355 First-in-human phase I study of NKTR-255 in patients with relapsed/refractory hematologic malignancies

Background NKTR-255, an investigational IL-15Rα-dependent polymer-conjugated recombinant human IL-15 (rhIL-15) agonist, maintains the full spectrum of IL-15 biology and provides sustained pharmacodynamic (PD) responses without the need for daily dosing. NKTR-255 engages IL-15Rα and IL-2/IL-15Rβγ leading to natural killer(NK) and CD8+ T-cell expansion, proliferation and activation. In preclinical studies, NKTR-255 enhanced antibody-dependent cellular cytotoxicity(ADCC) of each of daratumumab, rituximab, trastuzumab and cetuximab, resulting in synergistic anticancer activity. This ongoing phase 1 trial(NCT04136756) evaluates NKTR-255 in patients with hematologic malignancies. Methods Heavily pretreated patients with relapsed/refractory multiple myeloma(MM) or non-Hodgkin lymphoma(NHL) received escalating doses of NKTR-255 intravenously q3w. Patients were observed for 3 weeks following the first NKTR-255 dose for dose-limiting toxicity(DLT). Preliminary safety, PK and PD were evaluated in all patients and bone marrow biopsy was evaluated in one patient. NKTR-255-mediated activation of the immune system was assessed by flow cytometry and plasma cytokine analysis. Results As of June 25, 2020, 4 patients were dosed(1.5µg/kg:3 patients; 3µg/kg:1 patient). NKTR-255 was well tolerated. Most common treatment-related adverse events(AEs): flu-like symptoms, muscle stiffness, and myalgia. One Grade 3 event(pyrexia) was reported, resolving 24 hours with no accumulation following repeat dosing. NKTR-255 at 1.5µg/kg expanded NK and CD8+ T-cells in peripheral blood, with peak fold-changes in cell numbers of ~5-fold and ~3-fold respectively, maintained during the cycle. Bone marrow biopsy data indicate 7-fold(cycle 5) to 13-fold(cycle 9) increase from baseline in the CD56+ population in the MM patient. Proliferative capacity for NK and CD8+ T-cells was maintained across multiple treatment cycles. NKTR-255-dependent changes in inflammatory cytokines, including MCP-1 and IL-6, peaked by 6 hours and resolved to baseline levels by 24 hours, further supporting the safety of NKTR-255. Conclusions In heavily pretreated patients with hematologic malignancies, NKTR-255 is biologically active and demonstrated sustained increases in NK and CD8+ T-cells. NKTR-255 was well tolerated, with minimal treatment-related toxicities. Our preclinical and preliminary clinical data provide evidence of synergistic effects enhancing ADCC and support continued dose escalation of NKTR-255. Trial Registration NCT04136756 Ethics Approval The study was approved by the institutional review board of each participating site.