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