A double-blind, placebo-controlled, randomized, multicenter phase III study evaluating the efficacy and safety of pertuzumab in combination with trastuzumab and chemotherapy in patients with HER2-positive metastatic gastro-esophageal junction and gastric cancer

Disease-Specific Inclusion Criteria;1. Histologically confirmed (by enrolling center) metastatic adenocarcinoma of the stomach or GEJ;2. HER2-positive tumor defined as either IHC 3+ or IHC 2+, the latter in combination with ISH+, as assessed by a sponsor-designated central laboratory on a primary or metastatic tumor;Note: ISH positivity is defined as a ratio of * 2.0 for the number of HER2 gene copies to the number of signals for chromosome 17 centromere (CEP17). For IHC scoring, the cutoffs as approved by the Food and Drug Administration (FDA) in the context of ToGA apply. Availability of formalin-fixed paraffin-embedded (FFPE);representative tumor tissue for central confirmation of HER2 is mandatory. (See Section 4.5.1.1 for further details.);3. Measurable or evaluable non-measurable disease as assessed by the investigator, according to RECIST v1.1; see Appendix 3.;4. Eastern Cooperative Oncology Group (ECOG) PS 0 or 1;5. Life expectancy * 3 months;General Inclusion Criteria;6. Age* 18 years;7. Ability to comply with requirements of the protocol, as assessed by the investigator;8. Signed Informed Consent document

Cancer-Related Exclusion Criteria;
1. Previous systemic cytotoxic chemotherapy for advanced (metastatic) disease;
2. History of exposure to the following cumulative doses of anthracyclines;
a. Epirubicin >720 mg/m2;
b. Doxorubicin or liposomal doxorubicin > 360 mg/m2;
c. Mitoxantrone > 120 mg/m2 or idarubicin >90 mg/m2;
d. Other (e.g., liposomal doxorubicin or other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin);
e. If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.;
3. Evidence of disease progression documented within 6 months after completion of prior neoadjuvant or adjuvant cytotoxic chemotherapy, or both, or radiotherapy for gastric or GEJ adenocarcinoma;
4. Previous treatment with any HER2-directed therapy, at any time, for any duration;
5. Previous exposure to any investigational treatment within 30 days before the first dose of study treatment;
6. Radiotherapy within 30 days before the first dose of study treatment (within 2 weeks if given as palliation to bone metastases, if recovered from all toxicities);
7. History or evidence of brain metastasis;
8. Clinically significant active GI bleeding (Grade * 2 according to NCI CTCAE v4.03);
9. Residual toxicity resulting from previous therapy (e.g., hematologic, cardiovascular, or neurologic toxicity that is Grade * 2). Alopecia is permitted;
10. Other malignancy (in addition to GC) occurring within 5 years before enrollment, except for carcinoma in situ of the uterine cervix or squamous or basal cell carcinoma of the skin that has been previously treated with curative intent Clinical Laboratory Exclusion Criteria (must be confirmed within 7 days before first dose of study treatment);
11. Absolute neutrophil count (ANC) >1.5 × 109/L;
12. Platelet count >75 × 109/L;
13. Hemoglobin >9.0 g/dL;
14. Creatinine CL >60 mL/min (Cockcroft-Gault Formula, see Appendix 6);
15. Serum bilirubin (total) >1.5 × upper limit of normal (ULN) of laboratory normal range; in case of known Gilbert disease a total bilirubin of up to 2 × ULN is permitted.;
16. AST, ALT, and alkaline phosphatase (ALP) parameters;
a) In patients with no liver and no bone metastases;
i. AST or ALT >1.5 × ULN, and ALP >2.5 ×ULN;
ii. AST or ALT > 2.5 ×ULN;
b) In patients with liver metastases and no bone metastases;
i. AST or ALT >5 × ULN, and ALP >2.5 ×ULN;
c) In patients with liver metastases and bone metastases;
i. AST or ALT > 5 × ULN, and ALP > 10×ULN;
d) In patients with bone metastases and no liver metastases;
i. AST or ALT > 1.5 × ULN, and ALP > 10 ×ULN;
17. Serum albumin >25 g/L;
18. Serum pregnancy test positive in a female patient of childbearing potential;
General Exclusion Criteria;
19. Documented history of congestive heart failure (CHF) of any New York Heart Association (NYHA) criteria (see Appendix 5);
20. Angina pectoris requiring treatment;
21. Myocardial infarction within the past 6 months before the first dose of study treatment;
22. Clinically significant valvular heart disease or uncontrollable high-risk cardiac arrhythmia (i.e., atrial tachycardia with a heart rate >100/min at rest), significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular-block;
(second degree AV-block Type 2 [Mobitz 2] or third degree AV-block);
23. History or evidence of poorly controlled arterial hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure >100 mmHg);
24. Baseline LVEF value > 55%, assessed by echocardiogram [ECHO], multigated acquisition (MUGA) scan, or cardiac magnetic resonance imaging (MRI) scan;
25. Dyspnea at rest due to complications of advanced malignancy or other disease or requirement of supportive oxygen therapy;
26. Any significant uncontrolled intercurrent systemic illness (e.g., active infection, poorly controlled diabetes mellitus);
27. Previous major surgery within 30 days before the first dose of study treatment, unless completely recovered;
28. Known infection with HIV, hepatitis B virus, or hepatitis C virus that requires active treatment;
29. Ongoing chronic treatment or high-dose treatment with corticosteroids. Inhaled steroids, topical steroids and clinically indicated short courses of oral steroids are permitted.;
30. Known dihydropyrimidine dehydrogenase (DPD) deficiency;
31. Known hypersensitivity to any component of study treatment;
32. Current use of antiviral drug sorivudine or its chemically related analogs, such as brivudine;
33. Lactating female patient;
34. Any patient unwilling or unable to use adequate contraceptive measures (as described in Section 5.2.3) during study treatment and for at least 7 months after the last dose of pertuzumab or trastuzumab, except for a patient with documented surgical sterilization or a postmenopausal female