Phase I study of single agent NIZ985, a recombinant heterodimeric IL-15 agonist, in adult patients with metastatic or unresectable solid tumors

Abstract

Background: NIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors.

Methods: Single agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 µg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, in an accelerated 3+3 dose escalation trial design. IL-15 and endogenous cytokines were monitored by ELISA and multiplexed electrochemiluminescent assays. Multiparameter flow cytometry assessed the frequency, phenotype and proliferation of peripheral blood mononuclear cells. Preliminary antitumor activity was assessed by overall response rate (Response Evaluation Criteria in Solid Tumors V.1.1).

Results: As of March 2, 2020, median treatment duration was 7.5 weeks (range 1.1-77.1). Thirteen patients had discontinued and one (uveal melanoma) remains on treatment with stable disease. Best clinical response was stable disease (3 of 14 patients; 21%). The most frequent adverse events (AEs) were circular erythematous injection site reactions (100%), chills (71%), fatigue (57%), and fever (50%). Treatment-related grade 3/4 AEs occurred in six participants (43%); treatment-related serious AEs (SAEs) in three (21%). The per-protocol maximum tolerated dose was not reached. Pharmacokinetic accumulation of serum IL-15 in the first week was followed by significantly lower levels in week 2, likely due to more rapid cytokine consumption by an expanding lymphocyte pool. NIZ985 treatment was associated with increases in several cytokines, including interferon (IFN)-γ, IL-18, C-X-C motif chemokine ligand 10, and tumor necrosis factor-β, plus significant induction of cytotoxic lymphocyte proliferation (including natural killer and CD8+ T cells), increased CD16+ monocytes, and increased CD163+ macrophages at injection sites.

Conclusions: Subcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-γ and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy.

Trial registration number: NCT02452268.

Keywords: clinical trials as topic; cytokines; immunomodulation; immunotherapy; investigational; therapies.

Conflict of interest statement

Competing interests: AV, CB, BKF, and GNP report inventorship in issued patents of relevance to this work (licensed to Novartis; managed by the National Cancer Institute) and other support by Novartis during the conduct of this study. DGM and TAW report other support from Novartis during the conduct of the study. JT reports grants from Alpine Biosciences, other support from Novartis during the conduct of the study, other support from Pfizer, Five Prime, Merck, Trillium, Incyte and Xencor outside of the current work, and personal fees from Regeneron, Aveo, Neoleukin, Seattle Genetics, BJ Biosciences, and Calithera outside of the current work. SG reports other support from Novartis during the conduct of the study, other support from Bristol Myers Squibb, Rexahn, Incyte, LSK, Five Prime, Mirati, QED, Debiopharm, Merck, Pfizer, AstraZeneca, Medimmune, Clovis, and Seattle Genetics outside of the current work, and ownership of stock in Salerius Pharmaceuticals by spouse. RL reports grants and personal fees from Bristol Myers Squibb, personal fees from Merck, Oncolys, and Sanofi, and non-financial support from Clinigen outside of the current work. NSP, DL, SK, LHL, NRC and FB are, or were at the time of the work described, employees of Novartis Pharmaceuticals. KC, DCW, CJP, WF, ELP, MR and AW-G report nothing to disclose.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

NIZ985 injection site reaction is characterized by local immune cell infiltration. Micrographs from skin biopsy of patient treated with 2 μg/kg NIZ985. (A) H&E stain demonstrated subacute spongiotic dermatitis with superficial perivascular inflammation. (B–E) Immunohistochemistry micrographs for immune cell markers. (B) CD3+ cells (T cells) and (C) CD8+ cells were primarily found near dermal blood vessels (black arrows). (D) CD56+ cells were also found near the dermal/epidermal junction, while (E) CD163+ cells (monocyte lineage) were prominent throughout the affected dermis.

Figure 2

Pharmacokinetics and circulating serum IL-15 concentrations during cycle 1 of NIZ985 treatment in a subset of participants. (A) Serum IL-15 concentration–time profile (mean±SEM) after subcutaneous injection of NIZ985 on cycle 1, day 1. (B) Pooled analysis of serum IL-15 levels immediately before each injection of NIZ985 (1 and 2 μg/kg groups). Violin plots depict median, quartiles and range of data. Each data point represents an individual patient sample. Comparison between indicated time points was by mixed-effects ANOVA. ANOVA, analysis of variance; IL, interleukin.

Figure 3

Lymphocyte proliferation is consistently induced during NIZ985 treatment cycles. (A–D) Individual proliferative responses (percentage Ki67+ cells) induced during each cycle of NIZ985 in circulating CD4+ T cells, CD8+ T cells, γδ T cells, and NK cells. Insets show mean peak percentage Ki67+ cells by dosing group; (E) Individual percentage CD16+ monocytes (from total CD14+ monocytes) during each cycle of NIZ985. NK, natural killer.

Figure 4

(A–E) Mean peak induction (log2-transformed mean ratios of peak-to-baseline levels) of selected plasma cytokines during cycle 1 dosing; (F) Mean cytokine induction (24–240 hours post-dose) in the pooled 1.0 and 2.0 µg/kg dosing groups. X-axis: Log2-transformed mean ratios of peak to baseline cytokine levels in both groups; Y-axis: Correlation coefficients of the mean ratio across all dose groups and NIZ985 dose level. Bars identify regions of high correlation (Pearson’s r ≥0.8 or ≤–0.8) and high response (≥2-fold). C, cycle; CRP, C-reactive protein; CXCL10, C-X-C motif chemokine ligand 10; D, day; FC, fold-change; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.