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 (IMpassion031)

• ClinicalTrials.gov Identifier: NCT03197935
• Recruitment Status: Completed
• First Posted: June 23, 2017
• Results First Posted: June 2, 2021
• Last Update Posted: October 26, 2023
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: June 21, 2017
• First Posted Date: June 23, 2017
• Results First Submitted Date: March 29, 2021
• Results First Posted Date: June 2, 2021
• Last Update Posted Date: October 26, 2023
• Actual Study Start Date: July 24, 2017
• Actual Primary Completion Date: April 3, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 17, 2023)

• Number of Participants With Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System in ITT Population [ Time Frame: After neoadjuvant study treatment and surgery, up to primary analysis data cut off on 03 ApriI 2020 ]
  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.
• 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 [ Time Frame: After neoadjuvant study treatment and surgery, up to primary analysis data cut off on 03 ApriI 2020 ]
  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.

• Original Primary Outcome Measures (submitted: June 21, 2017): Percentage of Participants with Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System [ Time Frame: Week 21 ]

Current Secondary Outcome Measures (submitted: October 17, 2023)

• Event-Free Survival (EFS) in All Participants [ Time Frame: From randomization and up to study final analysis data cut off on 28 September 2022. ]
  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.
• Event-Free Survival (EFS) in Subpopulation With PD-L1-Postive Tumor Status [ Time Frame: From randomization and up to study final analysis data cut off on 28 September 2022. ]
  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.
• Disease-Free Survival (DFS) in All Participants Who Undergo Surgery [ Time Frame: From surgery and up to study final analysis data cut off on 28 September 2022. ]
  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.
• Disease-Free Survival (DFS) in Subpopulation of Participants With PD-L1-Positive Tumor Status Who Undergo Surgery [ Time Frame: From surgery and up to study final analysis data cut off on 28 September 2022. ]
  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.
• Overall Survival (OS) in All Participants [ Time Frame: From randomization and up to study final analysis data cut off on 28 September 2022. ]
  Overall survival (OS) defined as the time from randomization to the date of death from any cause in all participants.
• Overall Survival (OS) in Subpopulation With PD-L1-Positive Tumor Status [ Time Frame: From randomization and up to study final analysis data cut off on 28 September 2022. ]
  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.
• Mean Scores for Function (Role/Physical) and GHS/HRQoL by Cycle and Between Treatment Arms as Assessed by the EORTC QLQ-C30 [ Time Frame: From randomization and up to study final analysis data cut off on 28 September 2022. ]
  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).
• 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 [ Time Frame: From randomization and up to study final analysis data cut off on 28 September 2022. ]
  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).
• Percentage of Participants With at Least One Adverse Events (AEs) [ Time Frame: From randomization and up to study final analysis data cut off on 28 September 2022. ]
  Percentage of participants with at least one adverse event.
• Minimum Observed Serum Atezolizumab Concentration (Cmin) [ Time Frame: 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) ]
  Minimum observed serum atezolizumab concentration.
• Maximum Observed Serum Atezolizumab Concentration (Cmax) [ Time Frame: Day 1 of Cycle 1 post dose (cycle length = 28 days) ]
  Maximum observed atezolizumab concentration (Cmax).
• Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab [ Time Frame: Baseline up to approximately 20 months ]
  Percentage of participants with anti-drug antibodies (ADAs) to atezolizumab.

Original Secondary Outcome Measures (submitted: June 21, 2017)

• Percentage of Participants with pCR in Subpopulation with PD-L1-Selected Tumor Status (tumor-infiltrating immune cell [IC] 1/2/3) Using AJCC Staging System [ Time Frame: Week 21 ]
• Event-Free Survival (EFS) Using AJCC Staging System [ Time Frame: From randomization until documented disease recurrence, progression, or death from any cause (up to approximately 51 months) ]
• Overall survival (OS) [ Time Frame: From randomization to the date of death from any cause (up to approximately 51 months) ]
• Changes From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Score [ Time Frame: Baseline (Cycle 1 Day 1), and on Day 1 of every cycle thereafter (cycle length = 28 days from Cycles 1 to 5, and 21 days from Cycles 6 to 16) (up to approximately 15 months) ]
• Percentage of Participants with Adverse Events (AEs) [ Time Frame: Baseline up to approximately 51 months ]
• Serum Concentration of Atezolizumab [ Time Frame: Pre-infusion (0 hour), 30 minutes post-infusion on Week 1 Day 1; pre-infusion on Day 1 of Weeks 5, 9, 13, 21, 27, 39, 51; at treatment discontinuation (last dose = up to 15 months), 120 days after last dose (infusion length = 60 minutes) ]
• Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab [ Time Frame: Pre-infusion (0 hour) on Day 1 of Weeks 1, 5, 9, 13, 21, 27, 39, 51; at treatment discontinuation (last dose = up to 15 months), 120 days after last dose (infusion length = 60 minutes) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Triple-negative Breast Cancer

Intervention

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

Study Arms

• Experimental: Atezolizumab and Chemotherapy
  Participants received atezolizumab (840 milligrams [mg]) via intravenous (IV) infusion every 2 weeks in combination with nab-paclitaxel (125 milligrams per square meter [mg/m^2]) via IV infusion every week for 12 weeks, followed by atezolizumab (840 mg) every 2 weeks in combination with doxorubicin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants continued to receive unblinded atezolizumab post-surgery at a fixed dose of 1200 mg by IV infusion every 3 weeks for 11 doses, for a total of approximately 12 months of atezolizumab therapy.
  Interventions:

  • Drug: Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody
  • Drug: Nab-paclitaxel
  • Drug: Doxorubicin
  • Drug: Cyclophosphamide
  • Drug: Filgrastim
  • Drug: Pegfilgrastim
• Placebo Comparator: Placebo and Chemotherapy
  Participants received placebo matched to atezolizumab via IV infusion every 2 weeks in combination with nab-paclitaxel (125 mg/m^2) via IV infusion every week for 12 weeks, followed by placebo matched to atezolizumab every 2 weeks in combination with doxorubicin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants will be unblinded post-surgery and will continue to be followed.
  Interventions:

  • Drug: Placebo
  • Drug: Nab-paclitaxel
  • Drug: Doxorubicin
  • Drug: Cyclophosphamide
  • Drug: Filgrastim
  • Drug: Pegfilgrastim

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 29, 2021): 333
• Original Estimated Enrollment (submitted: June 21, 2017): 204
• Actual Study Completion Date: September 28, 2022
• Actual Primary Completion Date: April 3, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Brazil, Canada, Germany, Italy, Japan, Korea, Republic of, Poland, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03197935
• Other Study ID Numbers: WO39392; 2016-004734-22 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: October 2023