A Phase II, Randomized Study of T DM1 versus T DM1 plus short induction with docetaxel in first line treatment for locally advanced or metastatic HER2+ breast cancer.

INTERVENTION: Trade Name: Kadcyla Pharmaceutical Form: Powder for solution for injection/infusion INN or Proposed INN: TRASTUZUMAB EMTANSINE CAS Number: 1018448‐65‐1 Other descriptive name: TRASTUZUMAB EMTANSINE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 160‐ Pharmaceutical Form: Concentrate for solution for injection/infusion INN or Proposed INN: DOCETAXEL Other descriptive name: DOCETAXEL Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 20‐ Trade Name: Kadcyla Pharmaceutical Form: Powder for solution for injection/infusion INN or Proposed INN: TRASTUZUMAB EMTANSINE CAS Number: 1018448‐65‐1 Other descriptive name: TRASTUZUMAB EMTANSINE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 160‐ CONDITION: Progressive or recurrent, locally advanced unresectable or metastatic HER2+ breast carcinoma in patients who have not received previous chemotherapy for the advanced disease. Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: To compare the early efficacy (measured as the rate of PFS at 4 months) of T DM1 together with SI docetaxel versus monotherapy treatment with T DM1 Primary end point(s): To compare the early efficacy (measured as the rate of PFS at 4 months) of T DM1 together with SI docetaxel versus monotherapy treatment with T DM1, in patients recently diagnosed with progressive or recurrent, locally advanced or metastatic HER2+ breast cancer who have not received previous chemotherapy for the advanced disease. Secondary Objective: 2.To compare the combination of T DM1 together with SI docetaxel versus monotherapy treatment with T DM1 in terms of:; a.Overall Response Rate (ORR), measured as the percentage of patients who achieve Complete Response (CR) and/or Partial Response (PR), in accordance with the RECIST 1.1 criteria throughout the study treatment.; b.Clinical Benefit Rate (CBR), measured as the percentage of patients with CR, PR or Stable Disease (SD) with a duration of at least 6 months. ; c.Duration of Response (DR); d.Overall Survival (OS); e. Progression Free Survival (PFS); f.Breast cancer specific survival, measured as the time from randomization to death due to breast cancer.; 3. To compare the safety and tolerability of both treatment regimens.; 4. To compare the cardiac safety of both treatment regimens.; 5. To compare the hepatic safety of both treatment regimens. Timepoint(s) of evaluation of this end point: 24 months after the First Patient In. SECONDARY OUTCOME: Secondary end point(s): 2.To compare the combination of T DM1 together with SI docetaxel versus monotherapy treatment with T DM1 in terms of:; a.Overall Response Rate (ORR), measured as the percentage of patients who achieve Complete Response (CR) and/or Partial Response (PR), in accordance with the RECIST 1.1 criteria throughout the study treatment.; b.Clinical Benefit Rate (CBR), measured as the percentage of patients with CR, PR or Stable Disease (SD) with a duration of at least 6 months. ; c.Duration of Response (DR), measured as the time between achieving CR or PR until Disease Progression (DP).; d.Overall Survival (OS), measured as the time from randomization to death from any cause.; e.Progression Free Survival (PFS), measured as the time from randomization to progression or death from any cause.; f.Breast cancer specific survival, measured as the time from randomization to death due to breast cancer.; 3.To compare the safety and tolerability of both treatment regimens.; 4.To compare the cardiac safety of both treatment regimens.; 5.To compare the hepatic safety of both treatment regimens; Exploratory objectives; 6.To assess if the PAM50 intrinsic subtypes (HER2 enriched in comparison with the rest) predict benefit (in terms of ORR and PFS) based on the addition of docetaxel.; 7.To assess if the PAM50 intrinsic subtypes (HER2 enriched in comparison with the rest) predict the clinical outcome, in terms of CR or PFS, regardless of the addition of docetaxel ; 8.To assess if Ki67 predict benefit (in terms of ORR and PFS) based on the addition of docetaxel. Timepoint(s) of evaluation of this end point: At the end of the treatment INCLUSION CRITERIA: 1.Written Informed Consent for all study procedures in accordance with the local regulatory requirements prior to starting any Protocol specific procedures. 2.To provide tumor tissue or to have the possibility to collect newly tumor sample from the patient to be able to perform PAM50 analysis. The minimum conditions to achieve this are 1) presence of at least 1 tumor core with a minimum tissue area of 10mm2, 2) with at least 35% of tumoral cells and 3) enough tissue to perform at least 3 sections of 10 ?m each. 3.Women. 4.Age ? 18 years. 5.ECOG performance status of 0 or 1. 6.Invasive HER2+ breast cancer assessed centrally, defined by the clinical guidelines of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) (Wolff JCO 2013): a)IHC 3+ overexpression (circumferential membrane staining that is complete, intense, observed in >10% of the invasive tumor cells) b)In situ Hybridization positive (ISH: FISH/CISH