Phase I Trial of ALT-803, A Novel Recombinant IL15 Complex, in Patients with Advanced Solid Tumors

Abstract

Purpose: IL15 induces the activation and proliferation of natural killer (NK) and memory CD8+ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL15N72D:IL15RαSu/IgG1 Fc complex) over recombinant human IL15 (rhIL15) in animal models, we performed this first-in-human phase I trial of ALT-803 in patients with advanced solid tumors.Patients and Methods: Patients with incurable advanced melanoma, renal cell, non-small cell lung, and head and neck cancer were treated with ALT-803 0.3 to 6 μg/kg weekly intravenously or 6 to 20 μg/kg weekly subcutaneously for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, and lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity.Results: Twenty-four patients were enrolled; 11 received intravenous and 13 received subcutaneous ALT-803. Of these patients, nine had melanoma, six renal, three head and neck, and six lung cancer. Although total lymphocyte and CD8+ T-cell expansion were modest, NK cell numbers rose significantly. Neither anti-ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well tolerated, with adverse effects including fatigue and nausea most commonly with intravenous administration, whereas painful injection site wheal was reported most commonly with subcutaneous ALT-803.Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in patients with advanced cancer. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anticancer agents. Clin Cancer Res; 24(22); 5552-61. ©2018 AACR.

Trial registration: ClinicalTrials.gov NCT01727076.

©2018 American Association for Cancer Research.

Figures

Figure 1.. ALT-803 pharmacokinetics

ALT-803 levels were measured in serum samples obtained prior to (Pre) and 30 minutes, and 2, 4, 8 and 24 hours after the first dose of ALT-803 given intravenously (A), or subcutaneously (B) at Altor BioScience using a qualified ELISA as described in Materials and Methods. Individual subject levels are shown. Subjects are grouped according to dose cohort by color. ALT-803 levels in subjects receiving i.v. doses shown in panel (A) were 0.3 μg/kg (black), 0.5 μg/kg (gray), 1 μg/kg (brown), 3 μg/kg (lavender), and 6 μg/kg (orange). Subjects receiving s.c. doses shown in panel (B) were 6 μg/kg (green), 10 μg/kg (red), 15 μg/kg (blue), and 20 μg/kg (black). Only two subjects per dose cohort had samples tested in these analyses, as prescribed by the study protocol.

Figure 2.. Effect of ALT-803 treatment on white blood cell and absolute lymphocyte counts

Circulating white blood cell (WBC x 1000 cells/μL, A) and absolute lymphocyte counts (ALC, cells/μL, B), before and during s.c. ALT-803 treatment on Days 1, 8, 15 and 22 of each 6-week cycle. The mean WBC or ALC values from subjects enrolled in each dose cohort [6 μg/kg (green, N=3), 10 μg/kg (red, N=3), 15 μg/kg (blue, N=4), and 20 μg/kg (black, N=3)] are shown in the left-hand panels. The mean maximal fold increases for each dose cohort are shown in the right-hand panels, where columns represent the mean of the maximal fold increase for each subject during treatment compared to baseline (Day 1). The results shown were limited to data through Cycle 2 Day 4 to limit complexity.

Figure 3.. Circulating NK cell subset expansion during ALT-803 treatment

Data shown are from subjects who received s.c. ALT-803 on Days 1, 8, 15 and 22 of each 6-week cycle. Absolute cell frequencies are shown as means grouped by dose cohort in left panels: 6 μg/kg (green, N=3), 10 μg/kg (red, N=3), 15 μg/kg (blue, N=4), and 20 μg/kg (black, N=3). Circulating total CD56+ NK cells (A), and subsets CD56bright (C) and CD56dim (D) NK cell means for each dose cohort are represented by a single line/symbol. Total CD56+ NK cell numbers for individual subjects who received 15 μg/kg (blue lines/symbols) and 20 μg/kg (black lines/symbols) doses of ALT-803 are also shown (B), illustrating the inter-individual variability among patients at the same dose level. In the right panels, mean maximal fold-increases during treatment compared to baseline (Day 1) for each dose cohort are indicated. The results shown were limited to data through Cycle 2 Day 4 to limit complexity, since maximal increases in NK cell counts occurred prior to that time point.

Figure 4.. Effect of subcutaneous ALT-803 on circulating T cells

Representative plots of Ki-67 expression among CD3+CD8+ T cells at Days 1 (pre-treatment), 4 and 8 were generated as described in Materials and Methods (A). Results from individual subjects in the 15 μg/kg (blue) and 20 μg/kg (black) dose cohorts are shown as the percentage of Ki-67+ cells among CD8+ (left panel) or CD4+ (right panel) T cells at Days 1, 4 and 8 (B). Mean % HLA-DR expression among T cells at Day 1 (pre-treatment) and maximal time points during treatment are shown, grouped by dose cohort in left panels: 6 μg/kg s.c. (green, N=3), 10 μg/kg s.c. (red, N=3), 15 μg/kg s.c. (blue, N=4), and 20 μg/kg s.c. (black, N=3) (C,D). Mean maximal fold-increases during treatment compared to Day 1 (pre-treatment) for each dose cohort are indicated in right panels.