Study of Folfiri/Cetuximab in FcGammaRIIIa V/V Stage IV Colorectal Cancer Patients

NCT03874026 | Recruiting Phase 2 DMC

• 1 other identifier: 60/18
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Colorectal Cancer; ADCC

Outcome Measures

Primary Outcomes (1)

• Activity

  Activity assessed by RECIST criteria version 1.1

  1 year

Secondary Outcomes (4)

• Response duration

  1 year

• Progression-free survival (PFS)

  Through study completion, an average of 1 year

• Overall survival (OS)

  Through study completion, an average of 2 years

• Toxic effects

  At the end of Cycle 1 (each cycle is 14 days)

Other Outcomes (2)

• Percentage of antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro through the evaluation of tumor cell lysis after co-incubation of tumor cells, cetuximab and patient-derived lymphocytes.

  Before treatment start

• Type of cells infiltrating the tumor microenvironment.

  Before treatment start

Study Arms (1)

Folfiri/Cetuximab

EXPERIMENTAL

Cetuximab 400 mg/mq intravenously (iv) with "load" dose of 400 mg/mq at the first cycle followed by 250 mg/mq iv weekly by iv infusion in 90 minutes. The administration of irinotecan will precede that of cetuximab and will consist on a dose of 180 mg/mq iv in 60 minutes every two weeks and it will be followed by fluorouracil (5-FU) at a dose of 400 mg/mq in slow iv bolus at half of lederfolin 200 mg/mq 2-hours infusion. At the end of the infusion of lederfolin an elastomeric pump loaded with 5-FU 2400 mg/mq in continuous 46 hours iv infusion will be applied. Only at the first administration of CT ("load" dose of cetuximab), irinotecan will not be administered.

Drug: Folfiri/Cetuximab

Interventions

Folfiri/Cetuximab DRUG

Cetuximab 400 mg/mq intravenously (iv) with "load" dose of 400 mg/mq at the first cycle followed by 250 mg/mq iv weekly by iv infusion in 90 minutes. The administration of irinotecan will precede that of cetuximab and will consist on a dose of 180 mg/mq iv in 60 minutes every two weeks and it will be followed by fluorouracil (5-FU) at a dose of 400 mg/mq in slow iv bolus at half of lederfolin 200 mg/mq 2-hours infusion. At the end of the infusion of lederfolin an elastomeric pump loaded with 5-FU 2400 mg/mq in continuous 46 hours iv infusion will be applied. Only at the first administration of CT ("load" dose of cetuximab), irinotecan will not be administered.

Folfiri/Cetuximab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cytological or histological diagnosis of colorectal adenocarcinoma;
• KRAS, NRAS, BRAF wild-type;
• FcγRIIIaV/V genotype;
• stage IV;
• age \<75 years;
• at least 1 measurable lesion;
• ECOG (Eastern Cooperative Oncology Group) Performance Status 0 or 1;
• life expectancy\> 3 months;
• negative pregnancy test for all potentially childbearing women;
• written informed consent.

You may not qualify if:

• previous systemic anti-tumor treatment (allowed treatment with capecitabine or fluorouracil and radiotherapy in the neoadjuvant setting of rectal tumors with therapy terminated at least 6 months before);
• presence of primary non-treated stenosing colorectal neoplasm;
• neutrophils \<2000/mm³ or platelets \<100.000/mm³ or hemoglobin \<9 g/dl;
• serum creatinine level\> 1.5 times the maximum normal value;
• GOT (glutamic oxaloacetic transaminase) and/or GPT (glutamic pyruvic transaminase) \>5 times the maximum normal value and/or bilirubin level \>3 times the maximum normal value;
• previous malignant neoplasms (excluding basal or spinocellular cutaneous carcinoma or in situ carcinoma of the uterine cervix);
• active or uncontrolled infections;
• other concomitant uncontrolled diseases or conditions contraindicating the study - drugs at clinician evaluation;
• presence of brain metastases;
• refusal or inability to provide informed consent;
• impossibility to guarantee follow-up.

Sponsors & Collaborators

• National Cancer Institute, Naples: lead

Study Sites (1)

Istituto Nazionale dei Tumori,

Napoli, Italy

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Cetuximab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

Alessandro Ottaiano, MD

CONTACT

+39 081 5903510; ale.otto@libero.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2019
• First Posted: March 14, 2019
• Study Start: September 5, 2019
• Primary Completion: May 19, 2023
• Study Completion: September 1, 2025
• Last Updated: November 7, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)