A Study of Trastuzumab Emtansine, Paclitaxel, and Pertuzumab in Patients With HER2-Positive, Locally Advanced or Metastatic Breast Cancer

• Adverse events or changes in physical findings and clinical laboratory results during and following study drug administration that result in dose modification, dose delay, or discontinuation of trastuzumab emtansine, paclitaxel, and/or pertuzumab [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ] [ Designated as safety issue: No ]
• Frequency and nature of dose limiting toxicities (DLTs) and highest tolerable doses of trastuzumab emtansine and paclitaxel when given in combination [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ] [ Designated as safety issue: No ]
• Incidence, nature, and severity of adverse events and serious adverse events [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ] [ Designated as safety issue: No ]
• Pharmacokinetics of trastuzumab emtansine in the presence of paclitaxel, and of paclitaxel in the presence and absence of trastuzumab emtansine [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ] [ Designated as safety issue: No ]
• Phase IIa: Proportion of patients who receive paclitaxel weekly x 12 doses in combination with trastuzumab emtansine (with or without pertuzumab) [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ] [ Designated as safety issue: No ]

• Adverse events or changes in physical findings and clinical laboratory results during and following study drug administration that result in dose modification, dose delay, or discontinuation of T-DM1, paclitaxel, and/or pertuzumab [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ]
• Frequency and nature of dose limiting toxicities (DLTs) and highest tolerable doses of T-DM1 and paclitaxel when given in combination [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ]
• Incidence, nature, and severity of adverse events and serious adverse events [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ]
• Pharmacokinetics of T-DM1 in the presence of paclitaxel, and of paclitaxel in the presence and absence of T-DM1 [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ]

• Objective response rate based on investigator assessment [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ] [ Designated as safety issue: No ]
• Progression-free survival, duration of response and clinical benefit rate [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ] [ Designated as safety issue: No ]

• Objective response rate based on investigator assessment [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ]
• Progression-free survival, duration of response and clinical benefit rate [ Time Frame: Through study discontinuation or 12 months of study treatment, whichever occurs first ]

This Phase Ib-IIa, multi-institutional, open-label, dose-escalation study is designed to evaluate the safety, tolerability, pharmacokinetics and feasibility of trastuzumab emtansine (T-DM1) administered by intravenous (IV) infusion in combination with paclitaxel (and pertuzumab, if applicable) in patients with HER2-positive, locally advanced or metastatic breast cancer.

• Drug: paclitaxel
  Intravenous repeating dose
• Drug: pertuzumab [Perjeta]
  Intravenous repeating dose
• Drug: trastuzumab emtansine [Kadcyla]
  Intravenous escalating dose

Inclusion Criteria:

• Histologically documented HER2-positive locally advanced or metastatic breast cancer
• Tumor tissue blocks or 15-20 unstained tissue slides for confirmatory central laboratory HER2 status testing and other exploratory assessments
• Prior trastuzumab in any line of therapy (Phase Ib patients only)
• No prior trastuzumab emtansine (T-DM1) or pertuzumab therapy
• Measurable or evaluable disease
• Cardiac ejection fraction >=50% by either ECHO or MUGA scan
• Life expectancy >= 90 days as assessed by the investigator

Exclusion Criteria:

• Fewer than 21 days since the last anti-tumor therapy, including chemotherapy, biologic, experimental, immune, hormonal or radiotherapy for the treatment of breast cancer, with the following exceptions: hormone-replacement therapy or oral contraceptives are allowed; palliative radiation therapy involving <=25% of marrow-bearing bone is allowed if completed within >= 14 days prior to first study treatment
• History of intolerance or hypersensitivity to trastuzumab and/or adverse events related to trastuzumab, murine proteins, or any of the excipients that resulted in trastuzumab being permanently discontinued
• Peripheral neuropathy of Grade >= 2 per NCI CTCAE, Version 3.0, at the time of, or within 3 weeks prior to, the first study therapy (Phase Ib patients)
• Peripheral neuropathy of Grade >/=1 per NCI CTCAE, Version 3.0, at the time of, or within 3 weeks prior to, the first study therapy (Phase IIa patients)
• History of exposure to the following cumulative doses of anthracyclines: Doxorubicin > 500 mg/m^2; Liposomal doxorubicin > 900 mg/m^2; Epirubicin > 720 mg/m^2
• History of clinically significant cardiac dysfunction
• Brain metastases that are untreated, or progressive, or have required any type of therapy (including radiation, surgery, or steroids) to control symptoms from brain metastases within 60 days prior to the first study treatment.
• History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, basal cell carcinoma, or synchronous or subsequent HER2-positive breast cancer or other malignancy with a similar expected curative outcome