Conditions: Breast Cancer
Keywords: HER2-positive breast cancer Lapatinib Neoadjuvant Trastuzumab Biomarkers
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 102
Healthy volunteers: no

Brief summary:
Phase II randomized multicenter trial to compare Epirubicin and Cyclophosphamide plus Docetaxel and Trastuzumab with Epirubicin and Cyclophosphamide plus Docetaxel and Lapatinib for patients with positive HER2 and resectable or locally advanced breast cancer.

Detailed description:
This is a multicenter, open label, randomized phase II trial. Women with primary cancer and overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) who have not received prior treatment for invasive breast cancer will be included. The study will analyze the efficacy and tolerance of Lapatinib and Docetaxel and the Trastuzumab and Docetaxel after 4 cycles of Epirubicin and Cyclophosphamide in patients with breast cancer HER2 positive.

102 patients will be stratified according to tumor size and estrogen receptor status (positive or negative) to be randomized to receive one of the following treatment arms:

* Experimental arm: Epirubicin 90mg/m2 in combination with cyclophosphamide 600mg/m2 intravenous (IV) every 21 days for 4 cycles, followed by oral Lapatinib 1250mg once a day plus docetaxel 100mg/m2 IV every 21 days for 4 cycles with the administration of granulocyte-colony stimulating factor (G-CSF) between days 2 and 7 or on day +1 according to the G-CSF used by the site.
* Control arm: Epirubicin 90mg/m2 in combination with cyclophosphamide 600mg/m2 IV every 21 days for 4 cycles, followed by a loading dose of Trastuzumab 8mg/kg IV followed by Trastuzumab 6mg/kg IV every 3 weeks plus docetaxel 100mg/m2 IV every 21 days for 4 cycles with the administration of G-CSF between days 2 and 7 or on day +1 according to the G-CSF used by the site.

Treatment duration: The patients will be in treatment for an average of 6 months for both arms.

Study population: Patients with operable or locally advanced breast cancer, HER2 positive who are candidates to receive neoadjuvant treatment and who have not received pre-treatment for invasive breast cancer.

Population in study and number total of patients:

The aim is to determine if neoadjuvant treatment with selective therapy can increase the complete pathological response (pCR) in breast cancer by the determination of molecular markers in the tumoral sample before treatment. Then, and between 3 and 4 weeks after the last administration of Docetaxel, and 24 hours after the administration of Lapatinib, surgery will be performed and in the surgical sample will be determined the molecular markers analyzed before of the treatment in the tumor sample.

Patients with HER2 positive, defined as immunohistochemistry 3+ or positive fluorescence in situ hybridization (FISH), will be included. If immunohistochemistry 2+ it will be necessary to confirm the HER2 positive status by FISH. All results will be reevaluated later in the central laboratory.

Statistical consideration: The sample size has been calculated using the 2-stage Simon method and with pathological complete response (pCR) as the primary study end point. Sample size has been based on the null hypothesis of a pCR of 40% and an alternative hypothesis of a pCR of 60%. Assuming an alpha error of 0.05 and a test power of 80%, 92 evaluable patients will be required to be recruited and retained in the study. Sixteen patients per arm will be included in the first stage, for at least eight pCR per arm to be seen, and 30 additional patients per arm will be included in the second stage for a total of 46 evaluable patients in each arm. Assuming a 10% drop-out rate, 102 patients will be recruited.

The objective of the random distribution to treatment arms is to select the most active arm for a subsequent development. It is based on a standard of pCR of 40%, in order to detect an increase in the pCR rate of 60% in both arms, it would be necessary to include 46 patients in each arm (Simon's method in 2 stages (Optimal design)). It has been considered an error a = 0.05 and a power 80% statistics. Therefore, in the first stage it would be necessary to include 16 patients in each arm if we found more than 7 patients with pCR in each arm we will continue including until reaching the 46 in each arm. The results will be significant if we find at least 23 patients with pCR in each arm. Assuming that 10% of patients are not evaluable, the number The total number of patients to be included is 102 patients (51 patients per arm of treatment).

Arms:
arm 1: Epirubicin + Cyclophosphamide -\> Docetaxel + Lapatinib arm 2: Epirubicin + Cyclophosphamide -\> Docetaxel + Trastuzumab

Interventions: intervention 1: Epirubicin intervention 2: Cyclophosphamide intervention 3: Docetaxel intervention 4: Lapatinib intervention 5: Trastuzumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol document: