Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Phase III, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Onartuzumab (MetMAb) in Combination With 5-Fluorouracil, Folinic Acid, and Oxaliplatin (mFOLFOX6) in Patients With Metastatic HER2-Negative, MET-Positive Gastroesophageal Cancer
Brief Summary: This randomized, multicenter, double-blind, placebo-controlled study will evaluate the efficacy and safety of onartuzumab (MetMAb) in combination with 5-fluorouracil, folinic Acid, and oxaliplatin (mFOLFOX6) in participants with metastatic human epidermal growth receptor (HER) 2-negative and MET-positive adenocarcinoma of the stomach or gastroesophageal junction. Participants will be randomized in a 1:1 ratio to receive either onartuzumab or placebo in combination with mFOLFOX6. Participants may continue to receive onartuzumab or placebo until disease progression, unacceptable toxicity, participant or physician decision to discontinue treatment.


Options:
A: Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the stomach, including adenocarcinoma of the gastroesophageal junction and esophagus
* Metastatic disease
* Measurable disease (according to RECIST criteria)
* At least one prior chemotherapy for metastatic disease with progression during or no later than 6 months after last administration of chemotherapy. Chemotherapy must have contained a platinum compound (cisplatin or oxaliplatin)
* Her2 overexpression measured by FISH (amplification or increased gene copy number). Immunohistochemistry (ICH) 3+ can be included in case of an uncertain FISH test.
* Patient willing to allow for biomarker analyses on his tumor tissue.
* Written informed consent given prior to any protocol specific procedures according to the local regulatory requirements
* Age \>= 18 years
* Eastern Cooperative Oncology Group Performance Status (ECOG-PS) \<= 2
* Life expectancy \> 3 months
* Adequate hematological, hepatic and renal function defined by: Hematology: Neutrophils \>1.5x109/L; Platelets \>100x109/L; Hemoglobin \>8g/dL Hepatic function: Total bilirubin \<=1.5xULN; ASAT (SGOT) and ALAT (SGPT) \<= 2.5xULN; Alkaline phosphatase \<5xULN. Renal function: The calculated creatinine clearance should be .60 mL/min
* Eligibility of patients receiving medications or substances known to affect, or with the potential to affect the activity or pharmacokinetics of lapatinib will be determined following review of their use by the local Principal Investigator. A list of medications and substances known or with the potential to interact with CYP450 isoenzymes is provided in: Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 8TH ed. Hudson, OH; LexiComp Inc. 2000: 1364-1371
* Able to swallow and retain oral medication
* Negative pregnancy test (urine or serum) within 28 days prior to randomization for all women of childbearing potential (has to be verified within 7 days prior to randomization and during the study according the judgement of the investigator)
* Willingness to perform double-barrier contraception during study and 6 months after end of treatment
* Ability to understand and the willingness to sign a written informed consent document
* Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

* Previous non curatively treated malignant disease other than the current gastroesophageal cancer with a disease-free survival of less than 5 years
* History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
* History of active Hepatitis B or C or history of an HIV infection
* Active uncontrolled infection
* Treatment within any other clinical trial parallel to the treatment phase of the current study within 30 days prior to randomisation.
* Concurrent treatment with any other anti-cancer drug. Presence of other medication that may interfere with study treatment or the action of the investigational product or confuse the assessment of study results
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib or to any excipients
* History of allergic reactions attributed to compounds of similar chemical composition to capecitabine, fluorouracil or to any excipients
* Known DPD deficiency
* Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors
* Current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
* Active cardiac disease, defined as:

  * History of uncontrolled or symptomatic angina
  * History of arrhythmias requiring medications, or clinically significant, with the exception of asymptomatic atrial fibrillation requiring anticoagulation

    * Myocardial infarction \< 6 months from randomization
    * Uncontrolled or symptomatic congestive heart failure (\> New York Heart Association score 2)
    * Ejection fraction below the institutional normal limit
    * Any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
* Pregnancy and lactation
* History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product
B: -INCLUSION CRITERIA:

1. Histologically or cytologically confirmed gastric adenocarcinoma.
2. Metastatic disease must be measurable by computed tomography (CT) and/or magnetic resonance imaging (MRI)

   Or

   There must be a history of positive peritoneal washings or carcinomatosis
3. All disease should be deemed resectable to negative margins (NED) based on imaging studies.

   Note: Patients with both pulmonary and peritoneal metastases will be enrolled at the discretion of the Principal Investigator.
   * Esophageal invasion \< 4cm that does not require thoracotomy (Seiwert II and III lesions).
   * Hepatic metastases (unilateral or bilateral less than or equal to 5 lesions, less than or equal to 15 cm total diameter).
   * Primary peritoneal metastases (small disease load less than or equal to P2 disease) without massive ascites or intestinal obstruction.
   * Para-aortic lymph node metastases (stations 16 a1 and/or b2).
   * Lung metastases (less than or equal to 3 unilateral/bilateral, 9 cm total diameter).
   * Patients who present with both hepatic and peritoneal metastases must have no evidence of extensive para-aortic/retro-pancreatic lymph node metastases.
4. Greater than or equal to 18 years of age.
5. Must be able to understand and sign the Informed Consent Document.
6. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) less than or equal to 2.
7. Life expectancy of greater than three months.
8. Patients of both genders must be willing to practice birth control during and for four months after receiving chemotherapy.
9. Hematology:

   * Absolute neutrophil count greater than 1300/mm\^3 without the support of Filgrastim.
   * Platelet count greater than 75,000/mm\^3.
   * Hemoglobin greater than 8.0 g/dl.
10. Chemistry:

    * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less than or equal to 5 times the upper limit of normal. Except in the presence of obstructive liver metastases where ALT/AST may be up to 10 times the upper limit of normal.
    * Serum creatinine less than or equal to 1.5 mg/dl unless the measured creatinine clearance is greater than 60 mL/min/1.73 m\^2.
    * Total bilirubin less than or equal to 2 mg/dl, except in the presence of obstructive metastases.
    * Prothrombin time (PT) within 2 seconds of the upper limit of normal (International Normalized Ratio (INR) less than or equal to 1.8).
11. No history of prior/other malignancies within the 2 years prior to enrollment with the exception of basal cell carcinoma.

EXCLUSION CRITERIA:

1. Prior treatment with 5-FU, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) (treatment with any of the components as separate regimens is allowable).
2. Inability to tolerate any of the chemotherapeutic agents.
3. Grade 2 or greater neuropathy.
4. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the chemotherapy on the fetus or infant.
5. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system; myocardial infarction; cardiac arrhythmias; obstructive or restrictive pulmonary disease.
6. Brain metastases or a history of brain metastases.
7. Childs B or C cirrhosis or with evidence of severe portal hypertension by history, endoscopy, or radiologic studies.
8. Weight less than 40 kg.
9. Significant ascites, greater than 1000cc in the absence of peritoneal disease.
10. History of congestive heart failure and/or an left ventricular ejection fraction (LVEF) less than 40%.

    Note: Patients at increased risk for coronary artery disease or cardiac dysfunction (e.g., greater than 65yo, diabetes, history of hypertension, elevated low-density lipoprotein (LDL), first degree relative with coronary artery disease) will undergo full cardiac evaluation and will not be eligible if they demonstrate significant irreversible ischemia on stress thallium or an ejection fraction \< 40%.
11. Significant chronic obstructive pulmonary disease (COPD) or other chronic pulmonary restrictive disease with pulmonary function tests (PFT's) indicating an forced expiratory volume 1 (FEV1) less than 50% or a carbon monoxide diffusing capacity (DLCO) less than 40% predicted for age.

Note: Patients who have shortness of breath with minimal exertion or who are at risk for pulmonary disease (e.g., chronic smokers) will undergo pulmonary function testing and will not be eligible if their FEV1 is less than 50% of expected.
C: Inclusion Criteria:

* Signed and dated informed consent before the start of specific protocol procedures
* Histological proven gastric adenocarcinoma including adenocarcinoma of the esophagogastric junction or lower esophagus
* Failure of any prior chemotherapy (docetaxel and/or platinum-based chemotherapy); but patient has not previously received FOLFIRI treatment
* Measurable metastatic disease according to the RECIST criteria patients aged 18 years and older
* karnofsky index 100 - 70 %
* Life expectancy \> 12 weeks
* Adequate hematological, hepatic and renal functions
* At least 3 weeks from previous docetaxel- and/or platinum-based chemotherapy
* Recovery from hematological side effects (CTC grade \<1) and non-hematological side effects (CTC grade=\<1) of any prior therapy (except oxaliplatine induced neuropathy CTC grade =\<2)

Exclusion Criteria:

* History of another primary malignancy \>3 years, with the exception of non-melanoma skin cancer and in situ carcinoma of the uterine cervix
* Any prior palliative radiotherapy of the target lesions
* Concurrent treatment with any other medicinal anti-cancer therapy
* Prior treatment with a VEGF, VEGFR or RTK inhibitor, or prior enrolment on this study
* Known allergic/hypersensitivity reaction to any of the components of the treatment
* Treatment with potent CYP3A4 inhibitor within 7 days of Sunitinib/placebo dosing or with potent CYP3A4 inducer within 12 days of Sunitinib/placebo dosing
* Other serious illness or medical conditions within the last 12 months prior to study drug administration: Unstable cardiac disease despite treatment; myocardial infarction within 12 months prior to study entry; congestive heart failure NYHA grade 3 and 4; Hypertension that cannot be controlled by medication ; ongoing cardiac dysrhythmias of NCI CTCAE grade \>2, atrial fibrillation of any grade, or QTc interval \>450 msec for males or \>470 msec for females; History of significant neurologic or psychiatric disorders including dementia or seizures; Active uncontrolled infection; History of clinically significant bleeding within the past 6 months, including hemoptysis or haematuria, or underlying coagulopathy; Active disseminated intravascular coagulation; Cerebrovascular accident including transient ischemic attack; Pulmonary embolus; Bowel obstruction or chronic diarrhoea, history or presence of inflammatory enteropathy or extensive intestinal resection; History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrolment, unless affected area has been removed surgically
* Known deficit in DPD
* Hypercalcemia not controlled by bisphosphonates
* Contraindications to the use of atropine
* Pregnant or lactating women; female patients who are pregnant or lactating or men and women of reproductive potential not willing or not able to employ an effective method of birth control/contraception to prevent pregnancy during treatment and for 3 months after discontinuing study treatment
* Known drug abuse/alcohol abuse
* Current, recent, or planned participation in an experimental treatment drug study other than this protocol
* Major surgical procedure, open biopsy or significant traumatic injury within 4 weeks before starting treatment; anticipation of need for major surgical procedure (e.g. impending bowel obstruction) during the course of the study
* History of other medical or psychiatric condition, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the patient at high risk from treatment complications
D: Inclusion Criteria:

* Adenocarcinoma of the stomach or gastroesophageal junction with inoperable, metastatic disease, not amenable to curative therapy
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Life expectancy greater than (\>) 3 months
* Presence of tissue sample for IHC assay of MET receptor and HER2 status
* Tumor (primary or metastatic lesion) defined as MET-positive by IHC
* Measurable disease or non-measurable but evaluable disease, according to the RECIST v1.1; Participants with peritoneal disease would generally be regarded as having evaluable disease and allowed to enter the trial
* For women who are not postmenopausal or surgically sterile; agreement to use an adequate method of contraception (hormonal implant) during the treatment period and for at least 90 days after the last dose of onartuzumab/placebo and 6 months after the last dose of oxaliplatin
* For men: agreement to use a barrier method of contraception during the treatment period and for 90 days after the last dose of onartuzumab/placebo and 6 months after the last dose of oxaliplatin

Exclusion Criteria:

* HER2-positive tumor (primary tumor or metastasis)
* Previous chemotherapy for locally advanced or metastatic gastric carcinoma (adjuvant or neoadjuvant chemotherapy must be completed at least 6 months prior to randomization)
* Prior treatment with investigational drugs that target the human growth factor (HGF) or MET pathway
* History of another malignancy within the previous 5 years, except for appropriately treated and presumed cured carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer, and localized prostate cancer
* Pregnancy or lactation
* Receipt of an investigational drug within 28 days prior to study start
* Clinically significant gastrointestinal abnormalities, apart from gastric cancer, including uncontrolled inflammatory gastrointestinal diseases
* Significant history of cardiac disease
* Significant vascular disease
* Serious active infection at the time of randomization, or other serious underlying medical conditions that would impair the ability of the participant to receive protocol treatment
* Infection with human immunodeficiency virus, hepatitis B, or hepatitis C
* Radiotherapy within 4 weeks before start of study treatment
* Major surgery within 4 weeks before start of study treatment, without complete recovery
* Any condition (psychological, geographical) that does not permit compliance with study and follow-up procedures
* Peripheral neuropathy
* Prior unanticipated severe reaction to fluoropyrimidine therapy
* Known sensitivity or contraindication to any component of study treatment
* Active gastrointestinal bleeding

Answer: D