Dataset Information

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®), 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 ).

SUBMITTER: Ottaiano A

PROVIDER: S-EPMC6734266 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Ottaiano Alessandro A Scala Stefania S Normanno Nicola N Napolitano Maria M Capozzi Monica M Rachiglio Anna Maria AM Roma Cristin C Trotta Anna Maria AM D'Alterio Crescenzo C Portella Luigi L Romano Carmela C Cassata Antonino A Casaretti Rossana R Silvestro Lucrezia L Nappi Anna A Tafuto Salvatore S Avallone Antonio A De Stefano Alfonso A Tamburini Mario M Picone Carmine C Petrillo Antonella A Izzo Francesco F Palaia Raffaele R Albino Vittorio V Amore Alfonso A Belli Andrea A Pace Ugo U Di Marzo Massimiliano M Chiodini Paolo P Botti Gerardo G De Feo Gianfranco G Delrio Paolo P Nasti Guglielmo G

BMC cancer 20190909 1

<h4>Background</h4>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 ...[more]

PMID: 31500586

Similar Datasets

Project description:BackgroundThe multicenter, open-label, randomized, phase III EPIC study (EMR 062202-025) investigated cetuximab plus irinotecan versus irinotecan in patients with epidermal growth factor receptor-detectable metastatic colorectal cancer (mCRC) that progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy; we report the outcomes of patients with RAS-wild-type (wt) disease.Materials and methodsAvailable DNA samples from RAS-unselected patients (n = 1,164 of 1,298 [89.7%]) were reanalyzed for RAS mutations using beads, emulsion, amplification, and magnetics. Baseline characteristics, efficacy, safety, and poststudy therapy were assessed. RAS-wt status was defined as a mutated RAS allele frequency of ≤5%, with all relevant alleles being analyzable.ResultsBaseline characteristics were comparable between the groups (n = 452 patients with RAS-wt mCRC; cetuximab plus irinotecan n = 231, irinotecan n = 221) and between the RAS-wt and RAS-unselected populations. In the cetuximab plus irinotecan versus irinotecan arms, median overall survival was 12.3 versus 12.0 months, median progression-free survival (PFS) was 5.4 versus 2.6 months, and objective response rate (ORR) was 29.4% versus 5.0%, respectively. Quality of life (QoL) was improved in the cetuximab plus irinotecan arm. Serious adverse events occurred in 45.4% (cetuximab plus irinotecan) and 42.4% (irinotecan) of patients. In total, 47.1% of patients in the irinotecan arm received subsequent cetuximab therapy.ConclusionPFS, ORR, and QoL were improved with cetuximab plus irinotecan as a second-line treatment in patients with RAS-wt mCRC, confirming that cetuximab-based therapy is suitable in this population. Almost half of patients in the irinotecan arm received poststudy cetuximab, masking a potential overall survival benefit of cetuximab addition.Implications for practiceCetuximab is approved for the treatment of RAS-wild-type metastatic colorectal cancer (mCRC). In this retrospective analysis of the phase III EPIC study (cetuximab plus irinotecan vs. irinotecan alone as second-line treatment in patients with RAS-unselected mCRC), the subgroup of patients with RAS-wild-type mCRC who received cetuximab plus irinotecan had improved progression-free survival, objective response rate, and quality of life compared with the RAS-unselected population. These findings suggest that cetuximab-based therapy is a suitable second-line treatment for patients with RAS-wild-type mCRC.

Project description:BackgroundThe treatment of advanced colorectal cancer (CRC) has progressed slowly, with chemotherapy combined with targeted therapy being the first-line treatment for the disease, but the improvement in efficacy is not satisfactory. Compound Kushen injection (CKI) is one of the representative drugs of anti-cancer Chinese herbal injection drugs, which has been widely used in the adjunct treatment of cancer in China. The aim of this trial is to evaluate the efficacy and safety of CKI combined with first-line treatment of advanced CRC.MethodsThis is a multicenter, randomized, open-label controlled clinical trial in which 320 patients with advanced CRC will be randomly assigned to the treatment group or the control group in a 1:1 ratio. Both groups will receive at least 4 cycles of first-line therapy (FOLFOX/FOLFIRI/CAPEOX ± cetuximab/bevacizumab) in 14-21 day cycles, and the experimental group will receive additional CKI with a cumulative dose of 200 ml per cycle. Patients who achieve a complete response, partial response, or stable disease after 4-6 months will receive maintenance therapy until disease progression or another endpoint event, such as toxicity or death, occurs.. Follow-up will occur every 3 months until death or loss to follow-up. The primary outcome of this study will be progression-free survival (PFS). Secondary outcomes will be overall survival (OS), 1-year OS rate, 1-year PFS rate, objective response rate,disease control rate, symptoms and quality of life evaluation. Safety outcomes will be incidence of adverse events.DiscussionThis study will be the first randomized controlled trial to investigate the efficacy and safety of CKI when combined with first-line treatment in the treatment of advanced CRC, with PFS as the primary outcome. It aims to clarify the clinical advantages and therapeutic effect of CKI in the treatment of advanced CRC. To identify the benefit population of CKI in the treatment of patients with advanced CRC, an enrichment design based on biomarkers will be utilized. Metabolomics and gut microbiota analysis will be conducted on biological samples to explore the metabolic and gut microbiota differences associated with the efficacy of CKI, guiding further research into its mechanism of action.Trial registrationClinicalTrials.govNCT05894694. Registered on 4 August 2023.

Project description:The FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). Adding cetuximab to FOLFOX or FOLFIRI increased efficacy in patients with k-ras wild type mCRC. We explored the dose limiting toxicity and feasibility of the combination cetuximab, irinotecan, oxaliplatin, 5-FU and FA in mCRC patients.In a dose-escalation study patients with previously untreated mCRC and a WHO performance status 0-1 received cetuximab (500 mg/m2, 2 h), followed by irinotecan (95, 125, and 165 mg/m2 in the dose levels [DL] 1, 2, and 3 respectively), followed by oxaliplatin (85 mg/m2, 2 h) which was given parallel to FA (400 mg/m2, 2 h) and followed by 5-FU (3200 mg/m2, 46 h) in an outpatient setting every two weeks. The primary endpoints were the maximum tolerable dose and the safety. The trial was approved by the local ethics committee.From 2007 to 2008, twenty patients were treated in this trial. In the first dose level (irinotecan 95 mg/m2) one patient developed neutropenia grade 4. One patient experienced diarrhoea grade 3 as DLT in dose level 2 (irinotecan 125 mg/m2). In dose level 3 (irinotecan 165 mg/m2), three patients experienced a DLT (diarrhoea grade 3 and two patients with neutropenia grade 4). Thus, the recommended dose for a phase II trial is 125 mg/m2 irinotecan in combination with oxaliplatin, 5-FU/FA and cetuximab. Most common grade ?3 toxicities were neutropenia (40%), diarrhoea (25%) and acne-like rash (15%). No therapy associated death occurred.The confirmed overall response rate in all cohorts was 75% (95%-CI 51-91%). The best response was reached after a median of 3.0 (95%-CI 2.2 to 3.7) months. Median progression free survival (PFS) is 16 (95%-CI 12.6-19.4) months, overall survival (OS) 33 (95%-CI 26.2-39.8) months.The combination of cetuximab and FOLFOXIRIis feasible and has an acceptable toxicity profile in patients with a good performance status. The observed clinical activity with a confirmed response rate of 75% is promising and further evaluated in the ongoing CELIM2.http://www.clinicaltrials.gov: NCT00422773.

Dataset Information

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

Background

Methods/design

Discussion

Trial registration

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets