Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol.
Antibody-dependent cell-mediated cytotoxicity
Cetuximab
Colorectal Cancer
FcγR
Fluorouracule
Irinotecan
Phase II study
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
09 Sep 2019
09 Sep 2019
Historique:
received:
19
02
2019
accepted:
29
08
2019
entrez:
11
9
2019
pubmed:
11
9
2019
medline:
29
2
2020
Statut:
epublish
Résumé
Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients' selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity. CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses' duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients' cetuximab-mediated ADCC and characterize the tumor microenvironment. The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results' interpretation as well as provide new insights in host-tumor interactions and cetuximab activity. The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number ( NCT03874062 ).
Sections du résumé
BACKGROUND
BACKGROUND
Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients' selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity.
METHODS/DESIGN
METHODS
CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses' duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients' cetuximab-mediated ADCC and characterize the tumor microenvironment.
DISCUSSION
CONCLUSIONS
The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results' interpretation as well as provide new insights in host-tumor interactions and cetuximab activity.
TRIAL REGISTRATION
BACKGROUND
The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number ( NCT03874062 ).
Identifiants
pubmed: 31500586
doi: 10.1186/s12885-019-6109-z
pii: 10.1186/s12885-019-6109-z
pmc: PMC6734266
doi:
Substances chimiques
FCGR3A protein, human
0
Receptors, IgG
0
Irinotecan
7673326042
Cetuximab
PQX0D8J21J
Fluorouracil
U3P01618RT
Types de publication
Clinical Trial Protocol
Clinical Trial, Phase II
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
899Subventions
Organisme : IRCCS Pascale Istituto Nazionale Tumori di Napoli
ID : 60/18
Références
Blood. 2002 Feb 1;99(3):754-8
pubmed: 11806974
J Clin Oncol. 2003 Nov 1;21(21):3940-7
pubmed: 12975461
J Clin Invest. 2006 Aug;116(8):2132-2141
pubmed: 16862213
Cancer Res. 2007 Mar 15;67(6):2649-56
pubmed: 17363585
J Clin Oncol. 2007 Aug 20;25(24):3712-8
pubmed: 17704420
J Clin Oncol. 2008 Apr 10;26(11):1789-96
pubmed: 18347005
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
J Clin Oncol. 2009 Mar 1;27(7):1122-9
pubmed: 19164213
N Engl J Med. 2009 Apr 2;360(14):1408-17
pubmed: 19339720
J Clin Oncol. 2010 Mar 1;28(7):1254-61
pubmed: 20100961
Eur J Cancer. 2010 Jun;46(9):1703-11
pubmed: 20399639
Clin Ther. 2010 Mar;32(3):437-53
pubmed: 20399983
Eur Rev Med Pharmacol Sci. 2010 Apr;14(4):249-58
pubmed: 20496531
Semin Immunopathol. 2011 Jul;33(4):341-51
pubmed: 21499853
Expert Opin Biol Ther. 2011 Jul;11(7):937-49
pubmed: 21557708
Clin Cancer Res. 2011 Sep 1;17(17):5668-73
pubmed: 21788356
Clin Colorectal Cancer. 2011 Dec;10(4):238-44
pubmed: 21820973
J Immunol. 2011 Sep 15;187(6):3383-90
pubmed: 21832160
J Clin Oncol. 2012 Aug 10;30(23):2861-8
pubmed: 22753904
J Exp Med. 2012 Sep 24;209(10):1869-82
pubmed: 22927549
J Transl Med. 2012 Nov 21;10:232
pubmed: 23171437
J Hematol Oncol. 2013 Jan 04;6:1
pubmed: 23286345
J Natl Cancer Inst. 1990 Jul 4;82(13):1107-12
pubmed: 2359136
BMC Cancer. 2013 Apr 18;13:197
pubmed: 23597096
Oncol Rep. 2014 May;31(5):2115-22
pubmed: 24626880
Science. 2014 May 23;344(6186):921-5
pubmed: 24812208
Lancet Oncol. 2014 Sep;15(10):1065-75
pubmed: 25088940
Cancer Immunol Res. 2016 Apr;4(4):366-74
pubmed: 26817995
Control Clin Trials. 1989 Mar;10(1):1-10
pubmed: 2702835
PLoS One. 2016 Jun 17;11(6):e0157830
pubmed: 27314237
Ann Oncol. 2016 Aug;27(8):1386-422
pubmed: 27380959
J Leukoc Biol. 2017 Jan;101(1):285-295
pubmed: 27493241
World J Gastroenterol. 2016 Aug 14;22(30):6944-54
pubmed: 27570430
Eur J Cancer. 2017 Jan;70:87-98
pubmed: 27907852
Oncotarget. 2017 Jan 17;8(3):3980-4000
pubmed: 28002810
Nat Rev Cancer. 2017 Feb;17(2):79-92
pubmed: 28050011
Immunol Cell Biol. 2017 Apr;95(4):347-355
pubmed: 28138156
Curr Opin Immunol. 2017 Apr;45:73-81
pubmed: 28236750
Ann Oncol. 2017 Aug 1;28(8):1713-1729
pubmed: 28407110
Adv Exp Med Biol. 2017;1036:33-49
pubmed: 29275463
Oncoimmunology. 2017 Nov 13;7(2):e1393597
pubmed: 29308327
Cell Physiol Biochem. 2018;45(1):356-365
pubmed: 29402795
Histopathology. 2018 Aug;73(2):197-206
pubmed: 29457843
Clin Colorectal Cancer. 2018 Jun;17(2):85-96
pubmed: 29576427
Exp Cell Res. 2018 Oct 1;371(1):1-19
pubmed: 30098332
J Immunol Methods. 1997 Oct 27;208(2):151-8
pubmed: 9433470