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,

Iboctadekin (recombinant human interleukin-18; rhIL-18) is an immunostimulatory cytokine with anti-tumor activity in preclinical animal models. Phase I clinical trials have demonstrated that rhIL-18 is well-tolerated as monotherapy for patients with advanced solid tumors. Preclinical and clinical data indicate that rhIL-18 acts a costimulatory cytokine that may be optimally used in combination with other agents such as monoclonal antibodies. Methods: Patients with CD20+ B-cell non-Hodgkin's lymphoma (NHL) were given rituximab 375 mg/m2 IV weekly for 4 consecutive weeks in combination with rhIL-18 (in six dose cohorts of 1, 3, 10, 20, 30, and 100 mcg/kg) IV weekly for 12 weeks. Eligible patients had disease which progressed after standard therapy or for which there was no effective standard treatment. Assessments included safety/tolerability, pharmacokinetics, pharmacodynamics (serum cytokines, peripheral blood phenotypic markers and tumor biomarkers), immunogenicity, and anti-tumor activity. Results: Nineteen patients were enrolled on study (10 follicular NHL, 5 mantle cell lymphoma, 2 diffuse large B-NHL, 2 other subtypes). The combination was well-tolerated with a safety profile similar to that observed with rituximab or rhIL-18 given as monotherapy. The pharmacodynamic response is as expected based on results of prior clinical trials of rhIL-18 as monotherapy for cancer. Using the IWC response criteria, two (11%) of 18 evaluable patients had complete responses (CR) and 3 (16%) had partial responses (PR). Six (33%) patients had stable disease. Overall response rate for follicular lymphoma was 33% (1 CR, 2 PR). Conclusions: The combination of rhIL-18 and rituximab is safe, well-tolerated, and induces potent biological activity. A maximum tolerated dose of rhIL-18 was not identified. Further study of rhIL-18 plus rituximab in patients with CD20+ B cell malignancies is warranted.

Bauman:GlaxoSmithKline: Employment, Equity Ownership. Gardner:GlaxoSmithKline: Employment, Equity Ownership. Jonak:GlaxoSmithKline: Employment, Equity Ownership. Struemper:GlaxoSmithKline: Employment, Equity Ownership. Germaschewski:GlaxoSmithKline: Employment, Equity Ownership. Koch:GlaxoSmithKline: Employment, Equity Ownership. Murray:GlaxoSmithKline: Employment, Equity Ownership. Toso:GlaxoSmithKline: Employment, Equity Ownership.