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.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
17
06
2021
accepted:
24
11
2021
revised:
16
11
2021
pubmed:
15
12
2021
medline:
7
4
2022
entrez:
14
12
2021
Statut:
ppublish
Résumé
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. NCT03267316.
Sections du résumé
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.
Identifiants
pubmed: 34903842
doi: 10.1038/s41416-021-01657-7
pii: 10.1038/s41416-021-01657-7
pmc: PMC8980035
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antineoplastic Agents
0
IL1RAP protein, human
0
Interleukin-1 Receptor Accessory Protein
0
Banques de données
ClinicalTrials.gov
['NCT03267316']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1010-1017Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
Références
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.
pubmed: 28722720
pmcid: 5939996
doi: 10.1038/ni.3790
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.
pubmed: 30032820
doi: 10.1016/j.lungcan.2018.06.015
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.
pubmed: 24958470
doi: 10.1158/0008-5472.CAN-14-0960
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.
pubmed: 27320908
pmcid: 4927403
doi: 10.1016/j.celrep.2016.05.085
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.
pubmed: 29967259
doi: 10.1158/0008-5472.CAN-18-0118
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.
pubmed: 28970361
doi: 10.1158/1541-7786.MCR-17-0221
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.
pubmed: 23591198
pmcid: 3670479
doi: 10.1038/bjc.2013.174
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.
pubmed: 27797936
doi: 10.1136/gutjnl-2016-311585
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.
pubmed: 26500238
doi: 10.1158/1078-0432.CCR-14-3382
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.
pubmed: 21948958
pmcid: 3249446
doi: 10.1158/0008-5472.CAN-11-0588
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.
pubmed: 22264792
pmcid: 3360958
doi: 10.1016/j.ccr.2011.12.006
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.
pubmed: 21266527
pmcid: 3065716
doi: 10.1158/1078-0432.CCR-10-1561
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.
pubmed: 19435817
pmcid: 2856954
doi: 10.1158/1541-7786.MCR-08-0201
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.
pubmed: 23202296
doi: 10.1038/nm.2999
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.
pubmed: 29363544
pmcid: 5890818
doi: 10.1158/0008-5472.CAN-17-1366
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.
pubmed: 28855077
doi: 10.1016/S0140-6736(17)32247-X
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.
pubmed: 9820540
doi: 10.4049/jimmunol.161.10.5614
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.
pubmed: 7775431
doi: 10.1074/jbc.270.23.13757
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.
pubmed: 12530978
doi: 10.1016/S1074-7613(02)00514-9
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.
pubmed: 9627018
doi: 10.1002/1529-0131(199806)41:6<1083::AID-ART15>3.0.CO;2-9
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.
pubmed: 20805474
pmcid: 2941341
doi: 10.1073/pnas.1004408107
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.
pubmed: 23479569
doi: 10.1182/blood-2012-09-458935
Shastri A, Will B, Steidl U, Verma A. Stem and progenitor cell alterations in myelodysplastic syndromes. Blood. 2017;129:1586–94.
pubmed: 28159737
pmcid: 5364336
doi: 10.1182/blood-2016-10-696062
IL1RAP Summary. The Human Protein Atlas. 2020. https://www.proteinatlas.org/ENSG00000196083-IL1RAP . accessed 06 Sept 2020.
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.
pubmed: 26067823
doi: 10.1038/leu.2015.135
IL1RAP Pathology Atlas. The Human Protein Atlas. 2020. https://www.proteinatlas.org/ENSG00000196083-IL1RAP/pathology . accessed 12 Nov 2020.
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.
pubmed: 26261316
pmcid: 4553807
doi: 10.1073/pnas.1422749112
IL1RAP Protein Summary. The Human Protein Atlas. 2020. https://www.proteinatlas.org/ENSG00000196083-IL1RAP/summary/rna . accessed 06 Sept 2020.
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.
pubmed: 29382706
pmcid: 5899630
doi: 10.1158/0008-5472.CAN-17-2761
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.
pubmed: 29150554
pmcid: 5724250
doi: 10.1073/pnas.1705165114
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.
pubmed: 33758330
pmcid: 8144204
doi: 10.1038/s41416-021-01303-2
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.
pubmed: 27621309
doi: 10.1182/blood-2015-11-679985
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. https://cantargia.com/assets/uploads/Poster-PEGS-Europe-final.pdf .
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.
doi: 10.1158/1538-7445.AM2018-1769
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. https://cantargia.com/assets/uploads/Cantargia_San-Diego-CAN04-and-chemotherapy.pdf .
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.
doi: 10.1158/1538-7445.AM2020-2269
Vakkila J, Lotze MT. Inflammation and necrosis promote tumour growth. Nat Rev Immunol. 2004;4:641–48.
pubmed: 15286730
doi: 10.1038/nri1415
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.
pubmed: 16474845
doi: 10.1038/sj.onc.1209423
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.
doi: 10.1158/1078-0432.CCR-09-1624
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.
doi: 10.1016/j.ejca.2008.10.026
Ryman JT, Meibohm B. Pharmacokinetics of monoclonal antibodies. CPT Pharmacomet Syst Pharmacol. 2017;6:576–88.
doi: 10.1002/psp4.12224
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.
pubmed: 23129601
doi: 10.1161/CIRCULATIONAHA.112.122556
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.
pubmed: 10498591
doi: 10.1182/blood.V94.7.2217.419k02_2217_2224
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.
pubmed: 26308596
doi: 10.1056/NEJMoa1506348
Jean GW, Comeau JM. Role of obinutuzumab in the treatment of chronic lymphocytic leukemia. Am J Health Syst Pharm. 2015;72:933–42.
pubmed: 25987688
doi: 10.2146/ajhp140282
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.
pubmed: 18003886
doi: 10.1182/blood-2007-09-111781
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.
pubmed: 28881914
doi: 10.1093/annonc/mdx216
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.
pubmed: 18539196
pmcid: 2821937
doi: 10.1016/j.jaci.2008.04.005