Daily Everolimus in Combination With Trastuzumab and Vinorelbine in HER2/Neu Positive Women With Locally Advanced or Metastatic Breast Cancer (BOLERO-3)

• Overall survival (OS), defined as the time from date of randomization to the date of death from any cause. [ Time Frame: Every 3 months ] [ Designated as safety issue: No ]
• Overall response rate (ORR) defined as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST [ Time Frame: Every 6 weeks ] [ Designated as safety issue: No ]
• Patient reported outcome (PRO) questionnaires [ Time Frame: Every 6 weeks ] [ Designated as safety issue: No ]
• Clinical benefit rate (CBR) defined as the proportion of patients whose best overall response, according to RECIST, is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks. [ Time Frame: Every 6 weeks ] [ Designated as safety issue: No ]
• Laboratory assessments (hematology, chemistry, coagulation), AEs graded by CTCAE version 3.0 or equivalent [ Time Frame: Continuous until 28 days after the last dose of study drug ] [ Designated as safety issue: Yes ]

• Compare overall survival (OS) between the two treatment arms: everolimus, trastuzumab, and vinorelbine combination versus trastuzumab and vinorelbine combination. [ Time Frame: months after first randomization (384 OS events) ] [ Designated as safety issue: No ]
• Compare objective response rate (ORR) between the two treatment arms. [ Time Frame: 55 months after first randomization (384 OS events) ] [ Designated as safety issue: No ]
• Compare changes in Quality of Life (QoL) scores over time between the two treatment arms. [ Time Frame: at time of PFS analyses ] [ Designated as safety issue: No ]
• Compare clinical benefit rate (CBR) between the two treatment arms. [ Time Frame: at time of Overall Survival (OS) analysis ] [ Designated as safety issue: No ]
• Evaluate safety between the two treatment arms [ Time Frame: Monthly for certain pre-defined adverse event categories; at planned safety analysis after enrollment of first 60 patients (approximately 5 months after first randomization), and at PFS analyses ] [ Designated as safety issue: Yes ]

This phase III, double-blind, placebo-controlled multinational study will assess the combination everolimus, vinorelbine, and trastuzumab compared to the combination vinorelbine and trastuzumab with respect to progressive-free survival and over survival in HER2/neu positive women with locally advanced or metastatic breast cancer who are resistant to trastuzumab and have been pre-treated with a taxane.

• HER2/Neu Over-expressing Locally Advanced Breast Cancer
• Metastatic Breast Cancer

• Drug: everolimus, vinorelbine, trastuzumab
• Drug: Placebo + vinorelbine + trastuzumab

• Experimental: Everolimus + vinorelbine + trastuzumab
  Intervention: Drug: everolimus, vinorelbine, trastuzumab
• Placebo Comparator: placebo + vinorelbine + trastuzumab
  Intervention: Drug: Placebo + vinorelbine + trastuzumab

Inclusion Criteria:

• Histologically or cytologically confirmed invasive breast carcinoma with locally recurrent or radiological evidence of metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent.
• HER2+ status defined as IHC 3+ staining or in situ hybridization positive
• Patients with resistance to trastuzumab
• Prior taxane therapy
• Patients with an ECOG performance status of 0 - 2
• Patients with measurable disease as per RECIST criteria
• Documentation of negative pregnancy test for patients of child bearing potential prior to enrollment within 7 days prior to randomization. Sexually active pre-menopausal women must use adequate contraceptive measures, excluding estrogen containing contraceptives, while on study;
• Patients must meet laboratory criteria defined in the study within 21 days prior to randomization

Exclusion Criteria:

• Prior mTOR inhibitors or vinca alkaloid agents for the treatment of cancer
• More than three prior chemotherapy lines for advanced disease.
• Symptomatic CNS metastases or evidence of leptomeningeal disease. Previously treated asymptomatic CNS metastases are allowed provided that the last treatment for CNS metastases was completed >8 weeks prior to randomization
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
• Peripheral neuropathy ≥ grade 2 at randomization
• Active cardiac disease
• History of cardiac dysfunction
• Any malignancy within 5 years prior to randomization, with the exception of adequately treated in-situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer
• Known hypersensitivity to any study medication
• Breastfeeding or pregnant

Other protocol-defined inclusion/exclusion criteria may ap