Please select the eligibility criteria that correspond to the clinical trial below.
Title: REAL 3 : A Randomised Open-labelled Multicentre Trial of the Efficacy of Epirubicin, Oxaliplatin and Capecitabine (EOX) With or Without Panitumumab in Previously Untreated Advanced Oesophago-gastric Cancer
Brief Summary: To determine whether adding panitumumab, an antibody against the epidermal growth factor receptor (EGFR), to standard chemotherapy with epirubicin, oxaliplatin and capecitabine (EOX), improves the duration of survival of patients with advanced stomach and oesophageal cancer.


Options:
A: Inclusion Criteria:

* Disease Related

  * Histologically or cytologically confirmed adenocarcinoma of the stomach, gastroesophageal junction or distal esophagus with metastatic disease
  * Measurable or non-measurable disease per RECIST Guidelines
  * Prior gastrectomy (total or partial) may be allowed as long as subjects can take oral medications and meet all other inclusion/exclusion criteria. Subjects may not take crushed or dissolved capecitabine via a feeding/gastrostomy tube
  * Palliative radiotherapy for metastatic esophageal or gastric cancer prior to study entry may be allowed as long as all toxicities from radiotherapy have resolved and the radiotherapy was not to the only site of known metastatic disease
* Demographic

  •18 years of age or older at the time the written informed consent is obtained
* General

  * Able to swallow oral medication
  * ECOG performance status of 0 or 1
* Laboratory

  * Adequate organ and hematological function as evidenced by laboratory studies prior to randomization

Exclusion Criteria:

* Disease Related

  * Prior chemotherapy for metastatic disease (1st line)
  * Less than 12 months have elapsed from completion of previous adjuvant or neoadjuvant chemotherapy or chemoradiotherapy
  * Subjects with persistent gastric outlet obstruction, complete dysphagia or feeding jejunostomy
  * Radiotherapy ≤ 14 days prior to randomization. Subjects must have recovered from all radiotherapy-related toxicities
  * Current or prior history of central nervous system metastases
  * History of arterial or deep venous thromboembolism within 12 months prior to randomization
  * History of bleeding diathesis or clinically significant bleeding within 6 months prior to randomization
  * Major surgical procedure within 28 days prior to randomization
  * Minor surgical procedure, placement of central venous access device or fine needle aspiration within 3 days prior to randomization
  * Prior malignancy except: malignancy treated with curative intent and without evidence of active disease for ≥ 3 years prior to randomization and felt to be at low risk for recurrence by treating physician, adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease, adequately treated cervical carcinoma in situ without evidence of disease, prostatic intraepithelial neoplasia without evidence of prostate cancer
  * Prior malignancy (other than in situ cervical cancer, or basal cell cancer of the skin) unless treated with curative intent and without evidence of disease for ≥ 3 years prior to randomization
  * Clinically significant cardiovascular diseases within 12 months prior to randomization
  * Presence of clinically significant non-healing wound, ulcer (including gastrointestinal) or fracture as judged by the investigator
  * Ongoing or clinically significant active infection as judged by the investigator
  * Known hypersensitivity to bacterial proteins, or any of the drugs required in this study
  * Known peripheral neuropathy ≥Grade 1
  * Known dihydropyrimidine dehydrogenase deficiency
  * Known hypersensitivity to 5-FU/capecitabine
  * Known positive test for human immunodeficiency virus (HIV), hepatitis C, or hepatitis B surface antigen
  * Known active or chronic hepatitis
* Medications

  * Currently or previously treated with angiopoietin inhibitors, or inhibitors of TIE-1 or TIE-2
  * Treatment with immune modulators such as cyclosporine or tacrolimus within 30 days prior to randomization
  * Treatment with sorivudine or its chemically related analogues
  * Anticoagulants (other than aspirin and anti-platelet agents) within 7 days prior to randomization. The concurrent use of low molecular weight heparin or heparanoids or low dose warfarin (i.e, ≤ 1 mg daily) for prophylaxis against thrombosis is acceptable while on study
* General

  * Not yet completed at least 30 days since ending other investigational device/drug trial(s), or subject is receiving other investigational treatments
  * Pregnant or is breast feeding
B: Inclusion Criteria:

* Pathologically confirmed unresectable locally advanced or metastatic gastric or esophagogastric junction (EGJ) adenocarcinoma; tumors of the distal esophagus within 5 cm of the EGJ are eligible
* ECOG performance status 0 or 1
* Male or female ≥ 18 years of age

Exclusion Criteria:

* Previous systemic therapy (chemotherapy or biologic therapy) for locally advanced or metastatic gastric or esophagogastric adenocarcinoma
* Less than 6 months have elapsed from completion of prior neoadjuvant or adjuvant chemotherapy or chemoradiotherapy.
* Subjects with resectable disease or suitable for definitive chemoradiation
* Subjects with persistent gastric outlet obstruction, complete dysphagia or feeding jejunostomy
* Tumors of squamous cell histology
* Known central nervous system metastases
* Clinically significant upper gastro-intestinal bleeding ≤ 30 days prior to enrollment or randomization
* Serious or non-healing wound
C: Inclusion Criteria:

* Histologically verified inoperable locally advanced or metastatic adenocarcinoma or undifferentiated carcinoma of the oesophagus, oesophago-gastric junction, or stomach.
* Slides of tumour tissue should be available for centralised EGFR staining
* Uni-dimensionally measurable disease (CT or MRI as per RECIST).
* No prior chemotherapy including previous adjuvant chemotherapy
* No prior radiotherapy including adjuvant radiotherapy. Patients receiving palliative radiotherapy to sites of disease that are not measurable may be eligible and should be discussed with the Chief Investigator.
* Male/female patients aged ≥18 years.
* WHO Performance status 0, 1 or 2.
* Patients should have a projected life expectancy of at least 3 months.
* Completion of baseline quality of life questionnaire (EORTC QLQ C30).
* Adequate cardiac function; formal measurement of left ventricular ejection fraction is only required if clinically indicated.
* Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5x109/l; white blood cell count ≥ 3x109/l; platelets ≥ 100x109/l; haemoglobin (Hb) ≥ 9g/dl (can be post-transfusion).
* Adequate renal function: calculated creatinine clearance ≥50ml/minute.
* Adequate liver function: serum bilirubin ≤1.5x ULN; ALT/AST ≤2.5x ULN; ALP ≤3x ULN (in the absence of liver metastases). If liver metastases are present, serum transaminases ≤5x ULN are permitted.
* Written informed consent must be obtained from the patient before any study-specific procedures are performed (see Section 12.0).

Note: Epidermal growth factor receptor (EGFR) positivity by immunohistochemistry will not be required for study entry. Slides obtained from previously collected paraffin embedded archived specimens will be collected centrally for EGFR staining. A multivariate analysis will then be performed to exclude any effects of EGFR status on outcome measures

Exclusion Criteria:

* Tumours of squamous histology.
* Patients with locally advanced oesophageal cancer suitable for definitive chemoradiotherapy.
* Documented or symptomatic brain metastases and/or central nervous system metastases or leptomeningeal disease.
* Previous chemotherapy or radiotherapy. See Inclusion criteria for note regarding palliative radiotherapy.
* Any major surgery within 4 weeks prior to the start of study treatment.
* Any prior treatment with an EGFR signal transduction directed therapy.
* Treatment with non-permitted medication.
* Clinically significant (i.e. active) cardiac disease e.g. symptomatic coronary artery disease, uncontrolled cardiac dysrhythmia, or myocardial infarction within the last 12 months. Patients with any history of clinically significant cardiac failure are excluded from study entry.
* History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan.
* Known peripheral neuropathy \>Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible).
* Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication (administration of capecitabine by naso-gastric or jejunostomy feeding tube is permitted).
* Known dihydropyrimidine dehydrogenase (DPD) deficiency.
* Known hypersensitivity to panitumumab, components of the EOX regimen, or any of the constituents of these agents.
* Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection.
* Other clinically significant disease or co-morbidity which may adversely affect the safe delivery of treatment within this trial.
* Female patients who may be pregnant or breastfeeding. Potential female patients of childbearing potential must have a negative pregnancy test within 7 days prior to randomisation, or have had amenorrhea for more than 2 years.
* Patients of child-bearing potential not consenting to use adequate contraceptive precautions or abstinence during the course of the study and for 6 months after the last study drug administration for females, and 1 month for males.
* Any other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix).
* Treatment with another investigational agent within 30 days of commencing study treatment.
D: Key Inclusion Criteria:

* Pathologically confirmed unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma •Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1)
* Tumor MET-positive by immunohistochemistry (IHC)
* Evaluable (measurable or non-measurable) disease by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria

Key exclusion criteria:

* Human Epidermal Growth Factor Receptor 2 (HER2) -overexpressing locally advanced or metastatic gastric or GEJ adenocarcinoma •Previous systemic therapy for locally advanced or metastatic gastric or GEJ adenocarcinoma
* Less than 6 months have elapsed from completion of prior neoadjuvant or adjuvant chemotherapy or chemoradiotherapy to randomization
* Previous treatment with anthracyclines must not exceed total cumulative dose of epirubicin of 400 mg/m2
* Squamous cell histology
* Left ventricular ejection fraction (LVEF) \< 50%

Answer: C