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:

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 will receive 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 will continue 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 will receive 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

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

Primary Outcome Measures

Measure:Percentage of Participants with Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System
Time Frame:Week 21
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:From randomization to the date of death from any cause (up to approximately 51 months)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure:Percentage of Participants with Adverse Events (AEs)
Time Frame:Baseline up to approximately 51 months
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

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