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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.

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,

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.

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

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

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

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

5-FU

5-FU 2400 mg/m² iv over 46 h day 1-2, q d15

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

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

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

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

regorafenib

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

Irinotecan 125mg

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)

Cetuximab wkly

Volker Heinemann, Prof. Dr.

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.

The study will begin with FPFV: (first study visit of the first patient, signing the declaration of consent to participate in the study): scheduled for the 4th quarter of 2014

Patient recruitment: 36 months

Treatment duration per patient: Until the time of progression under the third-line treatment at the latest. Anticipated individual duration of treatment: 24 months (for patients who undergo all three treatment lines -included in part 1), or 6 months in patients who only receive third line treatment (included directly in part 2)

Duration of follow-up after the end of treatment: For all patients, until death or for at least 1 year following final termination of any study treatment regardless of the treatment line. In so doing, the follow-up period for patients included in part 1 of the study will be conducted for a maximum of 5 years from the time of randomisation 1; and for patients included in only part 2 of the study (third-line treatment), for a maximum of 3 years from the date of randomisation 2.

End of the study: last follow-up visit of the last study patient scheduled for the 4th quarter of 2020

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

A Randomised Study to Assess the Efficacy of Cetuximab Rechallenge in Patients With Metastatic Colorectal Cancer (RAS Wild-type) Responding to First-line Treatment With FOLFIRI Plus Cetuximab

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

Response rate ORR1, 2 \& 3 (assessment of ORR 1 and ORR 2 only if the patient was already included in part 1 of the study)

Progression-free survival PFS1, 2 \& 3 (assessment of PFS 1 and PFS 2 only if the patient was already included in part

1 of the study)

Overall survival (OS1) from randomisation to first-line treatment (assessment only if the patient was already included in part 1 of the study)

Investigation of depth of response during first-line treatment and third-line treatment.

Investigation of early tumour shrinkage during first-line treatment and third-line treatment.

Study of molecular biomarkers for prediction of sensitivity and secondary resistance to an anti-EGFR treatment with cetuximab (including tumour biopsies and liquid biopsies from blood samples)

Prospective validation of a biomarker score (RAS and BRAF)

Prospective analysis of tumour marker evolution (CEA and CA 19-9)

Recording of the safety and tolerance (NCI-CTCAE version 4.03 criteria) of the first-line and third-line treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Metastatic Colorectal Cancer (RAS-wildtype) After Response to First-line Treatment With FOLFIR Plus Cetuximab	NCT02934529	Metastatic Colo...	Irinotecan Folinic Acid 5-FU 5-FU Cetuximab Bevacizumab Capecitabine regorafenib Irinotecan 125m... Cetuximab wkly	18 Years -	Ludwig-Maximilians - University of Munich
Metastatic Colorectal Cancer (RAS-wildtype) After Response to First-line Treatment With FOLFIR Plus Cetuximab	NCT02934529	Metastatic Colo...	Irinotecan Folinic Acid 5-FU 5-FU Cetuximab Bevacizumab Capecitabine regorafenib Irinotecan 125m... Cetuximab wkly	18 Years -	Ludwig-Maximilians - University of Munich

Spots Global Cancer Trial Database for cetuximab wkly