Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized Phase III Study of 5-FU Continuous Infusion (5-FUci) Versus CPT-11 Plus CDDP (CP) Versus S-1 Alone (S-1) in Advanced Gastric Cancer (JCOG9912)
Brief Summary: To investigate the superiority of a combination of irinotecan and cisplatin and the non-inferiority of S-1 compared to continuous infusion of 5-FU in advanced gastric cancer


Options:
A: 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
B: Inclusion Criteria:

1. Signed written informed consent incl. participation in translational research
2. Male or female patient 18 years or older
3. Histologically confirmed metastatic or locally advanced unresectable gastric adenocarcinoma or adenocarcinoma of the esophagus or the esophagogastric junction (Her-2/neu negative or with unknown Her-2/neu status)
4. Adjuvant/neoadjuvant or perioperative chemotherapy or (chemo-)radiotherapy must have been finished at least 6 months before start of the induction therapy
5. For patients enrolled before induction therapy: No previous systemic treatment (i.e. chemotherapy) for metastatic disease
6. For patients enrolled after induction therapy: Having finished a three-months induction therapy (6 cycles of a bi-weekly regimen, 4 cycles of a three-weekly regimens or 3 cycles of a four-weekly regimen) without tumor progression or limiting toxicity
7. ECOG Performance Score 0-1 (Karnofsky Performance status \>= 80%)
8. Ability for oral intake of the study drug, patients with tumor-related problems with oral intake might be registered if the symptom is expected to be improved during induction therapy (e.g. due to a tumor stenosis)
9. Female patient of childbearing potential (i.e. did not undergo surgical sterilization - hysterectomy, bilateral tubal ligation, or bilateral oophorectomy - and is not post-menopausal for at least 24 consecutive months) with a negative pregnancy test
10. Hematology and biochemistry laboratory results within the limits normally expected for the patient population, defined by the following:

    * Absolute neutrophil count ≥ 1500/µl
    * Platelet count ≥ 100000/µl
    * Leukocyte count \> 3000/µl
    * Hemoglobin ≥ 9 g/dL or 5.59 mmol/l, previous transfusions (\>3 days) of erythrocytes are allowed
    * Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), in patients with known Meulengracht syndrom ≤3 x ULN
    * AST ≤ 3xULN in absence of liver metastases, or ≤5xULN in presence of liver metastases
    * ALT ≤ 3xULN in absence of liver metastases, or ≤5xULN in presence of liver metastases
    * Creatinine clearance ≥30 mL/min according to Cockcroft-Gault formula

Exclusion Criteria:

1. Previous major sugery within the last 28 days before the start of the induction treatment. The implantation of a central venous access (e.g. porth-a cath system) is allowed.
2. History of other malignant tumors within the last 5 years before start of induction treatment, except basal cell carcinoma or curatively excised cervical carcinoma in situ
3. Known brain metastases
4. Concurrent radiotherapy involving target lesions used for this study. Concurrent palliative radiation for non-target lesions is allowed if other target lesions are available outside the involved field; previous radiotherapy including target lesions must have been finished at least 28 days before start of induction treatment.
5. For patients enrolled before the induction therapy: Previous systemic treatment (i.e. chemotherapy) for metastatic disease
6. Known active HBV, HCV infection or documented HIV infection
7. Serious concomitant disease or medical condition that by judgment of the Investigator renders the patient at high risk of treatment complications
8. Clinically relevant coronary artery disease (NYHA functional angina classification III/IV), congestive heart failure (NYHA III/IV), clinically relevant cardiomyopathy, history of myocardial infarction in the last 3 months, or high risk of uncontrolled arrhythmia
9. Female patient pregnant or breast feeding
10. Female patient of childbearing potential (i.e. did not undergo surgical sterilization - hysterectomy, bilateral tubal ligation, or bilateral oophorectomy - and is not post-menopausal for at least 24 consecutive months) not willing to use an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks after the end of treatment. Male patient not willing to use an adequate method of contraception to avoid conception throughout the study and for up to 26 weeks after the end of treatment in such a manner that the risk of pregnancy is minimized.
11. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 60 days prior to start of induction (e.g. one of the allowed standard chemotherapies (see above) with or without additional placebo within a clinical trial is allowed)
12. Chronic diarrhea or short bowel syndrome
13. Known hypersensitivity to S-1, other fluoropyrimidines or platinum compounds. Contraindication to receive S-1 or the polychemotherapy (induction \& arm B) chosen for this patient as per current Summary of Product Characteristics. Known DPD deficiency
14. For patients enrolled before the induction therapy: Grade ≥2 peripheral neuropathy
15. Known drug abuse/alcohol abuse
C: Inclusion Criteria:

1. unresectable or recurrent histologically proved gastric cancer
2. adequate oral intake
3. age 20 or older and 75 or younger
4. Performance Status (ECOG):0, 1, 2
5. measurable or unmeasurable lesions
6. preserved organ functions
7. no severe medical condition
8. no prior chemotherapy for gastric cancer
9. written informed consent

Exclusion Criteria:

1. patient with marked infection or inflammation
2. patient with severe peritoneal metastasis
3. patient with massive pleural effusion
4. patient with metastasis to CNS
5. patient with diarrhea 4 or more times per day
6. patient severe medical condition
7. patient with other concurrent malignancy affecting on survival or adverse events
8. pregnant or nursing patient or with intent to bear baby
9. patient evaluated to be inadequate by a attending doctor
10. patient requiring nutritional support
D: 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%

Answer: C