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

Sponsor
Ludwig-Maximilians - University of Munich
Study ID
NCT02934529
Phase
PHASE3
Status
Completed

Conditions

  • Metastatic Colorectal Cancer

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Irinotecan — DRUG
    Irinotecan 180 mg/m² iv, 30 - 90 min., day 1, q d15
  • Folinic Acid — DRUG
    Folinic acid (racemic) 400 mg/m² iv, 120 min. day 1, q d15
  • 5-FU — DRUG
    5-FU 400 mg/m² bolus day 1, q d15
  • 5-FU — DRUG
    5-FU 2400 mg/m² iv over 46 h day 1-2, q d15
  • 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
  • Bevacizumab — DRUG
    Bevacizumab 7.5 mg/kg BW iv over 30 to 90 minutes: day 1
  • Capecitabine — DRUG
    Capecitabine 1250 mg/m2 2 x day p.o. day 1-14, q d15
  • regorafenib — DRUG
    160 mg per day (day 1-21) (repeated on day 28)
  • Irinotecan 125mg — DRUG
    Irinotecan 125 mg/m² iv, 60 - 90 min. weekly (D1, D8, D15, D22)
  • 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)

Study Details

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.

Key Dates

Start date
Mar 31, 2015
Status verified
Apr 2025
Primary completion
Jan 30, 2025
Completion
Jan 30, 2025

Study Design

Enrollment
673 participants (actual)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Active Comparator: A1
    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.
  • Experimental: B1
    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,
  • Experimental: B1 Switchover regimens
    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.
  • Active Comparator: A2 (third line)
    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
  • Experimental: B2 (third line)
    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

Primary Outcome Measure

Overall Survival [ Time Frame: up to 55 months ]

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