title: Phase I study of ONO-4007, a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide.
abstract: 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 alpha, the potentiation of tumor-infiltrating macrophages, and the inhibition of angiogenesis. Interleukin (IL)-1 alpha, IL-6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cells to up-regulate IFN-gamma 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 (approximately 1.3 ml/min) and a small volume of distribution (5-8 liters) with a long t1/2 of 74-95 h. The administration of ONO-4007 was shown to result in a significant increase in circulating levels of tumor necrosis factor alpha 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.
authors.affiliation: Cancer Research Campaign Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow, United Kingdom. gpmv08@udcf.gla.ac.uk
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
authors.forename: A G
authors.initials: AG
authors.lastname: Dalgleish
authors.forename: J
authors.initials: J
authors.lastname: Carmichael
authors.forename: J
authors.initials: J
authors.lastname: Diffley
authors.forename: F J
authors.initials: FJ
authors.lastname: Lofts
authors.forename: D
authors.initials: D
authors.lastname: Fyffe
authors.forename: S
authors.initials: S
authors.lastname: Ellard
authors.forename: R J
authors.initials: RJ
authors.lastname: Gordon
authors.forename: C J
authors.initials: CJ
authors.lastname: Brindley
authors.forename: T R
authors.initials: TR
authors.lastname: Evans
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008050:Lipid A / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D008050:Lipid A; C086889:ONO 4007; D014409:Tumor Necrosis Factor-alpha