Metastatic Colorectal Cancer (RAS-wildtype) After Response to First-line Treatment With FOLFIR Plus Cetuximab

NCT02934529 | Completed Phase 3

• 2 other identifiers: FIRE-42014-003787-21
• Study Type: interventional
• Target: 673
• Locations: 1 country
• Sites: 1

Brief Summary

The FIRE-4 study aims to define a treatment concept for patients with RAS wild-type tumours, optimised with regard to overall survival. The first-line treatment will be conducted with FOLFIRI plus cetuximab, which resulted in a significantly prolonged overall survival versus bevacizumab in the FIRE-3 study. Following initial progression (PD1) it is recommended that the treatment be continued with FOLFOX plus bevacizumab, as this concept led to significantly prolonged survival in the E3200 study. Owing to the encouraging results of the Santini study , a cetuximab rechallenge in combination with irinotecan-based chemotherapy is to be performed as part of the third-line treatment in patients who showed a response defined according to RECIST 1.1 during the first-line treatment (tumour diameter \< -30%) or presented with stable tumour disease for at least 6 months (tumour diameter +20 to -30%). The concept of the ideal sequence has not yet been studied to date in a clinical trial.

Conditions

Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  overall survival from randomisation to third-line treatment (OS3) under cetuximab rechallenge versus an anti-EGFR-free treatment in patients responding to treatment with cetuximab

  up to 55 months

Secondary Outcomes (9)

• Response Rate

  up to 55 months

• Progression-free survival

  up to 55 months

• Overall Survival (first-line treatment)

  up to 55 months

• Depth of Response

  up to 55 months

• Early tumor shrinkage

  up to 55 months

Study Arms (5)

A1

ACTIVE COMPARATOR

FOLFIRI plus cetuximab: one cycle (cycle duration 14 days) consists of Irinotecan, Folinic acid 5-FU, cetuximab Administration every two weeks until progression in first-line or emergence of unacceptable toxicity. De-escalation (e.g. to irinotecan plus cetuximab or FUFA plus cetuximab) is allowed, but cetuximab should be administered until progression if safety is adequate.

Drug: Irinotecan; Drug: Folinic Acid; Drug: 5-FU; Drug: Cetuximab

B1

EXPERIMENTAL

FOLFIRI plus cetuximab: one cycle (cycle duration 14 days) consists of Irinotecan, Folinic acid 5-FU, cetuximab Administration every 2 weeks for a maximum of 12 cycles * Treatment may be de-escalated to irinotecan plus cetuximab or FUFA plus cetuximab, prior to 12 cycles, for toxicity if necessary, if the best response has been SD, * Treatment may undergo 'switchover' to a fluoropyrimidine and bevacizumab, between 8 and 12 cycles, for toxicity if necessary, if the best response has been CR or PR,

Drug: Irinotecan; Drug: Folinic Acid; Drug: 5-FU; Drug: Cetuximab

B1 Switchover regimens

EXPERIMENTAL

Switchover to FUFA plus bevacizumab every three weeks (cycle duration 21 days) until progression in first-line or emergence of unacceptable toxicity. Folinic acid, 5-FU, Bevacizumab 1st administration 90 min. in case of good safety, the second 60 min. further administration 30 min. Or alternatively Switchover to capecitabine plus bevacizumab every three weeks (cycle duration 21 days) until progression in the first-line or emergence of unacceptable toxicity.

Drug: Folinic Acid; Drug: 5-FU; Drug: Bevacizumab; Drug: Capecitabine

A2 (third line)

ACTIVE COMPARATOR

Treatment at the treating physician's discretion depending on the patient's general condition, with the exclusion of any anti-EGFR treatment whatsoever (such as for example cetuximab, panitumumab). Recommendations include Regorafenib in line with Grothey A et al, Lancet. 2013 or alternatively another anti-EGFR-free treatment according to the investigating physician's choice Administration until progression occurs in the third line or unacceptable toxicity

Drug: regorafenib

B2 (third line)

EXPERIMENTAL

one cycle (cycle duration 14 days) consists of Irinotecan 125mg, Folinic acid, 5-FU, cetuximab wkly Administration every 2 weeks until progression occurs in the third line or unacceptable toxicity or depending on the patient's general condition and the study physician's decision Irinotecan plus cetuximab in line with Cunningham D et al, N Engl J Med. 2004

Drug: Irinotecan; Drug: Folinic Acid; Drug: 5-FU; Drug: Cetuximab; Drug: Irinotecan 125mg; Drug: Cetuximab wkly

Interventions

Irinotecan DRUG

Irinotecan 180 mg/m² iv, 30 - 90 min., day 1, q d15

Also known as: Campto

A1; B1; B2 (third line)

Folinic Acid DRUG

Folinic acid (racemic) 400 mg/m² iv, 120 min. day 1, q d15

Also known as: Folgamma mono

A1; B1; B1 Switchover regimens; B2 (third line)

5-FU DRUG

5-FU 400 mg/m² bolus day 1, q d15

Also known as: Fluorouracil

A1; B1; B1 Switchover regimens; B2 (third line)

Cetuximab DRUG

cetuximab initially 400 mg/m² as a 120 min. infusion (≤ 5mg/min); subsequently 250 mg/m² iv respectively as a 60 min. infusion (≤ 10mg/min) day 1 + 8

Also known as: Erbitux

A1; B1; B2 (third line)

Bevacizumab DRUG

Bevacizumab 7.5 mg/kg BW iv over 30 to 90 minutes: day 1

Also known as: Avastin

B1 Switchover regimens

Capecitabine DRUG

Capecitabine 1250 mg/m2 2 x day p.o. day 1-14, q d15

Also known as: Xeloda

B1 Switchover regimens

regorafenib DRUG

160 mg per day (day 1-21) (repeated on day 28)

Also known as: CAS #:755037-03-7

A2 (third line)

Irinotecan 125mg DRUG

Irinotecan 125 mg/m² iv, 60 - 90 min. weekly (D1, D8, D15, D22)

Also known as: Campto

B2 (third line)

Cetuximab wkly DRUG

Cetuximab initially 400 mg/m² as a 120 min. infusion (≤ 5mg/min); subsequently 250 mg/m² iv respectively as a 60 min. infusion (≤ 10mg/min) weekly (D1, D8, D15, D22, D29, D36)

Also known as: Erbitux

B2 (third line)

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed, UICC stage IV adenocarcinoma of the colon or rectum (metastatic colorectal cancer), primarily nonresectable or with surgery refused by the patient
• RAS wild-type tumour status (KRAS and NRAS exon 2-4) (proven in the primary tumour or metastasis) at any timepoint of randomisation
• Age ≥18
• ECOG performance status 0-1
• Patients suitable for chemotherapy administration
• Patient's written declaration of consent obtained
• Estimated life expectancy \> 3 months
• Presence of at least one measurable reference lesion according to the RECIST 1.1 criteria (chest and abdominal CT 4 weeks or less before randomisation)
• Primary tumour tissue available and patient consents to storage and molecular and genetic profiling of blood, plasma and tumour material (patients included directly at Part 2 of the study in whom primary tumour material is no longer available may be included in the study, provided that tumour material from the compulsory biopsy on progression following second-line treatment is available).
• Effective contraceptive measures in men and in women of childbearing age (Pearl index \<1)
• Adequate haematopoietic function:
• Leukocytes ≥ 3.0 x 109/L with neutrophils ≥ 1.5 x 109/L
• Thrombocytes ≥ 100 x 109/L,
• Haemoglobin ≥ 5.6 mmol/L (equivalent to 9 g/dL)
• Adequate hepatic function:

You may not qualify if:

• Proof of a RAS mutation (KRAS or NRAS, exons 2-4 in the tumour (proven in the primary tumour or metastasis) or absence of testing for RAS mutation
• Primarily resectable metastases and the patient wishes for resection
• Grade III or IV heart failure (NYHA classification)
• Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
• Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, cetuximab, oxaliplatin, irinotecan, bevacizumab and chemically related substances
• Known or clinically suspected brain metastases
• History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea
• Symptomatic peritoneal carcinosis
• Severe, non-healing wounds, ulcers or bone fractures
• Uncontrolled hypertension
• Marked proteinuria (nephrotic syndrome)
• Haemorrhagic diathesis or tendency towards thrombosis
• Known DPD deficiency (specific screening not required)
• Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not required)
• Known history of alcohol or drug abuse

Sponsors & Collaborators

• Ludwig-Maximilians - University of Munich: lead

Study Sites (1)

Klinikum der Universitaet Muenchen - Campus Grosshadern

Munich, 81377, Germany

Location

Related Publications (1)

• Stintzing S, Klein-Scory S, Fischer von Weikersthal L, Fuchs M, Kaiser F, Heinrich K, Modest DP, Hofheinz RD, Decker T, Gerger A, Angermeier S, Rumpold H, Dickhut A, Ohler L, Gruenberger B, Niedersuess-Beke D, Sandmann M, Winder T, Trojan J, Prager G, Held S, Kumbrink J, Schmiegel W, Baraniskin A, Heinemann V. Baseline Liquid Biopsy in Relation to Tissue-Based Parameters in Metastatic Colorectal Cancer: Results From the Randomized FIRE-4 (AIO-KRK-0114) Study. J Clin Oncol. 2025 Apr 20;43(12):1463-1473. doi: 10.1200/JCO.24.01174. Epub 2025 Feb 4.

  PMID: 39903881 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Irinotecan; Leucovorin; Fluorouracil; Cetuximab; Bevacizumab; Capecitabine; regorafenib

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)

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; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Volker Heinemann, Prof. Dr.

  Maximilians University of Munich, Comprehensive Cancer Center and Medical Dept. III

  PRINCIPAL INVESTIGATOR

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: Director of the Comprehensive Cancer Center (CCCLMU)

Study Record Dates

• First Submitted: March 19, 2015
• First Posted: October 17, 2016
• Study Start: March 1, 2015
• Primary Completion: January 30, 2025
• Study Completion: January 30, 2025
• Last Updated: April 16, 2025

Record last verified: 2025-04

Locations

DE (1)