Ado-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. To evaluate the progression free survival (PFS), duration of response, benefit rate (as
defined by stable disease, partial response, or complete response by Response Evaluation
Criteria in Solid Tumors [RECIST] v 1.1), overall response rate (as defined by partial or
complete response by RECIST v 1.1), and survival.

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

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

OUTLINE:

Patients receive ado-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

- 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:

- 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 prior to
randomization

- The patient has not recovered from any resulting acute toxicity (to grade =< 1)
prior to randomization

- Brain metastases that are untreated or symptomatic, or require any radiation,
surgery, or steroid therapy to control symptoms from brain metastases within 30 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 study treatment

- 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

- Current severe, uncontrolled 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