Safety, Tolerability, PK/PD and Preliminary Efficacy of NKTR-255, a Novel IL-15 Receptor Agonist, in Patients with Relapsed/Refractory Hematologic Malignancies
Authors: Shah Nina , Tan Alan , Budde Elizabeth , Hofmeister Craig C. , Cowan Andrew J. , Perales Miguel-Angel , Choi Taewoong , Saeed Hayder , Chavez Julio C. , Ye Jing C. , Cairo Mitchell S. , Rizzieri David A. , Orloff Gregory J. , Lee Zachary , Dixit Neha , Nieves Wildaliz , Zhao Qiang , Wang Xiaoli , Kai Kazuharu , Marcondes Mario Q. , Tagliaferri Mary A. , Zalevsky Jonathan , Patel Krina K. 
Published: November 2021

Abstract

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 (&gt;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

Disclosures
Shah: Sanofi: Consultancy; Precision Biosciences: Research Funding; Nektar: Research Funding; Karyopharm: Consultancy; Indapta Therapeutics: Consultancy; CareDx: Consultancy; Kite: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; Amgen: Consultancy; CSL Behring: Consultancy; GSK: Consultancy; Janssen: Research Funding; Oncopeptides: Consultancy; Sutro Biopharma: Research Funding; Poseida: Research Funding; Teneobio: Research Funding. Budde: Merck, Inc: Research Funding; Amgen: Research Funding; Astra Zeneca: Research Funding; Mustang Bio: Research Funding; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy; Beigene: Consultancy. Hofmeister: Sanofi: Other: National PI for CST; PI or co-PI IST; BMS/Celgene: Other: National PI for CST; PI or co-PI IST; Local PI of CST; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Oncolytics: Other: National PI for CST; PI or co-PI IST; Takeda: Other: Local PI of CST; Genzyme: Membership on an entity's Board of Directors or advisory committees; Myeloma360: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; BioAscend: Other: CME speaker; Philips Gilmore: Other: CME speaker; Non-pharma speaker for education, research, marketing; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Non-CME speaker; BlueBird Bio: Other: Non-CME speaker; Aptitude Health: Other: Non-pharma speaker for education, research, marketing; Verascity: Other: Non-pharma speaker for education, research, marketing; TRM Oncology: Other: Non-pharma speaker for education, research, marketing; DAVA Oncology: Other: Non-pharma speaker for education, research, marketing; Medscape: Other: Non-pharma speaker for education, research, marketing; Ohio State University: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: IP rights, Patents & Royalties. Cowan: Bristol Myers Squibb: Research Funding; GSK: Consultancy; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Cellectar: Consultancy; Harpoon: Research Funding; Secura Bio: Consultancy; Nektar: Research Funding; Sanofi Aventis: Consultancy, Research Funding. Perales: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Cidara: Honoraria; Equilium: Honoraria; Incyte: Honoraria, Other; Karyopharm: Honoraria; Kite/Gilead: Honoraria, Other; Medigene: Honoraria; Merck: Honoraria; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; Nektar Therapeutics: Honoraria, Other; NexImmune: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Sellas Life Sciences: Honoraria; Servier: Honoraria; Takeda: Honoraria. Choi: Janssen Biotech: Speakers Bureau. Saeed: MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Consultancy, Other: research investigator; Other-TG therapeutics: Consultancy, Other: investigator; Kite Pharma: Consultancy, Other: investigator; MEI Pharma Inc: Consultancy, Other: investigator; Celgene Corporation: Consultancy, Other: investigator; Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator; sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Company: Consultancy; Other-Epizyme, Inc.: Consultancy; Other-Secura Bio, Inc.: Consultancy; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chavez: AbbVie: Consultancy; Adaptive: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; BeiGene: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Consultancy; Kite/Gilead: Consultancy; Merck: Research Funding; MorphoSys: Speakers Bureau; Novartis: Consultancy. Ye: Alexion, AstraZeneca Rare Disease: Other: Study investigator. Cairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees. Rizzieri: Celltron/Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: presentation to FDA for biosimilar review ; Mustang: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Other: personal fee; Gilead: Other: personal fee; Incyte: Other: personal fee; Amgen: Other: personal fee; Kite: Other: personal fee; AROG: Other; Pharmacyclics: Other. Lee: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Dixit: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Nieves: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zhao: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Wang: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Kai: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Marcondes: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Tagliaferri: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zalevsky: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Patel: Pfizer: Consultancy; Janssen: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Oncopeptides: Consultancy.