Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Proof-of-concept Phase II Trial Comparing Therapy Based on Tumor Molecular Profiling Versus Conventional Therapy in Patients With Refractory Cancer.
Brief Summary: SHIVA is a proof of concept randomized phase II trial which compares two treatment strategies for patients with refractory cancer.

From a tumor biopsy, a molecular profile of the disease is established (mutations, amplifications, hormone receptor status). If a molecular abnormality is identified for which an approved targeted agent is available, patients are randomized randomized between two arms:

* Targeted therapy based on the molecular profile
* Conventional therapy based on investigator's choice.

A cross-over is proposed at disease progression.


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:

1. Patient with recurrent/metastatic solid tumor who failed or are not candidate for treatments usually proposed in first intentions and for whom a prospective clinical trial has been indicated in a tumor board
2. ECOG performance status of 0 or 1
3. Biopsiable disease (tumor biopsy mandatory for tumor profiling). The biopsy can be performed when patients are being treated with standard therapy for their recurrent/metastatic cancer if it is not planned to treat them with molecularly targeted agents in the future.
4. Measurable disease
5. Adequate renal function defined by a serum creatinine \<1.5xUNL (upper normal limit)
6. Adequate liver function test defined by SGOT \& SGPT \<3xUNL (5xUNL in case of liver metastases), and bilirubin level \<1.5xUNL
7. Adequate bone marrow function defined by platelets \>100,000/mm3, hemoglobin \>10 g/dL, and neutrophils \>1,000/mm3
8. Patients must be affiliated to the French Social Security System
9. Signed informed consent
10. For female of child-bearing potential: a negative pregnancy test \<72 hours before starting study treatment is required. If sexually active, female of childbearing potential must use "highly effective" methods of contraception for the study duration and for 3 months following the last treatment
11. For male of reproductive potential: any sexually active male patient must use a condom while on study treatment and for 3 months following the last treatment
12. Agreement to send the CD-ROMs of imaging for central review

Exclusion Criteria:

1. Patients who have only bone and/or brain metastases
2. Patients whose brain metastases have not been controlled for \>3 months
3. Patient participating in another clinical trial with an experimental drug
4. Patients who are candidate to receive a molecularly targeted agent that is approved for their disease
5. Anticoagulation with anti-vitamin K (Low Molecular Weight Heparin \[LMWH\] is allowed)
6. Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study, including uncontrolled diabetes, cardiac disease, uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infection within one year, chronic liver or renal disease, active gastrointestinal tract ulceration, severely impaired lung function
7. Pregnant and/or breastfeeding women
8. Individually deprived of liberty or placed under the authority of a tutor
9. Patients with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
10. Known HIV, HBV, or HCV infection

Eligibility criteria for the randomized part :

1. Identification of tumor molecular abnormalities for which the Therapeutic Decision Committee (TDC) recommends a molecularly targeted therapy available in the context of the trial (even if the molecular profile is incomplete)
2. Therapy recommended by the TDC is not approved for the patient's disease
3. ECOG performance status of 0 or 1
4. Adequate renal function defined by a serum creatinine \<1.5xUNL
5. Adequate liver function tests defined by SGOT \& SGPT \<3xUNL (5xUNL in case of liver metastases), and bilirubin level \<1.5xUNL
6. Adequate bone marrow function defined by platelets \>100,000/mm3, hemoglobin \>8 g/dL, and neutrophils \>1,000/mm3
7. Albumin, LDH and number of metastatic sites have been documented (in order to determine the RMH prognostic score)
8. LVEF \>50%
9. QTc \<480 ms on ECG
C: Inclusion Criteria:

* Voluntary written consent
* Locally advanced or metastatic solid tumors with the exception of primary brain tumor, and have failed or are not eligible for standard of care therapy
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Ability to swallow oral medications
* For women of child-bearing potential, negative serum or urine pregnancy test within 14 days prior to the first study drug administration and use of physician-approved method of birth control from 30 days prior to 30 days following the last study drug administration
* Male participants must be surgically sterile or must agree to use physician-approved contraception during the study and for 30 days following the last study drug administration
* Clinical laboratory values as specified in the protocol
* For expansion phase (Arm A) - HER2-/unknown participants will be enrolled
* For expansion phase (Arm B) - HER2+ cancer participants will be enrolled

Exclusion Criteria:

* Diagnosis of primary brain tumor
* Have received prior cancer or other investigational therapy within 2 weeks prior to the first administration of study drug
* Known impaired cardiac function or clinically significant cardiac disease
* Known treatment with systemic corticosteroid within one week prior to the first administration of study drug
* Diabetes mellitus
* Human immunodeficiency virus (HIV) infection
* Known active cardiovascular disease condition as specified in protocol
* Pregnancy (positive serum or urine pregnancy test) or breast feeding
* Malabsorption due to prior gastrointestinal (GI) surgery, GI disease
* Other clinically significant co-morbidities

Please note that there are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.

Site personnel will explain the trial in detail and answer any question you may have if you do qualify for the study. You can then decide whether or not you wish to participate. If you do not qualify for the trial, site personnel will explain the reasons
D: Inclusion Criteria:

* Written informed consent obtained prior to any study specific procedures.
* Age ≥ 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
* Life expectancy of at least 3 months.
* Able to comply with the protocol.
* Histologically confirmed adenocarcinoma of the stomach or gastro-oesophageal junction with inoperable, locally advanced, or metastatic disease, not amenable to curative therapy.
* Measurable disease or non-measurable but evaluable disease, according to the Response Evaluation Criteria in Solid Tumours (RECIST).
* Patient not receiving anticoagulant medication must have an International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 x Upper Limit of Normal (ULN) within 7 days prior to randomisation.

Exclusion Criteria:

* Previous chemotherapy for locally advanced or metastatic gastric cancer. Patients may have received prior neoadjuvant or adjuvant chemotherapy as long as it was completed at least 6 months prior to randomisation.
* Previous platinum or anti-angiogenic therapy (ie, anti-vascular endothelial growth factor \[VEGF\] or VEGF receptor tyrosine kinase inhibitor, etc.).
* Patients with locally advanced disease who are candidates for curative therapy (including operation and/or chemotherapy and/or radiotherapy).
* Radiotherapy within 28 days of randomisation.
* Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomisation, or anticipation of the need for major surgery during the course of the study treatment (planned elective surgery).
* Minor surgical procedures within 2 days prior to randomisation.
* Evidence of central nervous system (CNS) metastasis at baseline.
* History or evidence upon physical/neurological examination of CNS disease unrelated to cancer unless adequately treated with standard medical therapy, eg, uncontrolled seizures.
* History of another malignancy which could affect compliance with the protocol or interpretation of results.
* Inadequate bone marrow function.
* Inadequate liver function.
* Inadequate renal function.
* Uncontrolled hypertension or clinically significant (ie, active) cardiovascular disease.
* Active infection requiring intravenous antibiotics at randomisation.
* History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
* Serious or non-healing wound, peptic ulcer, or (incompletely healed) bone fracture.
* Active gastrointestinal bleeding.
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of randomisation.
* Neuropathy (eg, impairment of hearing and balance) ≥ grade II according to Common Terminology Criteria for Adverse Events (CTCAE) v3.0.
* Chronic daily treatment with aspirin or clopidogrel.
* Chronic daily treatment with oral corticosteroids; inhaled steroids and short courses of oral steroids for anti-emesis or as an appetite stimulant are allowed.
* Known hypersensitivity to any of the study drugs or excipients or to Chinese hamster ovary cell products or to other recombinant human or humanised antibodies.
* Known dihydropyrimidine dehydrogenase (DPD) deficiency.
* Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that may affect patient compliance with the study, or place the patient at high risk from treatment complications.
* Known acute or chronic-active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
* Pregnant or lactating females.
* Women of childbearing potential not using effective nonhormonal (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly, or surgically sterile) means of contraception.
* Sexually active men unwilling to practice contraception during the study.
* Current or recent (within the 28 days prior to randomisation) treatment with another investigational drug or participation in another investigational study.

Answer: B