Clinical Trials /

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

NCT03197935

Description:

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).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: WO39392
  • SECONDARY ID: 2016-004734-22
  • NCT ID: NCT03197935

Conditions

  • Triple-negative Breast Cancer

Interventions

DrugSynonymsArms
Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibodyAtezolizumab and Chemotherapy
PlaceboPlacebo and Chemotherapy
Nab-paclitaxelAtezolizumab and Chemotherapy
DoxorubicinAtezolizumab and Chemotherapy
CyclophosphamideAtezolizumab and Chemotherapy
FilgrastimAtezolizumab and Chemotherapy
PegfilgrastimAtezolizumab and Chemotherapy

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab and ChemotherapyExperimentalParticipants 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.
  • Atezolizumab (MPDL3280A), an engineered anti-PDL1 antibody
  • Nab-paclitaxel
  • Doxorubicin
  • Cyclophosphamide
  • Filgrastim
  • Pegfilgrastim
Placebo and ChemotherapyPlacebo ComparatorParticipants 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.
  • Placebo
  • Nab-paclitaxel
  • Doxorubicin
  • Cyclophosphamide
  • Filgrastim
  • Pegfilgrastim

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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 data cut-off on 03 ApriI 2020
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Event-Free Survival (EFS) in All Participants
Time Frame:Baseline up to approximately 63 months
Safety Issue:
Description:Event-free survival (EFS) defined as the time from randomization until documented disease recurrence, progression, or death from any cause in all participants. EFS events covered under "disease recurrence" will include local, regional, or distant recurrence and contralateral breast cancer. Ipsilateral or contralateral in situ disease and second primary non-breast cancers will not be counted as EFS events.
Measure:Event-Free Survival (EFS) in Subpopulation With PD-L1-Postive Tumor Status
Time Frame:Baseline up to approximately 63 months
Safety Issue:
Description:Event-free survival (EFS) defined as the time from randomization until documented disease recurrence, progression, or death from any cause in the subpopulation with PD-L1-positive tumor status. EFS events covered under "disease recurrence" will include local, regional, or distant recurrence and contralateral breast cancer. Ipsilateral or contralateral in situ disease and second primary non-breast cancers will not be counted as EFS events.
Measure:Disease-Free Survival (DFS) in All Participants Who Undergo Surgery
Time Frame:Baseline up to approximately 63 months
Safety Issue:
Description:Disease-free survival (DFS) defined as the time from surgery until documented disease recurrence or death from any cause in all patients (ITT population) who undergo surgery.
Measure:Disease-Free Survival (DFS) in Subpopulation of Participants With PD-L1-Positive Tumor Status Who Undergo Surgery
Time Frame:Baseline up to approximately 63 months
Safety Issue:
Description:Disease-free survival (DFS) defined as the time from surgery until documented disease recurrence or death from any cause in the subpopulation of participants with PD-L1-positive tumor status who undergo surgery.
Measure:Overall Survival (OS) in All Participants
Time Frame:Baseline up to approximately 63 months
Safety Issue:
Description:Overall survival (OS) defined as the time from randomization to the date of death from any cause in all participants.
Measure:Overall Survival (OS) in Subpopulation With PD-L1-Positive Tumor Status
Time Frame:Baseline up to approximately 63 months
Safety Issue:
Description: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.
Measure:Mean Scores for Function (Role/Physical) and GHS/HRQoL by Cycle and Between Treatment Arms as Assessed by the EORTC QLQ-C30
Time Frame:Baseline (Cycle 1 Day 1), on Day 1 of every cycle (C) thereafter (C=28 days from C1 to 5, and 21 days from C6 to 16), at Study Drug Completion/Early Discontinuation, Survival Follow-Up Months 3, 6, 9, 12, 18 and 24 (up to approximately 63 months)
Safety Issue:
Description: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 EORTC QLQ-C30 includes five functional scales; a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. 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).
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
Time Frame:Baseline (Cycle 1 Day 1), and on Day 1 of every cycle (C) thereafter (C length=28 days from C1 to 5, and 21 days from C6 to 16), at Study Drug Completion/Early Termination, Survival Follow-Up Months 12, 18, and 24 (up to approximately 63 months)
Safety Issue:
Description:Mean change from baseline score in function (role, physical) andglobal 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). Note: Cycle=C; Day=D.
Measure:Percentage of Participants With Adverse Events (AEs)
Time Frame:Baseline up to approximately 63 months
Safety Issue:
Description:Percentage of participants with adverse events.
Measure: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)
Safety Issue:
Description:Minimum observed serum atezolizumab concentration.
Measure:Maximum Observed Serum Atezolizumab Concentration (Cmax)
Time Frame:Day 1 of Cycle 1 post dose (cycle length = 28 days)
Safety Issue:
Description:Maximum observed atezolizumab concentration (Cmax).
Measure:Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
Time Frame:Baseline up to approximately 20 months
Safety Issue:
Description:Percentage of participants with anti-drug antibodies (ADAs) to atezolizumab.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

June 23, 2021