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
Debbie Robbrecht, Christiane Jungels, Morten Mau Sorensen, Iben Spanggaard, Ferry Eskens, Signe Ø Fretland, Tormod Kyrre Guren, Philippe Aftimos, David Liberg, Christer Svedman, Lars Thorsson, Neeltje Steeghs, Ahmad Awada, Debbie Robbrecht, Christiane Jungels, Morten Mau Sorensen, Iben Spanggaard, Ferry Eskens, Signe Ø Fretland, Tormod Kyrre Guren, Philippe Aftimos, David Liberg, Christer Svedman, Lars Thorsson, Neeltje Steeghs, Ahmad Awada
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.
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Source: PubMed