A Study to Investigate Atezolizumab and Chemotherapy Compared With Placebo and Chemotherapy in the Neoadjuvant Setting in Participants With Early Stage Triple Negative Breast Cancer

Triple-negative Breast Cancer Clinical Trial

— IMpassion031  

Official title:

A Phase III Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Neoadjuvant Anthracycline/Nab-Paclitaxel-Based Chemotherapy Compared With Placebo and Chemotherapy in Patients With Primary Invasive Triple-Negative Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03197935
• Other study ID #: WO39392
• Secondary ID: 2016-004734-22
• Status: Completed
• Phase: Phase 3
• Start date: July 24, 2017
• Est. completion date: September 28, 2022

Study information

• Verified date: October 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a global Phase III, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy and safety of neoadjuvant treatment with atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1] antibody) and nab-paclitaxel followed by doxorubicin and cyclophosphamide (nab-pac-AC), or placebo and nab-pac-AC in participants eligible for surgery with initial clinically assessed triple-negative breast cancer (TNBC).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 333
• Est. completion date: September 28, 2022
• Est. primary completion date: April 3, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Histologically documented TNBC (negative human epidermal growth factor receptor 2 [HER2], estrogen receptor [ER], and progesterone receptor [PgR] status)

• Confirmed tumor programmed death-ligand 1 (PD-L1) evaluation as documented through central testing of a representative tumor tissue specimen

• Primary breast tumor size of greater than (>) 2 centimeters (cm) by at least one radiographic or clinical measurement

• Stage at presentation: cT2-cT4, cN0-cN3, cM0

• Participant agreement to undergo appropriate surgical management including axillary lymph node surgery and partial or total mastectomy after completion of neoadjuvant treatment

• Baseline left ventricular ejection fraction (LVEF) greater than or equal to (>=) 53 percent (%) measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scans

• Adequate hematologic and end-organ function

• Representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen in paraffin blocks (preferred) or at least 20 unstained slides, with an associated pathology report documenting ER, PgR, and HER2 negativity

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm

• Women who are not postmenopausal or have undergone a sterilization procedure must have a negative serum pregnancy test result within 14 days prior to initiation of study drug

Exclusion criteria:

• Prior history of invasive breast cancer

• Stage 4 (metastatic) breast cancer

• Prior systemic therapy for treatment and prevention of breast cancer

• Previous therapy with anthracyclines or taxanes for any malignancy

• History of ductal carcinoma in situ (DCIS), except for participants treated exclusively with mastectomy >5 years prior to diagnosis of current breast cancer

• History of pleomorphic lobular carcinoma in situ (LCIS), except for participants surgically managed >5 years prior to diagnosis of current breast cancer

• Bilateral breast cancer

• Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes

• 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 with a negligible risk of metastasis or death

• Cardiopulmonary dysfunction

• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

• Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells

• Known allergy or hypersensitivity to the components of the formulations of atezolizumab, nab-paclitaxel, cyclophosphamide, or doxorubicin, filgrastim or pegfilgrastim

• Active or history of autoimmune disease or immune deficiency diseases except history of autoimmune-related hypothyroidism, controlled Type 1 diabetes mellitus, and dermatologic manifestations of eczema, psoriasis, lichen simplex chronicus, or vitiligo (e.g., participants with psoriatic arthritis are excluded)

• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted

• Positive human immunodeficiency virus (HIV) test at screening

• Active hepatitis B and hepatitis C virus infection

• Active tuberculosis

• Severe infections within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia

• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment, except prophylactic antibiotics

• Major surgical procedure within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study

• Prior allogeneic stem cell or solid organ transplantation

• Administration of a live attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study

• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk from treatment complications

• Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint-blockade therapies, including anti-cluster of differentiation 40 (anti-CD40), anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-L1 therapeutic antibodies

• Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to initiation of study treatment

• Treatment with systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressive medications during the study

• History of cerebrovascular accident within 12 months prior to randomization

• Pregnant or lactating, or intending to become pregnant during the study

Related Conditions & MeSH terms

• Breast Neoplasms
• Triple Negative Breast Neoplasms
• Triple-negative Breast Cancer

Intervention

Drug:
• Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody
Atezolizumab was administered as per schedule described in respective arm.
• Placebo
Placebo matched to atezolizumab was administered as per schedule described in respective arm.
• Nab-paclitaxel
Nab-paclitaxel was administered as per schedule described in the arms.
• Doxorubicin
Doxorubicin was administered as per schedule described in the arms.
• Cyclophosphamide
Cyclophosphamide was administered as per schedule described in the arms.
• Filgrastim
Filgrastim was administered according to local prescribing information as determined by the Investigator for 4 doses after completion of initial 12 weeks.
• Pegfilgrastim
Pegfilgrastim was administered according to local prescribing information as determined by the Investigator for 4 doses after completion of initial 12 weeks.

Locations

Country	Name	City	State
Australia	Fiona Stanley Hospital; FSH Cancer Centre Clinical Trials Unit	Bull Creek	Western Australia
Australia	Monash Medical Centre	Clayton	Victoria
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Belgium	UZ Leuven Gasthuisberg	Leuven
Belgium	Clinique Ste-Elisabeth	Namur
Belgium	Sint Augustinus Wilrijk	Wilrijk
Brazil	Iop Instituto de Oncologia Do Parana	Curitiba	PR
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	Clinicas Oncologicas Integradas - COI	Rio De Janeiro	RJ
Brazil	Santa Casa de Misericordia de Salvador	Salvador	BA
Brazil	Clinica de Pesquisa e Centro de Estudos em Oncologia Ginecologica e Mamaria Ltda	Sao Paulo	SP
Brazil	CETUS Hospital Dia Oncologia	Uberaba	MG
Canada	Hopital Sacre-Coeur Research Centre	Montreal	Quebec
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Hopital du Saint Sacrement	Quebec City	Quebec
Germany	Hochwaldkrankenhaus	Bad Nauheim
Germany	Ambulantes Tumorzentrum Spandau; Dres. Benno Mohr und Uwe Peters	Berlin
Germany	Praxisklinik Krebsheilkunde für Frauen / Brustzentrum (Dres. Kittel/Klare)	Berlin
Germany	Onkologische Schwerpunktpraxis Bielefeld	Bielefeld
Germany	Luisenkrankenhaus GmbH & Co. KG., Brustzentrum	Düsseldorf
Germany	Evangelische Kliniken Gelsenkirchen GmbH; Brustzentrum	Gelsenkirchen
Germany	Kooperatives Mammazentrum Hamburg Krankenhaus Jerusalem	Hamburg
Germany	Diakovere Henriettenstift, Frauenklinik	Hannover
Germany	Dres. Andreas Köhler und Roswitha Fuchs	Langen
Germany	St. Elisabeth-Krankenhaus, Senologie/Brustzentrum	Leipzig
Germany	Klinik & Poliklinik für Frauenheilkunde und Geburtshilfe, Campus Innenstadt	München
Germany	Universitätsklinikum Münster; Klinik für Frauenheilkunde und Geburtshilfe	Münster
Germany	Medizinisches Versorgungszentrum am Klinikum Oldenburg GmbH	Oldenburg
Italy	Irccs Ospedale San Raffaele	Milano	Lombardia
Italy	Ospedale San Gerardo	Monza	Lombardia
Italy	Azienda ULSS 8 Berica; Oncologia Medica - Ospedlae di Vicenza	Vicenza	Veneto
Japan	Aichi Cancer Center Hospital	Aichi
Japan	National Hospital Organization Shikoku Cancer Center	Ehime
Japan	Fukushima Medical University Hospital	Fukushima
Japan	Hiroshima City Hiroshima Citizens Hospital; Breast Surgery	Hiroshima
Japan	Kanagawa Cancer Center	Kanagawa
Japan	Tokai University Hospital	Kanagawa
Japan	National Hospital Organization Osaka National Hospital; Breast Surgery	Osaka
Japan	St. Luke's Internat. Hospital, Breast Surgical Oncology	Tokyo
Japan	The Cancer Inst. Hosp. of JFCR; Breast Oncology Center	Tokyo
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Poland	Narodowy Inst.Onkologii im.Sklodowskiej-Curie Panstw.Inst.Bad; Klinika Nowtw.Piersi i Chir.Rekonstr	Warszawa
Poland	Dolnoslaskie Centrum Onkologii, Pulmonologii i Hematologii; Oddz. Onkologii Klin. i Chemioterapii	Wroc?aw
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Spain	Hospital Universitario Virgen del Rocio; Servicio de Oncologia	Sevilla
Taiwan	Mackay Memorial Hospital; Dept of Surgery	Taipei
Taiwan	VETERANS GENERAL HOSPITAL; Department of General Surgery	Taipei
Taiwan	Chang Gung Medical Foundation Linkou Branch	Taoyuan City
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Barts & London School of Med; Medical Oncology	London
United Kingdom	Freeman Hospital	Newcastle upon Tyne
United States	Mercy Medical Center	Baltimore	Maryland
United States	Northwest Georgia Oncology Centers, a Service of Wellstar Cobb Hospital	Carrollton	Georgia
United States	Tennessee Oncology - Chattanooga; Tennessee Oncology - East Third Street	Chattanooga	Tennessee
United States	The Center for Cancer and Blood Disorders - Fort Worth	Fort Worth	Texas
United States	HCA Midwest Division	Kansas City	Missouri
United States	Tennessee Oncology	Nashville	Tennessee
United States	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Norwalk Hospital	Norwalk	Connecticut
United States	Stanford University Medical Center	Palo Alto	California
United States	The Valley Hospital; Valley Medical Group	Paramus	New Jersey
United States	Cancer Care Northwest	Spokane	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Germany,  Italy,  Japan,  Korea, Republic of,  Poland,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System in ITT Population	Number of participants with Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System in ITT Population. pCR is defined as eradication of invasive tumor from both breast and lymph nodes (ypT0/is ypN0). pCR was evaluated for each participant after neoadjuvant study treatment and surgery. Participants whose pCR assessment was missing will be counted as not achieving a pCR.	After neoadjuvant study treatment and surgery, up to primary analysis data cut off on 03 ApriI 2020
Primary	Number of Participants With pCR in Subpopulation With PD-L1-Positive Tumor Status (Tumor-infiltrating Immune Cell [IC] 1/2/3) Using AJCC Staging System	Number of participants with Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System in the subpopulation with programmed death-ligand1 (PD-L1)-positive tumor status(tumor-infiltrating immune cell [IC] IC1/2/3) . pCR is defined as eradication of invasive tumor from both breast and lymph nodes (ypT0/is ypN0). pCR was evaluated for each participant after neoadjuvant study treatment and surgery. Participants whose pCR assessment was missing will be counted as not achieving a pCR.	After neoadjuvant study treatment and surgery, up to primary analysis data cut off on 03 ApriI 2020
Secondary	Event-Free Survival (EFS) in All Participants	Event-free survival (EFS) defined as the time from randomization to the first documented occurrence of disease recurrence, disease progression, or death from any cause in all participants. Recurrent disease includes local, regional, or distant recurrence and contralateral breast cancer. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or recurrent disease.	From randomization and up to study final analysis data cut off on 28 September 2022.
Secondary	Event-Free Survival (EFS) in Subpopulation With PD-L1-Postive Tumor Status	Event-free survival (EFS) defined as the time from randomization to the first documented occurrence of disease recurrence, disease progression, or death from any cause in the subpopulation with PD-L1-positive tumor status. Recurrent disease includes local, regional, or distant recurrence and contralateral breast cancer. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or recurrent disease.	From randomization and up to study final analysis data cut off on 28 September 2022.
Secondary	Disease-Free Survival (DFS) in All Participants Who Undergo Surgery	Disease-free survival (DFS) defined as the time from surgery to the first documented disease recurrence or death from any cause, whichever occurs first. DFS is analyzed with the use of the same methodology as specified for EFS for all participants.	From surgery and up to study final analysis data cut off on 28 September 2022.
Secondary	Disease-Free Survival (DFS) in Subpopulation of Participants With PD-L1-Positive Tumor Status Who Undergo Surgery	Disease-free survival (DFS) defined as the time from surgery to the first documented disease recurrence or death from any cause, whichever occurs first. DFS is analyzed with the use of the same methodology as specified for EFS for the subpopulation of participants with PD-L1-positive tumor status.	From surgery and up to study final analysis data cut off on 28 September 2022.
Secondary	Overall Survival (OS) in All Participants	Overall survival (OS) defined as the time from randomization to the date of death from any cause in all participants.	From randomization and up to study final analysis data cut off on 28 September 2022.
Secondary	Overall Survival (OS) in Subpopulation With PD-L1-Positive Tumor Status	Overall survival (OS) defined as the time from randomization to the date of death from any cause in the subpopulation with PD-L1-positive tumor status.	From randomization and up to study final analysis data cut off on 28 September 2022.
Secondary	Mean Scores for Function (Role/Physical) and GHS/HRQoL by Cycle and Between Treatment Arms as Assessed by the EORTC QLQ-C30	Mean score in function (role, physical) and global health status(GHS)/ health-related quality of life (HRQoL) by cycle and between treatment arms as assessed by the functional and HRQoL scales of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core30(QLQ C30). The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms).	From randomization and up to study final analysis data cut off on 28 September 2022.
Secondary	Mean Change From Baseline Scores for Function (Role, Physical) and GHS/HRQoL by Cycle and Between Treatment Arms as Assessed by the EORTC QLQ-C30	Mean change from baseline score in function (role, physical) and global health status(GHS)/ health-related quality of life (HRQoL) by cycle and between treatment arms as assessed by the functional and HRQoL scales of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core30(QLQ C30).	From randomization and up to study final analysis data cut off on 28 September 2022.
Secondary	Percentage of Participants With at Least One Adverse Events (AEs)	Percentage of participants with at least one adverse event.	From randomization and up to study final analysis data cut off on 28 September 2022.
Secondary	Minimum Observed Serum Atezolizumab Concentration (Cmin)	Minimum observed serum atezolizumab concentration.	Pre-dose on Day 1 of Cycles 2, 3, 4, 6, 8, 12, and 16 (cycle length = 28 days from Cycles 1 to 5, and 21 days from Cycles 6 to 16)
Secondary	Maximum Observed Serum Atezolizumab Concentration (Cmax)	Maximum observed atezolizumab concentration (Cmax).	Day 1 of Cycle 1 post dose (cycle length = 28 days)
Secondary	Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab	Percentage of participants with anti-drug antibodies (ADAs) to atezolizumab.	Baseline up to approximately 20 months