| Eligibility |
Inclusion Criteria:
1. Signed informed consent form (ICF) prior to participation in any study-related
activities.
2. Male or female patients = 18 years at the time of signing ICF.
3. Ability to comply with the study protocol, in the investigator's judgment.
4. 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).
5. 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.
6. No prior chemotherapy and/or targeted therapy and/or immunotherapy and/or
antiangiogenic agent for triple negative 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.
7. 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).
8. Evidence of measurable disease or non-measurable disease as per RECIST v.1.1. Patients
with only bone lesions are also eligible.
9. 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 will be collected as soon as possible 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.
Note 2: Bone biopsies are only acceptable if performed on bone metastases with
associated soft tissue mass, where the biopsy is performed on the soft tissue mass,
and a decalcification process is not used. Cytology samples and decalcified bone
specimens are unacceptable due to lack of validation studies.
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
11. Life expectancy of =12 weeks.
12. Adequate hematologic and organ function within 14 days before the first study
treatment on Cycle 1 Day 1 (C1D1), defined by the following parameters:
a. Hematological: i. White blood cell (WBC) count > 3.0 x 109/L. ii. 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) iii. Lymphocyte count = 0.5 x
109/L (500 cells/uL) iv. Platelet count = 75.0 x 109/L (without transfusion within 2
weeks prior to Cycle 1 Day 1) v. 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.
b. Hepatic: Total 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).
c. Serum albumin = 2.5 g/dL
d. Renal: Serum creatinine < 1.5 × ULN or creatinine clearance = 50 mL/min based on
Cockcroft-Gault glomerular filtration rate estimation. No proteinuria by urinalysis.
In cases of proteinuria > ULN by urinalysis, proteinuria should be less than 500 mg by
24-hour urine collection.
e. 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.
13. 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 = 200 cells/uL, and have an undetectable
viral load.
14. 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.
Note: HBV DNA test only to be performed for patients with a positive total HBcAb test.
15. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody
test followed by a negative HCV RNA test at screening.
Note: HCV RNA test only to be performed for patients with a positive HCV antibody
test.
16. 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, 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, whichever is later.
Men with female partners of childbearing potential or pregnant female partners, must remain
abstinent or use a condom during the treatment period and 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, whichever is later, to avoid exposing the embryo. Men must refrain from
donating sperm during this same period. Due to the possibility of irreversible infertility
with paclitaxel, men receiving this chemotherapy should consult with their doctor regarding
conservation of sperm prior to treatment initiation.
Exclusion Criteria:
1. 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:
- Evidence of measurable disease or non-measurable disease as per RECIST v.1.1.
- 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.
2. History of leptomeningeal disease.
3. Uncontrolled tumor-related pain. Note 1: Patients requiring pain medication must be on
a stable regimen at study entry.
Note 2: Symptomatic lesions (e.g., bone metastases or metastases causing nerve
impingement) amenable to palliative radiotherapy should be treated prior to enrolment.
Patients should be recovered from the effects of radiation.
4. 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:
- 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.
- 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.
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures.
Note: Patients with indwelling catheters (e.g., PleurX® are allowed)
6. Uncontrolled or symptomatic hypercalcemia (ionized calcium >1.5 mmol/L; calcium >12
mg/dL).
7. 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 CT scan.
Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
8. Active tuberculosis.
9. 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.
10. Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated
acquisition (MUGA) scan or echocardiogram (ECHO).
11. Uncontrolled hypertension (systolic blood pressure greater than 160 mmHg and diastolic
blood pressure greater than 100 mmHg).
12. 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.
13. Concurrent malignancy(ies) or malignancy(ies) within 5 years prior to 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.
14. Treatment with therapeutic oral or intravenous (IV) antibiotics or severe infection
within 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.
15. Prior allogeneic stem cell or solid organ transplantation.
16. 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 the final dose of atezolizumab.
17. 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.
18. Treatment with investigational therapy within 28 days prior to initiation of study
treatment.
19. Treatment with systemic immunosuppressive medication 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:
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.
20. 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).
21. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion protein.
22. Breast-feeding women.
23. Any other concurrent severe and/or uncontrolled medical condition that would, in the
investigator's judgement, contraindicate patient participation in the clinical study.
24. Concurrent participation in other interventional clinical trials.
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