Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Randomised Phase II Trial on the Therapy of Advanced Gastric Cancer or Adenocarcinoma of the Esophagogastric Junction in Patients Older Than 65 Years With Specific Regard of Quality of Life and Pharmacogenetic Risk Profile
Brief Summary: In this trial, FLOT will be evaluated as therapy option for elderly patients (\>65 years) with advanced gastric cancer in comparison to the well established FLO scheme. The hypothesis is that FLOT is more effective than FLO in elderly patients with acceptable side effects.


Options:
A: Inclusion Criteria:

* Histologic or cytologic confirmation of adenocarcinoma of the esophagus, gastroesophageal junction (GEJ), or stomach
* Metastatic or locally advanced, unresectable disease at time of study entry
* Provided signed informed consent and is amenable to compliance with protocol schedules and testing
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 at study entry
* Adequate renal, hematological, and hepatic function
* Measurable or non-measurable disease at the time of study entry
* Resolution to Grade less than or equal to 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0, of all clinically significant toxic effects of prior locoregional therapy, surgery, or other anticancer therapy, except where otherwise mentioned in the eligibility criteria
* Eligible participants of reproductive potential (both sexes) must agree to use adequate contraceptive methods (hormonal or barrier methods) during the study period and at least 12 weeks after the last dose of study therapy
* Life expectancy of greater than or equal to 3 months
* Willingness to provide blood and tissue samples for research purposes. Submission of tumor specimen is mandatory for participation in this study, if a histologic, paraffin-embedded specimen exists (either from a surgical resection or biopsy); submission of paraffin block or a minimum of 8 unstained slides is required if sufficient sample. NOTE: If insufficient additional tissue exists (that is, all tissue has been utilized for prior diagnostic purposes), participation in the study is allowable without the requirement for an additional biopsy; this situation must be discussed with the study principal investigator and/or the ImClone medical monitor or designee.

Exclusion Criteria:

* The participant has received prior first-line systemic therapy for advanced/unresectable and/or metastatic disease (prior adjuvant or neo-adjuvant therapy is permitted)
* Previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to study entry
* Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the participant ineligible for entry into this study
* The participant is receiving chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs; for example, indomethacin, ibuprofen, naproxen, or similar agents) or other antiplatelet agents (for example, clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin use at doses up to 325 milligrams per day (mg/day) is permitted.
* The participant has significant third-space fluid retention (for example, ascites or pleural effusion), and is not amenable for required repeated drainage
* The participant is pregnant or breastfeeding
* Uncontrolled intercurrent illness including, but not limited to, active or uncontrolled clinically serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled thromboembolic, or hemorrhagic disorder, psychiatric illness/social situations, or other co-morbid systemic illnesses, or other severe concurrent disease
* Immunocompromised participants including participants known to be human immunodeficiency virus (HIV) positive.
* Progressive disease less than or equal to 12 months of completing platinum or 5-FU treatment, including capecitabine, if given previously in the perioperative (adjuvant or neoadjuvant) setting
* Current or recent (within 28 days prior to randomization) treatment with an investigational drug that has not received regulatory approval for any indication at the time of study entry, or participation in another interventional clinical trial. Participants participating in surveys or observational studies are eligible to participate in this study.
* Are currently enrolled in, or discontinued within the last 28 days from, a clinical trial involving ramucirumab drug product (DP), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
* Received prior therapy with an antiangiogenic agent (including but not limited to bevacizumab, sunitinib, or sorafenib)
* Major surgical procedure or significant traumatic injury less than 28 days prior to randomization, or anticipation of need for elective or planned major surgical procedure during the course of the study. Subcutaneous venous access device placement within 7 days prior to randomization
* Clinically significant peripheral neuropathy at the time of registration
* Known central nervous system metastases that are symptomatic or untreated
* New York Heart Association (NYHA) classification III-IV congestive heart failure
* Greater than normal risk of bleeding or coagulopathy in the absence of therapeutic anticoagulation; Grade 3/4 gastrointestinal bleeding within 3 months prior to registration; active bleeding (that is, within 14 days prior to first dose of study therapy); or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices)
* Participant has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, stroke, transient ischemic attack (TIA), cerebrovascular accident, or unstable angina, less than or equal to 6 months prior to registration
* Clinically significant vascular disease (for example, aortic aneurysm, aortic dissection) for which more than minimal intervention is being administered or planned
* History of hypertensive crisis or hypertensive encephalopathy or current poorly-controlled hypertension despite standard medical management
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess less than 6 months prior to registration
* Known hypersensitivity to any of the treatment components of modified FOLFOX6 (mFOLFOX6) (oxaliplatin, 5-FU, and leucovorin) or ramucirumab DP
B: Inclusion Criteria - All Patients

* Histologically verified inoperable locally advanced or metastatic adenocarcinoma of the oesophagus, oesophago-gastric junction, or stomach.
* Completion of 18 weeks of first-line chemotherapy with either CX/ CAPOX or FOLFOX (HER2 negative) or CX/ CF + trastuzumab (HER2 positive) for locally advanced / metastatic disease with \> stable disease on the end of treatment CT scan (HER2 positive patients must have received at least one cycle of trastuzumab alongside first line chemotherapy; patients receiving chemotherapy delivered on a 3-weekly basis eg CX/ CAPOX should have received 6 cycles and on a two weekly basis e.g. FOLFOX should have received 9 cycles).
* Disease which, following first-line chemotherapy, remains inoperable and unsuitable for definitive chemoradiotherapy.
* Able to proceed with maintenance treatment within 28 days of the last day of the last cycle of chemotherapy.
* Formalin fixed paraffin embedded (FFPE) blocks of diagnostic tissue available for biomarker analysis.
* Any prior chemotherapy or radiotherapy in the adjuvant setting must have been completed at least 6 months prior to the first occurrence of metastatic disease.
* No prior radiotherapy in the advanced disease setting. 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.
* 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; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤2.5 x ULN (5 × ULN is acceptable for ALT, AST and ALP if liver metastases are present).
* Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 7 months following the last dose of assigned study drug(s).
* Written informed consent must be obtained from the patient before any study-specific procedures are performed.

Exclusion Criteria - All Patients

* Concurrent enrolment in another clinical trial unless it is an observational (non-interventional) clinical study.
* Tumours of squamous histology.
* Documented brain metastases, central nervous system metastases or leptomeningeal disease.
* Patients who have not recovered from clinically significant effects of any prior surgery, radiotherapy or any other anti-neoplastic therapies. All toxicities must have resolved to grade 1 or less, with the exception of peripheral neuropathy which must be less than or equal to grade 2 according to NCI CTCAE version 4.0.
* Any major surgery within 4 weeks prior to the start of study treatment.
* Uncontrolled hypertension (systolic blood pressure \>180 mm Hg or diastolic blood pressure \>100 mm Hg).
* Clinically significant (i.e. active) cardiac disease e.g. symptomatic coronary artery disease, symptomatic congestive heart failure, uncontrolled cardiac dysrhythmia, or myocardial infarction within the last 12 months. Patients with any prior 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.
* Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication.
* Patients who are pregnant or lactating.
* Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis A or 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.
* Any other malignancies within the last 3 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.

Additional Inclusion / Exclusion Criteria - HER-2 Negative Patients (Arm A)

* Patients must have histologically or cytologically confirmed HER-2 negative disease (HER-2 0-2 by IHC; note if ISH testing is performed this must not demonstrate evidence of gene amplification).
* Patients with known capecitabine intolerance are excluded. This includes patients with previous coronary artery spasm or chest pain deemed to be capecitabine-related.
* Patients with homozygous DPYD gene mutations are excluded. Patients with heterozygous DPYD gene mutations who have tolerated dose-reduced fluoropyrimidines during first-line chemotherapy as per local guidelines are eligible.
* Prior treatment with a PARP inhibitor is excluded (only applicable for A4 \& A5 patients).
* Any Grade 3 or 4 GI bleeding within 3 months prior to enrollment are excluded
* Any Grade 3 or 4 venous thromboembolic event (VTE) that is considered by the investigator to be life threatening or that is symptomatic and not adequately treated by anticoagulation therapy, within 3 months prior to randomization are excluded.
* History of GI perforation within 6 months of randomisation are excluded
* History of hepatic encephalopathy or cirrhosis (level Child-Pugh B or worse) are excluded
* Patients must have adequate coagulation function as defined by International Normalised Ratio (INR) ≤1.5 and a partial thromboplastin time/activated partial thromboplastin time (PTT or aPTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy. Patients receiving warfarin must be switched to low molecular weight heparin prior to randomisation.
* Patients with a serious or non-healing wound, ulcer or bone fracture within 28 days prior to randomisation are excluded.
* The patient's urinary protein is ≤1+ on dipstick or routine urinalysis (if urine dipstick is

  * 2+, a 24 hour urine collection for protein must demonstrate \< 1000mg of protein in 24 hours.
* Patients experiencing thromboembolic events, including but not limited to myocardial infarction, transient ischaemic attack, cerebrovascular accident, unstable angina, within 6 months prior to first dose of protocol therapy are excluded.
* Patients who have undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/ subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy are excluded.
* Patients receiving chronic anti-platelet therapy or NSAIDS including ibuprofen, naproxen, dipyridamole or clopidogrel, or similar agents are excluded. Once daily aspirin use (up to 325mg/day) is permitted.

Additional Inclusion / Exclusion Criteria - HER-2 Positive Patients (Arm B)

* Patients must have histologically or cytologically confirmed HER-2 positive disease (HER-2 3+ by IHC or HER-2 2+ by IHC and HER-2 gene amplified by ISH).
* Patients must have left ventricular ejection fraction (LVEF) \>50% as measured by echocardiogram or \>45% measured by MUGA (must also be greater than lower limit of normal at institution).
* Patients with active or prior history of New York Heart Association (NYHA) congestive heart failure are excluded.
* Patients with a known history of hypersensitivity to trastuzumab or any of its components are excluded.
C: Inclusion Criteria:

* Has given written Informed Consent.
* Histologically confirmed, unresectable, metastatic diffuse gastric cancer including carcinoma of the gastro-esophageal junction.
* No prior chemotherapy for gastric cancer except adjuvant and/or neo-adjuvant chemotherapy more than 12 months ago.
* Life expectancy of at least 3 months.
* Able to take medications orally.
* Eastern Cooperative Oncology Group performance status 0 to 1.
* Adequate organ function (bone marrow, kidney and liver).

Exclusion Criteria:

* Certain type(s) of non-measurable lesion(s), if the only one(s).
* Certain serious illness or medical condition(s).
* Lost greater than or equal to 10% of body weight in the 3 months proceeding signing the Informed Consent Form.
* Treatment with drugs interacting with S-1, 5-FU, or cisplatin.
* Pregnant or lactating female.
* Known hypersensitivity to fluoropyrimidines or cisplatin.

Other protocol-defined inclusion/exclusion criteria may apply.
D: 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

Answer: D