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

• ClinicalTrials.gov Identifier: NCT00433927
• Recruitment Status: Unknown
• First Posted: February 12, 2007
• Last Update Posted: March 14, 2014
• Sponsor: PD Dr. med. Volker Heinemann
• Collaborator: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): PD Dr. med. Volker Heinemann, Ludwig-Maximilians - University of Munich

Tracking Information

• First Submitted Date: February 9, 2007
• First Posted Date: February 12, 2007
• Last Update Posted Date: March 14, 2014
• Study Start Date: January 2007
• Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 27, 2011): Objective response rate [ Time Frame: approximate 6 months after randomisation ]
• Original Primary Outcome Measures (submitted: February 9, 2007): Objective response rate

Current Secondary Outcome Measures (submitted: June 27, 2011)

• Median progression free survival [ Time Frame: approximate 6 months after randomisation ]
• Median overall survival [ Time Frame: approximate 3 years after randomisation ]
• Secondary resection rate with curative intent [ Time Frame: up to 3 months after end of treatment ]
• Safety and toxicity (according to NCI-CTCAE) [ Time Frame: approximate 6 months after randomisation ]

Original Secondary Outcome Measures (submitted: February 9, 2007)

• Median progression free survival
• Median overall survival
• Secondary resection rate with curative intent
• Safety and toxicity (according to NCI-CTCAE)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 5-FU, Folinic Acid and Irinotecan (FOLFIRI) Plus Cetuximab Versus FOLFIRI Plus Bevacizumab in First Line Treatment Colorectal Cancer (CRC)
• Official Title: Multicenter Randomized Trial Evaluating FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab in First Line Treatment of Metastatic Colorectal Cancer.
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Neoplasm Metastasis
• Colorectal Cancer

Intervention

• Drug: 5-FU
  5-FU 400 mg/m² Bolus day 1 5-FU 2400 mg/m² iv over 46 h day 1-2
• Drug: folinic acid
  Folinsäure (racemisch) 400 mg/m² iv, 120 min d 1
• Drug: irinotecan
  Irinotecan 180 mg/m² iv, 30 - 90 min day 1
• Drug: cetuximab
  Cetuximab initial 400mg/m² as 120 min infusion, than 250 mg/m² iv as 60 min infusion d 1 + 8
• Drug: bevacizumab
  Bevacizumab 5 mg/kg iv over 30 to 90 minutes d 1

Study Arms

• Active Comparator: Arm A
  FOLFIRI plus Cetuximab
  Interventions:

  • Drug: 5-FU
  • Drug: folinic acid
  • Drug: irinotecan
  • Drug: cetuximab
• Active Comparator: Arm B
  FOLFIRI plus Bevacizumab
  Interventions:

  • Drug: 5-FU
  • Drug: folinic acid
  • Drug: irinotecan
  • Drug: bevacizumab

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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. Erratum In: JAMA Oncol. 2017 Dec 1;3(12):1742.
• 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. Erratum In: Lancet Oncol. 2016 Oct;17 (10 ):e420. Lancet Oncol. 2016 Nov;17 (11):e479.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: January 28, 2009): 568
• Original Enrollment: Not Provided
• Estimated Study Completion Date: December 2016
• Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT00433927
• Other Study ID Numbers: FIRE-3
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: PD Dr. med. Volker Heinemann, Ludwig-Maximilians - University of Munich
• Original Responsible Party: Not Provided
• Current Study Sponsor: PD Dr. med. Volker Heinemann
• Original Study Sponsor: Ludwig-Maximilians - University of Munich
• Collaborators: Merck KGaA, Darmstadt, Germany

Investigators

• Principal Investigator: Volker Heinemann, MD; University of Munich - Klinikum Grosshadern

• PRS Account: Ludwig-Maximilians - University of Munich
• Verification Date: March 2014