Clinical Trials /

A Study of the Efficacy and Safety of Atezolizumab Plus Chemotherapy for Patients With Early Relapsing Recurrent Triple-Negative Breast Cancer

NCT03371017

Description:

This study will evaluate the efficacy and safety of atezolizumab plus chemotherapy compared with placebo plus chemotherapy in patients with inoperable recurrent triple-negative breast cancer (TNBC).

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study of the Efficacy and Safety of Atezolizumab Plus Chemotherapy for Patients With Early Relapsing Recurrent Triple-Negative Breast Cancer
  • Official Title: A Phase III, Randomised, Double-Blind, Placebo-Controlled, Multicentre Study Of The Efficacy And Safety Of Atezolizumab Plus Chemotherapy For Patients With Early Relapsing Recurrent (Inoperable Locally Advanced Or Metastatic) Triple-Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: MO39193
  • SECONDARY ID: 2016-005119-42
  • NCT ID: NCT03371017

Conditions

  • Triple Negative Breast Neoplasms

Interventions

DrugSynonymsArms
AtezolizumabAtezolizumab
PlaceboPlacebo
GemcitabineAtezolizumab
CapecitabineAtezolizumab
CarboplatinAtezolizumab

Purpose

This study will evaluate the efficacy and safety of atezolizumab plus chemotherapy compared with placebo plus chemotherapy in patients with inoperable recurrent triple-negative breast cancer (TNBC).

Trial Arms

NameTypeDescriptionInterventions
AtezolizumabExperimentalParticipants will receive Atezolizumab on day 1 of each 3-week treatment cycle
  • Atezolizumab
  • Gemcitabine
  • Capecitabine
  • Carboplatin
PlaceboPlacebo ComparatorParticipants will receive Placebo on day 1 of each 3-week treatment cycle
  • Placebo
  • Gemcitabine
  • Capecitabine
  • Carboplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed triple negative breast cancer (TNBC) that is either locally
             recurrent, inoperable and cannot be treated with curative intent or is metastatic

          -  Documented disease progression occurring within 12 months from the last treatment with
             curative intent

          -  Prior treatment (of early breast cancer) with an anthracycline and taxane

          -  Have not received prior chemotherapy or targeted systemic therapy for their locally
             advanced inoperable or metastatic recurrence. Prior radiation therapy for recurrent
             disease is permitted

          -  Measurable or non-measurable disease, as defined by RECIST 1.1

          -  Availability of a representative formalin-fixed paraffin-embedded (FFPE) tumour block
             (preferred) or at least 17 unstained slides, collected within 3 months prior to
             randomisation, with an associated pathology report, if available. If a tumour sample
             taken within 3 months before randomisation is not available and a tumour biopsy is not
             clinically feasible, the primary surgical resection sample or the most recent FFPE
             tumour biopsy sample may be used. Of these additional options, the most recent sample
             should be used.

          -  Eastern Cooperative Oncology Group performance status 0-1

          -  Life expectancy ≥ 12 weeks

          -  Adequate haematologic and end-organ function

          -  Negative human immunodeficiency virus (HIV) test ---Negative hepatitis B surface
             antigen (HBsAg) test at screening

          -  Negative total hepatitis B core antibody (HBcAb) test at screening, or positive HBcAb
             test followed by a negative hepatitis B virus (HBV) DNA test at screening

          -  The HBV DNA test will be performed only for patients who have a negative HBsAg and a
             positive HBcAb test.

          -  Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody
             test followed by a negative HCV RNA test at screening.

          -  Women of childbearing potential must agree to remain abstinent (refrain from
             heterosexual intercourse) or use a contraceptive method with a failure rate of ≤1% per
             year during the treatment period and for at least 5 months after the last dose of
             atezolizumab or 6 months after the last dose of capecitabine, whichever is later. In
             addition, women must refrain from donating eggs during the same time period.

          -  Men must agree to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive measures, and agree to refrain from donating sperm

        Inclusion criteria for patients enrolled after the recruitment of all-comers is complete:

        -PD-L1-positive tumour status (assessed centrally prior to randomisation), defined as PD-L1
        expression on tumour-infiltrating immune cells (IC) of 1% or greater.

        Exclusion Criteria:

          -  Spinal cord compression not definitively treated with surgery and/or radiation, or
             previously diagnosed and treated spinal cord compression without evidence that disease
             has been clinically stable for > 2 weeks prior to randomisation

          -  Symptomatic, untreated, or actively progressing central nervous system (CNS)
             metastases.

          -  Symptomatic or rapid visceral progression

          -  No prior treatment with an anthracycline and taxane

          -  History of leptomeningeal disease

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures (once monthly or more frequently) (patients with indwelling
             catheters such as PleurX® are allowed)

          -  Uncontrolled tumour-related pain

          -  Uncontrolled or symptomatic hypercalcemia

          -  Malignancies other than TNBC within 5 years prior to randomisation)

          -  Significant cardiovascular disease, within 3 months prior to randomisation, unstable
             arrhythmias, or unstable angina

          -  Presence of an abnormal ECG

          -  Severe infection requiring oral or IV antibiotics within 4 weeks prior to
             randomisation, including but not limited to hospitalization for complications of
             infection, bacteraemia, or severe pneumonia.

          -  Current treatment with anti-viral therapy for HBV.

          -  Major surgical procedure within 4 weeks prior to randomisation or anticipation of the
             need for a major surgical procedure during the course of the study other than for
             diagnosis

          -  Treatment with investigational therapy within 28 days prior to randomisation

          -  Pregnant or lactating, or intending to become pregnant during or within 5 months after
             the last dose of atezolizumab, or within 6 months after the last dose of capecitabine,
             whichever is later.

        Exclusion Criteria Related to Atezolizumab:

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanised antibodies or fusion proteins

          -  Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or to any component of the atezolizumab formulation

          -  History of autoimmune disease

          -  Prior allogeneic stem cell or solid organ transplantation

          -  History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
             pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic
             organizing pneumonia), or evidence of active pneumonitis on screening chest
             computerised tomography (CT) scan History of radiation pneumonitis in the radiation
             field (fibrosis) is permitted.

          -  Active tuberculosis

          -  Receipt of a live, attenuated vaccine within 4 weeks prior to randomisation or
             anticipation that a live, attenuated vaccine will be required during
             atezolizumab/placebo treatment or within 5 months after the last dose of
             atezolizumab/placebo

          -  Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or
             pathway targeting agents

          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug
             (whichever is longer) prior to randomisation

          -  Treatment with systemic corticosteroids or other systemic immunosuppressive
             medications within 2 weeks prior to randomisation, or anticipated requirement for
             systemic immunosuppressive medications during the trial

        Exclusion Criteria Related to Capecitabine:

          -  Inability to swallow pills

          -  Malabsorption syndrome, disease significantly affecting gastrointestinal function,
             resection of the stomach or small bowel, or ulcerative colitis

          -  Known dihydropyrimidine dehydrogenase (DPD) deficiency or history of severe and
             unexpected reactions to fluoropyrimidine therapy in patients selected to receive
             capecitabine

        Exclusion Criteria Related to Carboplatin/Gemcitabine:

        -Hypersensitivity to platinum containing compounds or any component of carboplatin or
        gemcitabine drug formulations in patients selected to receive carboplatin and Gemcitabine
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival (OS) in Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status
Time Frame:Baseline to end of study (approximately 58 months)
Safety Issue:
Description:OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population

Secondary Outcome Measures

Measure:Proportion of Participants Alive 12 Months
Time Frame:Randomization to 12 months post randomization
Safety Issue:
Description:
Measure:Proportion of Participants Alive 18 Months
Time Frame:Randomization to 18 months post randomization
Safety Issue:
Description:
Measure:Progression-Free Survival (PFS) in Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status
Time Frame:Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months)
Safety Issue:
Description:PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Measure:Progression-Free Survival (PFS) in mITT population
Time Frame:Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months)
Safety Issue:
Description:PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Measure:Objective Response Rate (ORR) in Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status
Time Frame:Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)
Safety Issue:
Description:ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Measure:Objective Response Rate (ORR) in Modified Intent-To-Treat (mITT) Popluation
Time Frame:Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)
Safety Issue:
Description:ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Measure:Duration of Objective Response (DoR)
Time Frame:Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months)
Safety Issue:
Description:DoR as determined by the investigator according to RECIST 1.1.
Measure:Clinical Benefit Rate (CBR)
Time Frame:8 weeks for the first 12 months after treatment initiation and every 12 weeks thereafter until disease progression (through the end of study, approximately 58 months)
Safety Issue:
Description:CBR is defined as the proportion of participants with a CR or a PR or stable disease as determined by the investigator according to RECIST 1.1.
Measure:Confirmed Objective Response Rate (C-ORR)
Time Frame:Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)
Safety Issue:
Description:
Measure:Duration of Response for Confirmed Responders (C-DoR)
Time Frame:Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months)
Safety Issue:
Description:
Measure:Time to Confirmed Deterioration (TTD) of GHS/QoL
Time Frame:Baseline to end of study (approximately 58 months)
Safety Issue:
Description:TTD of GHS/QoL, defined by a minimally important decrease of ≥10 points at two consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of the EORTC QLQ-C30.
Measure:Percentage of Participants With Adverse Events
Time Frame:Baseline to end of study (approximately 58 months)
Safety Issue:
Description:
Measure:Maximum Serum Concentration (Cmax) of Atezolizumab
Time Frame:At pre-defined intervals from Day 1, Cycle 1 through Cycle 4 (cycle = 21 days)
Safety Issue:
Description:
Measure:Minimum Serum Concentration (Cmin) of Atezolizumab
Time Frame:At pre-defined intervals from Day 1, Cycle 1 through Cycle 4 (cycle = 21 days)
Safety Issue:
Description:
Measure:Incidence of Anti-Drug Antibodies (ADAs) to Atezolizumab
Time Frame:Baseline to end of study (approximately 58 months)
Safety Issue:
Description:
Measure:Relationship Between PD-L1 Protein Expression in Screening Tumour Tissue and Clinical Outcomes
Time Frame:Baseline to end of study (approximately 58 months)
Safety Issue:
Description:
Measure:Overall Survival (OS) in China Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status
Time Frame:Baseline to end of study (approximately 58 months)
Safety Issue:
Description:OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population
Measure:Overall Survival (OS) in mITT China Popluation
Time Frame:Baseline to end of study (approximately 58 months)
Safety Issue:
Description:OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population
Measure:Proportion of Participants Alive 12 Months in China Population
Time Frame:Randomization to 12 months post randomization
Safety Issue:
Description:
Measure:Proportion of Participants Alive 18 Months in China Population
Time Frame:Randomization to 18 months post randomization
Safety Issue:
Description:
Measure:Progression Free Survival (PFS) in China Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status
Time Frame:Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months)
Safety Issue:
Description:PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Measure:Progression Free Survival (PFS) in mITT China Population
Time Frame:Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months)
Safety Issue:
Description:PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Measure:Objective Response Rate (ORR) in China Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status
Time Frame:Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)
Safety Issue:
Description:ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Measure:ORR in Modified Intent-To-Treat (mITT) China Popluation
Time Frame:Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)
Safety Issue:
Description:ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Measure:Duration of Objective Response (DoR) in China Population
Time Frame:Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months)
Safety Issue:
Description:DoR as determined by the investigator according to RECIST 1.1.
Measure:Clinical Benefit Rate (CBR) in China Population
Time Frame:8 weeks for the first 12 months after treatment initiation and every 12 weeks thereafter until disease progression (through the end of study, approximately 58 months)
Safety Issue:
Description:CBR is defined as the proportion of participants with a CR or a PR or stable disease as determined by the investigator according to RECIST 1.1.
Measure:Confirmed Objective Response Rate (C-ORR) in China Population
Time Frame:Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)
Safety Issue:
Description:
Measure:Duration of Response for Confirmed Responders (C-DoR) in China Population
Time Frame:Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months)
Safety Issue:
Description:
Measure:Time to Confirmed Deterioration (TTD) of GHS/QoL in China Population
Time Frame:Baseline to end of study (approximately 58 months)
Safety Issue:
Description:TTD of GHS/QoL, defined by a minimally important decrease of ≥10 points at two consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of the EORTC QLQ-C30.

Details

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

Last Updated

August 5, 2021