Clinical trial NCT03197935: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Triple-negative Breast Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-06-23
Enrollment: 333
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 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).


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System in ITT Population
timeFrame: After neoadjuvant study treatment and surgery, up to primary analysis data cut off on 03 ApriI 2020
measure: 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
timeFrame: After neoadjuvant study treatment and surgery, up to primary analysis data cut off on 03 ApriI 2020
Secondary outcomes:
measure: Event-Free Survival (EFS) in All Participants
timeFrame: From randomization and up to study final analysis data cut off on 28 September 2022.
measure: Event-Free Survival (EFS) in Subpopulation With PD-L1-Postive Tumor Status
timeFrame: From randomization and up to study final analysis data cut off on 28 September 2022.
measure: Disease-Free Survival (DFS) in All Participants Who Undergo Surgery
timeFrame: From surgery and up to study final analysis data cut off on 28 September 2022.
measure: Disease-Free Survival (DFS) in Subpopulation of Participants With PD-L1-Positive Tumor Status Who Undergo Surgery
timeFrame: From surgery and up to study final analysis data cut off on 28 September 2022.
measure: Overall Survival (OS) in All Participants
timeFrame: From randomization and up to study final analysis data cut off on 28 September 2022.
measure: Overall Survival (OS) in Subpopulation With PD-L1-Positive Tumor Status
timeFrame: From randomization and up to study final analysis data cut off on 28 September 2022.
measure: Mean Scores for Function (Role/Physical) and GHS/HRQoL by Cycle and Between Treatment Arms as Assessed by the EORTC QLQ-C30
timeFrame: From randomization and up to study final analysis data cut off on 28 September 2022.
measure: 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
timeFrame: From randomization and up to study final analysis data cut off on 28 September 2022.
measure: Percentage of Participants With at Least One Adverse Events (AEs)
timeFrame: From randomization and up to study final analysis data cut off on 28 September 2022.
measure: Minimum Observed Serum Atezolizumab Concentration (Cmin)
timeFrame: 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)
measure: Maximum Observed Serum Atezolizumab Concentration (Cmax)
timeFrame: Day 1 of Cycle 1 post dose (cycle length = 28 days)
measure: Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
timeFrame: Baseline up to approximately 20 months
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Norwalk
country: United States
facility: Norwalk Hospital
state: Connecticut
city: Carrollton
country: United States
facility: Northwest Georgia Oncology Centers, a Service of Wellstar Cobb Hospital
state: Georgia
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Kansas City
country: United States
facility: HCA Midwest Division
state: Missouri
city: Paramus
country: United States
facility: The Valley Hospital; Valley Medical Group
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chattanooga
country: United States
facility: Tennessee Oncology - Chattanooga; Tennessee Oncology - East Third Street
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Breast Center at One Hundred Oaks
state: Tennessee
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders - Fort Worth
state: Texas
city: Spokane
country: United States
facility: Cancer Care Northwest
state: Washington
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Bull Creek
country: Australia
facility: Fiona Stanley Hospital; FSH Cancer Centre Clinical Trials Unit
state: Western Australia
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Namur
country: Belgium
facility: Clinique Ste-Elisabeth
city: Wilrijk
country: Belgium
facility: Sint Augustinus Wilrijk
city: Salvador
country: Brazil
facility: Santa Casa de Misericordia de Salvador
state: BA
city: Goiania
country: Brazil
facility: Hospital Araujo Jorge; Departamento de Ginecologia E Mama
state: GO
city: Uberaba
country: Brazil
facility: CETUS Hospital Dia Oncologia
state: MG
city: Curitiba
country: Brazil
facility: Iop Instituto de Oncologia Do Parana
state: PR
city: Rio De Janeiro
country: Brazil
facility: Clinicas Oncologicas Integradas - COI
state: RJ
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas - PUCRS
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao
state: RS
city: Sao Paulo
country: Brazil
facility: Clinica de Pesquisa e Centro de Estudos em Oncologia Ginecologica e Mamaria Ltda
state: SP
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Montreal
country: Canada
facility: Hopital Sacre-Coeur Research Centre
state: Quebec
city: Quebec City
country: Canada
facility: Hopital du Saint Sacrement
state: Quebec
city: Bad Nauheim
country: Germany
facility: Hochwaldkrankenhaus
city: Berlin
country: Germany
facility: Praxisklinik Krebsheilkunde für Frauen / Brustzentrum (Dres. Kittel/Klare)
city: Berlin
country: Germany
facility: Ambulantes Tumorzentrum Spandau; Dres. Benno Mohr und Uwe Peters
city: Bielefeld
country: Germany
facility: Onkologische Schwerpunktpraxis Bielefeld
city: Düsseldorf
country: Germany
facility: Luisenkrankenhaus GmbH & Co. KG., Brustzentrum
city: Gelsenkirchen
country: Germany
facility: Evangelische Kliniken Gelsenkirchen GmbH; Brustzentrum
city: Hamburg
country: Germany
facility: Kooperatives Mammazentrum Hamburg Krankenhaus Jerusalem
city: Hannover
country: Germany
facility: Diakovere Henriettenstift, Frauenklinik
city: Langen
country: Germany
facility: Dres. Andreas Köhler und Roswitha Fuchs
city: Leipzig
country: Germany
facility: St. Elisabeth-Krankenhaus, Senologie/Brustzentrum
city: München
country: Germany
facility: Klinik & Poliklinik für Frauenheilkunde und Geburtshilfe, Campus Innenstadt
city: Münster
country: Germany
facility: Universitätsklinikum Münster; Klinik für Frauenheilkunde und Geburtshilfe
city: Oldenburg
country: Germany
facility: Medizinisches Versorgungszentrum am Klinikum Oldenburg GmbH
city: Milano
country: Italy
facility: Irccs Ospedale San Raffaele
state: Lombardia
city: Monza
country: Italy
facility: Ospedale San Gerardo
state: Lombardia
city: Vicenza
country: Italy
facility: Azienda ULSS 8 Berica; Oncologia Medica - Ospedlae di Vicenza
state: Veneto
city: Aichi
country: Japan
facility: Aichi Cancer Center Hospital
city: Ehime
country: Japan
facility: National Hospital Organization Shikoku Cancer Center
city: Fukushima
country: Japan
facility: Fukushima Medical University Hospital
city: Hiroshima
country: Japan
facility: Hiroshima City Hiroshima Citizens Hospital; Breast Surgery
city: Kanagawa
country: Japan
facility: Kanagawa Cancer Center
city: Kanagawa
country: Japan
facility: Tokai University Hospital
city: Osaka
country: Japan
facility: National Hospital Organization Osaka National Hospital; Breast Surgery
city: Tokyo
country: Japan
facility: St. Luke's Internat. Hospital, Breast Surgical Oncology
city: Tokyo
country: Japan
facility: The Cancer Inst. Hosp. of JFCR; Breast Oncology Center
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Warszawa
country: Poland
facility: Narodowy Inst.Onkologii im.Sklodowskiej-Curie Panstw.Inst.Bad; Klinika Nowtw.Piersi i Chir.Rekonstr
city: Wroc?aw
country: Poland
facility: Dolnoslaskie Centrum Onkologii, Pulmonologii i Hematologii; Oddz. Onkologii Klin. i Chemioterapii
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre; Servicio de Oncologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio; Servicio de Oncologia
city: Taipei
country: Taiwan
facility: VETERANS GENERAL HOSPITAL; Department of General Surgery
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital; Dept of Surgery
city: Taoyuan City
country: Taiwan
facility: Chang Gung Medical Foundation Linkou Branch
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: London
country: United Kingdom
facility: Barts & London School of Med; Medical Oncology
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020 Oct 10;396(10257):1090-1100. doi: 10.1016/S0140-6736(20)31953-X. Epub 2020 Sep 20.
citation: Perez-Garcia J, Soberino J, Racca F, Gion M, Stradella A, Cortes J. Atezolizumab in the treatment of metastatic triple-negative breast cancer. Expert Opin Biol Ther. 2020 Sep;20(9):981-989. doi: 10.1080/14712598.2020.1769063. Epub 2020 May 25.