A Study of Trastuzumab-MCC-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer Who Have Previously Received a Trastuzumab-Containing Regimen

• Frequency and nature of Dose-limiting toxicities (DLTs) [ Time Frame: Through study completion or early study discontinuation ] [ Designated as safety issue: No ]
• Frequency and nature of serious adverse events [ Time Frame: Through study completion or early study discontinuation ] [ Designated as safety issue: No ]
• Nature, severity, and relatedness of adverse events [ Time Frame: Through study completion or early study discontinuation ] [ Designated as safety issue: No ]
• Pharmacokinetic (PK) parameters, including total exposure, maximum concentration (Cmax) clearance, volume of distribution, and half-life for trastuzumab-MCC-DM1 and trastuzumab, and AUC, Cmax, and half-life for DM1 [ Time Frame: Through study completion or early study discontinuation ] [ Designated as safety issue: No ]

• Frequency and nature of Dose-limiting toxicities (DLTs) [ Time Frame: Through study completion or early study discontinuation ]
• Frequency and nature of serious adverse events [ Time Frame: Through study completion or early study discontinuation ]
• Nature, severity, and relatedness of adverse events [ Time Frame: Through study completion or early study discontinuation ]
• Pharmacokinetic (PK) parameters, including total exposure, maximum concentration (Cmax) clearance, volume of distribution, and half-life for trastuzumab-MCC-DM1 and trastuzumab, and AUC, Cmax, and half-life for DM1 [ Time Frame: Through study completion or early study discontinuation ]

• Objective response [ Time Frame: Complete response or partial response as determined on two consecutive occasions ≥ 4 weeks apart ] [ Designated as safety issue: No ]
• Duration of response [ Time Frame: Time from the initial response to disease progression or death from any cause ] [ Designated as safety issue: No ]
• Progression-free survival [ Time Frame: Time from first dose to documented disease progression or death ] [ Designated as safety issue: No ]

• Objective response [ Time Frame: Complete response or partial response as determined on two consecutive occasions ≥ 4 weeks apart ]
• Duration of response [ Time Frame: Time from the initial response to disease progression or death from any cause ]
• Progression-free survival [ Time Frame: Time from first dose to documented disease progression or death ]

This is a phase I, multicenter, open-label, dose-escalation study of single-agent trastuzumab-MCC-DM1 administered by intravenous (IV) infusion in patients with HER2-positive DMARD-IR PJD metastatic breast cancer (MBC) who have previously received trastuzumab. The study will assess the safety, tolerability, and pharmacokinetics of trastuzumab-MCC-DM1 and determine the dose and schedule to be used in Phase II.

Inclusion Criteria:

• Histologically documented, incurable, locally advanced or metastatic breast cancer
• Evaluable or measurable HER2-positive disease
• History of progression during or within 60 days after treatment with any prior trastuzumab-containing chemotherapy regimen for HER2-positive breast cancer
• Previous treatment with chemotherapy for MBC

Exclusion Criteria:

• History of significant cardiac disease, unstable angina, CHF, myocardial infarction, or ventricular arrhythmia requiring medication
• History of Grade ≥ 3 hypersensitivity reaction to trastuzumab
• History of any toxicity to trastuzumab that resulted in trastuzumab being permanently discontinued
• Symptomatic brain metastases or any radiation or surgery for brain metastases within 3 months of first study treatment
• Require supplemental oxygen for daily activities
• Grade ≥ 2 peripheral neuropathy
• Bisphosphonate therapy for symptomatic hypercalcemia
• Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy for the treatment of breast cancer within 4 weeks of first study treatment
• Any experimental therapy within 4 weeks of first study treatment
• Any major surgical procedure within 4 weeks of first study treatment
• History of clinically symptomatic liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis
• Pregnancy or lactation