Neoadjuvant Treatment of HER2 Positive Early High-risk and Locally Advanced Breast Cancer

NCT03595592 | Active Not Recruiting Phase 3 DMC

• 2 other identifiers: FM-17-B012017-000981-31
• Study Type: interventional
• Target: 650
• Locations: 4 countries
• Sites: 65

Brief Summary

n the present study the neoadjuvant approach with the anti-HER2 trastuzumab and pertuzumab combined with carboplatin and paclitaxel will be used to compare the Event-Free Survival (EFS) in regimens with and without atezolizumab. Following the neoadjuvant part of the study, after surgery all patients will continue to receive trastuzumab and pertuzumab to complete one year of anti-HER2 therapy. Similarly, patients allocated to receive atezolizumab will continue atezolizumab to complete one year In addition, several IHC and molecular assays will be performed before and during the period of chemotherapy administration and at surgery with the goal of defining a marker of efficacy to be later validated in a larger adjuvant setting.

Conditions

Invasive Breast Cancer

Keywords

Unilateral, HER2 positive

Outcome Measures

Primary Outcomes (1)

• Event Free Survival (EFS)

  Assess EFS (disease progression while on neoadjuvant therapy or disease recurrence after surgery) in the study arms

  5 years after the randomization of the last patient

Secondary Outcomes (5)

• Pathological complete response (pCR)

  At surgery, an expected average of 26 weeks after the randomization of the last patients

• Clinical objective response

  Participants will be followed for the duration of neoadjuvant therapy, an expected average of 22 weeks

• Distant Event Free Survival (DEFS)

  5 years after the randomization of the last patients

• Overall Survival (OS)

  5 years after the randomization of the last patient

• Number of participants with adverse events as a measure of safety and tolerability

  Participants will be followed for up to 5 years from the last randomized patient

Study Arms (3)

HPCT

ACTIVE COMPARATOR

Patients will receive a combination of trastuzumab, pertuzumab, carboplatin and paclitaxel as neoadjuvant therapy for 6 cycles every 3 weeks. Trastuzumab (H) will be delivered on day 1 at the dose of 8 mg/kg loading dose i.v., then 6 mg/kg i.v. Pertuzumab (P) will be delivered on day 1 at the dose of 840 mg loading dose i.v., then 420 mg i.v. Carboplatin (C) will be administered at AUC 2 i.v. on day 1 and day 8. Paclitaxel (T) will be given at 90 mg/m2 i.v. on day 1 and day 8. Definite surgery will be performed not later than 4 weeks after the last dose of neoadjuvant therapy. Trastuzumab and pertuzumab will then be delivered for 12 additional cycles as adjuvant therapy.

Drug: Trastuzumab; Drug: Pertuzumab; Drug: Carboplatin; Drug: Paclitaxel; Procedure: Surgery

ACy followed by HPCT and atezolizumab

EXPERIMENTAL

Patients will receive a combination of doxorubicin (A, 60 mg/m2 i.v.), cyclophosphamide (C, 600 mg/m2 i.v.) and atezolizumab (1200 mg i.v.) on day 1 every 3 week for 3 cycles. Subsequently they will be given trastuzumab on day 1 (H, at the loading dose of 8 mg/kg i.v. then 6 mg/kg i.v.), pertuzumab on day 1 (P, at the loading dose of 840 mg .v., then 420 mg i.v.), carboplatin (C) at AUC 2 i.v. on day 1 and day 8, paclitaxel (T) at 90 mg/m2 i.v. on day 1 and day 8, and atezolizumab 1200 mg i.v. on day 1 for 3 cycles every 3 weeks. Definite surgery will be performed not later than 4 weeks after the last dose of neoadjuvant therapy. Trastuzumab and pertuzumab will then be delivered for 15 additional cycles and atezolizumab for 12 additional cycles as adjuvant therapy.

Drug: Trastuzumab; Drug: Pertuzumab; Drug: Carboplatin; Drug: Paclitaxel; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Atezolizumab; Procedure: Surgery

HPCT and atezolizumab

EXPERIMENTAL

Patients will receive a combination of trastuzumab, pertuzumab, carboplatin, paclitaxel and atezolizumab as neoadjuvant therapy for 6 cycles every 3 weeks. Trastuzumab (H) will be delivered on day 1 at the dose of 8 mg/kg loading dose i.v., then 6 mg/kg i.v. Pertuzumab (P) will be delivered on day 1 at the dose of 840 mg loading dose i.v., then 420 mg i.v. Carboplatin (C) will be administered at AUC 2 i.v. on day 1 and day 8; paclitaxel (T) will be given at 90 mg/m2 i.v. on day 1 and day 8; atezolizumab at the dose of 1200 mg i.v. on day 1. Definite surgery will be performed not later than 4 weeks after the last dose of neoadjuvant therapy. Trastuzumab, pertuzumab and atezolizumab will then be delivered for 12 additional cycles as adjuvant therapy.

Drug: Trastuzumab; Drug: Pertuzumab; Drug: Carboplatin; Drug: Paclitaxel; Drug: Atezolizumab; Procedure: Surgery

Interventions

Trastuzumab DRUG

Trastuzumab will be given i.v. on day 1 every 3 weeks in arms HPCT, ACy followed by HPCT and atezolizumab and in arm HPCT and atezolizumab

Also known as: Herceptin

ACy followed by HPCT and atezolizumab; HPCT; HPCT and atezolizumab

Pertuzumab DRUG

Pertuzumab will be given i.v. on day 1 every 3 weeks in arms HPCT, ACy followed by HPCT and atezolizumab and in arm HPCT and atezolizumab

Also known as: Perjeta

ACy followed by HPCT and atezolizumab; HPCT; HPCT and atezolizumab

Carboplatin DRUG

Carboplatin will be given i.v. on day 1 and day 8 every 3 weeks in arms HPCT, ACy followed by HPCT and atezolizumab and in arm HPCT and atezolizumab

Also known as: Carboplatin Hospiria

ACy followed by HPCT and atezolizumab; HPCT; HPCT and atezolizumab

Paclitaxel DRUG

Paclitaxel will be given i.v. on day 1 and day 8 every 3 weeks in arms HPCT, ACy followed by HPCT and atezolizumab and in arm HPCT and atezolizumab

Also known as: Paclitaxel Hospiria

ACy followed by HPCT and atezolizumab; HPCT; HPCT and atezolizumab

Doxorubicin DRUG

Adriamycin will be delivered i.v. on day 1 every 3 weeks in arm ACy followed by HPCT for the first 3 cycles

Also known as: Doxorubicin Pfizer

ACy followed by HPCT and atezolizumab

Cyclophosphamide DRUG

Cyclophosphamide will be given i.v. on day 1 every 3 weeks in arm ACy followed by HPCT and atezolizumab for the first 3 cycles

Also known as: Cyclophosphamide Sandoz

ACy followed by HPCT and atezolizumab

Atezolizumab DRUG

Atezolizumab will be given i.v. on day 1 every 3 weeks in arm ACy followed by HPCT and atezolizumab and in arm HPCT and atezolizumab

Also known as: Tecentriq

ACy followed by HPCT and atezolizumab; HPCT and atezolizumab

Surgery PROCEDURE

Breast cancer surgery (breast and axilla) either conservative or radical not later than 4 weeks from the last dose of neoadjuvant therapy in all study arms

ACy followed by HPCT and atezolizumab; HPCT; HPCT and atezolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female patients aged 18 years or older with early high-risk ((T1cN1; T2N1; T3N0) or locally advanced and inflammatory breast cancers (stage III A-C according to AJCC) suitable for neoadjuvant treatment
• Histologically confirmed unilateral invasive breast cancer
• HER2 positive disease according to ASCO/CAP guidelines 2013 \[defined as IHC 3+ or ISH positive (by gene copy number or HER2 gene/CEP17 ratio of 2 or greater)\]
• Known estrogen (ER) and progesterone receptor (PgR)
• Availability of a representative paraffin-embedded (FFPE) tumor block taken at diagnostic biopsy for central confirmation of HER2 eligibility, for assessment of ER, PgR, Ki67 and PD-L1 expression and for biomarker evaluation is mandatory. Note: the diagnostic biopsy of the breast lesion may have been taken before the required screening procedures. If diagnostic sentinel node biopsy if performed, an FFPE block must be available. An FFPE tumor block is also mandatory after the first cycle of therapy. Surgery tissue (residual tumor or tumor bed in case of pCR and axillary node material) is also mandatory.
• Consent to the collection of blood samples mandatorily before starting neoadjuvant treatment, after the first cycle of therapy, at the end of neoadjuvant treatment (before surgery), 6 months after surgery and at the end of all treatments.
• ECOG performance status 0 or 1
• For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 6 months after the last dose of study drugs. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Examples of contraceptive methods with a failure rate of \< 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of \< 1% per year. Barrier methods must always be supplemented with the use of a spermicide
• Written informed consent to participate in the trial (approved by the Institutional Review Board \[IRB\]/ Independent Ethics Committee \[IEC\]) obtained prior to any study specific screening procedures
• Willing and able to comply with the protocol

You may not qualify if:

• Evidence of bilateral breast cancer or metastatic disease (M1)
• Patients with HER2-negative defined as 0-1+ by immunohistochemistry or 2+ by immunohistochemistry without HER2 amplification by either In Situ Hybridization (ISH) or other amplification tests done locally are considered not eligible for the study
• Pregnant or lactating women. Documentation of a negative pregnancy test must be available for premenopausal women with intact reproductive organs and for women less than one year after the last menstrual cycle
• Women with childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception, for example abstinence, an intra-uterine device, or double barrier method of contraception
• Previous treatment with chemotherapy, hormonal therapy or an investigational drug for any type of malignancy
• Previous investigational treatment for any condition other than malignancy within 4 weeks of randomization date
• Administration of a live, attenuated vaccine within 4 weeks before Day 1 or anticipation that such a live attenuated vaccine will be required during the study
• Previous or concomitant malignancy of any other type that could affect compliance with the protocol or interpretation of results. Patients with curatively treated basal cell carcinoma of the skin or in situ cervix cancer are generally eligible
• Pre-existing motor or sensory neuropathy of grade \> 1 for any reason
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
• Patients with prior allogeneic stem cell or solid organ transplantation
• History of autoimmune disease including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
• History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or evidence of active pneumonitis on screening chest computed tomography scan
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease

Sponsors & Collaborators

• Fondazione Michelangelo: lead
• Hoffmann-La Roche: collaborator

Study Sites (65)

Klinikum Klagenfurt am Wörthersee Abteilung für Innede Medizin und Hämatologie und internistische Onkologie

Klagenfurt, 9020, Austria

Location

Krankenhaus der Barmherzigen Schwestern

Linz, 4010, Austria

Location

Universitätsklinikum St. Pölten Klinische Abteilung für Innere Medizin

Sankt Pölten, 3100, Austria

Location

Klinische Abteilung für Allgemeine Gynäkologie und Gynäkologische Onkologie - Universitätsklinik für Frauenheilkunde Medizinische Universität Wien / AKH "

Vienna, 1090, Austria

Location

Klinik für Gynäkologie am Campus Charité Mitte (CCM)

Berlin, 10113, Germany

Location

Department of Gynecology and Obstetrics, Marienhospital

Bottrop, 46236, Germany

Location

Klinikum Coburg, Frauenklinik

Coburg, 96450, Germany

Location

St Johannes Hospital

Dortmund, 44137, Germany

Location

Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe - Universitätsklinikum Carl Gustav Carus

Dresden, 01307, Germany

Location

Markus Krankenhaus - Klinik für Gynäkologie und Geburtshilfe

Frankfurt, 60431, Germany

Location

SRH Waldklinikum

Gera, 07548, Germany

Location

Universitätsklinikum Greifswald, Frauenklinik

Greifswald, 17475, Germany

Location

Klinik und Poliklinik für Gynäkologie am Universitätsklinikum (Saale)

Halle, 06120, Germany

Location

Gynäkologisch-Onkologische Praxis

Hanover, 30177, Germany

Location

NCT Nationales Zentrum für Tumorerkrankungen Gynäkologische Onkologie, Frauenklinik

Heidelberg, 69120, Germany

Location

St. Marien-Klinik GmbH Frauenklinik der St. Vincentius-Kliniken gAG - Gynäkologisches Krebszentrum Karlsruhe - Brustzentrum Karlsruhe

Karlsruhe, 76135, Germany

Location

Städtisches Klinikum Magdeburg - Klinik für Allgemein - und Viszeralchirurgie

Magdeburg, 39130, Germany

Location

Am Schillerhain 1-8

Marktredwitz, 95615, Germany

Location

Klinikum Nürnberg Nord

Nuremberg, 90419, Germany

Location

Onkologische Praxis Velbert

Velbert, 42551, Germany

Location

Marien Hospital Witten

Witten, 58452, Germany

Location

Ospedale Papa Giovanni XXIII

Bergamo, 24128, Italy

Location

Presidio Ospedaliero Di Summa-Perrino

Brindisi, 72100, Italy

Location

Dipartimento di Oncologia Medica AUSL della Romagna

Faenza, 48018, Italy

Location

IST San Martino

Genova, 16132, Italy

Location

Istituto Scientifico Romagnolo per lo studio e la cura dei tumori

Meldola, 47014, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, 20133, Italy

Location

Istituto Europeo di Oncologia

Milan, 20141, Italy

Location

Ospedale Luigi Sacco

Milan, 20160, Italy

Location

Ospedale San Raffaele

Milan, Italy

Location

AO Universitaria Policlinico di Modena

Modena, 41124, Italy

Location

Ospedale Sacro Cuore - Don Calabria

Negrar, 37024, Italy

Location

Fondazione Salvatore Maugeri

Pavia, 27100, Italy

Location

Azienda Ospedaliero Universitaria Pisana Ospedale S. Chiara

Pisa, 56100, Italy

Location

Arcispedale Santa Maria Nuova - A.O. Reggio Emilia

Reggio Emilia, 42123, Italy

Location

Ospedale Infermi AUSL della Romagna

Rimini, 247900, Italy

Location

Istituto Nazionale Tumori - Regina Elena

Roma, 00144, Italy

Location

Ospedale Santa Maria della Misericordia

Udine, 33100, Italy

Location

Centro Oncologico de Galicia

A Coruña, 15009, Spain

Location

Hospital Virgen de Los Lirios

Alcoy, 03804, Spain

Location

Hospital General Unv. Alicante

Alicante, 03010, Spain

Location

"Hospital Infanta Cristina de Badajoz (CICAB - Centro de Investigación Clínica del Área de Salud de Badajoz)"

Badajoz, 06007, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08025, Spain

Location

Hospital Clinic Provincial

Barcelona, 08036, Spain

Location

Hospital del Mar - IMAS

Barcelona, Hospital del Mar - IMAS, Spain

Location

Hospital de Basurto

Bilbao, 48013, Spain

Location

Hospital San Pedro de Alcantara

Cáceres, 10003, Spain

Location

Hospital Virgen de la Nieves

Granada, 18012, Spain

Location

Hospital Juan Ramón Jimenez

Huelva, 21005, Spain

Location

Hospital Gregorio Marañon

Madrid, 28007, Spain

Location

MD Anderson Cancer Center

Madrid, 28033, Spain

Location

Hospital Clinico San Carlos

Madrid, 28040, Spain

Location

Hospital Unv. Fundación Jimenez Diaz

Madrid, 28040, Spain

Location

Hospital de Fuenlabrada

Madrid, 28942, Spain

Location

Complejo Hospitalario de Especialidades Virgen de la Victoria

Málaga, 29010, Spain

Location

Hospital General Universitario Morales Meseguer

Murcia, 30008, Spain

Location

Clinica Universitaria de Navarra

Pamplona, 31008, Spain

Location

Complejo Hospitalario de Salamanca

Salamanca, 37007, Spain

Location

Hospital de Donostia

San Sebastián, 20014, Spain

Location

Hospital Onkologikoa

San Sebastián, 20014, Spain

Location

Hospital Clinico Unv. de Santiago

Santiago de Compostela, 15706, Spain

Location

Hospital Virgen de la Salud de Toledo

Toledo, 45004, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, 46010, Spain

Location

Hospital Lozano Blesa

Zaragoza, 50009, Spain

Location

Hospital Miguel Servet

Zaragoza, 50009, Spain

Location

MeSH Terms

Interventions

Trastuzumab; pertuzumab; Carboplatin; Paclitaxel; Doxorubicin; Cyclophosphamide; atezolizumab; Surgical Procedures, Operative

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Coordination Complexes; Organic Chemicals; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Study Officials

• Luca Gianni, MD

  Ospedale San Raffaele

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Parallel randomization to the study arms

Study Record Dates

• First Submitted: July 11, 2018
• First Posted: July 23, 2018
• Study Start: September 7, 2018
• Primary Completion (Estimated): December 15, 2026
• Study Completion (Estimated): March 15, 2027
• Last Updated: March 6, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (4); DE (17); IT (17); ES (27)