Analysis of Biomarker Responses in Phase I Study of rhIL-18 in Combination with Rituximab in Non-Hodgkin’s Lymphoma to Support Phase 2 Dose Selection
H. Struemper (1), J. Bauman (2), Z. Jonak (2), S. Murray (2), S. Williams (2), M.J. Robertson (3), J.F. Toso (2)
(1) Clinical Pharmacology, Modeling & Simulation, GlaxoSmithKline, RTP, NC; (2) Biopharmaceutical Unit, Discovery Medicine, GlaxoSmithKline, RTP, NC and Philadelphia, PA; (3) Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN.
Objectives: The safety and biological activity of the combination of recombinant human interleukin-18 (rhIL-18) in combination with rituximab is currently being evaluated in a Phase 1 study in patients with CD20+ B cell non-Hodgkin's lymphoma. IL-18 has the potential to augment the cytotoxic effects of rituximab, (i) by directly enhancing antibody-dependent cell-mediated cytotoxicity (ADCC) through NK cell and monocyte activation and (ii) by inducing a sustained tumor-antigen-specific T cell and antibody response through its stimulatory effects on the adaptive immune response . The objective of the biomarker response analysis presented here is to support dose selection for a future Phase 2 study in the absence of dose-limiting toxicities.
Methods: An extensive panel of potential biomarkers including cell counts (total lymphocytes, B cells, CD4+ and CD8+ T cells, and NK cells), cell surface markers (CD69 and other markers of activation) and cytokine/chemokine levels was collected at various time points during the study. The timing of dosing and biomarker measurements was designed to assess the individual contributions of rhIL-18 and rituximab effects to biological and clinical effects. Emax curves for biomarker exposure response relationships were fit using S-Plus and prioritized according to their statistical and biological relevance.
Results: Biomarker samples were measured in a total of 18 subjects, 3 in each of 6 rhIL-18 dose groups (1, 3, 10, 20, 30, and 100 µg/kg qw). The presence of a definitive exposure response pattern depended on the type of biomarker as well as the time point of the measurement. Clear exposure response patterns were observed for NK and CD8+ T cell counts (likely indicating extravasation from the central circulation), for markers of NK cell activation and for select cytokine and chemokine levels. Several biomarkers showed a robust response at the lowest tested dose (1 µg/kg). Near maximal responses for the prioritized biomarker measurements were achieved at 20 µg/kg qw or above.
Conclusions: Dose selection for Phase 2 studies in oncology can be challenging based on Phase 1 studies with low subject numbers and without dose limiting toxicities. In the current Phase 1 study the biomarker analysis prioritized and quantified the biological activities affected by repeated rhIL-18 administration and provided crucial support for the dose selection for a future Phase 2 study.
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