This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sebastian de Bono, J. Articles by Evans, T. R. J. Search for Related Content PubMed PubMed Citation Articles by Sebastian de Bono, J. Articles by Evans, T. R. J.

Phase I Study of ONO-4007, a Synthetic Analogue of the Lipid A Moiety of Bacterial Lipopolysaccharide¹

Cancer Research Campaign Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow G11 6NT, United Kingdom [J. S. d. B., S. E., T. R. J. E.]; Department of Medical Oncology, St. George’s Hospital Medical School, London SW 17 0RE, United Kingdom [A. G. D., J. D., F. J. L.]; Cancer Research Campaign Department of Clinical Oncology, Nottingham City Hospital, Nottingham NG5 1PB, United Kingdom [J. C., D. F.]; Quintiles SA Strasbourg, Lingolshiem BP306, 67832 Tanneries Cedex, France [R. J. G.]; Quintiles Scotland Limited, Heriot-Watt University Research Park, Edinburgh EH14 4AP, United Kingdom [C. J. B.]

ONO-4007 is a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide, which exhibits antitumor activity by the induction of intratumoral tumor necrosis factor , the potentiation of tumor-infiltrating macrophages, and the inhibition of angiogenesis. Interleukin (IL)-1, IL-6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cells to up-regulate IFN- and nitric oxide synthase activity. ONO-4007 was given to 24 patients (13 males and 11 females; median age, 53 years) as a 30-min i.v. infusion on day 1, followed on day 15 by a first treatment cycle consisting of three weekly infusions at the same dose, followed by a rest period of 1 week. Cohorts of six patients received up to a maximum of four treatment cycles at increasing dose levels (75, 100, and 125 mg). The maximum tolerated dose was 125 mg, with grade 3 National Cancer Institute Common Toxicity Criteria toxicity (rigors with cyanosis) occurring in two of six patients at this dose level. An additional six patients were treated at 100 mg, the dose below the maximum tolerated dose. Other toxicities included grade 2 National Cancer Institute Common Toxicity Criteria myalgia, nausea, and hypotension. The pharmacokinetics of ONO-4007 appeared to be independent of dose and showed linearity with respect to time. ONO-4007 has a low systemic clearance (1.3 ml/min) and a small volume of distribution (5–8 liters) with a long t_1/2 of 74–95 h. The administration of ONO-4007 was shown to result in a significant increase in circulating levels of tumor necrosis factor and IL-6. No objective antitumor responses were observed. Seven patients maintained stable disease for at least two cycles, whereas five patients maintained stable disease for the full four-cycle duration of the study. Additional studies are required to determine the antitumor activity of ONO-4007.

This article has been cited by other articles:

				C.-K. Chang, G. Astrakianakis, D. B Thomas, N. S Seixas, R. M Ray, D. L. Gao, K. J Wernli, E D. Fitzgibbons, T. L Vaughan, and H. Checkoway Occupational exposures and risks of liver cancer among Shanghai female textile workers--a case-cohort study Int. J. Epidemiol., April 1, 2006; 35(2): 361 - 369. [Abstract] [Full Text] [PDF]

				I. Pollet, C. J. Opina, C. Zimmerman, K. G. Leong, F. Wong, and A. Karsan Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-{kappa}B and c-Jun N-terminal kinase Blood, September 1, 2003; 102(5): 1740 - 1742. [Abstract] [Full Text] [PDF]

				Y. N. Wong, D. Rossignol, J. R. Rose, R. Kao, A. Carter, and M. Lynn Safety, Pharmacokinetics, and Pharmacodynamics of E5564, a Lipid A Antagonist, during an Ascending Single-Dose Clinical Study J. Clin. Pharmacol., July 1, 2003; 43(7): 735 - 742. [Abstract] [Full Text] [PDF]