Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III Randomized Study of Cetuximab (Erbitux™, C225) and Best Supportive Care Versus Best Supportive Care in Patients With Pretreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Positive Colorectal Carcinoma
Brief Summary: RATIONALE: Monoclonal antibodies, such as cetuximab, can target tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Best supportive care is the use of drugs and other treatments to improve the quality of life of patients. Combining cetuximab with best supportive care may slow the growth of the tumor and help patients live longer and more comfortably. It is not yet known whether cetuximab combined with best supportive care is more effective than best supportive care alone in treating metastatic epidermal growth factor receptor-positive colorectal cancer.

PURPOSE: This randomized phase III trial is studying cetuximab and best supportive care to see how well they work compared to best supportive care alone in treating patients with metastatic epidermal growth factor receptor-positive colorectal cancer.


Options:
A: Inclusion Criteria:

Subjects with histologically confirmed kras wildtype (WT) colorectal carcinoma (CRC) with documented distant metastasis

* Prior oxaliplatin/fluoropyrimidine-containing regimen for the first-line treatment of metastatic disease
* Failed an oxaliplatin regimen for metastatic colorectal carcinoma (mCRC). Failure is defined as either progressive disease (PD) (clinical or radiologic) within 6 months of the last dose of any agent of an oxaliplatin-based regimen or intolerance to an oxaliplatin regimen. Intolerance to an oxaliplatin regimen is defined as discontinuation due to any of the following: severe allergic reaction, persistent severe neurotoxicity, or delayed recovery from toxicity preventing retreatment
* At least 1 radiographically documented measurable lesion in a previously non irradiated area according to Response Evaluation Criteria In Solid Tumors (RECIST, Version 1.0), i.e., this lesion must be adequately measurable in at least 1 dimension (longest diameter to be recorded) as greater than or equal to (\>=) 2 centimeter (cm) by conventional techniques or \>=1 cm by spiral computed tomography (CT) scan
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, or Karnofsky performance status (KPS) \>= 80 percent (%)
* Absolute Neutrophil Count (ANC) \>=1.5 x 10\^9/Liter
* Platelets \>=100 x 10\^9/Liter
* Hemoglobin \>=9 gram per deciliter (g/dL) (without transfusions)
* Bilirubin less than or equal to (\<=) 1.5 x upper limit normal (ULN)
* Aspartate transaminase (AST) \<=5 x ULN and alanine transaminase (ALT) \<=5 x ULN
* Serum creatinine \<=1.25 x ULN and/or creatinine clearance \>=50 milliliter per minute (mL/min)
* International Nationalized Ratio (INR), and partial thromboplastin time (PTT) within normal limits
* Sodium and potassium within normal limits or \<=10% above or below (supplementation permitted)

Exclusion Criteria:

* Previous treatment with any inhibitor of Epidermal Growth Factor Receptor (EGFR)
* Known brain metastasis and/or leptomeningeal disease
* Radiotherapy (except localized radiotherapy for pain relief), major surgery, or any investigational drug in the 30 days before the start of trial treatment entry; planned major surgery during the trial
* Concurrent chronic systemic immune or hormone therapy not indicated in this trial protocol (except for physiologic replacement; steroids up to 10 mg of prednisone equivalent or topical and inhaled steroids are allowed)
* Clinically relevant coronary artery disease (New York Heart Association \[NYHA\] functional angina classification III/IV), congestive heart failure (NYHA III/IV), clinically relevant cardiomyopathy, history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia
* Uncontrolled hypertension defined as systolic blood pressure \>=160 millimeter of mercury (mmHg) and/or diastolic blood pressure \>=100 mmHg under resting conditions
* History of coagulation disorder associated with bleeding or recurrent thrombotic events
* History of recent peptic ulcer disease (endoscopically proven gastric, duodenal or esophageal ulcer) within 6 months of trial treatment start
* Chronic inflammatory bowel disease, or acute/chronic ileus
* Active infection (requiring i.v. antibiotics), including active tuberculosis, active or chronic Hepatitis B or C, or ongoing HIV infection
B: Inclusion Criteria:

* Histologically or cytologically confirmed colorectal cancer, excluding primary tumors of appendiceal origin (participants are eligible to enroll irrespective of KRAS mutation status)
* Confirmed metastatic colorectal cancer (Stage IV)
* The participant has received first-line combination therapy of bevacizumab, oxaliplatin, and a fluoropyrimidine for metastatic disease and, a) Experienced radiographic disease progression during first-line therapy, or b) Experienced radiographic disease progression ≤6 months after the last dose of first-line therapy, or c) Discontinued part or all of first-line therapy due to toxicity and experienced radiographic disease progression ≤6 months after the last dose of first-line therapy. Note that a participant must have received a minimum of 2 doses of bevacizumab as part of a first-line regimen containing chemotherapy; in addition, a participant must have received at least 1 cycle of first-line therapy that included bevacizumab, oxaliplatin and a fluoropyrimidine in the same cycle. Note that a participant must not have received more than 2 different fluoropyrimidines as part of a first-line regimen; disease progression is not an acceptable reason for discontinuing 1 fluoropyrimidine and starting a second fluoropyrimidine
* Receipt of no more than 2 prior systemic chemotherapy regimens in any setting (only 1 prior regimen for metastatic disease is permitted). For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen. Note that rechallenge with oxaliplatin is permitted and will be considered part of the first-line regimen for metastatic disease, both initial oxaliplatin treatment and subsequent rechallenge are considered as 1 regimen
* Measurable or nonmeasurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
* Adequate hematologic, renal and hepatic function
* Adequate coagulation function \[International Normalized Ratio (INR) ≤1.5 and Partial Thromboplastin Time (PTT) or activated PTT (aPTT) ≤1.5 x upper limit of normal (ULN)). Participants on full-dose anticoagulation must be on a stable dose of anticoagulant therapy and if on oral anticoagulation, must have an INR ≤3 and have no clinically significant active bleeding or pathological condition that carries a high risk of bleeding
* Consent to provide a historical colorectal cancer tissue sample for assessment of biomarkers and the tumor tissue sample is available
* Ability to provide signed informed consent

Exclusion Criteria:

* Receipt of bevacizumab ≤28 days prior to randomization
* Receipt of any investigational therapy for non-oncology clinical indication ≤28 days prior to randomization
* Receipt of any previous systemic therapy, other than a combination of bevacizumab, oxaliplatin, and a fluoropyrimidine, for first-line treatment of metastatic colorectal cancer
* Known leptomeningeal disease or brain metastases or uncontrolled spinal cord compression (currently or in the past)
* Experience of any arterial thrombotic or arterial thromboembolic events, including, but not limited to, myocardial infarction, transient ischemic attack, or cerebrovascular accident, ≤12 months prior to randomization
* Pregnant (confirmed by serum beta human chorionic gonadotropin (ß HCG) test ≤7 days prior to randomization) or lactating
* History of inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization
* Acute or subacute bowel obstruction or history of chronic diarrhea which is considered clinically significant in the opinion of the investigator
* Grade 3 or higher bleeding event ≤3 months prior to randomization
* Experience of any of the following during first-line therapy with a bevacizumab-containing regimen: an arterial thrombotic/thromboembolic event, Grade 4 hypertension, Grade 3 proteinuria, a Grade 3-4 bleeding event, or bowel perforation
* Known history or clinical evidence of Gilbert's Syndrome, or is known to have any of the following genotypes: UGT1A1\*6/\*6, UGT1A1\*28/\*28, or UGT1A1\*6/\*28
* Known allergy to any of the study treatment components, including any components used in the preparation of ramucirumab, or other contraindication to receive the study treatments
* Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinical meaningful ascites resulting from cirrhosis; Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis
C: DISEASE CHARACTERISTICS:

* Histologically confirmed colorectal cancer

  * Metastatic disease
* Epidermal growth factor receptor (EGFR)-positive by immunochemistry
* Measurable or evaluable disease
* Not amenable to standard curative therapy

  * Best supportive care is the only available option
* Must have received a prior thymidylate synthase inhibitor (e.g., fluorouracil, capecitabine, raltitrexed, or fluorouracil-uracil) in the adjuvant or metastatic setting

  * Combination therapy with oxaliplatin or irinotecan allowed
* Must have failed\* a prior regimen containing irinotecan and a prior regimen containing oxaliplatin for metastatic disease OR relapsed within 6 months after an adjuvant regimen containing irinotecan or oxaliplatin OR have documented unsuitability for such regimens
* No symptomatic CNS metastases NOTE: \*Failure is defined as either disease progression (clinical or radiological) or intolerance to the regimen

PATIENT CHARACTERISTICS:

Age

* 16 and over

Performance status

* ECOG 0-2

Life expectancy

* Not specified

Hematopoietic

* See Disease Characteristics
* Absolute granulocyte count ≥ 1,500/mm\^3
* Platelet count ≥ 75,000/mm\^3
* Hemoglobin ≥ 8.0 g/dL

Hepatic

* AST and ALT ≤ 5 times upper limit of normal (ULN)
* Bilirubin ≤ 2.5 times ULN

Renal

* Creatinine ≤ 1.5 times ULN

Cardiovascular

* No uncontrolled angina
* No arrhythmias
* No cardiomyopathy
* No congestive heart failure
* No myocardial infarction\* within the past 6 months NOTE: \*Pre-treatment ECG as only evidence of infarction is allowed

Pulmonary

* No severe restrictive lung disease
* No interstitial lung disease by chest x-ray

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception for 4 weeks before, during, and for 4 weeks after study treatment
* No active pathological condition that would preclude study participation
* No psychological or geographical condition that would preclude study compliance
* No other malignancy within the past 5 years except adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

* No prior cetuximab
* No prior murine monoclonal antibody therapy (e.g., edrecolomab)

Chemotherapy

* See Disease Characteristics
* At least 4 weeks since prior chemotherapy and recovered
* No concurrent chemotherapy

Radiotherapy

* See Disease Characteristics
* At least 4 weeks since prior radiotherapy and recovered
* Concurrent palliative radiotherapy allowed except to index lesions

Surgery

* At least 4 weeks since prior major surgery and recovered

Other

* No prior EGFR-targeted therapy (e.g., erlotinib or gefitinib)
* More than 30 days since prior experimental therapeutic agents
* More than 4 weeks since prior investigational agents
* No concurrent enrollment in another clinical study
* No other concurrent EGFR-targeted therapy
* No other concurrent non-cytotoxic experimental agents
D: Inclusion Criteria:

* Pathologic diagnosis of colorectal adenocarcinoma (diagnostic tissue obtained by tissue biopsy)
* Metastatic colorectal carcinoma
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
* Documented evidence of disease progression during, or following treatment, with fluoropyrimidine, irinotecan and oxaliplatin chemotherapy for metastatic colorectal cancer
* Radiographic documentation of disease progression during or within 6 months following the most recent chemotherapy regimen
* Unidimensionally measurable disease
* Tumor expressing epidermal growth factor receptor (EGFr) by immunohistochemistry
* At least 2 but not more than 3 prior chemotherapy regimens for colorectal cancer
* Adequate hematologic, renal and hepatic function

Exclusion Criteria:

* Symptomatic brain metastases requiring treatment
* History or evidence of interstitial pneumonitis or pulmonary fibrosis
* Use of systemic chemotherapy or radiotherapy within 30 days prior to enrollment
* Prior epidermal growth factor receptor (EGFr) targeting therapies
* Prior anti-tumor therapies including prior experimental agents or approved anti-tumor small molecules and biologics of short (less than a week) serum half life within 30 days before enrollment, or prior experimental or approved proteins within 3 months before enrollment.

Answer: C