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 mu g/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)-gamma, IL-18, C-X-C motif
chemokine ligand 10, and tumor necrosis factor-beta, 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-gamma 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.
