Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical Studies

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



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.


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.


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.


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


This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Fig. 1: IL1RAP is required for both IL-1α and IL-1β signalling.
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.
Fig. 3: Analysis of relative change in biomarkers at baseline to before the third dose of CAN04, 2 weeks later.

Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.


  1. Netea MG, Balkwill F, Chonchol M, Cominelli F, Donath MY, Giamarellos-Bourboulis EJ, et al. A guiding map for inflammation. Nat Immunol. 2017;18:826–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Millares L, Barreiro E, Cortes R, Martinez-Romero A, Balcells C, Cascante M, et al. Grupo Colaborativo en Cáncer de Pulmón CIBERES- CIBERONC- SEPAR—Plataforma Biobanco Pulmonar. Tumor-associated metabolic and inflammatory responses in early stage non-small cell lung cancer: local patterns and prognostic significance. Lung Cancer. 2018;122:124–30.

    Article  PubMed  Google Scholar 

  3. Wang L, Zhang LF, Wu J, Xu SJ, Xu YY, Li D, et al. IL-1ß-mediated repression of microRNA-101 is crucial for inflammation-promoted lung tumorigenesis. Cancer Res. 2014;74:4720–30.

    Article  CAS  PubMed  Google Scholar 

  4. McLoed AG, Sherrill TP, Cheng DS, Han W, Saxon JA, Gleaves LA, et al. Neutrophil-derived IL-1β impairs the efficacy of NF-κB inhibitors against lung cancer. Cell Rep. 2016;16:120–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tsukamoto H, Fujieda K, Miyashita A, Fukushima S, Ikeda T, Kubo Y, et al. Combined blockade of IL6 and PD-1/PD-L1 signaling abrogates mutual regulation of their immunosuppressive effects in the tumor microenvironment. Cancer Res. 2018;78:5011–22.

    Article  CAS  PubMed  Google Scholar 

  6. Nomura A, Gupta VK, Dauer P, Sharma NS, Dudeja V, Merchant N, et al. NFκB-mediated invasiveness in CD133+ pancreatic TICs is regulated by autocrine and paracrine activation of IL1 signaling. Mol Cancer Res. 2018;16:162–72.

    Article  CAS  PubMed  Google Scholar 

  7. Mitsunaga S, Ikeda M, Shimizu S, Ohno I, Furuse J, Inagaki M, et al. Serum levels of IL-6 and IL-1β can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer. 2013;108:2063–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mace TA, Shakya R, Pitarresi JR, Swanson B, McQuinn CW, Loftus S, et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut. 2018;67:320–32.

    Article  CAS  PubMed  Google Scholar 

  9. Zhuang Z, Ju HQ, Aguilar M, Gocho T, Li H, Iida T, et al. IL1 receptor antagonist inhibits pancreatic cancer growth by abrogating NF-κB activation. Clin Cancer Res. 2016;22:1432–44.

    Article  CAS  PubMed  Google Scholar 

  10. Schmid MC, Avraamides CJ, Foubert P, Shaked Y, Kang SW, Kerbel RS, et al. Combined blockade of integrin-α4β1 plus cytokines SDF-1α or IL-1β potently inhibits tumor inflammation and growth. Cancer Res. 2011;71:6965–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, et al. KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:105–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Maker AV, Katabi N, Qin LX, Klimstra DS, Schattner M, Brennan MF, et al. Cyst fluid interleukin-1beta (IL1beta) levels predict the risk of carcinoma in intraductal papillary mucinous neoplasms of the pancreas. Clin Cancer Res. 2011;17:1502–08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Melisi D, Niu J, Chang Z, Xia Q, Peng B, Ishiyama S, et al. Secreted interleukin-1alpha induces a metastatic phenotype in pancreatic cancer by sustaining a constitutive activation of nuclear factor-kappaB. Mol Cancer Res. 2009;7:624–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bruchard M, Mignot G, Derangère V, Chalmin F, Chevriaux A, Végran F, et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med. 2013;19:57–64.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang D, Li L, Jiang H, Li Q, Wang-Gillam A, Yu J, et al. Tumor-stroma IL1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer. Cancer Res. 2018;78:1700–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:1833–42.

    Article  CAS  PubMed  Google Scholar 

  17. Cullinan EB, Kwee L, Nunes P, Shuster DJ, Ju G, McIntyre KW, et al. IL-1 receptor accessory protein is an essential component of the IL-1 receptor. J Immunol. 1998;161:5614–20.

    Article  CAS  PubMed  Google Scholar 

  18. Greenfeder SA, Nunes P, Kwee L, Labow M, Chizzonite RA, Ju G. Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Biol Chem. 1995;270:13757–65.

    Article  CAS  PubMed  Google Scholar 

  19. Smith DE, Hanna R, Della F, Moore, Chen H, Farese H, et al. The soluble form of IL-1 receptor accessory protein enhances the ability of soluble type II IL-1 receptor to inhibit IL-1 action. Immunity. 2003;18:87–96.

    Article  CAS  PubMed  Google Scholar 

  20. Jouvenne P, Vannier E, Dinarello CA, Miossec P. Elevated levels of soluble interleukin-1 receptor type II and interleukin-1 receptor antagonist in patients with chronic arthritis: correlations with markers of inflammation and joint destruction. Arthritis Rheum. 1998;41:1083–89.

    Article  CAS  PubMed  Google Scholar 

  21. Järås M, Johnels P, Hansen N, Agerstam H, Tsapogas P, Rissler M, et al. Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein. Proc Natl Acad Sci USA. 2010;107:16280–85.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Askmyr M, Ågerstam H, Hansen N, Gordon S, Arvanitakis A, Rissler M, et al. Selective killing of candidate AML stem cells by antibody targeting of IL1RAP. Blood. 2013;121:3709–13.

    Article  CAS  PubMed  Google Scholar 

  23. Shastri A, Will B, Steidl U, Verma A. Stem and progenitor cell alterations in myelodysplastic syndromes. Blood. 2017;129:1586–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. IL1RAP Summary. The Human Protein Atlas. 2020. accessed 06 Sept 2020.

  25. Landberg N, Hansen N, Askmyr M, Ågerstam H, Lassen C, Rissler M, et al. IL1RAP expression as a measure of leukemic stem cell burden at diagnosis of chronic myeloid leukemia predicts therapy outcome. Leukemia. 2016;30:253–257.

    Article  CAS  PubMed  Google Scholar 

  26. IL1RAP Pathology Atlas. The Human Protein Atlas. 2020. accessed 12 Nov 2020.

  27. Ågerstam H, Karlsson C, Hansen N, Sandén C, Askmyr M, von Palffy S, et al. Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia. Proc Natl Acad Sci USA. 2015;112:10786–91.

    Article  PubMed  PubMed Central  Google Scholar 

  28. IL1RAP Protein Summary. The Human Protein Atlas. 2020. accessed 06 Sept 2020.

  29. Liu S, Lee JS, Jie C, Park MH, Iwakura Y, Patel Y, et al. HER2 overexpression triggers an IL1α proinflammatory circuit to drive tumorigenesis and promote chemotherapy resistance. Cancer Res. 2018;78:2040–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Voigt C, May P, Gottschlich A, Markota A, Wenk D, Gerlach I, et al. Cancer cells induce interleukin-22 production from memory CD4+ T cells via interleukin-1 to promote tumor growth. Proc Natl Acad Sci USA. 2017;114:12994–12999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Winograd R, Simeone DM, Bar-Sagi D. A novel target for combination immunotherapy in pancreatic cancer: IL-1β mediates immunosuppression in the tumour microenvironment. Br J Cancer. 2021;124:1754–1756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ågerstam H, Hansen N, von Palffy S, Sandén C, Reckzeh K, Karlsson C, et al. IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models. Blood. 2016;128:2683–93.

    Article  PubMed  Google Scholar 

  33. Liberg, D, Sime, W, Riva, M, Massoumi, R, Forsberg, G, Von Wachenfeldt, K. The CAN04 antibody targets IL1RAP and inhibits tumor growth in a PDX model for NSCLC. 2016.

  34. Liberg D, Önnervik PO, Riva M, Larsson L, Forsberg G, Von Wachenfeldt K. Abstract 1769: Antibody blockade of ILRAP signaling reduces metastasis in a breast cancer model. Cancer Res. 2018;78:1769.

    Article  Google Scholar 

  35. Liberg, D. The CAN04 antibody targets IL1RAP and mediates tumor growth inhibition and increased cisplatin sensitivity in a patient-derived xenograft model for non-small cell lung cancer. 2018.

  36. Rydberg Millrud C, von Wachenfeldt K, Falk HH, Forsberg G, Liberg D. Abstract 2269: The anti-IL1RAP antibody CAN04 increases tumor sensitivity to platinum-based chemotherapy. Cancer Res. 2020;80:2269.

    Article  Google Scholar 

  37. Vakkila J, Lotze MT. Inflammation and necrosis promote tumour growth. Nat Rev Immunol. 2004;4:641–48.

    Article  CAS  PubMed  Google Scholar 

  38. Müerköster SS, Lust J, Arlt A, Häsler R, Witt M, Sebens T, et al. Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1beta and NO lead to inactivation of caspases. Oncogene. 2006;25:3973–81.

    Article  PubMed  Google Scholar 

  39. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–20.

    Article  CAS  Google Scholar 

  40. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  CAS  Google Scholar 

  41. Ryman JT, Meibohm B. Pharmacokinetics of monoclonal antibodies. CPT Pharmacomet Syst Pharmacol. 2017;6:576–88.

    Article  CAS  Google Scholar 

  42. Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, et al. Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012;126:2739–48.

    Article  CAS  PubMed  Google Scholar 

  43. Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood. 1999;94:2217–24.

    Article  CAS  PubMed  Google Scholar 

  44. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207–19.

    Article  CAS  PubMed  Google Scholar 

  45. Jean GW, Comeau JM. Role of obinutuzumab in the treatment of chronic lymphocytic leukemia. Am J Health Syst Pharm. 2015;72:933–42.

    Article  CAS  PubMed  Google Scholar 

  46. Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008;111:1094–1100.

    Article  CAS  PubMed  Google Scholar 

  47. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. ESMO Guidelines Committee. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2017;28:iv100–iv118.

    Article  PubMed  Google Scholar 

  48. Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol. 2008;121:1484–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


Drafting and editorial support was provided by Satyen Shenoy and Agnieszka Linkiewicz-Zegan on behalf of Proper Medical Writing, Poland.


This work was supported by Cantargia. Supplementary information is available at the British Journal of Cancer’s website.

Author information

Authors and Affiliations



DR, CJ, MMS, IS, FE, SØF, TKG, PA, NS and AA participated in patients’ enrolment. DR, DL, CS and LT analysed the data and wrote the manuscript. DL conducted and supervised the preclinical experiments. AA is the coordinating investigator of CANFOUR and participated in the protocol review. All authors reviewed the manuscript, approved the final version and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Debbie Robbrecht.

Ethics declarations

Ethics approval and consent to participate

The clinical study protocol and other relevant study documents were approved by the applicable regional review boards/ethic committees (not listed because of limited word space). Written informed consent was obtained from all patients prior to any study related procedure. The study was performed in accordance with the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Robbrecht, D., Jungels, C., Sorensen, M.M. et al. 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. Br J Cancer 126, 1010–1017 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links