Neoadjuvant TDM1 With Lapatinib and Abraxane Compared With Trastuzumab Plus Pertuzumab With Paclitaxel

This is a randomized, open label Phase II neoadjuvant study comparing the efficacy and safety
of trastuzumab emtansine (T-DM1) plus lapatinib (L) followed by abraxane (A) versus
trastuzumab plus pertuzumab followed by paclitaxel in patients with HER2-overexpressing
breast cancer. Patients will be randomized (1:1) to one of the two treatment arms: arm 1,
trastuzumab emtansine plus lapatinib for 6 weeks, followed by trastuzumab emtansine plus
lapatinib plus abraxane for 12 weeks; arm 2, trastuzumab plus pertuzumab for six weeks,
followed by trastuzumab plus pertuzumab plus paclitaxel for 12 weeks. Patients will undergo
surgery after neoadjuvant therapy. All patients will have a core needle biopsy at baseline,
after week 6, and at the time of disease progression. Surgical specimens will be obtained
after week 18.

Inclusion Criteria:

- Female gender;

- Age ≥18 years;

- Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1

- Histologically confirmed invasive breast cancer:

- Primary tumor greater than 1 cm diameter, measured by clinical examination and
mammography or ultrasound.

- Any N,

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

- Over expression and/or amplification of HER2 in the invasive component of the primary
tumor and confirmed by a certified laboratory prior to randomization.

- Known hormone receptor status.

- Hematopoietic status:

- CBC not less than .75 of institutional lower limit. Absolute neutrophil count ≥ 1,5 x
10^9/L, Platelet count ≥ 100 x 10^9/L, Hemoglobin at least 9 g/dl,

- Hepatic status:

Serum total bilirubin ≤ 2 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 (AST) and Alanine Aminotransferase (ALT) ≤ 3.5 times ULN, Alkaline
phosphatase ≤ 2.5 times ULN, • Renal status: Creatinine ≤ 1.5mg/dL,

• Cardiovascular: Baseline left ventricular ejection fraction (LVEF) ³ ≥50% measured by
echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan,

- Negative serum or urine β-hCG pregnancy test at screening for patients of childbearing
potential within 2-weeks (preferably 7 days) prior to randomization.

- Fertile patients must use effective contraception (barrier method - condoms, diaphragm
- also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable,
or implant hormonal contraceptives are not allowed)

- 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; Carcinoma in situ
of the cervix.

- Patients with a prior malignancy diagnosed more than 5 years prior to randomization
may enter the study.

- 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
therapy with oxygen;

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

- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
resection of the stomach or small bowel. Subjects with ulcerative colitis are also
excluded;

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

- 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, trastuzumab, lapatinib, paclitaxel,
abraxane or their components;

- Pregnant or lactating women;

- Concomitant use of CYP3A4 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

- Patients have an active infection and require IV or oral antibiotics.

- Pregnant or breast-feeding women

- Patients unwilling or unable to comply with the protocol