Abstract
Purpose
The safety and tolerability of vandetanib (ZACTIMA™; ZD6474) plus FOLFIRI was investigated in patients with advanced colorectal cancer (CRC).
Methods
Patients eligible for first- or second-line chemotherapy received once-daily oral doses of vandetanib (100 or 300 mg) plus 14-day treatment cycles of FOLFIRI.
Results
A total of 21 patients received vandetanib 100 mg (n = 11) or 300 mg (n = 10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort and one DLT of hypertension (CTCAE grade 3) in the 300 mg cohort. The most common adverse events were diarrhoea (n = 20), nausea (n = 12) and fatigue (n = 10). Two patients (one in each cohort) discontinued vandetanib due to adverse events (rash, 100 mg cohort; hypertension, 300 mg cohort). There was no apparent pharmacokinetic interaction between vandetanib and FOLFIRI. Preliminary efficacy results included two confirmed partial responses in the 100 mg cohort and 9 patients with stable disease ≥8 weeks (100 mg, n = 7; 300 mg, n = 2).
Conclusions
Once-daily vandetanib (100 or 300 mg) in combination with a standard FOLFIRI regimen was generally well tolerated in patients with advanced CRC.
Similar content being viewed by others
References
Ferlay J, Autier P, Boniol M et al (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18:581–592
Jemal A, Siegel R, Ward E et al (2007) Cancer Statistics, 2007. CA Cancer J Clin 57:43–66
Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan study group. N Engl J Med 343:905–914
Giacchetti S, Perpoint B, Zidani R et al (2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136–147
Kohne CH, Van Cutsem E, Wils J et al (2005) Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol 23:4856–4865
Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342
Tabernero J, Van Cutsem E, Diaz-Rubio E et al (2007) Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 25:5225–5232
Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345
Van Cutsem E, Lang I, D’Haens G et al (2008) KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. J Clin Oncol 26:2A
Bokemeyer C, Bondarenko I, Hartmann J et al (2008) KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26: Abst 4000
Townsley CA, Major P, Siu LL et al (2006) Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer 94:1136–1143
Hecht JR, Trarbach T, Jaeger E et al (2005) A randomized, double-blind, placebo-controlled, phase III study in patients (Pts) with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/5-fluorouracil/leucovorin and PTK787/ZK 222584 or placebo (CONFIRM-1). Proc Am Soc Clin Oncol abst 3
Saltz LB, Rosen LS, Marshall JL et al (2007) Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. J Clin Oncol 25:4793–4799
Porebska I, Harlozinska A, Bojarowski T (2000) Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 21:105–115
Ciardiello F, Caputo R, Bianco R et al (2001) Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7:1459–1465
Riedel F, Gotte K, Li M et al (2002) EGFR antisense treatment of human HNSCC cell lines down-regulates VEGF expression and endothelial cell migration. Int J Oncol 21:11–16
Saltz LB, Lenz HJ, Kindler HL et al (2007) Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 25:4557–4561
Punt CJ, Tol J, Rodenburg CJ et al (2008) Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). Proc Am Soc Clin Oncol 26
Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, Shahin S, Griffin T (2008) An updated analysis of safety and efficacy of oxaliplatin (Ox)/bevacizumab (bev) +/− panitumumab (pmab) for first-line treatment (tx) of metastatic colorectal cancer (mCRC) from a randomized, controlled trial (PACCE)
Wedge SR, Ogilvie DJ, Dukes M et al (2002) ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62:4645–4655
Ichihara M, Murakumo Y, Takahashi M (2004) RET and neuroendocrine tumors. Cancer Lett 204:197–211
Holden SN, Eckhardt SG, Basser R et al (2005) Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol 16:1391–1397
Tamura T, Minami H, Yamada Y et al (2006) A Phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors. J Thorac Oncol 1:1002–1009
Natale RB, Bodkin D, Govindan R et al (2009) Vandetanib versus gefitinib in patients with advanced NSCLC: results from a two-part, double-blind, randomized phase II study. J Clin Oncol (in press)
Heymach JV, Johnson BE, Prager D et al (2007) Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. J Clin Oncol 25:4270–4277
Heymach JV, Paz-Ares L, De Braud F et al (2008) 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 26:5407–5415
Herbst RS, Heymach JV, O’Reilly MS et al (2007) Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opin Investig Drugs 16:239–249
Klein CE, Gupta E, Reid JM et al (2002) Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide. Clin Pharmacol Ther 72:638–647
Messersmith WA, Laheru DA, Senzer NN et al (2004) Phase I trial of irinotecan, infusional 5-fluorouracil, and leucovorin (FOLFIRI) with erlotinib (OSI-774): early termination due to increased toxicities. Clin Cancer Res 10:6522–6527
Wolpin BM, Clark JW, Meyerhardt JA et al (2006) Phase I study of gefitinib plus FOLFIRI in previously untreated patients with metastatic colorectal cancer. Clin Colorectal Cancer 6:208–213
Douillard JY, Cunningham D, Roth AD et al (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355:1041–1047
Mross K, Drevs J, Muller M et al (2005) Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer 41:1291–1299
Faivre S, Delbaldo C, Vera K et al (2006) Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24:25–35
Drevs J, Siegert P, Medinger M et al (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25:3045–3054
Acknowledgments
This study, including editorial assistance provided by Chris Watson of Mudskipper Bioscience, was supported financially by AstraZeneca. ZACTIMA is a trademark of the AstraZeneca group of companies.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Saunders, M.P., Wilson, R., Peeters, M. et al. Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: results from an open-label, multicentre Phase I study. Cancer Chemother Pharmacol 64, 665–672 (2009). https://doi.org/10.1007/s00280-008-0914-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-008-0914-4