancers. Invest New Drugs 25, 165–172 (2007). https://doi.org/10.1007/s10637-006-9011-x
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DOI: https://doi.org/10.1007/s10637-006-9011-x