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
