A Study Comparing Atezolizumab (Anti PD-L1 Antibody) In Combination With Adjuvant Anthracycline/Taxane-Based Chemotherapy Versus Chemotherapy Alone In Patients With Operable Triple-Negative Breast Cancer

Phase 3TerminatedNCT03498716

Hoffmann-La Roche2,199 enrolled

Overview

This study will evaluate the efficacy, safety, and pharmacokinetics of adjuvant atezolizumab in combination with paclitaxel, followed by atezolizumab, dose-dense doxorubicin or epirubicin (investigator's choice), and cyclophosphamide, compared with paclitaxel followed by dose-dense doxorubicin or epirubicin (investigator's choice) and cyclophosphamide alone in patients with Stage II-III TNBC (Triple Negative Breast Cancer)

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

2,199

Conditions

Triple Negative Breast Cancer

Interventions

AtezolizumabDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Non-metastatic operable Stage II-III breast cancer * Histologically documented TNBC (Triple Negative Breast Cancer) * Confirmed tumor PD-L1 evaluation as documented through central testing of a representative tumor tissue specimen * Adequately excised: Patients must have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy * Adequate hematologic and end-organ function * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm. * No more than 8 weeks (56 days) may elapse between definitive breast surgery and randomization. * Representative formalin-fixed, paraffin embedded (FFPE) tumor specimen from surgical resection in paraffin blocks (preferred) or at least 25 unstained slides. Exclusion Criteria * Prior history of invasive breast cancer * For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment (e.g., neoadjuvant or adjuvant), including, but not limited to, chemotherapy, anti-HER2 therapy. * Previous therapy with anthracyclines or taxanes for any malignancy * Cardiopulmonary dysfunction * Prior malignancies within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome * Active or history of autoimmune disease or immune deficiency * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * Urinary outflow obstruction * Active tuberculosis * Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during study treatment or within 5 months following the last dose of Atezolizumab (for patients randomized to Atezolizumab) * Prior allogeneic stem cell or solid organ transplant * Treatment with systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressive medication during the study

Locations (364)

John Muir Health Clinical Research Center

Concord, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

Martin-O?Neil Cancer Center

St. Helena, California, United States

Baptist - MD Anderson Cancer Center

Jacksonville, Florida, United States

Advocate Illinois Masonic Outpatient Center for Advanced Care

Chicago, Illinois, United States

Outcomes

Primary Outcomes

Invasive Disease-Free Survival (iDFS)

iDFS was defined as the time from randomization until the date of the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive breast cancer recurrence (an invasive breast cancer in the axilla, regional lymph nodes, chest wall, \&/or skin of the ipsilateral breast); Ipsilateral second primary invasive breast cancer; Contralateral invasive breast cancer; Distant recurrence (evidence of breast cancer in any anatomic site \[other than the sites mentioned\]) that has either been histologically confirmed \&/or clinically/radiographically diagnosed as recurrent invasive breast cancer; \& Death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis or no post-baseline information were censored.

Time frame: From randomization until the occurrence of an iDFS event or death from any cause, whichever occurred earlier (up to 5 years)

Secondary Outcomes

Invasive Disease-Free Survival (iDFS) in the Subpopulation With Programmed Death-ligand 1 (PD-L1) Selected Tumor Status (IC1/2/3)

iDFS = the time from randomization until the date of the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive breast cancer recurrence (an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Ipsilateral second primary invasive breast cancer, Contralateral invasive breast cancer, Distant recurrence (i.e., evidence of breast cancer in any anatomic site \[other than the sites mentioned\]) that has either been histologically confirmed and/or clinically/radiographically diagnosed as recurrent invasive breast cancer and Death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis or no post-baseline information were censored.

Time frame: From randomization until the occurrence of an iDFS event or death from any cause, whichever occurred earlier (up to 5 years)

Invasive Disease-Free Survival (iDFS) in the Node Positive Subpopulation

iDFS = the time from randomization until the date of the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive breast cancer recurrence (an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Ipsilateral second primary invasive breast cancer; Contralateral invasive breast cancer; Distant recurrence (evidence of breast cancer in any anatomic site \[other than the sites mentioned\]) that has either been histologically confirmed and/or clinically/radiographically diagnosed as recurrent invasive breast cancer; and Death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis or no post-baseline information were censored.

Time frame: From randomization until the occurrence of an iDFS event or death from any cause, whichever occurred earlier (up to 5 years)

Overall Survival (OS)

Overall Survival (OS) is defined as the time from randomization to the date of death due to any cause. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis or no post-baseline information were censored.

Time frame: From randomization up to death from any cause (up to 5 years)

Invasive Disease-Free Survival (iDFS) Including Second Primary Non-Breast Invasive Cancer

iDFS = the time from randomization until the date of first occurrence of one of the events: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer involving same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive breast cancer recurrence (an invasive breast cancer in axilla, regional lymph nodes, chest wall, \&/or skin of the ipsilateral breast); Ipsilateral second primary invasive breast cancer; Second primary non-breast invasive cancer; Contralateral invasive breast cancer; Distant recurrence (i.e., evidence of breast cancer in any anatomic site \[other than sites mentioned\]) that has either been histologically confirmed \&/or clinically/radiographically diagnosed as recurrent invasive breast cancer; Death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis or no post-baseline information were censored.

Time frame: From randomization up to death from any cause (up to 5 years)

Recurrence-Free Interval (RFI)

Recurrence-Free Interval (RFI) was defined as the time from randomization to the first occurrence of any recurrence (local, regional \[including invasive ipsilateral tumor and invasive locoregional tumor\], or distant), as determined by investigators. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis, participants with no events who died, or participants with no post-baseline information were censored.

Time frame: From randomization up to 5 years

Distant Recurrence-Free Interval (DRFI)

Distant Recurrence-Free Interval (DRFI) was defined as the time from randomization to the distant breast cancer recurrence. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis, participants with no events who died, or participants with no post-baseline information were censored.

Time frame: From randomization up to 5 years

Disease-Free Survival (DFS)

Disease-Free Survival (DFS) was defined as the time from randomization to the first occurrence of disease recurrence or death from any cause. DFS events include: Ipsilateral invasive breast tumor recurrence; Ipsilateral local-regional invasive breast cancer recurrence; Distant recurrence that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer; Contralateral invasive breast cancer; Ipsilateral or contralateral DCIS; Second primary non-breast invasive cancer; Death attributable to any cause. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis or no post-baseline information were censored.

Time frame: From randomization up to first disease recurrence or death from any cause (up to 5 years)

Change From Baseline (CFB) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Patient-reported Function (Role Functioning [Q6, Q7])

The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. For the role functioning scale, participant responses to the 2 questions "Q6: Were you limited in doing either your work or daily activities" and "Q7: Were you limited in pursuing your hobbies or other leisure time activities" were scored on a 4-point scale (1=Not at All to 4=Very Much). The scores were linearly transformed on a scale of 0 to 100, with a low score indicating better functioning. Negative change from baseline indicated improvement.

Time frame: Baseline (Cycle 1 Day 1), Day 1 of Cycles 4, 6, 8, 10, 12, 14 & 16; end of treatment/discontinuation (approximately at Day 351); Follow up: Months 3 to 48 (Total duration is up to 5 years); Cycles 1-5= 28 day cycles; Cycles 6-16: 21 day cycles

Change From Baseline in EORTC QLQ-C30 Patient-reported Function (Physical Functioning [Q1-Q5])

The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. For the physical functioning scale, participant responses to 5 questions about daily activities (strenuous activities, long walks, short walks, bed/chair rest \& needing help with eating, dressing, washing themselves, or using the toilet) were scored on a 4-point scale (1=Not at All to 4=Very Much). The scores were linearly transformed on a scale of 0 to 100, with a high score indicating worst functioning. Negative change from baseline indicated improvement in functioning.

Change From Baseline in EORTC QLQ-C30 Global Health Status (GHS) [Q29] and Health-Related Quality of Life (HRQoL) [Q30] Combined Score

The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participant responses to the questions regarding Global Health Status (Q29:GHS; "How would you rate your overall health during the past week?") and Quality of Life (Q30: QoL; "How would you rate your overall quality of life during the past week?") are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better outcome. Negative change from Baseline values indicated deterioration in QOL or functioning and positive values indicated improvement.

Time frame: Baseline (Cycle 1 Day 1), Day 1 of Cycles 4, 6, 8, 10, 12, 14 & 16; end of treatment/discontinuation (approximately 351 days); Follow up: Months 3 to 48 (Total duration is up to 5 years); Cycles 1-5= 28 day cycles; Cycles 6-16: 21 day cycles

Number of Participants With Adverse Events (AE)

An Adverse Event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs are reported based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.

Time frame: Up to 5 years

Serum Concentration of Atezolizumab

Time frame: Postdose Day 1 of Cycle 1; Predose Day 1 of Cycles 2, 3, and 4; Predose Cycles 6, 10, and 14; Predose Day 2 of Cycle 16; Cycles 1-5= 28-day cycles; Cycles 6-16: 21-day cycles

Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab

Baseline evaluable participant= participant with an ADA assay result from a baseline sample(s). Post-baseline evaluable participant= participant with an ADA assay result from at least one postbaseline sample.

Time frame: Up to 5 years