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355 First-in-human phase I study of NKTR-255 in patients with relapsed/refractory hematologic malignancies
  1. Nina Shah1,
  2. Alan Tan2,
  3. Lihua Budde3,
  4. Craig Hofmeister4,
  5. Andrew Cowan5,
  6. Hayder Saeed6,
  7. Jing Ye7,
  8. Mitchell Cairo8,
  9. David Rizzieri9,
  10. Gregory Orloff10,
  11. Xue Snow Ge11,
  12. Zachary Lee11,
  13. Neha Dixit11,
  14. Wildaliz Nieves11,
  15. Mona Vimal11,
  16. Haijun Ma11,
  17. Takahiro Miyazaki11,
  18. Loui Madakamutil11,
  19. Mario Marcondes11,
  20. Wei Lin11,
  21. Mary Tagliaferri11,
  22. Jonathan Zalevsky11 and
  23. Krina Patel12
  1. 1University of California San Francisco, San Francisco, CA, USA
  2. 2Rush University Medical Center, Chicago, IL, USA
  3. 3City of Hope Comprehensive Cancer Center, Duarte, CA, USA
  4. 4Winship Cancer Institute of Emory University, Atlanta, GA, USA
  5. 5University of Washington, Seattle, WA, USA
  6. 6H. Lee Moffitt Cancer Center and Research Institute, Lutz, FL, USA
  7. 7University of Michigan, Ann Arbor, MI, USA
  8. 8New York Medical Center, Valhalla, NY, USA
  9. 9Duke University School of Medicine, Durham, NC, USA
  10. 10Virginia Cancer Specialists, Fairfax, VA, USA
  11. 11Nektar Therapeutics, San Francisco, CA, USA
  12. 12The University of Texas MD Anderson Cancer Center, Houston, TX, USA


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 over-the-counter medications. No NKTR-255-related DLTs or serious AEs occurred. Clinical activity was observed in 2/4 patients(NHL and MM). The NHL patient achieved reduced metabolic activity in all prespecified target lesions after 5 cycles. The MM patient achieved stable disease after 3 cycles on NKTR-255 monotherapy. This 63 y/o male had high-risk recurrent stage III MM with complex cytogenetics (relapsing after VRd, DRd, and carfilzomib plus dexamethasone). Preliminary PK analyses(1.5µg/kg) showed mean half-life of >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.

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