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:

* metastatic or locally advanced gastric cancer or adenocarcinoma of the esophagogastric junction
* no prior chemotherapy in metastatic state
* adequate blood and biochemistry parameters

Exclusion Criteria:

* hypersensitivity for 5-FU, Leucovorin, Oxaliplatin or Docetaxel
* KHK, cardiomyopathy or cardiac insufficiency
* malignancy \<5 years ago
* brain metastases
* severe internal disease or inadequate blood and biochemistry parameters
B: Inclusion Criteria:

Signed informed consent; Histologically confirmed gastric, esophageal, or gastro-esophageal junction adenocarcinoma; disease that is locally advanced (unresectable), metastatic, or locally recurrent disease; Measurable or non-measurable, but radiologically evaluable disease, according to RECIST; ErbB2 (HER2)positive; Age =18 years; ECOG Performance status = 2; Adequate organ function, including adequate hematologic, renal and liver function; Cardiac ejection fraction within institutional range of normal as measured by echocardiogram; Able to swallow and retain oral medications, and/or receive enteral medications via gastrectomy feeding tube; Women and men with potential to have children must be willing to practice acceptable methods of birth control during the study; Prior gastric surgery is permitted if \> 3 weeks prior and recovered; Prior chemotherapy for non-gastric malignancy if \> than 5 years; Prior neoadjuvant and/or adjuvant chemotherapy for early stage gastric cancer if \> 6 months since completion; At least 4 weeks since prior radiotherapy; Prior biologic, hormonal, or immunologic cancer treatment if \> 5 years since treatment.

Exclusion Criteria:

Pregnant or lactating females; Known history of active CNS disease; Uncontrolled ascites; Concurrent anti-cancer therapy; Gastric carcinoid, epidermoid, sarcomas, or squamous cell carcinoma; Prior palliative chemotherapy for the treatment of gastric cancer; Prior treatment with oxaliplatin \< 12 months; Malabsorption syndrome or uncontrolled inflammatory gastrointestinal disease; Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure; Pre-existing grade = 2 motor or sensory neuropathy; Uncontrolled infection; Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical condition that would interfere with the subject''s safety; Active hepatic or biliary disease; History of other malignancy except if disease-free for 5 years, a history of completely resected non-melanoma skin cancer, or a successfully treated in situ carcinoma; Unresolved or unstable serious toxicity from prior administration of another investigational drug and/or prior cancer treatment; Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent; Known history of DPD deficiency; Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to lapatinib, capecitabine, fluorouracil, platins or their excipients; Use of any investigational drug within 30 days prior randomization; Use of concurrent prohibited medications that would interact with study medications
C: Inclusion Criteria:

* Patients must have histologically or cytologically confirmed metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. GEJ adenocarcinoma may be classified according to Siewert's classification type I, II, or III\[43\].
* Histological documentation of local recurrence or metastasis is strongly encouraged, unless the risk of such a procedure outweighs the potential benefit of confirming the metastatic disease.
* If no histologic confirmation, then the metastases or recurrence will require documentation by a 2nd radiographic procedure (eg. PET/CT scan or MRI in addition to the CT scan). If the imaging procedure does not confirm recurrent or metastatic disease, biopsy confirmation will be required.
* Patients must have disease that can be evaluated radiographically. This may be measurable disease or non-measurable disease. Measurable disease is defined as that which can be measured in at least one dimension as \> 20 mm with conventional techniques, or \>10 mm by high resolution imaging. Disease that is identified on radiology studies, but does not meet the criteria for measurable disease, is considered non-measurable.
* Patients may have received no prior chemotherapy for metastatic or unresectable disease. Patients may have received prior adjuvant therapy (chemotherapy and/or chemoradiation) if more than 6 months have elapsed between the end of adjuvant therapy and registration. Patients may not have received prior docetaxel or cisplatin.
* Age 18 years or older.
* Karnofsky performance status \> than or = to 70% (ECOG performance status 0-1).
* Peripheral neuropathy \< than or = to grade 1.
* Hematologic (minimal values):

  * White blood cell count \> than or = to 3000/mm3
  * Absolute neutrophil count \> than or = to 1500 cells/ mm3
  * Hemoglobin \> than or = to 9.0 g/dl
  * Platelet count \> than or = to 100,000 / mm3
* Hepatic (minimal values):
* Total bilirubin \< or = to 1.5

  \* \* AST and ALT and Alkaline phosphatase must be within the eligible range. In determining eligibility, the more abnormal of the two values (AST or ALT) should be used. Patients with alkaline phosphatase elevation secondary to the bony metastases rather than liver dysfunction may proceed with treatment on protocol after discussion with the principal investigator.
* Kidney function (minimal values):

  \* Serum creatinine \< than or = to 1.5 mg/dl - if serum creatinine is 1.2-1.5 mg/dl, the creatinine clearance (either measured or calculated) must be 50 ml/min or greater
* The patient has a PT (INR) \< than or = to 1.5 and an PTT \< than or = to 3 seconds above the upper limits of normal if the patient is not on anticoagulation. If a patient is on full-dose anticoagulants, the following criteria should be met for enrollment:

  * The patient must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin or on stable dose of LMW heparin
  * The patient must not have active bleeding or pathological conditions that carry high risk of bleeding (e.g. tumor involving major vessels, known varices)
* Women of childbearing potential have a negative pregnancy test.
* Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter.
* Ability to understand informed consent and signing of written informed consent document prior to initiation of protocol therapy.
* Patients must have HER2-positive (FISH+ or IHC 3+) metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma to be eligible for trastuzumab. For the purposes of this protocol, FISH+ is defined as HER2:CEP17 ratio ≥ 2.0. Biopsy samples with cohesive IHC3+ or FISH+ clones are considered HER2 positive irrespective of size, i.e.\<10%. FISH+ defined as \>2 HER2:CEP17.
* Patients who are receiving trastuzumab must have a left ventricular ejection fraction of ≥ 50%.

Exclusion Criteria:

* Patients who have received previous chemotherapy for the treatment of metastatic or unresectable gastric or GEJ adenocarcinoma are ineligible.
* Patients who have received previous pre- or post-operative chemotherapy or chemoradiation are ineligible if therapy was completed less than 6 months prior to study registration. Patients must have recovered from adverse events from any previous therapy.
* Patients who have received previous docetaxel or cisplatin.
* Patients with a history of another neoplastic disease within the past three years, excluding basal cell carcinoma of the skin, cervical carcinoma in situ, or nonmetastatic prostate cancer.
* Patients with brain or central nervous system metastases, including leptomeningeal disease.
* Pregnant (positive pregnancy test) or breast feeding.
* Serious, non-healing wound, ulcer, or bone fracture.
* Significant cardiac disease as defined as:

unstable angina, New York Heart Association (NYHA) grade II or greater, congestive heart failure, history of myocardial infarction within 6 months

* Evidence of bleeding diathesis or coagulopathy.
* History of a stroke or CVA within 6 months
* Clinically significant peripheral vascular disease.
* Clinically significant hearing loss or ringing in the ears.
* Patients with a history of severe hypersensitivity reaction to Taxotere® or other drugs formulated with polysorbate 80.
* Inability to comply with study and/or follow-up procedures.
* Patients with any other medical condition or reason, in that investigator's opinion, makes the patient unstable to participate in a clinical trial.
* For patients who are Her2 positive and will be treated on the trastuzumab + mDCF cohort, prior trastuzumab treatment is not allowed.
* For patients who are Her2 positive and will be treated on the trastuzumab+mDCF cohort, left ventricular function \<50%
D: 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.

Answer: D