Study of Folfiri/Cetuximab in FcGammaRIIIa V/V Stage IV Colorectal Cancer Patients
Status:
Recruiting
Trial end date:
2023-03-31
Target enrollment:
Participant gender:
Summary
Patients' selection thorough the identification of predictive factors still represent a
challenge in metastatic colorectal cancer (mCRC). Cetuximab (Erbitux®), a chimeric monoclonal
antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the
Immunoglobulins (Ig) grade 1 subclass able to elicit 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 (Immunoglobulins Gamma subclass 1). Interestingly, the
high-affinity FcγRIIIa (FcγR type IIIa) 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 (Kirsten RAt Sarcoma), NRAS
(Neuroblastoma Rat Sarcoma), BRAF (B-Rapidly Accelerated Fibrosarcoma) 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 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.