Trial of Neoadjuvant Trastuzumab Emtansine in Patients With HER2-Equivocal Breast Cancer

NATURE is an open label, neoadjuvant, phase II study designed to evaluate the objective
response rate of trastuzumab emtansine in patients with newly diagnosed HER2-equivocal
breast cancer. Patients will receive trastuzumab emtansine at a dose of 3.6 mg/kg via
intravenous infusion every 3 weeks for a total of 6 weeks (2 21-day cycles). Patients who
achieve partial or complete response (responders) after the 6-week treatment will continue
on trastuzumab emtansine for an additional 12 weeks (4 cycles). The primary objective will
be objective response rate after 6 weeks of neoadjuvant trastuzumab emtansine. Secondary
objectives will include imaging response (ultrasound and magnetic resonance imaging) after
six weeks of neoadjuvant trastuzumab emtansine and toxicity and efficacy of trastuzumab
emtansine. After completion of continued trastuzumab emtansine treatment, pathological
complete response rate of responders as a whole and according to estrogen receptor status
will be explored. Markers related to the mechanism of action of trastuzumab emtansine (HER2
copy number in circulating tumor cells; tissue expression of PTEN, PI3K, and other potential
candidate markers) will also be explored.

Inclusion Criteria:

- Female gender;

- Age ≥18 years;

- Eastern Cooperative Oncology Group performance status of 0-1;

- Histologically confirmed invasive breast cancer;

- Primary tumor greater than or equal to 1 cm diameter, as measured by clinical
examination and mammography or ultrasound;

- Any N;

- No evidence of metastasis (M0) (isolated supra-clavicular node involvement allowed);

- HER2 low or equivocal status in the invasive component of the primary tumor
(confirmed by a central certified laboratory prior to study entry)

- HER2 low expression: 1+/2+ by immunohistochemistry and/or HER2/CEP17 ratio <2.0
with HER2 copy number <6.0 signals/cell

- HER2 equivocal expression: HER2 copy number ≥4.0 and <6.0 signals/cell;

- Hematopoietic status:

Absolute neutrophil count ≥ 1.0 x 10^9/L, Platelet count ≥ 100 x 10^9/L, Hemoglobin at
least 9 g/dL;

• Hepatic status: Serum total bilirubin ≤1 x upper limit of normal (ULN; In the case of
known Gilbert's syndrome, a higher serum total bilirubin [< 1.5 x ULN] is allowed),
Aspartate aminotransferase and alanine aminotransferase ≤1.5 x ULN, Alkaline phosphatase ≤
1.5 x ULN;

• Renal status: Creatinine ≤1.5 mg/dL;

- International Normalized Ratio ≤1.5 x ULN;

- Baseline left ventricular ejection fraction ≥50%, as measured by echocardiography or
multigated acquisition scan;

- Negative serum or urine β-human chorionic gonadotropin pregnancy test within 7 days
prior study entry for patients of childbearing potential. Women of childbearing
potential must use effective contraception (barrier method [condoms, diaphragm] in
conjunction with spermicidal jelly, or total abstinence. Oral, injectable, and
implantable hormonal contraceptives are not allowed) for the duration of the study
and for at least 7 months after the last dose of study treatment;

- Signed informed consent form (ICF);

- Patient accepts to make available tumor samples for submission to central laboratory
to conduct translational studies as part of this protocol.

Exclusion Criteria:

- Previous (less than 5 years) or current history of malignant neoplasms, except for
curatively treated basal and squamous cell carcinoma of the skin and carcinoma in
situ of the cervix;

- Patients with a prior malignancy diagnosed more than 5 years prior to study entry;

- Preexisting peripheral neuropathy ≥ grade 2;

- Known history of uncontrolled or symptomatic angina, clinically significant
arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled
hypertension (≥180/110), unstable diabetes mellitus, dyspnea at rest, or chronic
oxygen therapy;

- Concurrent disease or condition that would make the patient inappropriate for study
participation or any serious medical disorder that would interfere with the patient's
safety;

- Unresolved or unstable serious adverse events from prior administration of another
investigational drug;

- Dementia, altered mental status, or any psychiatric condition that would prevent the
understanding or rendering of ICF;

- Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy,
immunotherapy, or biologic therapy other than the trial therapy);

- Concurrent treatment with an investigational agent or participation in another
therapeutic clinical trial;

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to trastuzumab emtansine or its components;

- Ejection fraction <55% or below the lower limit of the institutional normal range;

- Pregnant or lactating women;

- Concomitant use of cytochrome P450 3A4 inhibitors or inducers;

- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
active or uncontrolled infection, uncontrolled diabetes) that could cause
unacceptable safety risks or compromise compliance with the protocol;

- Active infection requiring intravenous or oral antibiotics;

- Patients unwilling or unable to comply with the protocol.