Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Multicenter, Adaptive Phase II/III Study To Evaluate The Efficacy And Safety Of Trastuzumab Emtansine (T-DM1) Versus Taxane (Docetaxel Or Paclitaxel) In Patients With Previously Treated Locally Advanced Or Metastatic HER2-Positive Gastric Cancer, Including Adenocarcinoma Of The Gastroesophageal Junction
Brief Summary: This multicenter, randomized, adaptive Phase II/III study will evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) compared to standard taxane (docetaxel or paclitaxel) treatment in participants with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. At the start of the trial (stage 1), participants will be randomized with a ratio 2:2:1 to one of three treatment arms: Arm A: trastuzumab emtansine 3.6 milligram per kilogram (mg/kg) per intravenous injection (IV) every 3 weeks; Arm B: trastuzumab emtansine 2.4 mg/kg IV every week; Arm C: standard taxane therapy (docetaxel 75 milligram per meter square \[mg/m\^2\] IV every 3 weeks or paclitaxel 80 mg/m\^2 kg IV every week per investigator choice). At the end of the first stage of the study, the dose and schedule of trastuzumab emtansine that will be used in the second stage of the study will be selected by an Independent Data Monitoring Committee (IDMC). The regimen selection analysis will be made after approximately 100 participants across all three study arms have been treated for at least 12 weeks.

Once a trastuzumab emtansine regimen has been selected, Stage I participants who were assigned to the treatment arm which was selected for Stage II of the study and participants who were in the standard taxane group will continue to receive their assigned treatment regimen. Stage I participants who were assigned to the regimen that was not selected for further evaluation will continue to receive their assigned regimen and will continue to be followed for efficacy and safety. In Stage II of the study, additional participants will be recruited and randomized with a ratio 2:1 to either the selected regimen of trastuzumab emtansine or to the standard taxane therapy. Participants will receive study treatment until disease progression, unacceptable toxicity, initiation of another cancer therapy or withdrawal.


Options:
A: Inclusion Criteria:

* Histologically- or cytologically-confirmed diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ
* Metastatic disease or locally advanced, unresectable disease
* Life expectancy of greater than 3 months
* Measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
* Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
* Documented radiographic or clinical disease progression on no more or less than one previous line of standard therapy
* Can provide either a newly obtained or archival tumor tissue sample for intra-tumoral immune-related testing and for anti-programmed cell death (PD)-1
* Participants of reproductive potential must be willing to use adequate contraception 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, docetaxel or irinotecan
* Adequate organ function

Exclusion Criteria:

* Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study treatment
* Active autoimmune disease that has required systemic treatment in past 2 years
* 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 treatment
* Known central nervous system (CNS) metastases and/or carcinomatous meningitis (includes past history or current metastasis)
* Has received prior anti-cancer monoclonal antibody (mAb), 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
* Has had a severe hypersensitivity reaction to treatment with another mAb
* Prior therapy with a PD-1, anti-PD-Ligand 1 (PD-L1), or anti-PD-L2 agent, or previously participated in Merck pembrolizumab (MK-3475) study
* Has a known additional malignancy that has progressed or required active treatment within the last 5 years with the exception of curatively treated basal cell and squamous cell carcinoma of the skin and/or curatively resected in-situ cervical and/or breast cancers, and in-situ or intra-mucosal pharyngeal cancer
* Received a live vaccine within 30 days of the first dose of study treatment
* Known history of human immunodeficiency virus (HIV) infection
* Known history of or is positive for hepatitis B or known active hepatitis C
* History of non-infectious 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 study
* Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study starting with the screening visit through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel, docetaxel or irinotecan
* Known allergy, hypersensitivity, or contraindication to paclitaxel, docetaxel, or irinotecan or any components used in their preparation
* Experienced weight loss \>10% over approximately 2 months prior to first dose of study treatment
* Has ascites or pleural effusion by physical exam
* Has experienced documented objective radiographic or clinical disease progression during or after receiving \>1 line of therapy
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:

* Men \& women ≥20 years of age
* Unresectable advanced or recurrent gastric cancer (including esophagogastric junction cancer)
* Histologically confirmed adenocarcinoma
* Refractory to or intolerant of standard therapy
* ECOG Performance Status score 0 or 1
* A life expectancy of at least 3 months

Exclusion Criteria:

* Current or past history of severe hypersensitivity to any other antibody products
* Patients with multiple primary cancers
* Patients with any metastasis in the brain or meninx that is symptomatic or requires treatment
* Patients with active, known or suspected autoimmune disease
D: Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Life expectancy of at least 12 weeks from the first dose of study treatment
* Measurable and/or evaluable disease based on Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)
* Adequate organ function as determined by the following laboratory results, within 28 days prior to randomization
* Participants must have a history of advanced gastric cancer (AGC), defined as unresectable and locally advanced or metastatic gastric cancer, including adenocarcinoma of the gastroesophageal junction (GEJ), and must have experienced disease progression during or after first-line therapy for their disease
* HER2-positive tumor (primary tumor or metastatic lesion) as confirmed by central laboratory HER2 testing (immunohistochemistry and/or in-situ hybridization)
* Participants must have received at least one prior chemotherapy regimen for AGC; prior therapy does not need to have included HER2-directed therapy.
* First-line therapy for AGC, including adenocarcinoma of the GEJ, must have included a combination of at least a platinum- and a fluoropyrimidine-based treatment given concurrently; prior therapy does not need to have included a HER2-directed therapy.
* Adjuvant or neoadjuvant therapy for AGC is allowed.

Exclusion Criteria:

* An interval shorter than 21 days from the last dose of chemotherapy or HER2-directed therapy until the time of randomization
* Prior treatment with trastuzumab emtansine, docetaxel, or paclitaxel either as single agents or as part of a treatment regimen.
* Treatment with any investigational anticancer drug within 21 days of the first study treatment administration
* More than one prior line of therapy for advanced gastric cancer
* History of other malignancy within the previous 5 years except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other malignancies with an expected curative outcome
* Brain metastases that are untreated or symptomatic or require any radiation, surgery, or steroid therapy to control symptoms from brain metastases within 1 month of randomization
* Peripheral neuropathy Grade \>/=2
* Uncontrolled cardiopulmonary dysfunction (e.g., high blood pressure, serious cardiac arrhythmia)
* Other current, severe, uncontrolled systemic disease (e.g., clinically significant metabolic disease, wound healing disorders, ulcers)
* Clinically significant bleeding within 30 days before enrollment
* For female participants, current pregnancy or lactation
* Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
* Infection with Human immunodeficiency virus (HIV) or hepatitis B virus, hepatitis C virus

Answer: D