Phase I study of ONO-4007, a synthetic analogue of the lipid a moiety of bacterial lipopolysaccharide

ONO-4007 is a synthetic analogue of the lipid A moiety of bacterial lipopol ysaccharide, which exhibits antitumor activity by the induction of intratum oral tumor necrosis factor alpha, the potentiation of tumor-infiltrating ma crophages, and the inhibition of angiogenesis. Interleukin (IL)-1 alpha, IL -6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cell s to up-regulate IFN-gamma and nitric oxide synthase activity, ONO-4007 was given to 24 patients (13 males and ii females; median age, 53 years) as a 30-min i.v. infusion on day 1, followed on day 15 by a first treatment cycl e 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 maxi mum tolerated dose was 125 mg, with grade 3 National Cancer Institute Commo n Toxicity Criteria toxicity (rigors,vith cyanosis) occurring in two of six patients at this dose level. An additional sis patients were treated at 10 0 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 independe nt of dose and showed linearity with respect to time. ONO-4007 has a low sy stemic clearance (similar to 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 tum or necrosis factor alpha and IL-6, No objective antitumor responses were ob served. Seven patients maintained stable disease for at least two cycles, w hereas five patients maintained stable disease for the full four-cycle dura tion of the study. Additional studies are required to determine the antitum or activity of ONO-4007.