First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours

Abstract

Background: Interleukin-1 (IL-1) signalling is involved in various protumoural processes including proliferation, immune evasion, metastasis and chemoresistance. CAN04 is a first-in-class monoclonal antibody that binds IL-1 receptor accessory protein (IL1RAP), required for IL-1 signalling. In this first-in-human phase 1 study, we assessed safety, recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of CAN04 monotherapy.

Methods: Patients with advanced solid tumours known to express IL1RAP and refractory to standard treatments were enrolled in a dose-escalation study with 5 dose levels (1.0-10.0 mg/kg) of weekly CAN04.

Results: Twenty-two patients were enrolled. Most common adverse events were infusion-related reactions (41%), fatigue (32%), constipation (27%), diarrhoea (27%), decreased appetite (23%), nausea (23%) and vomiting (23%). One dose limiting toxicity was reported. No maximum tolerated dose was identified. Pharmacokinetics analyses indicate higher exposures and slower elimination with increasing doses. Decreases in serum IL-6 and CRP were observed in most patients. Twenty-one patients were evaluable for response, 43% had stable disease per immune-related response criteria with no partial/complete responses.

Conclusions: The IL1RAP targeting antibody CAN04 can be safely administered to patients up to 10.0 mg/kg weekly, which was defined as the RP2D. Serum biomarkers supported target engagement and IL-1 pathway inhibition.

Clinical trial registration: NCT03267316.

Conflict of interest statement

DR, CJ, MMS, FE, SØF and TKG report no personal conflict of interest to declare regarding this manuscript. IS reports no personal conflict of interest except for travel expenses and accommodation from Roche. PA reports consulting for Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius and Deloitte; honoraria from Synthon, Amgen, Novartis and Gilead; travel grants from Amgen, MSD, Pfizer and Roche. DL and LT are Cantargia employees. CS is a consultant for Cantargia. NS reports consultation or attending advisory boards for AIMM Therapeutics, Boehringer Ingelheim and Ellipses Pharma; receiving research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, Amgen, Array, AstraZeneca/MedImmune, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, Cytovation, Deciphera, Genentech/Roche, GlaxoSmithKline, Incyte, InteRNA, Lilly, Merck Sharp & Dohme, Merus, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Taiho and Takeda (outside the submitted work). AA reports advisory role, research grants to the Institute and speaker fees from: Roche, Lilly, Amgen, EISAI, BMS, Pfizer, Novartis, MSD, Genomic Health, Ipsen, AstraZeneca, Bayer and Leo Pharma. Erasmus MC Cancer Institute, Rotterdam, was financially supported by Cantargia to perform their part of this clinical trial. Department of Oncology, Rigshospitalet, Copenhagen, collaborates and received research funding from: AstraZeneca, Bristol-Myers Squibb, Loxo/Lilly, Alligator Bioscience, Cantargia, Incyte, Pfizer, Orion, Roche, MSD, Genentech, Loxa/Bayer, Symphogen, Puma Biotechnology, Genmab, and Novartis. Institut Jules Bordet—Université Libre de Bruxelles, Brussels, received research funding from Roche.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Figures

Fig. 1. IL1RAP is required for both IL-1α and IL-1β signalling.

CAN04 is a potent inhibitor IL-1α and IL-1β signalling and induces ADCC in preclinical models. a IL1RAP is required for IL-1α and IL-1β signalling, which leads to tumour inflammation and progression. b CAN04 binds to IL1RAP, disrupts signalling, and is recognised by NK cells which become activated and attack the IL1RAP-expressing cell by ADCC. Right top and centre panels: CAN04 blocks signalling of IL-1α and IL-1β. IL-1α or IL-1β was added to HEK-Blue™ IL-1β cells (InvivoGen) in the presence of increasing amounts of CAN04. The inhibition of signalling by CAN04 is plotted in the graph with the corresponding half maximal inhibitory concentration (IC50). Right bottom panel: CAN04 induces ADCC of IL1RAP+ SKMEL5 melanoma cells. Human NK cells were added to SKMEL5 cells in the presence of increasing amounts of CAN04, the graph shows the number of dead cells (DAPI+ cells) as a function of increased concentration of CAN04 and the corresponding IC50 value. ADCC antibody-dependent cellular cytotoxicity, IL1R primary interleukin-1 receptor, IL1RAP interleukin-1 receptor accessory protein, NK natural killer cell.

Fig. 2. Analysis of cytokine levels during first infusion in relation to observed IRR with boxplots on change (ratio) in IL-6, IL-10, IFN-γ and IL2RA from baseline to peak.

In general, the patterns are consistent with limited release of pro-inflammatory cytokines as indicated by marked increase of IL-6, IL-10, IFN-ϒ and IL2RA levels versus baseline.

Fig. 3. Analysis of relative change in biomarkers at baseline to before the third dose of CAN04, 2 weeks later.

There was a significant change from baseline to sample taken prior to third dose in WBC, eosinophils, monocytes, lymphocytes and IL-6 and a strong trend (P = 0.08) in CRP. For neutrophils the reduction was not significant (P = 0.31). a WBC white blood cells; b Neutrophils; c Eosinophils; d Monocytes; e Lymphocytes; f CRP c-reactive protein; g IL-6 interleukin-6; h sIL1RAP soluble interleukin-1 receptor assembly protein. D/U/I number of patients deceased/unchanged/increased.