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

Breast Cancer Clinical Trial

— IMpassion050  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03726879
• Other study ID #: BO40747
• Status: Completed
• Phase: Phase 3
• Start date: January 11, 2019
• Est. completion date: August 24, 2023

Study information

• Verified date: January 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 454
• Est. completion date: August 24, 2023
• Est. primary completion date: February 5, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Atezolizumab
Atezolizumab will be administered as per the schedule specified in the respective arm.
• Placebo
Placebo matched to atezolizumab will be administered as per the schedule specified in the respective arm.
• Doxorubicin
Doxorubicin will be administered as per the schedule specified in the respective arm.
• Cyclophosphamide
Cyclophosphamide will be administered as per the schedule specified in the respective arm.
• Paclitaxel
Paclitaxel will be administered as per the schedule specified in the respective arm.
• Trastuzumab
Trastuzumab will be administered as per the schedule specified in the respective arm.
• Pertuzumab
Pertuzumab will be administered as per the schedule specified in the respective arm.
• Trastuzumab Emtansine
Participants without pCR have the option of receiving adjuvant atezolizumab/placebo combined with Trastuzumab Emtansine 3.6 mg/kg IV Q3W.

Locations

Country	Name	City	State
Brazil	Hospital Araujo Jorge; Departamento de Ginecologia E Mama	Goiania	GO
Brazil	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS
Brazil	Hospital Sao Lucas - PUCRS	Porto Alegre	RS
Brazil	Hospital Sao Rafael - HSR	Salvador	BA
Brazil	Hospital Perola Byington	Sao Paulo	SP
Canada	Tom Baker Cancer Centre-Calgary	Calgary	Alberta
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Hopital du Saint Sacrement	Quebec City	Quebec
Canada	BCCA-Vancouver Cancer Centre	Vancouver	British Columbia
Czechia	Masarykuv onkologicky ustav	Brno
Czechia	Fakultni nemocnice Olomouc; Onkologicka klinika	Olomouc
Germany	Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum	Essen
Germany	Praxis für Interdisziplinäre Onkologie und Hämatologie GbR	Freiburg
Germany	Kooperatives Mammazentrum Hamburg Krankenhaus Jerusalem	Hamburg
Germany	Sankt Elisabeth Krankenhaus; Gynaekology	Leipzig
Germany	Rotkreuzklinikum München; Frauenklinik	Muenchen
Germany	Universitätsklinikum Münster; Klinik für Frauenheilkunde und Geburtshilfe	Münster
Germany	St. Vincenz-Krankenhaus Paderborn; Haus 3 Frauenklinik	Paderborn
Germany	Universitätsfrauenklinik Ulm; Abteilung Gynäkologie	Ulm
Italy	Irccs Centro Di Riferimento Oncologico (CRO); Dipartimento Di Oncologia Medica	Aviano	Friuli-Venezia Giulia
Italy	ASST DEGLI SPEDALI CIVILI DI BRESCIA; Oncologia Medica	Brescia	Lombardia
Italy	Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico	Candiolo	Piemonte
Italy	ASST DI MONZA; Oncologia Medica	Monza	Lombardia
Italy	Istituto Nazionale Tumori Irccs Fondazione g. PASCALE;U.O.C. Oncologia Medica Senologica	Napoli	Campania
Italy	Università degli Studi Federico II; Clinica di Oncologia Medica	Napoli	Campania
Italy	IOV - Istituto Oncologico Veneto - IRCCS; Oncologia Medica II	Padova	Veneto
Italy	Policlinico Universitario Agostino Gemelli	Roma	Lazio
Italy	Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia	Rozzano	Lombardia
Japan	National Hospital Organization Shikoku Cancer Center	Ehime
Japan	Fukushima Medical University Hospital	Fukushima
Japan	Hiroshima City Hiroshima Citizens Hospital	Hiroshima
Japan	Hiroshima University Hospital	Hiroshima
Japan	National Hospital Organization Hokkaido Cancer Center	Hokkaido
Japan	Hyogo Cancer Center	Hyogo
Japan	Kanagawa Cancer Center	Kanagawa
Japan	Tokai University Hospital	Kanagawa
Japan	Kumamoto Shinto General Hospital	Kumamoto
Japan	Niigata Cancer Center Hospital	Niigata
Japan	Saitama Medical University International Medical Center	Saitama
Japan	Showa University Hospital	Tokyo
Japan	Toranomon Hospital	Tokyo
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Samsung Medical Centre; Oncology	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Poland	Instytut "Centrum Zdrowia Matki Polki"; Klinika Onkologii	?ód?
Poland	Narodowy Inst.Onkol.im.Sklodowskiej-Curie Panstw.Inst.Bad Gliwice; Centr.Diagn.i Lecz.Chor.Piersi	Gliwice
Poland	Regionalny Szpital Specjalistyczny im. W. Bieganskiego; Oddzial Onkologii Klinicznej	Grudzi?dz
Poland	Szpital Uniwersytecki w Krakowie, Oddzia? Kliniczny Kliniki Onkologii	Kraków
Poland	Narodowy Inst.Onkologii im.Sklodowskiej-Curie Panstw.Inst.Bad; Klinika Nowtw.Piersi i Chir.Rekonstr	Warszawa
Russian Federation	Republican Clinical Oncology Dispensary of Ministry of Healthcare of Tatarstan Republic	Kazan	Tatarstan
Russian Federation	City Clinical Oncology Hospital	Moscow	Moskovskaja Oblast
Russian Federation	Blokhin Cancer Research Center; Combined Treatment	Moskva	Moskovskaja Oblast
Russian Federation	SBIH "Moscow Clinical Scientific and Practical Center named after A.S. Loginov of DHM"	Moskva	Moskovskaja Oblast
Russian Federation	FSBI National Medical Research Radiological Center; A. TSYB MEDICAL RADIOLOGICAL RESEARCH CENTER	Obninsk	Kaluga
Russian Federation	Petrov Research Inst. of Oncology	Sankt Petersburg
Spain	Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia	Badalona	Barcelona
Spain	Hospital Clínic i Provincial; Servicio de Hematología y Oncología	Barcelona
Spain	Complejo Asistencial Universitario De Burgos; Servicio de Oncologia	Burgos
Spain	Hospital Universitario Virgen de La Arrixaca; Servicio De Oncologia	El Palmar	Murcia
Spain	Hospital Clinico de Granada; Servicio de Oncologia	Granada
Spain	Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia	Jaen
Spain	Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Oncologia	Lerida
Spain	Centro Integral Oncologico Clara Campal; Servicio de Oncología	Madrid
Spain	Clinica Universidad de Navarra Madrid; Servicio de Oncología	Madrid
Spain	Clinica Universitaria de Navarra; Servicio de Oncologia	Pamplona	Navarra
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Sant Andreu de La Barca	Barcelona
Spain	Hospital Universitario Virgen del Rocio; Servicio de Oncologia	Sevilla
Spain	Hospital Universitario Virgen Macarena; Servicio de Oncologia	Sevilla
Taiwan	China Medical University Hospital; Surgery	Taichung
Taiwan	Mackay Memorial Hospital; Dept of Surgery	Taipei
Taiwan	Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology	Taipei City
Taiwan	Chang Gung Medical Foundation - Linkou; Dept of Surgery	Taoyuan
United States	HCA Midwest Division	Kansas City	Missouri
United States	Tennessee Oncology	Nashville	Tennessee
United States	New York University Medical Center PRIME; NYU Langone Medical Center	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Hoffmann-La Roche	Chugai Pharmaceutical

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Czechia,  Germany,  Italy,  Japan,  Korea, Republic of,  Poland,  Russian Federation,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Pathological Complete Response (pCR) in the PD-L1-Positive Population (IC 1/2/3)	pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). Treatment comparison was made using Cochran-Mantel-Haenszel test stratified by disease stage (T2 vs. T3-4) and hormone receptor status (estrogen receptor (ER) positive and/or progesterone receptor (PgR) positive vs. ER negative and PgR negative).	From randomization to approximately 6 months
Primary	pCR in the ITT Population	pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition). Treatment comparison was made using Cochran-Mantel-Haenszel test stratified by disease stage (T2 vs. T3-4) and hormone receptor status (ER positive and/or PgR positive vs. ER negative and PgR negative).	From randomization to approximately 6 months
Secondary	Percentage of Participants With pCR Based on Hormone Receptor Status	pCR (ypT0/is ypN0) based upon hormone receptor status (estrogen receptor [ER]/progesterone receptor [PgR] positive or ER/PgR negative).	From randomization to approximately 24 months
Secondary	Percentage of Participants With pCR in the PD-L1-Negative Population	pCR (ypT0/is ypN0) in the IC 0 Population	From randomization to approximately 24 months
Secondary	Event-Free Survival (EFS)	EFS defined as the time from randomization to the first documented disease recurrence, unequivocal tumor progression determined by the treating investigator, or death from any cause, whichever occurs first, in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3).	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)
Secondary	Disease-Free Survival (DFS)	DFS defined as the time from surgery to the first documented disease recurrence or death from any cause, whichever occurs first, in all patients who undergo surgery and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3).	Time from surgery to first documented disease recurrence or death from any cause (up to approximately 54 months)
Secondary	Overall Survival (OS)	OS defined as the time from randomization to death from any cause in all patients and based upon hormone receptor status (ER/PgR positive or ER/PgR negative) and PD-L1 status (IC 0; IC 1/2/3).	From randomization to date of death from any cause (up to approximately 54 months)
Secondary	Mean Changes From Baseline in Function (Role, Physical)	EORTC QLQ-C30 is a self-reported questionnaire that included functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), global health scale/quality of life (GHS/QOL) and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Questions 1-28 on the QLQ-C30 were on a 4-point scale (1=Not at All to 4=Very Much). Questions 29-30 (GHS scale) were on a 7-point scale (1=Very Poor to 7=Excellent). For this instrument, GHS/QOL and functional scales were linearly transformed so each score ranged 0-100, where lower scores indicate poorer functioning (e.g., worsening) and higher scores indicate better functioning (e.g., improvement).	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.
Secondary	Mean Changes From Baseline in Global Health Status	EORTC QLQ-C30 is a self-reported questionnaire that included functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), GHS/QOL and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Questions 1-28 on the QLQ-C30 were on a 4-point scale (1=Not at All to 4=Very Much). Questions 29-30 (GHS scale) were on a 7-point scale (1=Very Poor to 7=Excellent). For this instrument, GHS/QOL and functional scales were linearly transformed so each score ranged 0-100, where lower scores indicate poorer functioning (e.g., worsening) and higher scores indicate better functioning (e.g., improvement).	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.
Secondary	Percentage of Participants With Adverse Events		From randomization up until clinical cut-off date (approximately 24 months)
Secondary	Maximum Serum Concentration (Cmax) of Atezolizumab	Cmax is the maximum (or peak) concentration that a study drug achieves in the body.	30 minutes post infusion on Day 1 Cycle (C) 1.
Secondary	Minimum Serum Concentration (Cmin) of Atezolizumab	Cmin is the minimum (or trough) concentration that a study drug achieves in the body.	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).
Secondary	Trough Concentration (Ctrough) for Pertuzumab and Trastuzumab in Serum		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).
Secondary	Cmax of Trastuzumab Emtansine in Serum	Cmax is the maximum (or peak) concentration that a study drug achieves in the body.	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).
Secondary	Cmin of Trastuzumab Emtansine in Serum	Cmin is the minimum (or trough) concentration that a study drug achieves in the body.	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).
Secondary	Number of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs) to Atezolizumab	Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected).	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).
Secondary	Number of Participants With Treatment-Emergent ADAs to Trastuzumab	Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected).	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).
Secondary	Number of Participants With Treatment-Emergent ADAs to Pertuzumab	Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected).	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).
Secondary	Number of Participants With Treatment-Emergent ADAs to Trastuzumab Emtansine	Participants were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be treatment-emergent ADA-negative if they were ADA-negative or were missing data at baseline and all post-baseline samples were negative, or if they were ADA-positive at baseline but did not have any post-baseline samples with a titer that was at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected).	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).
Secondary	Percentage of Participants With pCR Based on PIK3CA Mutation Status	pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0/is ypN0 in the current American Joint Committee on Cancer [AJCC] staging system, 8th edition).	From randomization to approximately 24 months
Secondary	EFS Based on PIK3CA Mutation Status		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)
Secondary	DFS Based on PIK3CA Mutation Status		Time from surgery to first documented disease recurrence or death from any cause (up to approximately 54 months)
Secondary	OS Based on PIK3CA Mutation Status		From randomization to date of death from any cause (up to approximately 54 months)