A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE)

• Progression Free Survival (PFS) based on tumor assessments performed by an Independent Review Facility (IRF) [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]
• Incidence of adverse events (AEs) [ Time Frame: Up to approximately 78 months after study start ] [ Designated as safety issue: No ]

• Progression Free Survival (PFS) based on tumor assessments reviewed by an Independent Review Facility (IRF) [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]
• Incidence of adverse events (AEs) [ Time Frame: Up to approximately 78 months after study start ] [ Designated as safety issue: No ]

• 1-year survival rate [ Time Frame: From baseline to 1 year ] [ Designated as safety issue: No ]
• Overall Survival (OS) rate [ Time Frame: Up to approximately 78 months after study start ] [ Designated as safety issue: No ]
• Time-to-Treatment Failure as assessed by IRF [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]
• Overall or objective response rate [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]
• Clinical benefit rate [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]
• Duration of response [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]
• Overall Survival (OS) truncated at 2 years [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]

• 1-year survival rate [ Time Frame: From baseline to 1 year ] [ Designated as safety issue: No ]
• Overall Survival (OS) rate [ Time Frame: Up to approximately 78 months after study start ] [ Designated as safety issue: No ]
• Time-to-Treatment Failure as assessed by IRF [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]
• Overall or objective response rate [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]
• Clinical benefit rate [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]
• Duration of response [ Time Frame: Up to approximately 48 months after study start ] [ Designated as safety issue: No ]

This randomized, 3-arm, multicentre, phase III study will evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) with pertuzumab or trastuzumab emtansine (T-DM1) with pertuzumab-placebo (blinded for pertuzumab), versus the combination of trastuzumab (Herceptin) plus taxane (docetaxel or paclitaxel) in patients with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer. Patients will be randomized to 1 of 3 treatment arms (Arms A, B or C). Arm A will be open-label, whereas Arms B and C will be blinded.

• Drug: trastuzumab emtansine
  3.6 mg/kg intravenously every 3 weeks
• Drug: pertuzumab
  840 mg intravenously on day 1 of cycle 1 followed by 420 mg intravenously every 3 weeks in subsequent cycles
• Drug: pertuzumab-placebo
  840 mg intravenously on day 1 of cycle 1 followed by 420 mg intravenously every 3 weeks in subsequent cycles
• Drug: trastuzumab [Herceptin]
  trastuzumab [Herceptin] doses when administered with docetaxel: 8 mg/kg intravenously on cycle 1 followed by 6 mg/kg every 3 weeks in subsequent cycles or trastuzumab (Herceptin) doses when administered with paclitaxel: 4 mg/kg intravenously on day 1 of cycle 1 followed by 2 mg/kg weekly starting on day 8 of cycle 1.
• Drug: docetaxel
  75 mg/m2 or 100 mg/m2 intravenously every 3 weeks for a minimum of 6 cycles.
• Drug: paclitaxel
  80 mg/m2 intravenously weekly for a minimum of 18 weeks

• Experimental: Trastuzumab + Taxane (docetaxel or paclitaxel)
  Interventions:

  • Drug: trastuzumab [Herceptin]
  • Drug: docetaxel
  • Drug: paclitaxel
• Experimental: Trastuzumab emtansine + pertuzumab
  Interventions:

  • Drug: trastuzumab emtansine
  • Drug: pertuzumab
  • Drug: pertuzumab-placebo
• Experimental: Trastuzumab emtansine + pertuzumab placebo
  Interventions:

  • Drug: trastuzumab emtansine
  • Drug: pertuzumab
  • Drug: pertuzumab-placebo

Inclusion Criteria:

• Adult patients >/=18 years of age
• HER2-positive breast cancer
• Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and be a candidate for chemotherapy. Patients with locally advanced disease must have recurrent or progressive disease, which must not be amenable to resection with curative intent.
• Patients must have measurable and/or non-measurable disease which must be evaluable per RECIST 1.1
• ECOG Performance Status 0 or 1
• Adequate organ function as determined by laboratory results

Exclusion Criteria:

• History of prior (or any) chemotherapy for metastatic breast cancer or recurrent locally advanced disease
• An interval of <6 months from the last dose of vinca-alkaloid or taxane cytotoxic chemotherapy until the time of metastatic diagnosis
• Hormone therapy <7 days prior to randomization
• Trastuzumab therapy and/or lapatinib (neo- or adjuvant setting) <21 days prior to randomization
• Prior trastuzumab emtansine or pertuzumab therapy