"Neo-Adjuvant Treatment With Palbociclib: Effect on Ki67 and Apoptosis Before, During and After Treatment "

Overview

This is a multicenter neoadjuvant trial conducted under the sponsorship and overall trial management of the Fondazione Michelangelo in Italy. Women with a diagnosis of invasive unilateral non metastatic ER-positive breast cancer expressing HER2 and suitable for neoadjuvant therapy Patients in this study will receive: Trastuzumab+Pertuzumab+Palbociclib with or without Fulvestrant (HPPF) Trastuzumab 8 mg/kg loading dose IV, then 6 mg/kg IV q.3 wks (repeat for a total of 6 administrations) Pertuzumab 840 mg loading dose IV, then 420 mg IV q. 3 wks (repeat for a total of 6 administrations) Palbociclib 125 mg po q.d. x 21 q. 4 wks (= 1 cycle; repeat for a total of 5 cycles) Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks (repeat for 5 times) with an additional 500 mg dose given two weeks after the initial dose (total administrations including the additional one = 6) The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and fulvestrant (5 administrations every 4 weeks plus the additional dose given two weeks after the initial dose) was selected to match as closely as possible the total duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab Definitive surgery will be performed not earlier than 14 days and not later than 28 days after the last dose of any of the drugs in the combination reported above After completion of the neoadjuvant and surgical treatment patients will receive irradiation as locally acceptable. Patients will also continue to receive systemic drug therapy including chemotherapy (plus standard anti-HER2 treatment until completion of full 1 year if HER2 3+ or neu amplified, i.e. cohorts A and B) and endocrine therapy according to local guidelines at the Investigator's discretion.

This is a multicenter neoadjuvant trial conducted under the sponsorship and overall trial management of the Fondazione Michelangelo in Italy. Three cohorts of patients are planned Patients with ER positive tumors (\> 10%) and HER2 3+ or neu amplified Cohort A Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF) Cohort B Trastuzumab+Pertuzumab+Palbociclib (HPP) Allocation to Cohort B will be started after recruitment to Cohort A has been completed Patients with ER positive tumors (\> 10%), PgR positive, HER2 1+/2+ (without amplification) and Ki67 \> 20% Cohort C Trastuzumab+Pertuzumab+Palbociclib+Fulvestrant (HPPF) Trastuzumab 8 mg/kg loading dose IV, then 6 mg/kg IV q.3 wks (repeat for a total of 6 administrations) Pertuzumab 840 mg loading dose IV, then 420 mg IV q. 3 wks (repeat for a total of 6 administrations) Palbociclib 125 mg po q.d. x 21 q. 4 wks (= 1 cycle; repeat for a total of 5 cycles) Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks (repeat for 5 times) with an additional 500 mg dose given two weeks after the initial dose (total administrations including the additional one = 6) The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and fulvestrant (5 administrations every 4 weeks plus the additional dose given two weeks after the initial dose) was selected to match as closely as possible the total duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab Definitive surgery will be performed not earlier than 14 days and not later than 28 days after the last dose of any of the drugs in the combination reported above After completion of the neoadjuvant and surgical treatment patients will receive irradiation as locally acceptable. Patients will also continue to receive systemic drug therapy including chemotherapy (plus standard anti-HER2 treatment until completion of full 1 year if HER2 3+ or neu amplified, i.e. cohorts A and B) and endocrine therapy according to local guidelines at the Investigator's discretion. Primary objectives: * Characterize changes of Ki67 from baseline before therapy and at 2 weeks and at surgery (approximately 22 weeks after start of neoadjuvant therapy with HPPF). * Characterize changes in apoptosis from baseline before therapy and at surgery (approximately 22 weeks after start of neoadjuvant therapy with HPPF). * Study the tolerability profile of the combination Secondary objectives: * Assess the rate of pathological complete response (pCR) defined as ypT0-ypTis ypN0 at surgery * Define the clinical objective response rate at the end of the combination * Conduct molecular and clinical analyses to assess the presence of informative markers of benefit in addition to Ki67 and apoptosis