Non-randomized, open label, multicentric translational research study in women with untreated invasive breast carcinoma eligible for primary surgery (Stage I-IIIA).

The aim of PAMELA is to test the hypothesis that PAM50 HER2-enriched (HER2-E) subtype better predicts response to neoadjuvant dual anti-HER2 blockade, with or without endocrine therapy, compared to traditional clinical HER2 classification. Furthermore, we posit that characterization of gene expression patterns may identify profiles of those who may be safely spared chemotherapy.

PAMELA is a non-randomized, open label, multicentric translational research study of neoadjuvant dual HER2 blockade therapy without chemotherapy. Although efficacy and safety will be investigated, the primary goal is to identify profiles predictive of clinical benefit from targeted therapy. Eligible patients must be women with untreated primary HER2-overexpressing and/or amplified breast tumors of more than 1 cm in diameter amenable to definitive surgery (stage I-IIIA).

The PAMELA study is designed to test the hypothesis that the PAM50 HER2-E subtype is able to predict clinical response to neoadjuvant dual HER2 blockade with lapatinib and trastuzumab, with or without endocrine therapy, assessed by pathological complete response in the breast (pCRB) rate at the time of surgery, compared to traditional clinical HER2 classification. Furthermore, we posit that characterization of gene expression patterns may identify profiles of those who may be safely spared chemotherapy.

Patients will first undergo screening, tumor measurement, and mandatory collection of core tumor biopsies for central determination of HER2 and HR status. These biopsies will be used to determine gene expression patterns once the patient is included in the study. Patients will be treated with dual HER2 blockade consisting of lapatinib and trastuzumab for a total of 18 weeks. Patients who are HR-positive will also be given endocrine therapy, letrozole or tamoxifen depending on their menopausal status, for the same 18 weeks. If tumor progression is observed by ultrasound (US) at week 6, tumors will be identified as resistant, and paclitaxel will be added to dual HER2 blockade, maintaining trastuzumab at the same original dose and reducing lapatinib dose for safety reasons. In those patients with HR-positive disease, endocrine therapy will be withdrawn in order to avoid its adverse interactions with chemotherapy.

Two weeks after the first administration of study medication, all patients will undergo mandatory repeat tumor tissue acquisition that will be used for secondary endpoint assessment.

Post treatment tissue acquisition will be obtained at the time of surgery from the specimen excised.

US of the breast and axillary lymph nodes will be performed at baseline, Day 14, week 6, and prior to surgery, and will be correlated with pCR. If tumor progression is observed on week 6, the US will be repeated on week 10 to discard the progression continues despite the addition of paclitaxel at neoadjuvant regimen.

Mammography is required at baseline and prior to surgery, but will not be used for the objective response assessment.

Treatment will be given until definitive surgery, clinical signs of disease progression after paclitaxel addition, unacceptable toxicity or withdrawal of patient consent.

Breast surgery will be carried out 1 to 3 weeks after completion of dual HER2 blockade with or without endocrine therapy, and 2 to 3 weeks after completion of paclitaxel plus dual HER2 blockade, should it had been initiated for progressive disease.

Following surgical excision, adjuvant treatment will be as per investigator´s choice and local standards of care outside the scope of this protocol.

End of study is 30 days (±14 days) after surgery with a safety follow-up visit.

Inclusion Criteria:

• Written informed consent prior to beginning specific protocol procedures
• Untreated invasive breast carcinoma eligible for primary definitive surgery (stage I-IIIA)
• Histologically confirmed invasive breast carcinoma, with all of the following characteristics: primary tumor ≥1 cm in largest diameter, cN0-2, No evidence of distant metastasis (M0)
• HER2-positive invasive breast cancer by central assessment, defined by ASCO/CAP guidelines
• Female patients
• Age ≥18 years
• ECOG performance status of 0 or 1
• Adequate organ function defined as: Absolute neutrophil count (ANC) ≥1.5 × 109/L, Hemoglobin (Hgb) ≥10 g/dL, Platelets >100 000/mm3, Creatinine ≤1.6 mg/dL, ALT and AST ≤2.5 × ULN, Alkaline phosphatase ≤5 ULN, Total bilirubin ≤1.5 mg/dL, Baseline LVEF ≥50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan
• Negative β-HCG pregnancy test (serum) for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after the menopause. All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control from 2 weeks before administration of the first dose of investigational product until 28 days after last dose of investigational product
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• In the case of multifocal tumor (defined as the presence of two or more tumor foci in the same quadrant of the breast), the largest lesion must be ≥ 1 cm, and "target lesion" must be designated for all subsequent tumor assessments. In all tumor foci should be documented HER2 status as positive
• Availability of enough tumor sample or possibility to take a new biopsy for PAM50 analysis

Exclusion Criteria:

• Stage III inoperable breast cancer or known metastatic disease
• Patients for whom upfront chemotherapy including taxanes and anthracyclines is clinically judged appropriate as optimal neoadjuvant treatment
• Prior chemotherapy, radiotherapy or surgery for invasive breast cancer, other than excision of tumor in the contralateral breast, and provided that the patient did not previously receive adjuvant radiotherapy or chemotherapy
• Subjects with a concurrently active second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Subjects with other non-mammary malignancies must have been disease-free for at least 5 years
• Known or suspected hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances
• Concurrent congestive heart failure or LVEF <50%
• Clinically significant (i.e. active) cardiovascular disease, including cerebrovascular accident (<6 months before enrollment), unstable angina pectoris, myocardial infarction ≤6 months before enrollment, uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or high-risk uncontrolled arrhythmias
• Uncontrolled diabetes mellitus, active peptic ulcer disease or uncontrolled epilepsy
• Active uncontrolled infection at the time of enrollment
• History of significant comorbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with informed consent
• Use of any investigational agent or participation in another therapeutic clinical trial concurrently or in the previous 30 days before the enrollment
• Patients who are pregnant or breast-feeding
• Women of child-bearing potential who are unable or unwilling to use contraceptive measures
• Inability or unwillingness to abide by the study protocol or cooperate fully with the investigator
• 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)
• Concomitant use of CYP3A4 inhibitors or inducers