Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: The CIFRA study protocol

Alessandro Ottaiano, Stefania Scala, Nicola Normanno, Maria Napolitano, Monica Capozzi, Anna Maria Rachiglio, Cristin Roma, Anna Maria Trotta, Crescenzo D'Alterio, Luigi Portella, Carmela Romano, Antonino Cassata, Rossana Casaretti, Lucrezia Silvestro, Anna Nappi, Salvatore Tafuto, Antonio Avallone, Alfonso De Stefano, Mario Tamburini, Carmine PiconeAntonella Petrillo, Francesco Izzo, Raffaele Palaia, Vittorio Albino, Alfonso Amore, Andrea Belli, Ugo Pace, Massimiliano Di Marzo, Paolo Chiodini, Gerardo Botti, Gianfranco De Feo, Paolo Delrio, Guglielmo Nasti

Research output: Contribution to journalArticle

Abstract

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: 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: 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: 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).

Original languageEnglish
Article number899
JournalBMC Cancer
Volume19
Issue number1
DOIs
Publication statusPublished - Sep 9 2019

Fingerprint

irinotecan
Antibody-Dependent Cell Cytotoxicity
Colorectal Neoplasms
oxaliplatin
Therapeutics
National Library of Medicine (U.S.)
Cetuximab
Tumor Microenvironment
Fc Receptors
Antibodies

Keywords

  • Antibody-dependent cell-mediated cytotoxicity
  • Cetuximab
  • Colorectal Cancer
  • FcγR
  • Fluorouracule
  • Irinotecan
  • Phase II study

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

@article{4e4119cd266942f3a4fb38313dbbc39c,
title = "Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: The CIFRA study protocol",
abstract = "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{\circledR}), 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: 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: 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: 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).",
keywords = "Antibody-dependent cell-mediated cytotoxicity, Cetuximab, Colorectal Cancer, FcγR, Fluorouracule, Irinotecan, Phase II study",
author = "Alessandro Ottaiano and Stefania Scala and Nicola Normanno and Maria Napolitano and Monica Capozzi and Rachiglio, {Anna Maria} and Cristin Roma and Trotta, {Anna Maria} and Crescenzo D'Alterio and Luigi Portella and Carmela Romano and Antonino Cassata and Rossana Casaretti and Lucrezia Silvestro and Anna Nappi and Salvatore Tafuto and Antonio Avallone and {De Stefano}, Alfonso and Mario Tamburini and Carmine Picone and Antonella Petrillo and Francesco Izzo and Raffaele Palaia and Vittorio Albino and Alfonso Amore and Andrea Belli and Ugo Pace and {Di Marzo}, Massimiliano and Paolo Chiodini and Gerardo Botti and {De Feo}, Gianfranco and Paolo Delrio and Guglielmo Nasti",
year = "2019",
month = "9",
day = "9",
doi = "10.1186/s12885-019-6109-z",
language = "English",
volume = "19",
journal = "BMC Cancer",
issn = "1471-2407",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients

T2 - The CIFRA study protocol

AU - Ottaiano, Alessandro

AU - Scala, Stefania

AU - Normanno, Nicola

AU - Napolitano, Maria

AU - Capozzi, Monica

AU - Rachiglio, Anna Maria

AU - Roma, Cristin

AU - Trotta, Anna Maria

AU - D'Alterio, Crescenzo

AU - Portella, Luigi

AU - Romano, Carmela

AU - Cassata, Antonino

AU - Casaretti, Rossana

AU - Silvestro, Lucrezia

AU - Nappi, Anna

AU - Tafuto, Salvatore

AU - Avallone, Antonio

AU - De Stefano, Alfonso

AU - Tamburini, Mario

AU - Picone, Carmine

AU - Petrillo, Antonella

AU - Izzo, Francesco

AU - Palaia, Raffaele

AU - Albino, Vittorio

AU - Amore, Alfonso

AU - Belli, Andrea

AU - Pace, Ugo

AU - Di Marzo, Massimiliano

AU - Chiodini, Paolo

AU - Botti, Gerardo

AU - De Feo, Gianfranco

AU - Delrio, Paolo

AU - Nasti, Guglielmo

PY - 2019/9/9

Y1 - 2019/9/9

N2 - 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: 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: 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: 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).

AB - 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: 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: 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: 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).

KW - Antibody-dependent cell-mediated cytotoxicity

KW - Cetuximab

KW - Colorectal Cancer

KW - FcγR

KW - Fluorouracule

KW - Irinotecan

KW - Phase II study

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