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

• Published in: Clinical cancer research 2000-02, Vol.6 (2), p.397-405
• Main Authors: DE BONO, J. S, DALGLEISH, A. G, CARMICHAEL, J, DIFFLEY, J, LOFTS, F. J, FYFFE, D, ELLARD, S, GORDON, R. J, BRINDLEY, C. J, EVANS, T. R. J
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Chemotherapy; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Lipid A - administration & dosage; Lipid A - adverse effects; Lipid A - analogs & derivatives; Lipid A - pharmacokinetics; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Neoplasms - blood; Neoplasms - drug therapy; Pharmacology. Drug treatments; Tumor Necrosis Factor-alpha - analysis
• ISSN: 1078-0432; 1557-3265

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 α, the potentiation of tumor-infiltrating macrophages, and the inhibition of angiogenesis. Interleukin (IL)-1α, IL-6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cells to up-regulate IFN-γ 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 α 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.