Continuous or Intermittent Cetuximab Plus FOLFIRI as First-line Treatment in RAS/BRAF Wild-type mCRC Patients

NCT07004413 | Not Yet Recruiting Phase 3

• 3 other identifiers: U1111-1319-83572025-522377-12-00AIO-KRK-0524
• Study Type: interventional
• Target: 267
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to learn if the application of the chemotherapy FOLFIRI and cetuximab works better when given with scheduled breaks or continuously in adults with metastatic colorectal cancer. The main question it aims to answer is, whether worsening of disease after 12 months of treatment is lower when the treatment is given with breaks or given continuously. It will also answer the question whether the quality of life is better and side effects are less if chemotherapy is given with breaks. Additionally, the treatment breaks will be controlled by blood tests and imaging examinations. A novel blood test will be introduced to investigate, whether worsening of the disease might be detected before the imaging, and whether a quicker reaction by re-starting the therapy would help the patients. Participants will:

• receive an established chemotherapy mit FOLFIRI and cetuximab
• Receive blood tests every 4 weeks and imaging investigations every 12 weeks
• fill out questionnaires to report their quality of life

Conditions

Colorectal Cancer Metastatic

Keywords

Metastatic colorectal cancer; RAS; BRAF; cetuximab; ctDNA; treatment break

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS) on treatment rate at 12 months

  Percentage of patients who did not experience disease progression or death, whichever occurs first, while receiving active treatment for 12 months starting from randomization.

  12 months

Secondary Outcomes (9)

• PFS1 to PFSN

  up to 24 months

• Overall survival (OS)

  At least 5 years after randomization

• Objective Response Rate (ORR)

  up to 24 months

• Dynamics of the tumor markers CEA and CA19-9

  Up to 24 months

• Early Tumor Shrinkage (ETS)

  8 weeks

Other Outcomes (1)

• Translational research

  up to 5 years

Study Arms (2)

FOLFIRI+cetuximab, continuously applied

ACTIVE COMPARATOR

Continuous application of FOLFIRI+cetuximab until disease progression according to standard of care

Drug: FOLFIRI+cetuximab

FOLFIRI+cetuximab, applied with scheduled treatment breaks

EXPERIMENTAL

Scheduled treatment break after up to 6 cycles of FOLFIRI+cetuximab until radiological (or, in part 2, ctDNA-based) disease progression

Drug: FOLFIRI+cetuximab; Diagnostic Test: Guardant360 ctDNA assay

Interventions

FOLFIRI+cetuximab DRUG

Cetuximab 500 mg/m², 90 min IV infusion on d1; Irinotecan: 180 mg/m², 90-120 min IV infusion on d1; Folinic acid: 400mg/m², 1-2h IV Infusion on d1; 5-FU: 2400 mg/m², 46 h IV infusion on d1. Cycles are repeated on day 15.

Also known as: Cetuximab, Irinotecan, Folinic acid, 5-fluorouracil (FU)

FOLFIRI+cetuximab, applied with scheduled treatment breaks; FOLFIRI+cetuximab, continuously applied

Guardant360 ctDNA assay DIAGNOSTIC_TEST

Determination of circulating tumor DNA (ctDNA) in the peripheral blood, part 1: retrospective threshold determination to predict radiological disease progression in Arm 2; part 2: prospective validation of the in part 1 identified ctDNA threshold to guide the scheduled treatment breaks and treatment in Arm 2

FOLFIRI+cetuximab, applied with scheduled treatment breaks

Eligibility Criteria

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

You may qualify if:

• Patient's signed informed consent
• Histologically confirmed, UICC stage IV unresectable adenocarcinoma of the colon or rectum
• Locally confirmed RAS/BRAF wild-type tumor status (KRAS and NRAS exon 2, 3, 4, BRAF exon 11/15)
• a) Note: A maximum of two cycles FOLFIRI is allowed prior to start of induction treatment until the molecular characterization is fully reported
• Centrally confirmed RAS/BRAF wild-type status by liquid biopsy during screening phase
• Age 18 or older at the time of written informed consent
• ECOG performance status below or equal 1
• Presence of at least one measurable reference lesion according to the RECIST 1.1 criteria
• Archival tumor tissue available
• Consent to storage, molecular and genetic profiling of tumor material and blood
• Adequate bone marrow function:
• Leukocytes ≥ 3.0 x 109/L with neutrophils ≥ 1.5 x 109/L
• Thrombocytes ≥ 100 x 109/L
• Hemoglobin ≥ 8 g/dL)
• Adequate hepatic function:

You may not qualify if:

• Proof of a RAS or BRAF mutation (KRAS/NRAS exons 2, 3, 4 or BRAF exon 15) in the tumor (proven in the primary tumor or metastasis) or liquid biopsy during screening phase.
• Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before written informed consent.
• New York Heart Association Class III or greater heart failure by clinical judgement.
• Myocardial infarction, balloon angioplasty (PTCA) with or without stenting, and cerebral vascular accident/stroke within the past 12 months before randomization
• Unstable angina pectoris
• Unstable cardiac arrhythmia \> grade 2 NCI CTCAE despite anti-arrhythmic therapy.
• Active uncontrolled infection by investigator's perspective.
• Pre-existing pulmonary fibrosis or immune pneumonitis
• Participation in a clinical study or experimental drug treatment within 30 days prior to written informed consent or within a period of 5 half-lives of the substances administered in a clinical study or during an experimental drug treatment prior to written informed consent, depending on which period is longest or simultaneous participation in another study while taking part in the study
• Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, cetuximab, irinotecan and chemically related substances and/or hypersensitivity to any of the components in the formulations of the aforementioned substances, including known hypersensitivity reactions to monoclonal antibodies NCI CTC grade ≥ 3.
• Known hypersensitivity to Chinese hamster ovary cell (CHO) -cellular products or other recombinant human or humanized monoclonal antibodies
• History of acute or subacute intestinal occlusion, inflammatory bowel disease, immune colitis or chronic diarrhea
• Symptomatic peritoneal carcinosis
• Severe, non-healing wounds, ulcers or bone fractures
• Requirement for immunization with live vaccine including attenuated live vaccine from at least 4 weeks before begin of induction treatment until 6 months after the administration of IMPs.

Sponsors & Collaborators

• Charite University, Berlin, Germany: lead
• Merck Healthcare Germany GmbH, an affiliate of Merck KGaA, Darmstadt, Germany: collaborator
• Guardant Health, Inc.: collaborator

Study Sites (1)

Charite University, Berlin

Berlin, 10117, Germany

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Cetuximab; Irinotecan; Leucovorin; Fluorouracil

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; Camptothecin; Alkaloids; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Central Study Contacts

Arndt Stahler, MD

CONTACT

+49 30 450 613 478; arndt.stahler@charite.de

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med.

Model Details: open-label, randomized, controlled, multicenter, phase III study with two parallel arms

Study Record Dates

• First Submitted: May 27, 2025
• First Posted: June 4, 2025
• Study Start: January 1, 2026
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2031
• Last Updated: June 4, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)