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Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR-255, a Novel IL-15 Receptor Agonist, in Patients with Relapsed/Refractory Hematologic Malignancies

Publication ,  Conference
Shah, N; Tan, A; Budde, E; Hofmeister, CC; Cowan, AJ; Perales, M-A; Choi, T; Saeed, H; Chavez, JC; Ye, JC; Cairo, MS; Rizzieri, DA; Lee, Z ...
Published in: Blood
November 5, 2021

Introduction: NKTR-255, an investigational novel polymer-conjugated recombinant human interleukin (IL)-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 the safety, tolerability, and pharmacokinetic (PK)/PD of NKTR-255 in patients with hematologic malignancies, including determination of the recommended Phase 2 dose (RP2D).Methods: Heavily pretreated patients with relapsed/refractory multiple myeloma (MM) or non-Hodgkin lymphoma (NHL) received escalating doses of NKTR-255 intravenously every 3 weeks. Patients were observed following the first NKTR-255 dose for dose-limiting toxicity. Preliminary PK and PD analyses were conducted. NKTR-255-mediated activation of the immune system was assessed by flow cytometry and plasma cytokine analysis. Fold change was calculated as treatment with NKTR-255 over baseline (baseline = 1).Results: As of June 8, 2021, 14 patients were enrolled, ranging in age from 49 to 80 years; 71% male. Eight (57%) had MM and 6 (43%) had NHL. Two (25%) of 8 patients with MM and 2 (33%) of 6 patients with NHL had received prior chimeric antigen receptor T-cell (CAR-T) therapy. The 14 patients were dosed at 4 levels: (1.5 µg/kg: 3 patients; 3.0 µg/kg: 4 patients; 4.5 µg/kg: 4 patients; 6.0 µg/kg: 3 patients). Among the 11 response-evaluable patients, 7 patients (64%) reported disease stabilization (4/5 [80%] MM patients; 3/6 [50%] NHL patients). Treatment-related adverse events occurring in ≥30% of patients were pyrexia (12/14; 86%), chills (10/14; 71%), nausea (8/14; 57%), headache (6/14; 43%), infusion-related reaction (5/14; 36%), and fatigue (5/14; 36%). Most adverse events were transient and resolved spontaneously, or by using standard treatment protocols. No dose-limiting toxicities were observed, and no patients discontinued NKTR-255 due to adverse events. NKTR-255- induced dose dependent, transient changes in inflammatory cytokines, including interferon-γ, monocyte chemoattractant protein-1 and IL-6 peaked at 3 to 6 hours post-infusion and resolved to baseline levels by 24 to 48 hours, supporting the safety profile of NKTR-255. Preliminary PK analyses showed target mediate disposition at the lowest dose level (1.5 µg/kg) and linear PK toward higher dose levels (>3.0 µg/kg). The average half-life of NKTR-255 was ~39 hours. No accumulation was observed following repeat dosing. There was a dose-dependent expansion in cell numbers of NK and CD8+ T cells in the peripheral blood of patients, with peak fold-changes of ~8-fold and ~2-fold respectively, within the first 2 cycles of NKTR-255 treatment at the 6.0 µg/kg dose. Consistent with NKTR-255 mechanism of action, minimal induction of Tregs was observed at all dose levels tested. Moreover, NK and CD8 + T cells demonstrated proliferative ability, which was maintained across multiple treatment cycles at all dose levels.Conclusions: In this heavily pretreated relapsed/refractory patient population with hematologic malignancies, NKTR-255 was biologically active, and demonstrated sustained increases in NK and CD8 + T cells. NKTR-255 was well tolerated with minimal treatment-related toxicities and transient upregulation and rapid decline of cytokines to baseline levels. RP2D for NKTR-255 monotherapy has not yet been reached; and dose escalation is ongoing at 9.0 µg/kg. NKTR-255 is currently being evaluated in multiple clinical studies in both hematologic malignancies and solid tumors as a monotherapy and in combination with agents that induce ADCC.Ethics approval: The study was approved by the institutional review board of each participating site.Trial registration: ClinicalTrials.gov NCT04136756

Duke Scholars

Published In

Blood

DOI

EISSN

1528-0020

ISSN

0006-4971

Publication Date

November 5, 2021

Volume

138

Issue

Supplement 1

Start / End Page

3134 / 3134

Publisher

American Society of Hematology

Related Subject Headings

  • Immunology
  • 3213 Paediatrics
  • 3201 Cardiovascular medicine and haematology
  • 3101 Biochemistry and cell biology
  • 1114 Paediatrics and Reproductive Medicine
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology
 

Citation

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Shah, N., Tan, A., Budde, E., Hofmeister, C. C., Cowan, A. J., Perales, M.-A., … Patel, K. K. (2021). Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR-255, a Novel IL-15 Receptor Agonist, in Patients with Relapsed/Refractory Hematologic Malignancies. In Blood (Vol. 138, pp. 3134–3134). American Society of Hematology. https://doi.org/10.1182/blood-2021-147758
Shah, Nina, Alan Tan, Elizabeth Budde, Craig C. Hofmeister, Andrew J. Cowan, Miguel-Angel Perales, Taewoong Choi, et al. “Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR-255, a Novel IL-15 Receptor Agonist, in Patients with Relapsed/Refractory Hematologic Malignancies.” In Blood, 138:3134–3134. American Society of Hematology, 2021. https://doi.org/10.1182/blood-2021-147758.
Shah N, Tan A, Budde E, Hofmeister CC, Cowan AJ, Perales M-A, et al. Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR-255, a Novel IL-15 Receptor Agonist, in Patients with Relapsed/Refractory Hematologic Malignancies. In: Blood. American Society of Hematology; 2021. p. 3134–3134.
Shah, Nina, et al. “Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR-255, a Novel IL-15 Receptor Agonist, in Patients with Relapsed/Refractory Hematologic Malignancies.” Blood, vol. 138, no. Supplement 1, American Society of Hematology, 2021, pp. 3134–3134. Crossref, doi:10.1182/blood-2021-147758.
Shah N, Tan A, Budde E, Hofmeister CC, Cowan AJ, Perales M-A, Choi T, Saeed H, Chavez JC, Ye JC, Cairo MS, Rizzieri DA, Orloff GJ, Lee Z, Dixit N, Nieves W, Zhao Q, Wang X, Kai K, Marcondes MQ, Tagliaferri MA, Zalevsky J, Patel KK. Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR-255, a Novel IL-15 Receptor Agonist, in Patients with Relapsed/Refractory Hematologic Malignancies. Blood. American Society of Hematology; 2021. p. 3134–3134.

Published In

Blood

DOI

EISSN

1528-0020

ISSN

0006-4971

Publication Date

November 5, 2021

Volume

138

Issue

Supplement 1

Start / End Page

3134 / 3134

Publisher

American Society of Hematology

Related Subject Headings

  • Immunology
  • 3213 Paediatrics
  • 3201 Cardiovascular medicine and haematology
  • 3101 Biochemistry and cell biology
  • 1114 Paediatrics and Reproductive Medicine
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology