A Study of Perjeta (Pertuzumab) in Combination With Herceptin (Trastuzumab) and Chemotherapy in Patients With HER2-Positive Metastatic Gastroesophageal Junction or Gastric Cancer

• Progression-free survival: Time from randomization to first occurrence of disease progression, as determined by the investigator according to RECIST v1.1 criteria, or death of any cause [ Time Frame: approximately 4.5 years ] [ Designated as safety issue: No ]
• Overall objective response (partial response + complete response) occurring on two consecutive occasions >/= 4 weeks apart, as determined by the investigator according to RECIST v1.1 criteria [ Time Frame: approximately 4.5 years ] [ Designated as safety issue: No ]
• Duration of objective response: Time from occurrence of objective response to progressive disease, as determined by investigator according to RECIST v1.1 criteria, or death of any cause [ Time Frame: approximately 4.5 years ] [ Designated as safety issue: No ]
• Clinical benefit rate: Best response of complete response or partial response or stable disease for 6 weeks or longer, as determined by the investigator according to RECIST v1.1 criteria [ Time Frame: approximately 4.5 years ] [ Designated as safety issue: No ]
• Safety: Incidence of adverse events [ Time Frame: approximately 4.5 years ] [ Designated as safety issue: No ]
• Safety: Incidence of left ventricular systolic dysfunction (symptomatic or asymptomatic) [ Time Frame: approximately 4.5 years ] [ Designated as safety issue: Yes ]

This double-blind, placebo-controlled, randomized, multicenter, international, parallel arm study will evaluate the efficacy and safety of Perjeta (pertuzumab) in combination with Herceptin (trastuzumab), fluoropyrimidine and cisplatin as first-line treatment in patients with HER2-positive metastatic gastroesophageal junction or gastric cancer. Patients will be randomized to receive Perjeta 840 mg or placebo intravenously (iv) every 3 weeks in combination with Herceptin (initial dose of 8 mg/kg iv followed by 6 mg/kg iv every 3 weeks) and cisplatin and fluoropyrimidine (capecitabine or 5-fluorouracil) for the first 6 treatment cycles. Patients will continue to receive Perjeta or placebo and Herceptin until disease progression or unacceptable toxicity occurs.

• Drug: pertuzumab [Perjeta]
  840 mg iv every 3 weeks
• Drug: placebo
  pertuzumab placebo iv every 3 weeks
• Drug: trastuzumab [Herceptin]
  8 mg/kg iv initial dose on Day 1, followed by 6 mg/kg iv every 3 weeks
• Drug: cisplatin
  80 mg/m2 iv every 3 weeks, 6 cycles
• Drug: capecitabine
  1000 mg/m2 orally twice daily, evening of Day 1 to morning of Day 15 (28 doses) every 3 weeks, 6 cycles (or 5-fluorouracil)
• Drug: 5-fluorouracil
  800 mg/m2/24 hours iv by continuous infusion for 120 hours (Days 1-5) every 3 weeks, 6 cycles (or capecitabine)

• Experimental: Pertuzumab + TFP
  Interventions:

  • Drug: pertuzumab [Perjeta]
  • Drug: trastuzumab [Herceptin]
  • Drug: cisplatin
  • Drug: capecitabine
  • Drug: 5-fluorouracil
• Placebo Comparator: Placebo + TFP
  Interventions:

  • Drug: placebo
  • Drug: trastuzumab [Herceptin]
  • Drug: cisplatin
  • Drug: capecitabine
  • Drug: 5-fluorouracil

Inclusion Criteria:

• Adult patients, >/= 18 years of age
• HER2-positive metastatic adenocarcinoma of the stomach or gastroesophageal junction
• Measurable or evaluable non-measurable disease as assessed by the investigator according to RECIST v1.1 criteria
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Life expectancy >/= 3 months

Exclusion Criteria:

• Previous cyctotoxic chemotherapy for advanced (metastatic) disease
• Evidence of disease progression documented within 6 months after completion of prior neoadjuvant or adjuvant cytotoxic chemotherapy, or both, or radiotherapy for GEJ adenocarcinoma
• Previous treatment with any HER2-directed therapy, at any time, for any duration
• Previous exposure to any investigational treatment within 30 days before the first dose of study treatment
• Radiotherapy within 30 days before the first dose of study treatment (within 2 weeks if given as palliation to peripheral bone metastases, if recovered from all toxicities)
• History or evidence of brain metastases
• Clinically significant active GI bleeding (Grade >/= 2 according to NIC-CTCAEv.4.03)
• Other malignancy (in addition to GC) within 5 years before enrollment, except for carcinoma in situ of the cervix or squamous or basal cell carcinoma of the skin that has been previously treated with curative intent
• Inadequate hematologic, renal or liver function
• Pregnant or lactating women
• History of congestive heart failure of any New York Heart Association (NYHA) criteria
• Angina pectoris requiring treatment
• Myocardial infarction within the past 6 months before the first dose of study drug
• Clinically significant valvular heart disease or uncontrollable high-risk cardiac arrhythmia
• History or evidence of poorly controlled hypertension
• Baseline left ventricular ejection fraction (LVEF) value < 55%
• Any significant uncontrolled intercurrent systemic illness
• Positive for hepatitis B, hepatitis C or HIV infection