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

Hoffmann-La Roche595 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

595

Conditions

Triple Negative Breast Neoplasms

Interventions

AtezolizumabDRUG

Atezolizumab will be administered, 1200 mg by IV infusion with : gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle or with capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle

PlaceboDRUG

Placebo will be administered, 1200 mg by IV infusion with : gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle or with capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle

GemcitabineDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 obtained from relapsed metastatic or locally advanced diseases may be submitted, if clinically feasible, with an associated pathology report, if available. If a fresh tumour sample is not clinically feasible, either the diagnosis sample, the primary surgical resection sample, or the most recent FFPE tumour biopsy 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 start of study treatment, 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

Locations (124)

Outcomes

Primary Outcomes

Overall Survival (OS) in PD-L1-positive Population

OS was defined as time from randomization to death from any cause. Participants without a reported death event at the time of the analysis were censored on the date they were last known to be alive. If no post-baseline data were available, OS was censored at the date of randomization +1 day.

Time frame: Time from randomization to death (Up to 68 months)

OS in Modified Intent-to-treat (mITT) Population

Time frame: Time from randomization to death (Up to 68 months)

Secondary Outcomes

12-month Survival Rate in PD-L1-positive Population

12-month survival rate was defined as the percentage of participants alive 12 months after randomization. The 12-month survival rates were estimated by Kaplan-Meier methodology. Percentages have been rounded off to the nearest whole number.

Time frame: 12 months

12-month Survival Rate in mITT Population

Time frame: 12 months

18-month Survival Rate in PD-L1-positive Population

18-month survival rate was defined as the percentage of participants alive 18 months after randomization. The 18-month survival rates were estimated by Kaplan-Meier methodology. Percentages have been rounded off to nearest whole number.

Time frame: 18 months

Data from ClinicalTrials.gov

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Gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle

CapecitabineDRUG

Capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle

CarboplatinDRUG

Carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle

Florida Cancer Specialists - Fort Myers (Broadway)

Fort Myers, Florida, United States

Florida Cancer Specialists & Research Institute

St. Petersburg, Florida, United States

The Valley Hospital

Paramus, New Jersey, United States

Magee-Woman's Hospital

Pittsburgh, Pennsylvania, United States

SCRI Oncology Partners

Nashville, Tennessee, United States

Inova Schar Cancer Institute

Fairfax, Virginia, United States

Hospital Provincial del Centenario

Rosario, Argentina

Instituto de Oncología de Rosario

Rosario, Argentina

Clinical center University of Sarajevo

Sarajevo, Bosnia and Herzegovina

Oncocentro Serviços Medicos E Hospitalares Ltda

Fortaleza, Ceará, Brazil

...and 114 more locations

18-month Survival Rate in mITT Population

Time frame: 18 months

Progression-free Survival (PFS) in PD-L1-positive Population

PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 millimeters (mm). Data for participants not experiencing PD or death were censored at the last tumour assessment date. If no tumor assessment was performed after randomisation, data were censored at the date of randomisation +1 day.

Time frame: Time from randomization to the first occurrence of PD or death (Up to 68 months)

PFS in mITT Population

PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Data for participants not experiencing PD or death were censored at the last tumour assessment date. If no tumor assessment was performed after randomisation, data were censored at the date of randomisation +1 day.

Time frame: Time from randomization to the first occurrence of PD or death (Up to 68 months)

Objective Response Rate (ORR) in Response-evaluable Population, Subset of PD-L1-positive Population

ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented unconfirmed objective response (OR). OR was defined as either a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number.

Time frame: Baseline up to end of study (Up to 68 months)

ORR in Response-evaluable Population, Subset of mITT Population

ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented unconfirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number.

Time frame: Baseline up to end of study (Up to 68 months)

Duration of Objective Response (DoR) in DoR-evaluable Population Subset of PD-L1-positive Population

DoR was defined as the time from the first occurrence of a documented unconfirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.

Time frame: Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months)

DoR in DoR-evaluable Population Subset of mITT Population

Time frame: Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months)

Clinical Benefit Rate (CBR) in Response-evaluable Population Subset of PD-L1-positive Population

CBR was defined as the percentage of participants with either an unconfirmed CR or PR or stable disease (SD) that lasts at least 6 months as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Percentages have been rounded off to nearest whole number.

Time frame: Up to 68 months

CBR in Response-evaluable Population Subset of mITT Population

CBR was defined as the percentage of participants with either an unconfirmed CR or PR or SD that lasts at least 6 months as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Percentages have been rounded off to nearest whole number.

Time frame: Up to 68 months

Confirmed Objective Response Rate (C-ORR) in Response-evaluable Population Subset of PD-L1-positive Population

C-ORR was defined as percentage of participants with measurable disease at baseline who achieved a documented confirmed OR. OR was defined as either a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off to nearest whole number.

Time frame: Up to 68 months

C-ORR in Response-evaluable Population Subset of mITT Population

Time frame: Up to 68 months

DoR for Confirmed Responders (C-DoR) in C-DoR-evaluable Population Subset of PD-L1-positive Population

C-DoR was defined as the time from the first occurrence of a documented confirmed response (CR or PR) until the date of PD as determined by the investigator from tumor assessments using RECIST v1.1 or death from any cause, whichever occurs first. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.

Time frame: Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months)

C-DoR in C-DoR-evaluable Population Subset of mITT Population

Time frame: Time from the first occurrence of a documented OR until the date of PD/death (Up to 68 months)

Time to Confirmed Deterioration (TTD) in Global Health Status/Quality of Life (GHS/QoL) According to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) in PD-L1-positive Population

TTD in GHS/QoL, defined by a minimally important decrease of ≥10 points at 2 consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of EORTC QLQ-C30, which consists of 30 questions that assess 5 aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), GHS and QoL, \& six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. Participant responses to questions regarding GHS (Question 29: GHS; "How would you rate your overall health during the past week?") \& QoL (Question 30: QoL; "How would you rate your overall quality of life during the past week?") were assessed \& were scored on a 7-point scale (1= Very poor; 7=Excellent). Scores are linearly transformed on a scale of 0 to 100, with a high score indicating better QoL.

Time frame: Up to 68 months

TTD in GHS/QoL According to EORTC QLQ-C30 in mITT Population

Time frame: Up to 68 months

Number of Participants With Adverse Events (AEs)

An 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 that worsen during a study are also considered AEs.

Time frame: From treatment initiation up to 90 days after last dose (up to 71 months)

Serum Concentration of Atezolizumab

Time frame: Pre-dose on Day 1 of Cycles 1, 2, 3 and 4; Post-dose on Day 1 of Cycles 1 and 3 and Treatment Discontinuation Visit (up to 69 months) (1 Cycle= 3 weeks)

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

Number of ADA-positive participants after drug administration was determined for participants exposed to atezolizumab. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the baseline titer result. The sum of participants who were ADA-positive at postbaseline visits of Cycles 1 to 4 and treatment discontinuation has been reported here.

Time frame: Cycles 1 to 4 and Treatment Discontinuation visit (up to 69 months)

Number of Participants With PD-L1 Protein Expression in Screening Tumour Tissue and Post-baseline Assessment

Time frame: Baseline up to 68 months