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Neoplasm MetastasisPhase 3NCT00433927

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

A Phase 3 study testing 5-FU, folinic acid and irinotecan in people with Neoplasm Metastasis and Colorectal Cancer, run by PD Dr. med. Volker Heinemann at 1 site in Germany.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Neoplasm Metastasis, Colorectal Cancer
What is being tested?
5-FU, folinic acid and irinotecan
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
568 participants
Where
1 siteGermany
Study dates
Jan 2007to Dec 2016
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
Show all 16Show fewer
  • 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.

Who cannot join

  • 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.
Show all 23Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

Germany1 site

  • University of Munich - Klinikum Grosshadern

    Munich, 81377

Other trials in Germany

About this study

Official title: Multicenter Randomized Trial Evaluating FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab in First Line Treatment of Metastatic Colorectal Cancer.

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.

Being tested
5-FU, folinic acid, irinotecan, cetuximab, bevacizumab
Keywords
metastatic
Medical subject headings
Neoplasm Metastasis, Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 5-FUDrug

    5-FU 400 mg/m² Bolus day 1 5-FU 2400 mg/m² iv over 46 h day 1-2

  • folinic acidDrug

    Folinsäure (racemisch) 400 mg/m² iv, 120 min d 1

  • irinotecanDrug

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

  • cetuximabDrug

    Cetuximab initial 400mg/m² as 120 min infusion, than 250 mg/m² iv as 60 min infusion d 1 + 8

  • bevacizumabDrug

    Bevacizumab 5 mg/kg iv over 30 to 90 minutes d 1

Study groups in NCT00433927
Study groupRoleWhat they receive
Arm AActive comparatorFOLFIRI plus Cetuximab
Receives: Drug: 5-FU; Drug: folinic acid; Drug: irinotecan; Drug: cetuximab
Arm BActive comparatorFOLFIRI plus Bevacizumab
Receives: Drug: 5-FU; Drug: folinic acid; Drug: irinotecan; Drug: bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Objective response rate

    Measured: approximate 6 months after randomisation

Secondary outcomes (4)

  1. Median progression free survival

    Measured: approximate 6 months after randomisation

  2. Median overall survival

    Measured: approximate 3 years after randomisation

  3. Secondary resection rate with curative intent

    Measured: up to 3 months after end of treatment

  4. Safety and toxicity (according to NCI-CTCAE)

    Measured: approximate 6 months after randomisation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Feb 2007 (estimated)
  2. Study startJan 2007
  3. Primary completionApr 2014 (estimated)
  4. Study completionDec 2016 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
568 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00433927
Sponsor's protocol ID
FIRE-3
Status last verified
Mar 2014
First submitted
9 Feb 2007
Last updated
14 Mar 2014
Results posted
No

Publications

  • 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.

    PubMed 41252656

  • 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.

    PubMed 35637412

  • 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.

    PubMed 33154570

  • 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.

    PubMed 32917529

  • 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.

    PubMed 31868905

  • 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.

    PubMed 30293873

  • 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.

    PubMed 29195117

  • 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.

    PubMed 27722750

  • 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.

    PubMed 27575024

  • 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.

    PubMed 27234640

  • 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.

    PubMed 26261259

  • 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.

    PubMed 25088940

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing 5-FU, folinic acid and irinotecan in people with Neoplasm Metastasis and Colorectal Cancer, run by PD Dr. med. Volker Heinemann at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 14 Mar 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective response rate (time frame: approximate 6 months after randomisation). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00433927, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Mar 2014.

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