A phase I trial evaluating the safety and biological activity of iboctadekin (rhIL-18) in combination with rituximab in patients with CD20+ B-cell non-Hodgkin's lymphoma

8566 Background: Iboctadekin (rhIL-18) is an immunostimulatory cytokine that has demonstrated anti-tumor activity in several preclinical models. When administered as monotherapy in phase I clinical studies, rhIL-18 was safe, well tolerated and induced potent biological responses (e.g. Th1 cytokine production and expression of activation markers on NK, CD8+ and CD4+ cells). These data affirm the endogenous role of IL-18 as a co-stimulatory cytokine and suggest that its optimal use would be in a combination with other immune modulators such as rituximab. Methods: Patients with CD20+ B cell non-Hodgkin's lymphoma are being given rituximab (375 mg/m2) IV weekly for 4 consecutive weeks in combination with ascending doses of intravenous rhIL-18 (1 to 100 mcg/kg in 6 cohorts of 3 patients each) IV weekly for 12 weeks to identify a dose that is safe and tolerable and gives a maximum biological effect. Eligible patients must have disease which progressed after standard therapy or for which there is no effective standard treatment. Assessments include safety/tolerability, pharmacokinetics, pharmacodynamics (serum cytokines, peripheral blood phenotypic markers and tumor biomarkers), immunogenicity and anti-tumor activity. Results: To date, thirteen subjects have been enrolled in the first four cohorts (1, 3, 10 and 20 mcg /kg of rhIL-18). The combination is well tolerated with a safety profile similar to that observed with rituximab or rhIL-18 monotherapy. The pharmacodynamic response is as expected with a dose-dependent decrease in circulating activated (CD69+) NK cells within 4 hours after completing the rhIL-18 infusion which rebound to pre-dose levels within 2–4 days. Using the International Working Group response criteria for lymphoma, two subjects had complete responses at 10 and 20 mcg/kg, one subject had a partial response at 10 mcg/kg and three subjects had stable disease at 1, 3 and 3 mcg/kg. Conclusions: These data show that the combination of rhIL-18 and rituximab is safe, well tolerated and induces potent biological activity. This study will define the dose level to be used in a future phase II trial evaluating this combination in patients with relapsed or refractory follicular lymphoma. [Table: see text]