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

This is an open label, neoadjuvant phase II study to evaluate the objective response, toxicity, and safety of trastuzumab emtansine in patients with newly diagnosed HER2-equivocal breast cancer. Trastuzumab emtansine at a dose of 3.6 mg/kg will be intravenously administered every 3 weeks for a total of 6 weeks. Patients who achieve a partial or complete response after the 6-week treatment (responders) will continue on trastuzumab emtansine for an additional 12 weeks.

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.

Eligibility Criteria:
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.