Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised, Double Blinded, Multicentre Phase II Study to Assess the Efficacy of Olaparib (AZD2281, KU-0059436) in Combination With Paclitaxel Versus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer Who Progress Following First-line Therapy
Brief Summary: To assess the efficacy of olaparib when given in combination with paclitaxel compared with paclitaxel alone as defined by progression-free survival (PFS), in all patients with recurrent and metastatic gastric cancer who progress following first-line therapy.


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: 1. Metastatic disease of the esophagus or gastroesophageal junction

   1. Histologic, cytologic or radiologic documentation of metastatic squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction. Radiologic, endoscopic, histologic or cytologic evidence of locally recurrent or locally residual (post-resection) disease is also permitted.
   2. For the purposes of this study, undifferentiated adenocarcinomas and adenosquamous tumors will be considered as adenocarcinomas. In addition, tumors involving the gastroesophageal junction will be defined by the Siewert classification.
   3. Patients with gastroesophageal junction tumors who are eligible:

      * AEG Type I: Adenocarcinoma of the distal esophagus which usually arises from an area with specialized intestinal metaplasia of the esophagus (eg, Barrett's esophagus, and may infiltrate the esophagogastric junction from above).
      * AEG Type II: True carcinoma of the cardia arising from the cardiac epithelium or short segments with intestinal metaplasia at the esophagogastric junction.
   4. Patients with gastroesophageal junction tumors who are NOT eligible:

      * AEG Type III: Subcardial gastric carcinoma which infiltrates the esophagogastric junction and distal esophagus from below.
2. Patients must have at least one paraffin block available (or at least 15 unstained slides for analysis of tumor EGFR status.

   1. Patients with a history of esophageal and GE junction carcinoma treated by surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless an interval of greater than five years has elapsed between the primary surgery and the development of metastatic disease OR the primary cancer was stage I.
   2. Clinicians should consider biopsy of lesions to establish the diagnosis of metastatic esophageal or GE junction carcinoma if there is substantial clinical ambiguity regarding the nature or source of apparent metastases.
3. Patients with Measurable Disease - Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan.
4. Prior Treatment:

   1. No prior chemotherapy or radiotherapy. No prior therapy which specifically and directly targets the EGF(R) pathway.
   2. No prior allergic reaction to chimerized or murine monoclonal antibody therapy or documented presence of human anti-mouse antibodies (HAMA).
   3. Patients must have completed any major surgery ≥ 4 weeks or any minor surgery ≥ 2 weeks before registration. Patients must have fully recovered from the procedure. Insertion of a vascular access device is not considered major or minor surgery.
   4. No concurrent use of investigational agents is allowed while participating in this study.
5. Patient Characteristics:

   1. ECOG Performance Status of 0-2
   2. ≥ 18 years of age
   3. Patients must be documented to have a stable weight (or less than one pound weight loss) for at least one week prior to registration.
   4. Non-pregnant and not breast-feeding. The effects of cetuximab, cisplatin, epirubicin, fluorouracil, leucovorin, irinotecan, and oxaliplatin on a developing human fetus are not well-known. Because the risk of toxicity in nursing infants secondary to cetuximab, cisplatin, epirubicin, fluorouracil, irinotecan, and oxaliplatin treatment of the mother is unknown but may be harmful, breastfeeding must be discontinued.
6. No myocardial infarction \< 6 months prior to registration or New York Heart Association classification III or IV.
7. No ≥ grade 2 diarrhea within 7 days prior to registration.
8. Patients may not concurrently have any of the following conditions:

   1. Known central nervous system metastases or carcinomatous meningitis
   2. Interstitial pneumonia or symptomatic interstitial fibrosis of the lung
   3. Seizure disorder or active neurological disease requiring anti-epileptic medication
   4. ≥ grade 2 peripheral neuropathy
9. No evidence of Gilbert's Syndrome - Patients with Gilbert's Syndrome may have a greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38, the active metabolite of irinotecan. Evidence of Gilbert's Syndrome would include documentation of elevation of indirect bilirubin at any time in the patient's medical history.
10. Required Initial Laboratory Data:

    1. Granulocytes ≥ 1500/µl
    2. Platelet count ≥ 100,000/µl
    3. Creatinine ≤ 1.5 mg/dL
    4. AST (SGOT) ≤ 5.0 x Upper limits of normal
    5. Total bilirubin ≤ 1.5 mg/dL
    6. Albumin ≥ 2.5 grams/dL
C: Inclusion Criteria:

* Histologically- or cytologically-confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma
* Confirmed metastatic or locally advanced, unresectable disease (by computed tomography \[CT\] scan or clinical evidence)
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Progression on or after prior first-line therapy containing any platinum/fluoropyrimidine doublet
* Willing to provide tumor tissue for PD-L1 biomarker analysis (new or archived specimens with agreement of Sponsor). As of 20 March 2016, participants must be PD-L1 positive to be enrolled.
* Human epidermal growth factor receptor 2 (HER-2/neu) status known and participants with HER2/neu positive tumors show documentation of disease progression on treatment containing trastuzumab
* Female participants of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel.
* Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel.
* Adequate organ function

Exclusion Criteria:

* Currently participating and receiving study therapy, or participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of medication
* Squamous cell or undifferentiated gastric cancer
* Active autoimmune disease that has required systemic treatment in past 2 years (replacement therapy is not considered a form of systemic treatment
* Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
* Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from AEs due to agents administered more than 4 weeks earlier
* Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or not recovered from adverse events due to a previously administered agent or surgery
* Known additional malignancy that is progressing or requires active treatment (with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy)
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* History of (noninfectious) pneumonitis that required steroids or current pneumonitis
* Active infection requiring systemic therapy
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel.
* Prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or previously participated in Merck pembrolizumab (MK-3475) clinical trial
* Known history of human immunodeficiency virus (HIV)
* Known active Hepatitis B or Hepatitis C
* Live vaccine within 30 days of planned start of study therapy
* Known allergy or hypersensitivity to paclitaxel or any components used in the paclitaxel preparation or other contraindication for taxane therapy
D: Inclusion Criteria:

* Recurrent or metastatic gastric cancer that has progressed following first line-therapy
* Confirmed ATM protein status by IHC archival tumour sample
* At least one lesion (measurable and/or non-measurable) that can be accurately assessed by imaging (CT/MRI) at baseline and follow up visits

Exclusion Criteria:

* More than one prior chemotherapy regimen for the treatment of gastric cancer in the metastatic or recurrent setting
* Any previous treatment with a PARP inhibitor, including olaparib
* Patients with second primary cancer, except; adequately treated non melanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for \>5 years

Answer: D