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

• Median progression free survival [ Time Frame: approximate 6 months after randomisation ] [ Designated as safety issue: No ]
• Median overall survival [ Time Frame: approximate 3 years after randomisation ] [ Designated as safety issue: No ]
• Secondary resection rate with curative intent [ Time Frame: up to 3 months after end of treatment ] [ Designated as safety issue: No ]
• Safety and toxicity (according to NCI-CTCAE) [ Time Frame: approximate 6 months after randomisation ] [ Designated as safety issue: Yes ]

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

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.

• Neoplasm Metastasis
• Colorectal Cancer

• 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

• 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

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.