Clinical trial NCT03726879: A Study To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer
Official title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Chugai Pharmaceutical
First posted: 2018-11-01
Enrollment: 454
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study (also known as IMpassion050) will evaluate the efficacy and safety of atezolizumab compared with placebo when given in combination with neoadjuvant dose-dense anthracycline (doxorubicin) + cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab (ddAC-PacHP) in patients with early HER2-positive breast cancer (T2-4, N1-3, M0).


Eligibility criteria: Inclusion Criteria:

* Confirmed diagnosis of HER2-positive breast cancer, and hormonal and PD-L1 status, as documented through central testing of a representative tumor tissue specimen
* Primary breast tumor size of \> 2 cm by any radiographic measurement
* Stage at presentation: T2-T4, N1-N3, M0 as determined by AJCC staging system, 8th edition
* Pathologic confirmation of nodal involvement with malignancy must be determined by fine needle aspiration or core-needle biopsy. Surgical excision of lymph nodes is not permitted.
* Patients with multifocal tumors are eligible provided at least one focus is sampled and centrally confirmed as HER2-positive.
* Patients with multicentric tumors are eligible provided all discrete lesions are sampled and centrally confirmed as HER2-positive.
* Eastern Cooperative Oncology Group Performance Status of 0 or 1
* Baseline LVEF \>= 55% measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scans
* Adequate hematologic and end-organ function obtained within 14 days prior to initiation of study treatment
* For women of childbearing potential: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating eggs
* For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm

Exclusion Criteria:

* Prior history of invasive breast cancer
* Stage IV (metastatic) breast cancer
* Patients with synchronous bilateral invasive breast cancer
* Prior systemic therapy for treatment of breast cancer
* Previous therapy with anthracyclines or taxanes for any malignancy
* Ulcerating or inflammatory breast cancer
* Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes
* Sentinel lymph node procedure or axillary lymph node dissection prior to initiation of neoadjuvant therapy
* History of other malignancy within 5 years prior to screening, with the exception of those patients who have a negligible risk of metastasis or death
* Cardiopulmonary dysfunction
* Dyspnea at rest
* Active or history of autoimmune disease or immune deficiency
* Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab/placebo, 6 months after the final dose of doxorubicin, 12 months after the final dose of cyclophosphamide, 6 months after the final dose of paclitaxel, or 7 months after the final dose of trastuzumab, pertuzumab, or trastuzumab emtansine whichever occurs last

Exclusion Criteria Related to Trastuzumab Emtansine in the Adjuvant Setting:

* Patients who achieved pCR
* Evidence of clinically evident gross residual or recurrent disease following neoadjuvant therapy and surgery
* Unable to complete surgery with curative intent after conclusion of neoadjuvant systemic therapy
* Patient discontinued treatment with trastuzumab because of toxicity during the neoadjuvant phase of the study
* Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, autoimmune hepatic disorders, or sclerosis cholangitis
* Patients with Grade \>=2 peripheral neuropathy
* Prior treatment with trastuzumab emtansine

Primary outcomes:
measure: Percentage of Participants With Pathological Complete Response (pCR) in the PD-L1-Positive Population (IC 1/2/3)
timeFrame: From randomization to approximately 6 months
measure: pCR in the ITT Population
timeFrame: From randomization to approximately 6 months
Secondary outcomes:
measure: Percentage of Participants With pCR Based on Hormone Receptor Status
timeFrame: From randomization to approximately 24 months
measure: Percentage of Participants With pCR in the PD-L1-Negative Population
timeFrame: From randomization to approximately 24 months
measure: Event-Free Survival (EFS)
timeFrame: From randomization to first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause (up to approximately 54 months)
measure: Disease-Free Survival (DFS)
timeFrame: Time from surgery to first documented disease recurrence or death from any cause (up to approximately 54 months)
measure: Overall Survival (OS)
timeFrame: From randomization to date of death from any cause (up to approximately 54 months)
measure: Mean Changes From Baseline in Function (Role, Physical)
timeFrame: Baseline; Day 1 of Cycle 1-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow up visit. Cycle 1-4, each cycle is 14 days. Cycle 5-22, each cycle is 21 days.
measure: Mean Changes From Baseline in Global Health Status
timeFrame: Baseline; Day 1 of Cycle 1-9, on Day 1 of every other cycle thereafter until Cycle 22; at the treatment discontinuation or early termination visit and follow up visit. Cycle 1-4, each cycle is 14 days. Cycle 5-22, each cycle is 21 days.
measure: Percentage of Participants With Adverse Events
timeFrame: From randomization up end of study (approximately 4 years and 7 months)
measure: Maximum Serum Concentration (Cmax) of Atezolizumab
timeFrame: 30 minutes post infusion on Day 1 Cycle (C) 1.
measure: Minimum Serum Concentration (Cmin) of Atezolizumab
timeFrame: Pre-dose on Day 1 Cycle (C) 2, 3, 4, 8, 12, 16, ATDV (an average of 1 year). C 2-4, each C is 14 days. C 8-16, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).
measure: Trough Concentration (Ctrough) for Pertuzumab and Trastuzumab in Serum
timeFrame: Pre-dose on Day 1 Cycle (C) 8, 12, and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).
measure: Cmax of Trastuzumab Emtansine in Serum
timeFrame: Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year).
measure: Cmin of Trastuzumab Emtansine in Serum
timeFrame: Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year).
measure: Number of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs) to Atezolizumab
timeFrame: Day 1 Cycle (C) 1, 2, 3, 4, 8, 12, 16, at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-16, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).
measure: Number of Participants With Treatment-Emergent ADAs to Trastuzumab
timeFrame: Day 1 Cycle (C) 1, 8, 12 and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).
measure: Number of Participants With Treatment-Emergent ADAs to Pertuzumab
timeFrame: Day 1 of Cycle (C) 1, 8, 12, and at treatment discontinuation visit (ATDV) (an average of 1 year). C 1-4, each C is 14 days. C 8-12, each C is 21 days. With protocol version 5, collection is only required ATDV/completion (an average of 1 year).
measure: Number of Participants With Treatment-Emergent ADAs to Trastuzumab Emtansine
timeFrame: Day 1 of Cycle 9 and Cycle 12, at treatment disontinuation visit (an average of 1 year). Cycle 9 and 12 are each 21 days. With protocol version 5, collection is only required at the time of treatment discontinuation/completion (an average of 1 year).
measure: Percentage of Participants With pCR Based on PIK3CA Mutation Status
timeFrame: From randomization to approximately 24 months
measure: EFS Based on PIK3CA Mutation Status
timeFrame: From randomization to first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause (up to approximately 54 months)
measure: DFS Based on PIK3CA Mutation Status
timeFrame: Time from surgery to first documented disease recurrence or death from any cause (up to approximately 54 months)
measure: OS Based on PIK3CA Mutation Status
timeFrame: From randomization to date of death from any cause (up to approximately 54 months)
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: HCA Midwest Division
state: Missouri
city: New York
country: United States
facility: New York University Medical Center PRIME; NYU Langone Medical Center
state: New York
city: Nashville
country: United States
facility: Tennessee Oncology - Nashville
state: Tennessee
city: Salvador
country: Brazil
facility: Hospital Sao Rafael - HSR
state: BA
city: Goiania
country: Brazil
facility: Hospital Araujo Jorge; Departamento de Ginecologia E Mama
state: GO
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas - PUCRS
state: RS
city: Sao Paulo
country: Brazil
facility: Hospital Perola Byington
state: SP
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre-Calgary
state: Alberta
city: Vancouver
country: Canada
facility: BCCA-Vancouver Cancer Centre
state: British Columbia
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Quebec City
country: Canada
facility: Hopital du Saint Sacrement
state: Quebec
city: Brno
country: Czechia
facility: Masarykuv onkologicky ustav
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc; Onkologicka klinika
city: Essen
country: Germany
facility: Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum
city: Freiburg
country: Germany
facility: Praxis für Interdisziplinäre Onkologie und Hämatologie GbR
city: Hamburg
country: Germany
facility: Kooperatives Mammazentrum Hamburg Krankenhaus Jerusalem
city: Leipzig
country: Germany
facility: Sankt Elisabeth Krankenhaus; Gynaekology
city: Muenchen
country: Germany
facility: Rotkreuzklinikum München; Frauenklinik
city: Münster
country: Germany
facility: Universitätsklinikum Münster; Klinik für Frauenheilkunde und Geburtshilfe
city: Paderborn
country: Germany
facility: St. Vincenz-Krankenhaus Paderborn; Haus 3 Frauenklinik
city: Ulm
country: Germany
facility: Universitätsfrauenklinik Ulm; Abteilung Gynäkologie
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Irccs Fondazione g. PASCALE;U.O.C. Oncologia Medica Senologica
state: Campania
city: Napoli
country: Italy
facility: Università degli Studi Federico II; Clinica di Oncologia Medica
state: Campania
city: Aviano
country: Italy
facility: Irccs Centro Di Riferimento Oncologico (CRO); Dipartimento Di Oncologia Medica
state: Friuli-Venezia Giulia
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
state: Lazio
city: Brescia
country: Italy
facility: ASST DEGLI SPEDALI CIVILI DI BRESCIA; Oncologia Medica
state: Lombardia
city: Monza
country: Italy
facility: ASST DI MONZA; Oncologia Medica
state: Lombardia
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia
state: Lombardia
city: Candiolo
country: Italy
facility: Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico
state: Piemonte
city: Padova
country: Italy
facility: IOV - Istituto Oncologico Veneto - IRCCS; Oncologia Medica II
state: Veneto
city: Ehime
country: Japan
facility: National Hospital Organization Shikoku Cancer Center
city: Hiroshima
country: Japan
facility: Hiroshima City Hiroshima Citizens Hospital
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Hokkaido
country: Japan
facility: National Hospital Organization Hokkaido Cancer Center
city: Hyogo
country: Japan
facility: Hyogo Cancer Center
city: Kanagawa
country: Japan
facility: Kanagawa Cancer Center
city: Kanagawa
country: Japan
facility: Tokai University Hospital
city: Kumamoto
country: Japan
facility: Kumamoto Shinto General Hospital
city: Miyagi
country: Japan
facility: Fukushima Medical University Hospital
city: Niigata
country: Japan
facility: Niigata Cancer Center Hospital
city: Saitama
country: Japan
facility: Saitama Medical University International Medical Center
city: Tokyo
country: Japan
facility: Toranomon Hospital
city: Tokyo
country: Japan
facility: Showa University Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Centre; Oncology
city: ?ód?
country: Poland
facility: Instytut "Centrum Zdrowia Matki Polki"; Klinika Onkologii
city: Gliwice
country: Poland
facility: Narodowy Inst.Onkol.im.Sklodowskiej-Curie Panstw.Inst.Bad Gliwice; Centr.Diagn.i Lecz.Chor.Piersi
city: Grudzi?dz
country: Poland
facility: Regionalny Szpital Specjalistyczny im. W. Bieganskiego; Oddzial Onkologii Klinicznej
city: Kraków
country: Poland
facility: Szpital Uniwersytecki w Krakowie, Oddzia? Kliniczny Kliniki Onkologii
city: Warszawa
country: Poland
facility: Narodowy Inst.Onkologii im.Sklodowskiej-Curie Panstw.Inst.Bad; Klinika Nowtw.Piersi i Chir.Rekonstr
city: Obninsk
country: Russian Federation
facility: FSBI National Medical Research Radiological Center; A. TSYB MEDICAL RADIOLOGICAL RESEARCH CENTER
state: Kaluga
city: Moscow
country: Russian Federation
facility: City Clinical Oncology Hospital
state: Moskovskaja Oblast
city: Moskva
country: Russian Federation
facility: SBIH "Moscow Clinical Scientific and Practical Center named after A.S. Loginov of DHM"
state: Moskovskaja Oblast
city: Moskva
country: Russian Federation
facility: Blokhin Cancer Research Center; Combined Treatment
state: Moskovskaja Oblast
city: Kazan
country: Russian Federation
facility: Republican Clinical Oncology Dispensary of Ministry of Healthcare of Tatarstan Republic
state: Tatarstan
city: Sankt Petersburg
country: Russian Federation
facility: Petrov Research Inst. of Oncology
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia
state: Barcelona
city: Sant Andreu de La Barca
country: Spain
facility: Hospital Univ Vall d'Hebron; Servicio de Oncologia
state: Barcelona
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de La Arrixaca; Servicio De Oncologia
state: Murcia
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra; Servicio de Oncologia
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial; Servicio de Hematología y Oncología
city: Burgos
country: Spain
facility: Complejo Asistencial Universitario De Burgos; Servicio de Oncologia
city: Granada
country: Spain
facility: Hospital Clinico de Granada; Servicio de Oncologia
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia
city: Lerida
country: Spain
facility: Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Oncologia
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra Madrid; Servicio de Oncología
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal; Servicio de Oncología
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena; Servicio de Oncologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio; Servicio de Oncologia
city: Taichung
country: Taiwan
facility: China Medical University Hospital; Surgery
city: Taipei City
country: Taiwan
facility: Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital; Dept of Surgery
city: Taoyuan
country: Taiwan
facility: Chang Gung Medical Foundation - Linkou; Dept of Surgery
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Huober J, Barrios CH, Niikura N, Jarzab M, Chang YC, Huggins-Puhalla SL, Pedrini J, Zhukova L, Graupner V, Eiger D, Henschel V, Gochitashvili N, Lambertini C, Restuccia E, Zhang H; IMpassion050 Trial Investigators. Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial. J Clin Oncol. 2022 Sep 1;40(25):2946-2956. doi: 10.1200/JCO.21.02772. Epub 2022 Jun 28.