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

A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Trastuzumab-MCC-DM1 (PRO132365) Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer Who Have Previously Received a Trastuzumab-Containing Regimen

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 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
• Granulocyte count ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 9 g/dL
• Serum bilirubin ≤ 1.5 mg/dL; AST, ALT, and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN) except for: Patients with hepatic metastases: ALT and AST ≤ 5 × ULN Patients with hepatic and/or bone metastases: alkaline phosphatase ≤ 5 × ULN
• Serum creatinine ≤ 1.5 mg/dL or creatinine clearance of ≥ 60 mL/min based on a 24-hour urine collection
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
• Women of childbearing potential and men must agree to use an effective method of birth control (e.g., hormonal, barrier) while receiving study treatment

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
• Cardiac troponin I ≥ 0.2 ng/mL
• Ejection fraction < 50% or below the lower limit of normal determined by echocardiogram or MUGA scan
• Prior cumulative doxorubicin dose of > 360 mg/m2 or equivalent