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

BMC Cancer

Antonino Cassata¹  Carmela Romano¹  Rossana Casaretti¹  Lucrezia Silvestro¹  Anna Nappi¹  Monica Capozzi¹  Antonio Avallone¹  Alfonso De Stefano¹  Salvatore Tafuto¹  Nicola Normanno²  Anna Maria Rachiglio²  Cristin Roma²  Andrea Belli³  Ugo Pace³  Massimiliano Di Marzo³  Paolo Delrio³  Raffaele Palaia⁴  Vittorio Albino⁴  Francesco Izzo⁴  Guglielmo Nasti⁵  Alessandro Ottaiano⁵  Paolo Chiodini⁶  Alfonso Amore⁷  Crescenzo D’Alterio⁸  Stefania Scala⁸  Luigi Portella⁸  Anna Maria Trotta⁸  Maria Napolitano⁸  Carmine Picone⁹  Antonella Petrillo⁹  Gerardo Botti^1,10  Mario Tamburini^1,10  Gianfranco De Feo^1,10 

[1] Abdominal Oncology Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”;Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”;Colorectal Cancer Surgery Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”;Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”;Innovative Therapies for Abdominal Metastases Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”;Medical Statistics Unit, University of Campania;Melanoma and Sarcoma Surgery Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”;Molecular Immunology and Immunoregulation Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”;Radiology Unit, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”;Scientific Directorate, Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”;

关键词: Colorectal Cancer;    Antibody-dependent cell-mediated cytotoxicity;    Cetuximab;    Irinotecan;    Fluorouracule;    FcγR;   

DOI  :  10.1186/s12885-019-6109-z

来源: DOAJ

【 摘 要 】

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).

【 授权许可】

Unknown