Signed informed consent form (ICF) prior to participation in any study-related activities
Male or female patients ≥ 18 years at the time of signing ICF
Ability to comply with the study protocol, in the investigator's judgment
Histologically confirmed TNBC -regardless of PD-L1 status- per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria based on local testing on the most recent analyzed biopsy. Triple-negative is defined as <1% expression for estrogen receptor (ER) and progesterone receptor (PgR) as determined by immunohistochemistry (IHC) and negative for HER2 (0-1+ by immunohistochemistry [IHC] or 2+ and negative by in situ hybridization [ISH] test)
Unresectable locally advanced or metastatic disease documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent
No prior chemotherapy and/or targeted therapy and/or immunotherapy and/or antiangiogenic agent for MBC. Patients who have received (neo)adjuvant taxane-based chemotherapy and/or immunotherapy and/or an antiangiogenic agent are required to have a disease-free interval (DFI) of at least 12 months after completion of each of these treatments. For (neo)adjuvant non-taxane-based chemotherapy, a DFI of at least 6 months is required
Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the NCI-CTCAE v.5.0 (except for alopecia, grade ≤ 2 peripheral neuropathy, or other toxicities not considered a safety risk for the patient at investigator's discretion)
Evidence of measurable disease or non-measurable disease as per RECIST v.1.1. Patients with only bone lesions are also eligible
Willingness and ability to provide the most recent tumor biopsy since last progression from either metastatic or primary tissues at the time of the inclusion to perform exploratory studies. If not feasible, patient eligibility should be evaluated by a Sponsor's qualified designee. An additional tumor biopsy from either metastatic or primary (only if metastatic biopsies cannot be obtained for inaccessible lesion or subject safety concern) tissues would be collected at disease progression or study termination whenever it is feasible
Note: Patients for whom tumor biopsies cannot be obtained (e.g., inaccessible
tumor or safety concern) may submit archived pathological material from either
metastatic or primary sites, but the most recent tumor biopsy from the patient
should be obtained when available
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Life expectancy of ≥12 weeks
Adequate hematologic and organ function within 14 days before the first study treatment on Cycle 1 Day 1 (C1D1), defined by the following parameters
Hematological: White blood cell (WBC) count > 3.0 x 109/L; Absolute neutrophil count (ANC) > 1.5 X 109/L (without granulocyte colony- stimulating factor [G-CSF] support within 2 weeks prior to Cycle 1 Day1); Lymphocyte count 3 0.5 x 109/L (500μL); Platelet count 3 75.0 x 109/L (without transfusion within 2 weeks prior to Cycle 1 Day 1); Hemoglobin > 9.0 g/dL (Patients may be transfused or receive erythropoietic treatment to meet this criterion)
Note: Patients cannot be transfused platelets within 14 days prior to C1D1 to
meet this criterion. The use of G-CSF within 14 days prior to C1D1 is also
prohibited
Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (× ULN) (≤ 3 x ULN in the case of Gilbert's disease); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (in the case of liver metastases ≤ 5 × ULN); alkaline phosphatase (ALP) ≤ 2.5 × ULN (≤ 5 × ULN in the case of liver and/or bone metastases)
Serum albumin ≥ 2.5 g/dL
Renal: Serum creatinine < 1.5 × ULN or creatinine clearance ≥ 50 mL/min based on Cockcroft-Gault glomerular filtration rate estimation. No proteinuria by dipstick urinalysis (trace proteinuria is allowed). In cases of proteinuria at least 1+ by urinalysis, proteinuria should be less than 500 mg by 24-hour urine collection
Coagulation: For patients not receiving therapeutic anticoagulation: Partial Thromboplastin Time (PTT) (or activated Partial Thromboplastin Time [aPTT]) and International Normalized Ratio (INR) ≤ 1.5 × ULN. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
Negative human immunodeficiency virus (HIV) test at screening. Patients with a
positive HIV test at screening are eligible provided they are stable on anti-
retroviral therapy, have a CD4 count 3 200/μL, and have an undetectable viral
load
Negative hepatitis B surface antigen (HBsAg) test and negative total hepatitis B core antibody (HBcAb) tests at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. Current treatment with anti-viral therapy for HBV is not allowed
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 have a negative serum pregnancy test within 14 days before study treatment initiation and agree to remain abstinent (refrain from heterosexual intercourse) or use one highly effective contraceptive method, or two effective contraceptive methods, as defined in the protocol during the treatment period for at least 5 months after the last dose of atezolizumab, and for at least 6 months after the last dose of paclitaxel and bevacizumab (Avastin®)
Note: HBV DNA test only to be performed for patients with a positive total
HBcAb test
Note: HCV RNA test only to be performed for patients with a positive HCV
antibody test
Active or history of autoimmune disease or immune deficiency, including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis for a more comprehensive list of autoimmune diseases and immune deficiencies, with the following exceptions
Yes for Active or history of autoimmune disease or immune deficiency, including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis for a more comprehensive list of autoimmune diseases and immune deficiencies, with the following exceptions exclusion criteria 1
No for Active or history of autoimmune disease or immune deficiency, including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis for a more comprehensive list of autoimmune diseases and immune deficiencies, with the following exceptions exclusion criteria 1
Not sure for Active or history of autoimmune disease or immune deficiency, including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis for a more comprehensive list of autoimmune diseases and immune deficiencies, with the following exceptions exclusion criteria 1
No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures
Note: Patients with indwelling catheters (e.g., PleurX®) are allowed
Known active uncontrolled or symptomatic central nervous system (CNS) metastases as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases are eligible if they meet the following criteria
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L; calcium > 12 mg/dL)
Evidence of measurable disease or non-measurable disease as per RECIST v.1.1
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
The patient has no history of intracranial hemorrhage
The patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment. The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. Anticonvulsant therapy at a stable dose is permitted
History of leptomeningeal disease
Active tuberculosis
Uncontrolled tumor-related pain
Significant cardiovascular disease 6 months prior to initiation of study treatment. These include New York Heart Association Class II or greater cardiac disease, myocardial infarction, unstable arrhythmia, or unstable angina, symptomatic pericarditis, ventricular arrhythmias - except for benign premature ventricular contractions-, arrhythmias or conduction abnormalities requiring a pacemaker or not controlled with medication, and prior peripheral vascular disease including any cerebrovascular accident including transient ischemic attack, any pulmonary embolism, any prior deep vein thrombosis, and/or any grade ≥ 2 peripheral vascular disease
Yes for Significant cardiovascular disease 6 months prior to initiation of study treatment. These include New York Heart Association Class II or greater cardiac disease, myocardial infarction, unstable arrhythmia, or unstable angina, symptomatic pericarditis, ventricular arrhythmias - except for benign premature ventricular contractions-, arrhythmias or conduction abnormalities requiring a pacemaker or not controlled with medication, and prior peripheral vascular disease including any cerebrovascular accident including transient ischemic attack, any pulmonary embolism, any prior deep vein thrombosis, and/or any grade ≥ 2 peripheral vascular disease exclusion criteria 15
No for Significant cardiovascular disease 6 months prior to initiation of study treatment. These include New York Heart Association Class II or greater cardiac disease, myocardial infarction, unstable arrhythmia, or unstable angina, symptomatic pericarditis, ventricular arrhythmias - except for benign premature ventricular contractions-, arrhythmias or conduction abnormalities requiring a pacemaker or not controlled with medication, and prior peripheral vascular disease including any cerebrovascular accident including transient ischemic attack, any pulmonary embolism, any prior deep vein thrombosis, and/or any grade ≥ 2 peripheral vascular disease exclusion criteria 15
Not sure for Significant cardiovascular disease 6 months prior to initiation of study treatment. These include New York Heart Association Class II or greater cardiac disease, myocardial infarction, unstable arrhythmia, or unstable angina, symptomatic pericarditis, ventricular arrhythmias - except for benign premature ventricular contractions-, arrhythmias or conduction abnormalities requiring a pacemaker or not controlled with medication, and prior peripheral vascular disease including any cerebrovascular accident including transient ischemic attack, any pulmonary embolism, any prior deep vein thrombosis, and/or any grade ≥ 2 peripheral vascular disease exclusion criteria 15
Note 1: Patients requiring pain medication must be on a stable regimen at
Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
study entry
Uncontrolled hypertension (systolic blood pressure greater than 160 mmHg and diastolic blood pressure greater than 100 mmHg)
Note 2: Symptomatic lesions (e.g., bone metastases or metastases causing nerve
Major surgical procedure (defined as requiring general anesthesia) or significant traumatic injury within 28 days of start of study drug, or patients who have not recovered from the side effects of any major surgery
impingement) amenable to palliative radiotherapy should be treated prior to
Concurrent malignancy(ies) or malignancy(ies) within 5 years of study enrollment except for carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required
enrolment. Patients should be recovered from the effects of radiation
Treatment with therapeutic oral or IV antibiotics or severe infection 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
Prior allogeneic stem cell or solid organ transplantation
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
Extracranial radiotherapy or limited-field palliative radiotherapy within seven days prior to study enrolment, or patients who have not recovered from radiotherapy-related toxicities to baseline or grade ≤ 1
Treatment with investigational therapy within 28 days prior to initiation of study treatment
Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-a agents) or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions
Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
Patients with eczema, psoriasis, lichen simplex chronicum, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are
met
Rash must cover < 10% of body surface area
Disease is well controlled at baseline and requires only low-potency topical corticosteroids
Chronic daily intake of antiplatelet drugs (e.g., aspirin doses of 325 mg/day or higher or non-steroidal anti-inflammatory medication known to inhibit platelet function)
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or
Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgement, contraindicate patient participation in the clinical study
Concurrent participation in other interventional clinical trials
Note: History of radiation pneumonitis in the radiation field (fibrosis) is
permitted
Note 1: Patients who have received acute, low-dose systemic immunosuppressant
medication or a one-time pulse dose of systemic immunosuppressant medication
(e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for
the study after Medical Monitor approval has been obtained
Note 2: Patients who are receiving mineralocorticoids (e.g., fludrocortisone)
inhaled corticosteroids for chronic obstructive pulmonary disease (COPD) or
asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal
insufficiency are eligible for the study