Purpose: This phase I study (EudraCT No. 2006-001177-25) investigated aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients with advanced solid tumors. Patients and Methods: Patients received 2, 4, or 6 mg/kg of intravenous aflibercept with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 5-fluorouracil 750 mg/m2 in 3-week cycles until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLTs) during cycle 1 and to determine the recommended phase II dose. Pharmacokinetics, tolerability, and antitumor activity were also investigated. Results: Forty-four patients were enrolled and treated (29 patients in a dose-escalation phase and 15 patients in an expansion cohort). Following three cases of febrile neutropenia in patients receiving aflibercept at 4 mg/kg, the protocol was amended to allow earlier granulocyte colony-stimulating factor support (from day 6) and prophylactic use of ciprofloxacin. Subsequently, there were two DLTs: febrile neutropenia (2 mg/kg) and grade 4 pulmonary embolism (6 mg/kg). An excess of free over VEGF-bound aflibercept was observed at 6 mg/kg. The most frequent grade 3/4 adverse events (AEs) were neutropenia (54.5%), lymphopenia (47.7%), and stomatitis (38.6%). AEs associated with VEGF blockade (any grade) included epistaxis (61.4%), dysphonia (40.9%), hypertension (38.6%), and proteinuria (11.4%). There were 15 partial responses, including 9 in patients with gastroesophageal cancers. Thirteen patients had stable disease. Conclusion: Aflibercept 6 mg/kg administered every 3 weeks in combination with docetaxel, cisplatin, and 5- fluorouracil is the recommended dose for further clinical development based on tolerability, pharmacokinetics, and antitumor activity.

1.
Ferrara N: VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002;2:795-803.
2.
Hicklin DJ, Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:1011-1027.
3.
Holash J, Davis S, Papadopoulos N, et al: VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 2002;99:11393-11398.
4.
Verheul HMW, Hammers H, van Erp K, et al: Vascular endothelial growth factor Trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. Clin Cancer Res 2007;13:4201-4208.
5.
Presta LG, Chen H, O'Connor SJ, et al: Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57:4593-4599.
6.
Huang J, Frischer JS, Serur A, et al: Regression of established tumors and metastases by potent vascular endothelial growth factor blockade. Proc Natl Acad Sci USA 2003;100:7785-7790.
7.
Byrne AT, Ross L, Holash J, et al: Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 2003;9:5721-5728.
8.
Fukasawa M, Korc M: Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines. Clin Cancer Res 2004;10:3327-3332.
9.
Lejeune P, Chiron M, Le Moigne R, et al: Combination of the antiangiogenic agent aflibercept (VEGF Trap) with docetaxel or gemcitabine results in greater antitumor activity in tumor bearing mice. Proc Am Assoc Can Res 2008;1:abstr 1107.
10.
Chiron M, Vrignaud P, Lejeune P, et al: Synergistic activity of aflibercept (VEGF Trap) in combination with 5-fluorouracil and irinotecan in preclinical tumor models. AACR Meeting Abstracts, 2007, A13.
11.
Lockhart AC, Rothenberg ML, Dupont J, et al: Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 2010;28:207-214.
12.
Isambert N, Freyer G, Zanetta S, et al: Phase I dose-escalation study of intravenous aflibercept in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res 2012;18:1743-1750.
13.
Coleman RL, Duska LR, Ramirez PT, et al: Phase 1-2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer. Lancet Oncol 2011;12:1109-1117.
14.
Kilickap S, Yalcin S, Ates O, et al: The first line systemic chemotherapy in metastatic gastric carcinoma: a comparison of docetaxel, cisplatin and fluorouracil (DCF) versus cisplatin and fluorouracil (CF); versus epirubicin, cisplatin and fluorouracil (ECF) regimens in clinical setting. Hepatogastroenterology 2011;58:208-212.
15.
Kos FT, Uncu D, Ozdemir N, et al: Comparison of cisplatin-5-fluorouracil-folinic acid versus modified docetaxel-cisplatin-5-fluorouracil regimens in the first-line treatment of metastatic gastric cancer. Chemotherapy 2011;57:230-235.
16.
Yamasaki M, Miyata H, Tanaka K, et al: Multicenter phase I/II study of docetaxel, cisplatin and fluorouracil combination chemotherapy in patients with advanced or recurrent squamous cell carcinoma of the esophagus. Oncology 2011;80:307-313.
17.
Ajani JA: Optimizing docetaxel chemotherapy in patients with cancer of the gastric and gastroesophageal junction: evolution of the docetaxel, cisplatin, and 5-fluorouracil regimen. Cancer 2008;113:945-955.
18.
Tanaka Y, Yoshida K, Sanada Y, et al: Biweekly docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy for advanced esophageal squamous cell carcinoma: a phase I dose-escalation study. Cancer Chemother Pharmacol 2010;66:1159-1165.
19.
Lorch JH, Goloubeva O, Haddad RI, et al: Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011;12:153-159.
20.
Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-216.
21.
Van Cutsem E, Moiseyenko VM, et al: Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first line therapy for advanced gastric cancer: a report of the V325 study group. J Clin Oncol 2006;24:4991-4997.
22.
Felici A, Loos WJ, Verweij J, et al: A pharmacokinetic interaction study of docetaxel and cisplatin plus or minus 5-fluorouracil in the treatment of patients with recurrent or metastatic solid tumors. Cancer Chemother Pharmacol 2006;58:673-680.
23.
Harvey V, Mouridsen H, Semiglazov V, et al: Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 2006;24:4963-4970.
24.
Leighl NB, Raez LE, Besse B, Rosen PJ, et al: A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinum- and erlotinib-resistant adenocarcinoma of the lung. J Thorac Oncol 2010;5:1054-1059.
25.
Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342.
26.
Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-2550.
27.
Miles DW, Chan A, Dirix LY, et al: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010;28:3239-3247.
28.
Shah MA, Jhawer M, Ilson DH, et al: Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol 2011;29:868-874.
29.
Freyer G, Isambert N, You B, et al: Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours. Br J Cancer 2012;107:598-603.
30.
Van Cutsem E, Khayat D, Verslype C, 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;49:17-24.
31.
Khayat D, Tejpar S, Spano JP, et al: Intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours: results from the expansion cohort of a phase I study. Eur J Cancer 2013;49:790-797.
32.
Van Cutsem E, Tabernero J, Lakomy R, et al: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30:3499-506.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.