Trastuzumab Emtansine in Treating Patients With HER2-Positive Metastatic or Locally Advanced Breast Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To assess change in thrombokinetics (platelet circulation life span).

SECONDARY OBJECTIVES:

I. Benefit rate (as defined by stable disease, partial response, or complete response by Response Evaluation Criteria in Solid Tumors [RECIST] v 1.1) at the end of study activities.

II. To evaluate the safety of trastuzumab emtansine (ado-trastuzumab emtansine) (non-platelet toxicity).

III. To evaluate the pharmacokinetics of ado-trastuzumab emtansine.

OUTLINE:

Patients receive trastuzumab emtansine intravenously (IV) over 30-90 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving response may continue treatment.

After completion of study treatment, patients are followed up periodically.

Inclusion criteria

• Signed study-specific informed consent form
• Histologically or cytologically documented breast cancer
• Metastatic or unresectable locally advanced/recurrent breast cancer
• HER2-positive disease documented as in situ hybridization (ISH)-positive and/or 3+ by immunohistochemistry (IHC) on previously collected tumor tissue
• Absolute neutrophil count (ANC) > 1500 cells/mm^3
• Platelet count > 100,000/mm^3
• Hemoglobin > 9.0 g/dL (patients are allowed to receive transfused red blood cells [RBC] to achieve this level)
• Total bilirubin =< 1.5 × upper limit of normal (ULN), except in patients with previously documented Gilbert's syndrome, in which case the direct bilirubin should be less than or equal to the ULN
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 × ULN
• Alkaline phosphatase =< 2.5 × ULN (patients with hepatic and/or bone metastases: alkaline phosphatase =< 5 × ULN)
• Serum creatinine < 1.5 × ULN
• International normalized ratio (INR) < 1.5 × ULN
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Left ventricular ejection fraction (LVEF) >= 50% by either echocardiogram (ECHO) or multigated acquisition scan (MUGA)
• Negative results of serum pregnancy test for premenopausal women of reproductive capacity and for women < 12 months after entering menopause
• For women of childbearing potential and men with partners of childbearing potential, agreement by the patient and/or partner to use a highly effective, non-hormonal form of contraception or two effective forms of non-hormonal contraception; female patients of childbearing potential must agree to use two effective forms of non-hormonal contraception; effective methods of contraception include: intrauterine device (IUD); female condom; male condom; diaphragm with spermicide; cervical cap; or a sterile sexual partner; male patients with partners of childbearing potential must use barrier contraception; in addition, male patients should also have their partners use another method of contraception from the time of informed consent through the duration of study activity
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including thrombokinetic studies and platelet function studies

Exclusion criteria

CANCER-RELATED CRITERIA

• Known platelet disorder, such as von Willebrand's disease or baseline platelet count of < 100,000/mm^3
• Chemotherapy =< 21 days before first study treatment
• Trastuzumab =< 21 days before first study treatment
• Lapatinib =< 14 days before first study treatment
• Investigational therapy or any other therapy =< 28 days before first study treatment
• Any prior ado-trastuzumab emtansine
• Previous radiotherapy for the treatment of unresectable, locally advanced/recurrent or metastatic breast cancer is not allowed if:

• The last fraction of radiotherapy has been administered within 14 days of first on-study thormbokinetic study
• The patient has not recovered from any resulting acute toxicity (to grade =< 1) prior to first on-study thormbokinetic study
• Brain metastases that are untreated or symptomatic, or require any radiation, surgery, or steroid therapy to control symptoms from brain metastases within 14 days of first on-study thrombokinetic study; for patients with newly diagnosed brain metastases or unequivocal progression of brain metastases on screening scans, localized treatment (i.e., surgery, radiosurgery, and/or whole brain radiotherapy) is required before study enrollment; subjects with known brain metastases must have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 14 days of stable neurologic function prior to the first thrombokinetic procedure; patients with small brain metastases not symptomatic and deemed requiring treatment by managing clinicians or study investigators may be permitted to enroll on study
• History of intolerance (including grade 3 or 4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins
• Current peripheral neuropathy of grade >= 3 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v. 4.0
• Current use of any platelet functioning inhibitors (including aspirin) within 14 days of first on-study thrombokinetic study

CARDIOPULMONARY FUNCTION CRITERIA

• Current unstable ventricular arrhythmia requiring treatment
• History of symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] classes II-IV)
• History of myocardial infarction or unstable angina within 6 months of enrollment
• History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab treatment
• Severe dyspnea at rest due to complications of advanced malignancy or requiring current continuous oxygen therapy

GENERAL CRITERIA

• Current severe, uncontrolled non-cancer systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) resulting in a life expectancy of < 6 months
• Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of the need for major surgery during the course of study treatment
• Current pregnancy or lactation
• Current known active infection with human immunodeficiency virus (HIV), hepatitis B, and/or hepatitis C virus; for patients who are known carriers of hepatitis B virus (HBV), active hepatitis B infection must be ruled out based on negative serologic testing and/or determination of HBV deoxyribonucleic acid (DNA) viral load per local guidelines
• Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol