Please select the eligibility criteria that correspond to the clinical trial below.
Title: Open, Randomized, Controlled, Multicenter Phase III Study Comparing 5FU/ FA Plus Irinotecan Plus Cetuximab Versus 5FU/FA Plus Irinotecan as First-line Treatment for Epidermal Growth Factor Receptor-expressing Metastatic Colorectal Cancer
Brief Summary: Drugs used against cancer work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Giving combination chemotherapy together with cetuximab as first treatment after diagnosis of a metastatic colorectal cancer ('1st-line' treatment) may improve the treatment efficacy. However, it is not yet known whether giving combination chemotherapy together with cetuximab is more effective than combination chemotherapy alone. This open-label trial investigates the effectiveness of cetuximab in combination with a standard and effective chemotherapy (5-Fluorouracil (5FU)/Folinic acid (FA) plus irinotecan) for metastatic colorectal cancer in first-line setting, compared to the same chemotherapy alone on patient expressing the epidermal growth factor (EGF) receptor.

Patients expressing this EGF Receptor will be randomly assign in one of the 2 groups to either receive the combination chemotherapy alone or with cetuximab (open-label study) and will then be treated until progression of the disease or unacceptable toxicity occur. Regular efficacy assessments (every 8 weeks) based on imaging will be performed throughout the study together with regular safety assessments (e.g. safety labs). An independent Safety Board of experts will also monitor safety data.

After participant discontinuation from the trial, regular updates on further treatments and survival status will be requested from the investigator.

The entire study (from the first patient entering the study to the last collect of follow-up information) is 4-5 years long.


Options:
A: Inclusion Criteria:

Histology and Staging Disease

* Histologically proven advanced colorectal cancer (CRC); not amenable to curative surgery
* Of Note: In case of a single metastasis, histological or cytological proof of colorectal carcinoma should be obtained prior to randomisation.
* Unidimensionally measurable disease (\>= 1 cm on spiral CT scan or \>= 2 cm on chest X-ray; liver ultrasound not allowed). Index lesions should not be in a previously irradiated area. Serum carcinoembryonic antigen (CEA) may not be used as a parameter for disease evaluation.
* In case of previous radiotherapy, at least one measurable lesion should be located outside the irradiated field.

General Conditions

* Signed written informed consent
* Age 18 years and above
* World Health Organization (WHO) performance status 0-1
* Adequate bone marrow function (white blood cell count \[WBC\] \> 3.0 x 10\^9/L, platelets \> 100 x 10\^9/L, hemoglobin \[Hb\] \> 6 mmol/L)
* Adequate hepatic function: total bilirubin \< 2 x upper normal limit, aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) \< 3 x upper normal limits (in case of liver metastases \< 5 x upper normal limits)
* Adequate renal function: serum creatinine \< 1.5 x upper normal limit
* Urinary protein excretion \< 0.5 gram/24h
* Expected adequacy of follow-up

Exclusion Criteria:

* Prior chemotherapy for advanced disease; prior adjuvant chemotherapy is allowed provided that the last administration was given \> 6 months prior to randomisation, and that patients have recovered from all toxic events related to adjuvant chemotherapy, and that safety evaluations during adjuvant chemotherapy do not present any risk for serious adverse events during the administration of protocol treatment.
* Previous radiotherapy for rectal cancer or for symptomatic treatment of distant metastases is allowed, provided that at least one measurable lesion is located outside the irradiated field, irradiation has been completed for at least 4 weeks, and patients have recovered from all side effects.
* Previous epidermal growth factor receptor (EGFR) targeting therapy
* Sensory neuropathy \> grade 1
* Bleeding diathesis or coagulation disorders or the need for full-dose anticoagulation
* Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to the start of drug administration
* Anticipated major surgical procedure during the course of the study
* Serious non-healing wound or ulcer
* Any condition preventing the intake or absorption of oral drugs
* Significant cardiovascular disease (unstable angina pectoris, recent myocardial infarction \< 12 months, uncontrolled hypertension, previous cerebrovascular disease)
* Pregnancy or lactation
* Patients (males/females) with reproductive potential not implementing adequate contraceptive measures
* Central nervous system metastases (in asymptomatic patients no screening is required)
* Serious active infections
* Other serious concomitant diseases preventing the safe administration of study drugs or likely to interfere with the study assessments
* Other malignancies in the past 5 years with the exception of adequately treated carcinoma in situ of the cervix or squamous or basal cell carcinoma of the skin
* Concomitant treatments: concomitant (or within 4 weeks before randomisation) administration of any other experimental drug under investigation; concurrent treatment with any other anti-cancer therapy; full-dose anticoagulation
* Continuous use of immunosuppressive agents
B: Inclusion Criteria

* Diagnosis of metastatic adenocarcinoma of the colon or rectum that cannot, in the opinion of the investigator, be cured by surgical resection at the time of randomization
* Wild-type KRAS expressing mCRC from the primary tumor or metastasis.
* Failure of prior first-line oxaliplatin-based chemotherapy with bevacizumab (at least four therapeutic doses of oxaliplatin-based chemotherapy and bevacizumab) for mCRC.
* At least one uni-dimensionally measurable lesion per modified RECIST criteria.
* Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Man or woman 18 years of age or older
* Hematology, chemistry, coagution, metabolic functions within normal or protocol-defined limits

Exclusion Criteria

* Previous irinotecan, anti-EGFr therapy (eg, cetuximab, panitumumab, erlotinib, gefitinib, lapatinib) or vaccine for the treatment of mCRC
* Radiotherapy ≤ 14 days before randomization
* Evidence of central nervous system (CNS) metastases
* Unresolved toxicities from prior anti-cancer therapy that, in the opinion of the investigator, precludes subject from participation
* History of other invasive primary cancer, except:
* Curatively resected or treated non-melanomatous skin cancer
* Curatively treated cervical carcinoma in situ
* Other primary solid tumor treated curatively and no treatment administered ≤ 2 years before randomization and, in the investigator's opinion, it is unlikely that there will be a recurrence ≤ 2 years post randomization

Medications

* C hronic daily treatment (as determined by the investigator) with aspirin (\> 325 mg/day) or non steroidal anti inflammatory agents known to inhibit platelet function
* Infection requiring a course of systemic anti-infectives that was completed ≤ 14 days before randomization (exception can be made at the judgment of the investigator for oral treatment of an uncomplicated urinary tract infection \[UTI\])
* Subjects concurrently receiving any investigational agent or therapy ≤ 30 days before randomization

General:

* Significant cardiovascular risk as defined by the protocol
* History of peripheral arterial ischemia ≤ 24 weeks before randomization (subjects with brief, reversible, exercise-induced claudication are eligible)
* History of visceral arterial ischemia ≤ 24 weeks before randomization
* Significant bleeding risk:
* Major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 days before randomization
* Anticipation of need for major surgical procedures during the course of the study
* C ore biopsy or other minor procedure, excluding placement of a vascular access device ≤ 7 days before randomization
* A ny significant bleeding that is not related to the primary colon tumor ≤ 24 weeks before randomization
* P re-existing bleeding diathesis or coagulopathy with the exception of well-controlled chronic anticoagulation therapy
* Serious or non-healing wounds, skin ulcers, or unhealed bone fractures
* Gastroduodenal ulcer(s) determined by endoscopy to be active or uncontrolled gastrointestinal ulcer ≤ 28 days before randomization
* History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest x-ray (CXR) or computed tomography (CT) scan
* Clinically significant ascites
* Subjects known to be human immunodeficiency virus (HIV) positive or known to have chronic or active hepatitis B or C infection
* Men and women of childbearing potential (women who are post-menopausal \< 52 weeks, not surgically sterilized, or not abstinent) who do not consent to use adequate contraception (according to institutional standard of care) during the course of the study and after the last date of receiving second-line treatment (24 weeks for women, 4 weeks for men)
* Women who test positive for serum or urine pregnancy test ≤ 72 hours before randomization or are breast-feeding
* Subjects allergic to any component that is part of the treatment regimen
C: Inclusion Criteria:

* Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum
* Inoperable metastatic disease
* Immunohistochemical evidence of epidermal growth factor receptor expression in tumor tissue
* Presence of at least 1 bi-dimensionally measurable index lesion

Exclusion Criteria:

* Previous irinotecan-based chemotherapy
* Previous chemotherapy for colorectal cancer except adjuvant treatment if terminated more than 6 months before the start of study treatment
* Radiotherapy, surgery (excluding prior diagnostic biopsy) or any investigational drug in the 30 days before the start of study treatment
* Brain metastasis
D: Inclusion Criteria:

1. Metastatic colorectal adenocarcinoma.
2. Confirmed K-RAS mutant tumor
3. Disease progression on oxaliplatin- AND irinotecan-containing regimens, with at least one of these regimens containing bevacizumab.
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.

Exclusion Criteria:

1. Use of chemotherapy, hormonal therapy, immunotherapy or any other cancer or experimental treatment ≤ 28 days prior to the first day of the first cycle.
2. Radiotherapy for up to ≥ 30% of the bone marrow.
3. Surgery ≤ 28 days before day 1 of the first cycle (minimally invasive interventions for diagnostic purposes or disease staging are permitted).
4. Previous treatment with cetuximab, panitumumab, pomalidomide (CC-4047), lenalidomide or thalidomide.
5. Untreated, symptomatic brain metastases (brain imaging not required).
6. Venous thromboembolism ≤ 6 months before day1 of the first cycle.
7. Current congestive heart failure (classes II to IV of the New York Heart Association).
8. Myocardial infarction ≤ 12 months before day1 of the first cycle.
9. Uncontrolled hypertension.

Answer: C