Phase I Study Of Recombinant Interleukin-15 In Combination With Checkpoint Inhibitors Nivolumab And Ipilimumab In Subjects With Refractory Cancers.

TPS3128 Background: Interleukin-15 is a stimulatory cytokine. Recombinant human IL-15 (rhIL-15), a nonglycosylated single-chain peptide, increased circulating CD8+T-cells, NK cells and inflammatory cytokines in clinical trials (Conlon et al, 2015. JCO). Simultaneous in vivo administration of IL-15 with anti-CTLA-4 and anti-PD-L1 is associated with increased levels of tumor antigen-specific CD8+T cells and T-cell tumor lytic activity, increased antigen-specific IFN-γ release, decreased tumor growth, and improved mouse survival; as well as inhibition of suppressive functions of CD4+CD25+ and CD8+CD122+ regulatory T-cells (Yu et al, Proc Natl Acad Sci. 2012). Therefore we postulate the combination of checkpoint inhibitors+rhIL-15, which act on different stages of T-cell activation, will enhance anti-tumor immune responses through T-cell expansion, differentiation, and cytotoxic activity. Methods: Open label phase I trial of the rhIL-15+ipilimumab+nivolumab combination following a 3+3 design, with safety lead-in doublets of rhIL-15+nivolumab (Cohort A) or rhIL-15+ipilimumab (Cohort B). Estimated enrollment: 45 patients (pts). 42-day cycles: rhIL-15 administered subcutaneously on days 1-8 and 22-29 for the first 4 cycles only; nivolumab intravenously (IV) day 8, 22 and 36; ipilimumab IV day 1. Pts must be ≥18 years of age, have histologically confirmed solid tumors that have progressed on standard of care therapy, ECOG PS ≤2. Pts with treated brain metastasis with stable disease ≥4 weeks without requiring steroids/anti-seizure medication, and who do not response on any 2/3 agents, are eligible. Exclusion criteria include grade3 immune related adverse events during prior checkpoint inhibitor treatment, active/chronic autoimmune disease, systemic steroid use or HIV/hepatitis infection. Currently, cohort A has enrolled 1 of 3 planned pts. Assessment of intrinsic apoptosis biomarkers, PD-L1 levels, T-cell phenotypic markers, markers of T-cell activation/inhibition (Zap70 pY493/pY580 SHP2), cell enumeration, proximity of tumor cells to T cells at the maximally tolerated dose using a validated/quantitative immunofluorescence assay, is planned. Clinical trial information: NCT03388632.