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NCT00433927 · CITED IN SOURCE DOCUMENTS

5-FU, Folinic Acid and Irinotecan (FOLFIRI) Plus Cetuximab Versus FOLFIRI Plus Bevacizumab in First Line Treatment Colorectal Cancer (CRC)

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
UNKNOWN
Registry last update
2014-03-14

The FIRE-3 trial is a multicenter randomized phase III trial investigating 5-FU, folinic acid and irinotecan (FOLFIRI) plus cetuximab versus FOLFIRI plus bevacizumab in first line treatment of metastatic colorectal cancer. Planned accrual is 284 evaluable patients per treatment arm. The primary study endpoint is objective response rate. Secondary endpoints are median progression free survival, median overall survival, safety, and secondary resection rate.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
eligibility Criteria
Inclusion Criteria: * KRAS-Wildtype status * Histologically confirmed adenocarcinoma of the colon or rectum. * Stage IV disease. * ECOG 0-2. * Patients considered suitable for application of chemotherapy. * Age 18 - 75 years. * In- or outpatient treatment. * Estimated life expectancy \> 3 months. * Measurable index lesion according to RECIST criteria. Evaluation of tumor manifestations ≤ 2 weeks prior to treatment start. * Effective contraception. * Adequate hematologic function: leukocytes \>= 3000/µl, neutrophils \>= 1500/µl, platelets \>= 100.000/µ, and hemoglobin \>= 9g/dl. * Bilirubin \<= 1,5x upper limit of normal (ULN). * ALAT and ASAT \<= 2,5x ULN, in case of liver metastases \<= 5x ULN. * Serum creatinine \<= 1,5x ULN. * No operations within 4 weeks prior to treatment start. No cytologic biopsies within 1 week prior to treatment start. Operation sequels need to be completely healed. Major operations must not be expected at time of study begin, except for potential secondary resection of liver metastases. In case of secondary resection of liver metastases, bevacizumab must be discontinued 6-8 weeks prior to surgery. * No relevant toxicities due to prior medical treatment at time of study entry. Exclusion Criteria: * KRAS-Mutation of the tumor * Prior treatment directed against the epidermal growth factor receptor (EGFR). * Prior treatment with bevacizumab. * Prior chemotherapy for colorectal cancer, except for adjuvant chemotherapy dating back \> 6 months prior to study entry. * Experimental medical treatment within 30 days prior to study entry. * Known hypersensitivity reaction to any study medication. * Pregnant or breast feeding women (pregnancy needs to be excluded by testing of beta-HCG). * Known or suspected cerebral metastases. * Clinically significant coronary heart disease, myocardial infarction within the last 12 months or high risk of uncontrolled arrhythmia. * Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhea. * Symptomatic peritoneal carcinosis. * Severe chronic wounds, ulcera or bone fracture. * Uncontrolled hypertension. * Severe proteinuria (nephrotic syndrome). * Arterial thromboembolic events or hemorrhage within 6 months prior to study entry (except tumor bleeding surgically treated by tumor resection). * Bleeding diatheses or coagulopathy. * Full dose anticoagulation. * Known DPD-deficiency (special screening not required). * Known glucuronidation-deficiency (special screening not required). * Medical history of other malignant disease within 5 years prior to study entry, except for basalioma, and in-situ cervical carcinoma if treated with curative intent. * Known alcohol or drug abuse. * Medical or psychiatric condition which contradicts participation of study. * Limited legal capacity.
healthy Volunteers
false
maximum Age
75 Years
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    FOLFIRI plus Cetuximab
    intervention Names
    1. Drug: 5-FU
    2. Drug: folinic acid
    3. Drug: irinotecan
    4. Drug: cetuximab
    label
    Arm A
    type
    ACTIVE_COMPARATOR
  2. description
    FOLFIRI plus Bevacizumab
    intervention Names
    1. Drug: 5-FU
    2. Drug: folinic acid
    3. Drug: irinotecan
    4. Drug: bevacizumab
    label
    Arm B
    type
    ACTIVE_COMPARATOR
interventions
  1. arm Group Labels
    1. Arm A
    2. Arm B
    description
    5-FU 400 mg/m² Bolus day 1 5-FU 2400 mg/m² iv over 46 h day 1-2
    name
    5-FU
    type
    DRUG
  2. arm Group Labels
    1. Arm A
    2. Arm B
    description
    Folinsäure (racemisch) 400 mg/m² iv, 120 min d 1
    name
    folinic acid
    type
    DRUG
  3. arm Group Labels
    1. Arm A
    2. Arm B
    description
    Irinotecan 180 mg/m² iv, 30 - 90 min day 1
    name
    irinotecan
    type
    DRUG
  4. arm Group Labels
    1. Arm A
    description
    Cetuximab initial 400mg/m² as 120 min infusion, than 250 mg/m² iv as 60 min infusion d 1 + 8
    name
    cetuximab
    type
    DRUG
  5. arm Group Labels
    1. Arm B
    description
    Bevacizumab 5 mg/kg iv over 30 to 90 minutes d 1
    name
    bevacizumab
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
568
type
ESTIMATED
Registered outcome plans (not posted results)
primary Outcomes
  1. measure
    Objective response rate
    time Frame
    approximate 6 months after randomisation
secondary Outcomes
  1. measure
    Median progression free survival
    time Frame
    approximate 6 months after randomisation
  2. measure
    Median overall survival
    time Frame
    approximate 3 years after randomisation
  3. measure
    Secondary resection rate with curative intent
    time Frame
    up to 3 months after end of treatment
  4. measure
    Safety and toxicity (according to NCI-CTCAE)
    time Frame
    approximate 6 months after randomisation
Full study description
brief Summary
The FIRE-3 trial is a multicenter randomized phase III trial investigating 5-FU, folinic acid and irinotecan (FOLFIRI) plus cetuximab versus FOLFIRI plus bevacizumab in first line treatment of metastatic colorectal cancer. Planned accrual is 284 evaluable patients per treatment arm. The primary study endpoint is objective response rate. Secondary endpoints are median progression free survival, median overall survival, safety, and secondary resection rate.
Source references
references
  1. citation
    Stahler A, Modest DP, Stintzing S, Borelli B, Keller T, Held S, Fischer von Weikersthal L, Muller L, Graeven U, Decker T, Heintges T, Kahl C, Hoppe B, Kiani A, Kaiser F, Schwaner I, Fruehauf S, Karthaus M, Trarbach T, Klauschen F, Horst D, Cremolini C, Heinemann V. Individual Patient Data Meta-Analysis of Consensus Molecular Subtypes as Biomarkers of First-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer. J Clin Oncol. 2026 Jan;44(1):31-41. doi: 10.1200/JCO-25-00596. Epub 2025 Nov 18.
    pmid
    41252656
    type
    DERIVED
  2. citation
    Fischer LE, Stintzing S, von Weikersthal LF, Modest DP, Decker T, Kiani A, Kaiser F, Al-Batran SE, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Giessen-Jung C, Uhlig J, Peuser B, Denzlinger C, Stahler A, Weiss L, Heinrich K, Held S, Jung A, Kirchner T, Heinemann V. Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3. Br J Cancer. 2022 Sep;127(5):836-843. doi: 10.1038/s41416-022-01854-y. Epub 2022 May 30.
    pmid
    35637412
    type
    DERIVED
  3. citation
    Heinemann V, von Weikersthal LF, Decker T, Kiani A, Kaiser F, Al-Batran SE, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Moehler M, Scheithauer W, Held S, Miller-Phillips L, Modest DP, Jung A, Kirchner T, Stintzing S. FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial. Br J Cancer. 2021 Feb;124(3):587-594. doi: 10.1038/s41416-020-01140-9. Epub 2020 Nov 6.
    pmid
    33154570
    type
    DERIVED
  4. citation
    Froelich MF, Petersen EL, Heinemann V, Norenberg D, Hesse N, Gesenhues AB, Modest DP, Sommer WH, Hofmann FO, Stintzing S, Holch JW. Impact of Size and Location of Metastases on Early Tumor Shrinkage and Depth of Response in Patients With Metastatic Colorectal Cancer: Subgroup Findings of the Randomized, Open-Label Phase 3 Trial FIRE-3/AIO KRK-0306. Clin Colorectal Cancer. 2020 Dec;19(4):291-300.e5. doi: 10.1016/j.clcc.2020.06.005. Epub 2020 Jun 22.
    pmid
    32917529
    type
    DERIVED
  5. citation
    Stintzing S, Wirapati P, Lenz HJ, Neureiter D, Fischer von Weikersthal L, Decker T, Kiani A, Kaiser F, Al-Batran S, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Moehler M, Scheithauer W, Held S, Modest DP, Jung A, Kirchner T, Aderka D, Tejpar S, Heinemann V. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial. Ann Oncol. 2019 Nov 1;30(11):1796-1803. doi: 10.1093/annonc/mdz387.
    pmid
    31868905
    type
    DERIVED
  6. citation
    Tokunaga R, Cao S, Naseem M, Lo JH, Battaglin F, Puccini A, Berger MD, Soni S, Millstein J, Zhang W, Stintzing S, Loupakis F, Cremolini C, Heinemann V, Falcone A, Lenz HJ. Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy. Clin Colorectal Cancer. 2019 Mar;18(1):e8-e19. doi: 10.1016/j.clcc.2018.09.003. Epub 2018 Sep 13.
    pmid
    30293873
    type
    DERIVED
  7. citation
    Modest DP, Denecke T, Pratschke J, Ricard I, Lang H, Bemelmans M, Becker T, Rentsch M, Seehofer D, Bruns CJ, Gebauer B, Modest HI, Held S, Folprecht G, Heinemann V, Neumann UP. Surgical treatment options following chemotherapy plus cetuximab or bevacizumab in metastatic colorectal cancer-central evaluation of FIRE-3. Eur J Cancer. 2018 Jan;88:77-86. doi: 10.1016/j.ejca.2017.10.028. Epub 2017 Nov 28.
    pmid
    29195117
    type
    DERIVED
  8. citation
    Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, Esser R, Lenz HJ, Heinemann V. Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials. JAMA Oncol. 2017 Feb 1;3(2):194-201. doi: 10.1001/jamaoncol.2016.3797.
    pmid
    27722750
    type
    DERIVED
  9. citation
    Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Held S, Giessen-Jung C, Moehler M, Jagenburg A, Kirchner T, Jung A, Heinemann V; FIRE-3 investigators. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016 Oct;17(10):1426-1434. doi: 10.1016/S1470-2045(16)30269-8. Epub 2016 Aug 27.
    pmid
    27575024
    type
    DERIVED
  10. citation
    Michl M, Stintzing S, Fischer von Weikersthal L, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmueller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Mueller S, Lerch MM, Modest DP, Kirchner T, Jung A, Heinemann V; FIRE-3 Study Group. CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial). Ann Oncol. 2016 Aug;27(8):1565-72. doi: 10.1093/annonc/mdw222. Epub 2016 May 27.
    pmid
    27234640
    type
    DERIVED
  11. citation
    Modest DP, Stintzing S, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Held S, Mohler M, Jung A, Kirchner T, Heinemann V. Impact of Subsequent Therapies on Outcome of the FIRE-3/AIO KRK0306 Trial: First-Line Therapy With FOLFIRI Plus Cetuximab or Bevacizumab in Patients With KRAS Wild-Type Tumors in Metastatic Colorectal Cancer. J Clin Oncol. 2015 Nov 10;33(32):3718-26. doi: 10.1200/JCO.2015.61.2887. Epub 2015 Aug 10.
    pmid
    26261259
    type
    DERIVED
  12. citation
    Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Muller S, Link H, Niederle N, Rost A, Hoffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. doi: 10.1016/S1470-2045(14)70330-4. Epub 2014 Jul 31.
    pmid
    25088940
    type
    DERIVED
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    Preserved source evidence · Independent clinical review pending · Not medical advice